[Article in German]
Kley HK, Nieschlag E, Wiegelmann W, Kruskemper HL
Aktuelle Gerontol 1976 Feb;6(2):61-7

Alterations of sexual hormones in plasma of ageing males occur between the 50th and 60th year of life with individual variations: 1. Decreased values of testosterone in plasma and a poor response to gonado trophins demonstrate a diminished synthesizing capacity of the testes in old men. 2. The decreased testosterone plasma values are followed by an increase in LH. The response of the anterior pituitary gland to LH-RH stimulation in old men is normal. 3. Under basal conditions estrone as well as estradiol plasma concentrations increase significantly with age because of increased conversion from androgens. 4. Parallel to estrogen plasma values an increased concentration of the sexual hormone binding globulin (SHBG) is found, resulting in a steep decrease of the free (= active) testosterone fraction. 5. Decreased testosterone, which is more strongly bound to SHBG and increased estrone and estradiol plasma values result in an androgen/estrogen imbalance in old men.

Moroz EV, Verkhratsky NS
Arch Gerontol Geriatr 1985 Apr;4(1):13-9

The concentration of sex and gonadotropic hormones in blood plasma of 280 reasonably healthy men aged 20-105 was determined using radioimmunoassay kits. Compared to men aged 20-39, the statistically significant decrease in testosterone level was registered in men aged 55-59, the increase in oestradiol in men aged 60-64, progesterone in men aged 55-59, and in LH and FSH in the group aged 65-69. The reactivity of central and peripheral links of the hypothalamic-gonadal system to direct and feed-back control influences.

Zumoff B, Strain GW, Kream J, O'Connor J, Rosenfeld RS, Levin J, Fukushima DK
J Clin Endocrinol Metab 1982 Mar;54(3):534-8

The 24-h mean plasma concentrations of androgens (dihydrotestosterone and total and free testosterone), estrogens (estrone and estradiol), and gonadotropins (LH and FSH) were measured in 35 healthy men, aged 21-85 yr, who were rigorously screened to exclude factors known or suspected to alter endocrine function. The plasma total testosterone concentration showed a slow continuous decline with age, decreasing about 35% between 21 and 85 yr of age; the free testosterone level was closely correlated with that of total testosterone over the entire observed concentration range. The concentrations of dihydrotestosterone, estrone, estradiol, and LH were age invariant. The concentration of FSH showed a continuous linear increase with age; the level at age 85 was about 2.5 times the level at age 21. The following conclusions were drawn. 1) Testosterone secretion appears to decline slowly and continuously throughout adult life in men. 2) Measurement of the plasma free testosterone level adds no independent information in healthy men, since its level is closely correlated with that of total testosterone at all concentrations. 3) The continuous rise with age in FSH concentration while LH is age invariant cannot be explained by changes in testosterone or estrogen production, but might be due to a decline of inhibin production with age.

Drafta D, Schindler AE, Stroe E, Neacsu E
J Steroid Biochem 1982 Dec;17(6):683-7

Plasma cortisol, 17-hydroxyprogesterone (17-OH-P), testosterone (T), 5 alpha-dihydrotestosterone (DHT, estrone (E1) and estradiol (E2), were measured in 94 normal adult men aged between 20-99, using RIA methods after chromatographic separation of steroids on Sephadex LH-20 columns. All plasma steroids except 17-OH-P, were age dependent: cortisol, testosterone and DHT decreased significantly with age, whereas estrone and estradiol were significantly increased in elderly men. Cortisol, testosterone, T/DHT ratio and estradiol levels were significantly correlated with age. The age related changes of plasma steroids in elderly men, were suggestive of decreased cortisol secretion, and decreased testicular function with increased peripheral conversion of androgens into estrogens. Testosterone was positively correlated with its precursor (17-OH-P) and respectively its peripheral metabolites (DHT and E2). The negative correlation between estrone and 17-OH-P found in elderly men, suggested that increased estrogen level in aging males may be considered able to inhibit the testicular androgen production.

Baker HW, Burger HG, de Kretser DM, Hudson B, O'Connor S, Wang C, Mirovics A, Court J, Dunlop M, Rennie GC
Clin Endocrinol (Oxf) 1976 Jul;5(4):349-72

In order to provide a comprehensive account of pituitary-testicular function in man, 466 subjects, ranging in age from 2 to 101 years, were studied to examine blood levels of the pituitary gonadotrophins (LH and FSH), the sex steroids testosterone and oestradiol, the binding capacity of the sex hormone binding globulin (SHBG), the free testosterone and oestradiol fractions, and the transfer constant for the peripheral conversion of testosterone to oestradiol. The results were compared with clinical indices of testicular size, sexual function and secondary sex hair distribution. Serum LH and FSH were low before puberty, increased in pubertal adolescents to levels somewhat above those of adults and subsequently increased progressively over the age of 40 years. Testosterone levels fell slowly after the age of 40, while there was a slight rise in plasma oestradiol with increasing age. FSH and testosterone showed small seasonal variations in young adult men, the lowest values being seen in winter. SHBG binding capacity was high in two prepubertal boys, fell in adult men, but increased in old age. Free testosterone and oestradiol levels fell in old age. The metabolic clearance rates (MCR) of testosterone and oestradiol also fell in old age, while the conversion of testosterone to oestradiol was increased. Many correlations were observed between various hormonal and clincial measurements. The evidence is consistent with a primary decrease in testicular function over the age of 40 years.

Aiman J, Brenner PF, MacDonald PC
J Clin Endocrinol Metab 1980 Feb;50(2):380-6

Gynecomastia developed in three men 1-30 yr after the occurrence of testicular atrophy due to mumps orchitis. At the time of study, these men were 63-68 yr of age. In these men the mean plasma production rate of testosterone was 816 microgram/24 h, a value 20% of that found in normal elderly men without gynecomastia. The plasma production rate of androstenedione averaged 1317 microgram/24 h. The mean production rates of 17 beta-estradiol and estrone in these subjects were 33 and 48 microgram/24 h, values comparable to those of normal young men. Extraglandular formation of estrogen from plasma prehormones accounted for all of the 17 beta-estridiol and most of the estrone produced by these elderly men with gynecomastia. Serum gonadotropin concentrations were elevated in these men, probably because plasma testosterone production rates were decreased. These findings are consistent with the view that the capacity of Leydig cells to secrete testosterone was impaired after mumps orchitis in these subjects, but the capacity to form estrogen was not similarly impaired, since most estrogen is formed in extraglandular sites. Thus, the impairment in Leydig cell testosterone secretion after mumps orchitis together with the normal increase in extraglandular aromatization that accompanies aging bring about a striking reduction in the ratio of testosterone to estrogen production rates, and gynecomastia may result.

Tenover Joyce S
Journal of Clinical Endocrinology & Metabolism 75 ( 4 ): p 1092-1098 1992

Serum androgen levels decline with aging in normal males, such that a significant number of men over 60 yr of age will have a mean serum total testosterone (T) level near the low end of the normal adult range. It is not known whether lower T levels in older men have an effect on androgen-responsive organ systems, such as muscle, bone, bone marrow, and prostate, nor are there data to evaluate the relative benefits and risks of T supplementation in older men. We assessed the physiological and biochemical effects of T therapy in 13 healthy men, 57-76 yr old, who had low or borderline low serum T levels ( ltoreq 13.9 nmol/L). Intramuscular testosterone enanthate (TE; 100 mg weekly) and placebo injections were given for 3 months each. Before treatment and at the end of both 3-month treatment regimens, lean body mass, body fat, biochemical parameters of bone turnover, hematological parameters, lipoprotein profiles, and prostate parameters (such as prostate-specific antigen (PSA)) were evaluated. Serum T level rose in all subjects with TE treatment, such that the lowest level of T during a week's period was 19.7 +- 0.7 nmol/L (mean +- SE). After 3 months of TE treatment, lean body mass was significantly increased, and urinary ydroxyproline excretion was significantly depressed. With TE treatment, there was a significant increase in hematocrit, a decline in total cholesterol and low density lipoprotein cholesterol, and a sustained increase in serum PSA levels. Placebo treatment led to no significant changes in any of these parameters. We conclude that short term (3 months) TE supplementation to healthy older men who have serum T levels near or below the lower limit of normal for young adult men results in an increase in lean body mass and possibly a decline in bone resorption, as assessed by urinary hydroxyproline excretion, with some effect on serum lipoproteins, hematological parameters, and PSA. The sustained stimulation of PSA and the increase in hematocrit that occur with physiological TE supplementation suggest that older men should be screened carefully and followed periodically throughout T therapy.

[Article in Japanese]
Suzuki K, Inaba S, Takeuchi H, Takezawa Y, Fukabori Y, Suzuki T, Imai K, Yamanaka H, Honma S
Division of Urology, Shakai Hoken Mishima Hospital.
Nippon Hinyokika Gakkai Zasshi 1992 May;83(5):664-71

To determine the influence of endocrine factors on benign prostatic hyperplasia (BHP), the levels of three sex steroid hormones i.e., total testosterone (Total-T), free testosterone (Free-T) and estradiol (E2), were measured in serum of healthy 154 men. Their ages ranged from 18 to 91 years old. In 59 men, prostatic size was estimated by digital examination and was subdivided into three groups: smaller than or equal to walnut size, small hen's egg size and equal to or larger than hen's egg size. Firstly, relationships of sex hormone levels with age were studied. There was a slight decrease in Total-T over 60 years old, a significant decrease in Free-T, and no change in E2 with age. Thus, E2/Total-T and E2/Free-T ratio increased significantly after middle-age. Secondly, relationships of hormone levels with prostatic size were studied. In the larger prostate group, a significantly lower level of Total-T and significantly higher level of E2 were detected. But there was no difference in Free-T. Thus, the prostatic size was correlated positively with E2 level, E2/Total-T and E2/Free-T ratio. These suggest that the endocrine environment tended to be estrogens-dominant with age, in particular, after middle-age, and that patients with large prostates have more estrogens-dominant environments. We conclude that estrogens are key hormones for the induction and the development of BPH.

Wu SZ, Weng XZ
Department of Internal Medicine, Beijing Red Cross Chao Yang Hospital.
Chin Med J (Engl) 1993 Jun;106(6):415-8

The elevated estradiol/testosterone (E2/T) ratio had been proved to be a risk factor for coronary heart disease (CHD) in elderly men. We conducted a randomized placebo controlled crossover study on the effects of a new androgenic preparation "Andriol" in 62 elderly men with CHD over a period of 2.5 months. The results showed significant differences between Andriol- and placebo-treated groups at the end of this period: in the former, serum T level was elevated significantly (P < 0.001), E2 level was unchanged (P > 0.05), E2/T ratio was reduced (P < 0.05), angina pectoris (AP) was relieved (total effective rate, 77.4%), and myocardial ischemia in ECG and Holter recordings were improved (total effective rate, respectively 68.8% and 75%). Doppler echocardiography showed that 12 parameters of cardiac function were unchanged in both groups. No obvious side effect was found in those who took Andriol.

Simon D, Preziosi P, Barrett-Connor E, Roger M, Saint-Paul M, Nahoul K, Papoz L
Am J Epidemiol 1992 Apr 1;135(7):783-91

From April 1985 to July 1987, 1,408 healthy white men aged 20-60 years in Paris, France, recruited on an occupational basis, underwent a physical examination and measurements of plasma sex hormones in a cross-sectional study. Both total testosterone and estradiol showed a significant stepwise decrease with age (p less than 0.001) starting in the early adult years, while estrone did not vary. These relations of testosterone and estradiol with age remained significant after adjustment for body mass index, subscapular skinfold, and tobacco and alcohol consumptions, and they were not modified by exclusion of the men who reported chronic disease. Both the mechanism for the early decrease in testosterone and its clinical significance merit further investigation.

Lewis JG, Ghanadian R, Chisholm GD
Acta Endocrinol (Copenh) 1976 Jun;82(2):444-8

Serum 5alpha-dihydrotestosterone (DHT) and testosterone (T) were measured in 98 normal adult men aged between 20-80 years, separating T and DHT by thin layer chromatography and using a sensitive and reliable radio-immunoassay. In three age groups between 20-40, 40-60 and 60-80, the means +/- SEM for serum DHT were 84 +/- 4, 79 +/- 3 and 67 +/- 3 (ng/100 ml) respectively. The corresponding values for testosterone were 559 +/- 25, 491 +/- 25 and 475 +/- 28 (ng/100 ml). A significant decrease was observed in the DHT level of the 60-80 years age group compared to either the 20-40 (P less than 0.01) or the 40-60 (P less than 0.02) age groups. There was a moderate decline in the testosterone level of the 60-80 years age group compared to 20-40 years (P less than 0.05) but there were no significant changes in the testosterone levels between other groups.

Ferrini RL, Barrett-Connor E
Am J Epidemiol 1998 Apr 15;147(8):750-4

The role of endogenous sex hormones in many diseases makes understanding factors that influence levels of these hormones increasingly important. This study examined age-associated variations in total and bioavailable testosterone and estradiol levels among community-dwelling Caucasian men in Rancho Bernardo, California. Plasma samples obtained from 810 men aged 24-90 years in 1984-1987 were analyzed in 1993 using radioimmunoassay. Analyses of age-hormone associations, adjusting for weight, body mass index, alcohol ingestion, smoking, physical activity, caffeine intake, specimen storage time, and disease status, were undertaken. Bioavailable testosterone and bioavailable estradiol levels decreased significantly with age independently of covariates. Total testosterone and estradiol levels decreased with age only when analyses were controlled for confounders. The importance of the age-associated decline in endogenous sex hormone levels, particularly levels of bioavailable testosterone and bioavailable estradiol, and their relation to disease and function in men deserve further research.

Carlson LE, Sherwin BB
Department of Psychology, McGill University, Montreal, Canada.
lindac@ego.psych.mcgill.ca
Psychoneuroendocrinology 1998 Aug;23(6):583-603

Men (n = 31), women estrogen-users (n = 14), and women estrogen non-users (n = 41), whose average age was 72.1 +/- 5.6 years, were tested with a battery of psychological tests measuring verbal memory, visual memory, concentration and attention, language fluency and semantic memory, and mood. Plasma levels of testosterone (T), estradiol (E2), cortisol (CRT) and dehydroepiandrosterone-sulfate (DHEAS) were assessed by radioimmunoassay. The ratio of DHEAS to CRT was calculated to determine it's relationship to memory functioning. The men had higher T and DHEAS levels than both groups of women. Women estrogen-users had higher E2 levels than both men and estrogen non-users and the men had higher E2 levels and a higher DHEAS/CRT ratio than the (female) estrogen non-users. There were no group differences in CRT levels. Men and estrogen-users had higher total (p < .01) and forward (p < .001) digit span scores compared with non-users. Women estrogen-users also had higher backward digit span scores than non-users (p < .05), while both groups of women performed better than men on category retrieval (p < .01). The implications of these findings with respect to hormonal influences on memory in elderly men and women are discussed.

Greenblatt RB, Oettinger M, Bohler CS
J Am Geriatr Soc 1976 Apr;24(4):173-8

The influence of aging on serum levels of gonadotropins (FSH and LH), testosterone and estradiol was studied in the following groups: 4 normal men (ages 30 to 50), 38 men with symptoms of the male climacteric (ages 51 to 84), 25 men with relative impotence (ages 31 to 50), 10 normal women (ages 24 to 31), and 6 menopausal women (ages 58 to 76). FSH and LH levels began to rise in men in their 40's, and the increase became more conspicuous in the later age decades. The degree of elevation was nowhere comparable to that observed in the aging women. In the male, the serum testosterone levels showed a progressive decrease from the fifth age decade onward, whereas in the female there was an increase after the menopause. Estradiol levels showed no significant change in the aged male, but they were somewhat higher than in the aged female. Exceptions to the low-testosterone and low-gonadotropin relationship were observed in individual cases and might be explained by relatively high estradiol values. Proper replacement therapy by means of estrogens for the postmenopausal female and androgens for the aging male is often of great benefit, physically and emotionally.

Zmuda JM, Fahrenbach MC, Younkin BT, Bausserman LL, Terry RB, Catlin DH, Thompson PD
Department of Medicine, Miriam Hospital, Providence, RI.
Metabolism 1993 Apr;42(4):446-50

Stanozolol, an oral 17 alpha-alkylated androgen, increases hepatic triglyceride lipase activity (HTGLA) and decreases high-density lipoprotein cholesterol (HDL-C) levels, whereas intramuscular testosterone has comparatively little effect. In the present study, we tested the hypothesis that aromatization of androgen to estrogen blunts the lipid and lipase effects of exogenous testosterone. Fourteen male weightlifters received testosterone enanthate (200 mg/wk intramuscularly), the aromatase inhibitor testolactone (250 mg four times per day), or both drugs together in a randomized cross-over design. Serum testosterone level increased during all three drug treatments, whereas estradiol level increased only with testosterone alone (+47%, P < .05), demonstrating that testolactone effectively inhibited testosterone aromatization. Testosterone decreased HDL-C(-16%, P < .05), HDL2-C(-23%, NS), and apoprotein (apo) A-I (-12%, P < .05) levels, effects that were consistently but not significantly greater with simultaneous testosterone and testolactone administration (HDL-C, -20%; HDL2-C, -30%; apo A-I, -15%; P < .05 for all). In contrast, both testosterone regimens decreased HDL3-C levels by 13% (P < .05 for both). HTGLA increased 21% during testosterone treatment and 38% during combined testosterone and testolactone treatment (P < .01 for both). Lipoprotein lipase activity (LPLA) increased only during combined testosterone and testolactone treatment (+31%, P < .01), suggesting that estrogen production may counteract the effects of testosterone on LPLA. Testolactone alone had little effect on any lipid, lipoprotein, apoprotein, or lipase concentration.

Worgul TJ, Santen RJ, Samojlik E, Irwin G, Falvo RE
Am J Physiol 1981 Sep;241(3):E246-50

A variety of data suggest an independent role for androgens and estrogens in the regulation of luteinizing hormone (LH) secretion in the male. Estrogens, in the male are primarily derived from testicular androgens that are aromatized both in peripheral tissues and in the CNS. Our prior data suggested a pharmacologic regimen that blocked CNS aromatization without lowering peripheral estrogen or testosterone levels. Such experimental conditions would permit assessment of the relative roles of CNS versus peripheral aromatization in the regulation of LH secretion. We utilized this regimen (aminoglutethimide, a potent aromatase inhibitor, and hydrocortisone) in seven adult male dogs for 14 days. Plasma LH rose to castrate levels, 450% above control values on days 7 and 14. These LH increments stimulated similar rises in androstenedione, testosterone, and dihydrotestosterone. In contrast, plasma estrone and estradiol concentrations remained constant. The induction of castrate LH levels without a concomitant fall in peripheral androgens or estrogens is best explained by a block of central aromatization and thus a reduction in local hypothalamic concentrations. We conclude that aromatization in the CNS rather than peripheral tissues is the more important site with respect to LH negative feedback in the male dog.

MacDonald PC, Madden JD, Brenner PF, Wilson JD, Siiteri PK
J Clin Endocrinol Metab 1979 Dec;49(6):905-16

The purpose of this study was to quantify the various sources of estrone (E1) and 17 beta-estradiol (E2) production in normal men and in women with testicular feminization. The mean production rate of E1 in four young adult men was 58 micrograms/24 h, while that of E2 was 44 micrograms/24 h. In these men, E1 production could be accounted for totally by extraglandular formation through 1) aromatization of plasma androstenedione, 2) conversion of E2 which was formed from the aromatization of plasma testosterone, and 3) conversion of secreted E2. In these men, only 12 micrograms or less of E2 production could not be accounted for by extraglandular formation from plasma C19 precursors, and is presumed to have arisen by testicular secretion. In six women with testicular feminization, the mean production rate of E1 was 99 micrograms/24 h, while that of E2 was 77 micrograms/24 h. The amount of E2 production that arose by glandular secretion could be computed in four of these women and was considerably greater than that found in the young adult men. In these women with testicular feminization, an average of 44 micrograms/24 h E2 could not be accounted for by extraglandular formation and is presumed to have arisen by testicular secretion. The mean plasma production rate of testosterone in the normal men was 5.7 mg/24 h, while that in the women with testicular feminization was 8.3 mg/24 h. However, the range of plasma production rates of testosterone in the women with testicular feminization was large (1.3--17.0 mg/24 h).

Berkovitz GD, Guerami A, Brown TR, MacDonald PC, Migeon CJ
J Clin Invest 1985 Jun;75(6):1763-9

We evaluated a family in which gynecomastia occurred in five males in two generations. In each affected subject, gynecomastia and male sexual maturation began at an early age. The ratio of the concentration of plasma estradiol-17 beta to that of plasma testosterone was elevated in each affected subject. In the three siblings with gynecomastia, the transfer constant of conversion of androstenedione to estrone (i.e., the fraction of plasma androstenedione that was converted to estrone as measured in the urine) was 10 times that of normal persons. The transfer constant of conversion of testosterone to estradiol-17 beta in the one subject studied also was 8-10 times that of normal men, whereas the transfer constants of conversion of estrone to estradiol-17 beta and of estradiol-17 beta to estrone were normal. Despite the elevation in extraglandular aromatase activity, there was a normal response of the hypothalamic-pituitary axis to provocative stimuli. This is the second documentation of gynecomastia that is associated with increased extraglandular aromatase activity, and the first time that the defect was found to be familial with a probable X-linked (or autosomal dominant, sex limited) mode of inheritance.

White CM, Ferraro-Borgida MJ, Moyna NM, McGill CC, Ahlberg AW, Thompson PD, Chow MS, Heller GV
University of Connecticut School of Pharmacy, Hartford, USA.
J Clin Pharmacol 1998 Sep;38(9):792-7

Intracoronary testosterone injections have recently been shown to possess coronary vasodilating effects. The same may be true for intravenous testosterone, but the pharmacokinetic and hemodynamic aspects need exploration before pharmacologic studies can begin. This trial determined the pharmacokinetic and hemodynamic properties of 300 microg of testosterone given intravenously. Degree of testosterone aromatization to 17-beta estradiol after exogenous administration and overall patient tolerability also were evaluated. Eleven elderly men with coronary artery disease participated in the study and were given 300 microg of testosterone intravenously over 10 minutes. Serum blood concentrations of testosterone and 17-beta estradiol were measured at baseline and then periodically. Testosterone serum concentrations were stripped and fit to a two-compartment model for all patients. The volume of distribution (Vdarea) was 80.36 +/- 24.51 L, and the elimination half-life was 55.93 +/- 23.06 minutes. No hemodynamic differences or side effects were noted. The serum concentrations of 17-beta estradiol were significantly increased from baseline beginning 5 minutes after infusion to the end of the study (180 minutes after infusion).

Yu Z, Gupta SK, Hwang SS, Kipnes MS, Mooradian AD, Snyder PJ, Atkinson LE
ALZA Corporation, Palo Alto, California 94303-0802, USA.
J Clin Pharmacol 1997 Dec;37(12):1139-45

This open-label, randomized, placebo lead-in, three-treatment crossover study in 19 hypogonadal men (27-82 years of age) evaluated dose proportionality of serum testosterone concentrations with application of one or two investigational transdermal testosterone systems for application to the arm or torso. Testosterone in vivo kinetics profiles were determined using DeMonS, a recently developed numerical deconvolution method that estimates drug absorption at different time intervals and/or drug disposition model parameters. After application of the investigational transdermal systems, the mean serum testosterone, dihydrotestosterone, estradiol, and free testosterone concentrations were elevated to normal levels. Treatment allowed approximation of the normal circadian pattern of endogenous testosterone secretion, and the increase in serum testosterone concentrations was proportional to the surface area of systems applied. The investigational transdermal system provided effective testosterone replacement therapy as judged by pharmacokinetic parameters.

Zmuda JM, Bausserman LL, Maceroni D, Thompson PD
University of Pittsburgh Medical Center, PA 15213, USA.
Atherosclerosis 1997 Apr;130(1-2):199-202

Elevated total homocysteine (tHcy) levels are associated with increased risk for atherosclerotic cardiovascular disease. tHcy levels are higher in men than in women, and estrogen replacement therapy may reduce tHcy levels in postmenopausal women. The effect of androgenic hormones on tHcy levels in men has not been examined. The present study determined the effect of supraphysiologic doses of testosterone, with or without its aromatization to estradiol, on fasting tHcy levels in 14 normal male weightlifters aged 19-42 years. Subjects received testosterone-enanthate (200 mg/week intramuscularly), the aromatase inhibitor, testolactone (1 g/day orally), or both drugs together in a crossover design. Each treatment lasted 3 weeks and each treatment was separated by a 4-week washout. Both testosterone regimens increased serum testosterone levels, whereas estradiol increased only during testosterone alone. Mean tHcy levels were not significantly altered when testosterone was given alone or together with testolactone. Testolactone did not significantly influence tHcy levels. We conclude that short-term, high-dose testosterone administration does not affect fasting tHcy levels in normal men.

[Article in Japanese]
Itoh N, Kumamoto Y, Maruta H, Tsukamoto T, Takagi Y, Mikuma N, Nanbu A, Tachiki H
Department of Urology, Sapporo Medical College.
Nippon Hinyokika Gakkai Zasshi 1991 Feb;82(2):204-9

To our knowledge, the action of estradiol which is produced from testosterone by aromatase on human spermatogenesis has not been fully clarified. In oligozoospermia, with high values of E2/T ratio, it is considered that the role of estradiol is suppressive to spermatogenesis. In this study, alteration of spermatogenesis was evaluated when serum estradiol levels were decreased by suppression of aromatase activity. Nine male infertile patients were treated with testolactone (Teslac: 1.0 g/day, for 3 months), one of the aromatase inhibitors. Four of them had an increase in sperm count (more than 10 x 10(6)/ml relative to base line). In endocrinological findings, serum estradiol levels and E2/free T ratio were significantly decreased after treatment. Serum free testosterone levels were significantly increased in all cases, presumably from decreased sex hormone binding globulin (SHBG) levels. These findings suggested the effectiveness of the administrated aromatase inhibitor. In particular four patients whose sperm counts were improved after testolactone treatment had high values of basal serum estradiol levels and E2/free T ratio before treatment, and these values were normalized after treatment. In conclusion we suggest that an aromatase inhibitor may be effective to male infertile patients with high serum estradiol levels.

Meikle AW, Stanish WM, Taylor N, Edwards CQ, Bishop CT
Metabolism 1982 Jan;31(1):6-9

We investigated whether familial factors influence the plasma content of sex-steroids and sex-hormone-binding globulin (SHBG) in 98 adult males of 66 families. They had no apparent endocrine dysfunction, The 0800-1100 hr plasma levels of testosterone, 5 alpha-dihydrotestosterone (DHT), estradiol-17 beta (E2) and estrone (E1) were measured by radioimmunoassay. The free fractions of E2 and testosterone were determined by equilibrium dialysis, and binding capacity of SHBG was also calculated. The data were analyzed by analysis of variance. We observed that the differences in the plasma content of testosterone (p = .02). SHBG binding capacity (p = 0.1), and E2 (p = 0.3), free E2 index (p = .05) were all substantially less variable within groups of brothers than among non-brothers. The variability of the plasma concentration of DHT, free testosterone and E1 was not significantly less within brothers than among non-brothers. The correlation between either plasma testosterone content (r = .14) or SHBG binding capacity (r = .12) and percent of ideal body weight was not significant statistically. Age had no effect on the results. Our data suggest that genetic and/or environmental factors may affect the plasma content of testosterone, E2 and SHBG

Gordon GG, Olivo J, Rafil F, Southren AL
J Clin Endocrinol Metab 1975 Jun;40(6):1018-26

The contribution, by peripheral conversion, of androstenedione and testosterone to the circulating estrogens was determined in men with cirrhosis of the liver. The conversion ratio of androstenedione to estrone, estradiol and testosterone and the conversion ratio of testosterone to estrone (but not estradiol) and androstenedione were significantly increased. The plasma concentrations of androstenedione and testosterone were increased and decreased respectively; the mean plasma concentration of androstenedione being similar to that found in normal women. The metabolic clearance rate of androstenedione was not altered in cirrhosis although the metabolic clearance rate of testosterone was decreased. The production rate of androstenedione was elevated while that of testosterone was reduced. The instantaneous contribution of plasma androstenedione to estrone and estradiol was increased in cirrhosis as was the contribution of testosterone to estrone (but not to estradiol). Thus the increased estradiol levels in cirrhosis result, in large part, from increased peripheral conversion from the androgens. The percent contribution of plasma testosterone to plasma androstenedione was decreased although the absolute amount derived by conversion was normal. The percent contribution of plasma androstenedione to plasma testosterone was increased sevenfold in cirrhosis. The fraction of the daily androstenedione production derived from the plasma testosterone pool was not significantly altered. However, a significant fraction of the daily production rate of testosterone was derived from androstenedione. Thus, 15% of the circulating testosterone is not secreted but is derived by peripheral conversion from androstenedione. Normal levels of gonadotropins were found in cirrhosis.

Sherins RJ, Patterson AP, Brightwell D, Udelsman R, Sartor J
Ann N Y Acad Sci 1982;383:295-306

The data suggest that in the absence of the testis: (1) testosterone can maintain both FSH and LH concentrations chronically within the physiological range; (2) that estradiol preferentially suppresses plasma LH concentration, indicating that the androgenic component of testosterone modulates FSH secretion; and (3) that subphysiological testosterone concentrations accompanied by physiological estradiol levels permit FSH to escape to midcastrate levels while maintaining LH concentration at intact levels. An alteration in the testosterone: estradiol ratio can account for a selective FSH elevation when testosterone production is low. The data provide an alternative explanation for the inhibin phenomenon.

Cantrill JA, Dewis P, Large DM, Newman M, Anderson DC
Clin Endocrinol (Oxf) 1984 Aug;21(2):97-107

Three different forms of testosterone (T) replacement therapy were compared; they were the intramuscular injection of mixed testosterone esters 250 mg; the subcutaneous implantation of 6 X 100 mg pellets of fused testosterone; and the oral administration of testosterone undecanoate (TU) 80 mg twice daily. Six hypogonadal males were treated with oral TU for an eight week period, during which time serial serum hormonal estimations were performed over 10 h at the initiation and after four and eight weeks of therapy. Serum T levels showed marked variability both between subjects and within the same subject on different occasions. We attribute this to variability in absorption of TU, which is formulated in oleic acid. The overall mean T level calculated from the areas under the profiles of TU was 12.0 nmol/l. Hormone responses to injected T esters were studied in nine hypogonadal males. Serum T rose to supraphysiological peak concentrations (mean 71 nmol/l) 24-48 h after an injection, followed by an exponential decay to reach baseline concentrations after 2-3 weeks. The overall calculated mean T level in subjects receiving testosterone esters 250 mg every three weeks was 27.7 nmol/l. Subcutaneous implantation of testosterone in six hypogonadal men produced a gradual rise in serum T followed by a slow decline, with T levels remaining within the normal range for 4-5 months. The calculated overall mean T level over 21 weeks after implantation was 17.0 nmol/l. Serum oestradiol (E2) levels remained within the normal male range throughout the study periods on both TU and T implant therapy but showed a supraphysiological peak (mean 347 pmol/l) 24-48 h after a T injection. 5 alpha-dihydrotestosterone (DHT) levels appeared to parallel those of T on the three forms of therapy, with DHT:T ratios being highest for TU therapy. This was also true for the target organ metabolite 5 alpha-androstane-3 alpha,17 beta-diol. At the doses studied drug costs were similar for T implantation (every 5 months) and T ester injections (every 3 weeks), but were 7-8 times higher for TU (80 mg twice a day). We conclude that T implantation remains overall the most physiological form of androgen replacement therapy, is generally well accepted and attended by few side effects; TU may have a useful role in the initial phases of therapy.

Kley HK, Niederau C, Stremmel W, Lax R, Strohmeyer G, Kruskemper HL
J Clin Endocrinol Metab 1985 Jul;61(1):1-6

Hypogonadism is common in patients with some liver diseases, such as idiopathic hemochromatosis (IHC) and alcoholic cirrhosis (AC). However, gynecomastia, a typical feature in AC, does not occur in IHC. To determine the hormonal basis for this difference, the following parameters were determined in patients with IHC and AC as well as in normal men: plasma concentrations of androgens and estrogens, metabolic clearance and production rates of androstenedione and testosterone, and the contribution of peripheral conversion of androstenedione and testosterone to the circulating estrogens. Severe impotence in both patients with IHC and those with AC was associated with more than 50% reduction in plasma testosterone. The reduction was due to 63% and 70% decreases in testosterone production in IHC and AC, respectively. The MCRs were less affected in IHC and AC (19% and 37% reductions, respectively). In IHC, the fall in testosterone concentrations was accompanied by decreased production and plasma concentrations of androstenedione, a precursor for estrogen synthesis. In contrast, production and plasma concentrations of androstenedione were significantly increased in AC. Patients with IHC had estradiol und estrone levels similar to those in normal men (mean +/- SD, 16.2 +/- 4.6 vs. 20.3 +/- 3.7 pg/ml; P = NS), whereas in AC, estradiol and estrone were significantly elevated (38.0 +/- 5.3 and 68.5 +/- 17.2 pg/ml, respectively). In IHC, sex hormone-binding globulin levels were in the same range as in the normal men, whereas sex hormone-binding globulin was increased in AC. In IHC, the instantaneous contribution of plasma androstenedione to estrone and estradiol was normal, whereas that of plasma testosterone to plasma estrogens was decreased by about 50%. In contrast, in AC, the instantaneous contribution of plasma androstenedione to estrogens was greatly enhanced, and that of testosterone was in the normal range. Since the MCRs of androgens and the conversion ratios of androgens to estrogens indicate normal peripheral metabolism of sex hormones in IHC, decreased androgen formation implies decreased testicular synthesis. This was confirmed by a significantly decreased LH level in IHC (5.5 +/- 1.9 vs. 10.5 +/- 3.1 mU/ml in normal men), indicating pituitary failure. In AC, however, increased LH (20.0 +/- 2.7 mU/ml) may be indicative of primary testicular failure. These results confirm clinical features of hypogonadism and normal estrogenic activity in patients with IHC.

Stuenkel CA, Dudley RE, Yen SS
Department of Reproductive Medicine, School of Medicine, University of California-San Diego, La Jolla 92093.
J Clin Endocrinol Metab 1991 May;72(5):1054-9

In search of a more physiological testosterone (T) replacement therapy for hypogonadal states, we evaluated an inclusion complex of T with 2-hydroxypropyl-beta-cyclodextrin (HPBCD). HPBCD enhances T solubility and absorption, but HPBCD is not absorbed. Five hypogonadal men (mean age, 32.4 +/- 2.3 yr) with serum T levels below the normal range were treated in two separate experimental phases with either a 2.5- or 5.0-mg tablet of sublingual (SL) T-HPBCD three times daily for 7 days. Acute pharmacodynamic changes were monitored at baseline and 10, 20, and 40 min and 1, 1.5, 2, 3, 4, and 8 h after administration of the first dose. At the 5-mg dose, a maximal concentration (Cmax) of T (85.4 +/- 11.0 nmol/L) was achieved in 20 min (63 +/- 24-fold increase), followed by a rapid decline to below the normal range (less than 12 nmol/L) at 2 h, with an estimated half-life of decline of 1.87 +/- 0.19 h. The dihydrotestosterone (DHT) Cmax (4.1 +/- 0.5 nmol/L) occurred at 32 +/- 5 min (8.9 +/- 1.3-fold increase) and declined to below the normal range (less than 1.2 nmol/L) after 3 h. The integrated 8 h value for the ratio of T/DHT was 10.0 +/- 1.1, which fell within the normal range. The increment in androstenedione paralleled that in T, and the Cmax (6.8 +/- 0.9 nmol/L) was reached in 24 +/- 4 min (2.3 +/- 0.6-fold increase). Compared to baseline, the Cmax was significantly greater for T (P less than 0.005), DHT (P less than 0.0005), and androstenedione (P less than 0.005). Both estradiol (E2) and estrone (E1) remained in the normal range (less than 200 pmol/L), although the Cmax for E1 was significantly greater than baseline (P less than 0.05). Serum LH levels were suppressed (19.0 +/- 2.6%) at 2 h (P less than 0.05), without a significant change in FSH. During 7 days of treatment, there was no cumulative increase in basal T, DHT, and E2 levels or further decline in LH or FSH levels. There was no change in sex hormone-binding globulin levels. Similar results were observed with the 2.5-mg dose, suggesting that the capacity of SL absorption may be limited to a certain dose of T-HPBCD. The fluctuations in T after SL administration of T-HPBCD resemble endogenous episodic secretion. We conclude that T, complexed with HPBCD, is rapidly absorbed by the SL route and quickly metabolized without sustained elevations of DHT or E2.

Phillips GB, Pinkernell BH, Jing TY
Department of Medicine, Columbia University College of Physicians and Surgeons, St. Luke's-Roosevelt Hospital Center, New York, NY, USA.
Arterioscler Thromb Vasc Biol 1996 Nov;16(11):1383-7

Both hyperestrogenemia and hypotestosteronemia have been reported in association with myocardial infarction (MI) in men. It was previously observed that the serum testosterone concentration correlated negatively with the degree of coronary artery disease (CAD) in men who had never had a known MI. The present study investigated the relationship of sex hormone levels to the thrombotic component of MI by comparing these levels in 18 men who had had an MI (ie, thrombosis) and 50 men with no history of MI (ie, no thrombosis) whose degree of CAD was in the same range. The mean degree of CAD, age, and body mass index in these two groups was not significantly different. The mean serum estradiol level in the men who had had an MI (38.5 +/- 8.8 pg/mL) was higher (P = .002) than the level in the men who had not had an MI (31.9 +/- 7.1 pg/mL). The mean levels of testosterone, free testosterone, sex hormone-binding globulin, insulin, dehydroepiandrosterone sulfate, cholesterol, HDI, cholesterol, and systolic and diastolic blood pressure did not differ significantly. Estradiol was the only variable measured that showed a significant relationship to MI (P < .003 by multivariate logistic regression). These findings suggest that hyperestrogenemia may be related to the thrombosis of MI.

De Pergola G, De Mitrio V, Sciaraffia M, Pannacciulli N, Minenna A, Giorgino F, Petronelli M, Laudadio E, Giorgino R
Institute of Medical Clinic, Endocrinology and Metabolic Disease, University of Bari, School of Medicine, Italy.
Metabolism 1997 Nov;46(11):1287-93

The purpose of this study was to examine the relationships between androgenic status and plasma levels of both prothrombotic and antithrombotic factors in men, irrespective of obesity, body fat distribution, and metabolic parameters. Sixty-four apparently healthy men, 40 with a body mass index (BMI) greater than 25 kg/m2 (overweight and obese [OO]) and 24 non-obese controls with a BMI less than 25, were selected and evaluated for (1) plasma concentrations of plasminogen activator inhibitor-1 (PAI-1) antigen, PAI-1 activity, fibrinogen, von Willebrand factor (vWF) antigen, vWF activity, and factor VII (FVII) as the prothrombotic factors; (2) plasma levels of tissue plasminogen activator (TPA) antigen, protein C, and antithrombin III as the antithrombotic factors; (3) fasting plasma concentrations of insulin and glucose and the lipid pattern (triglycerides [TG] and total and high-density lipoprotein [HDL] cholesterol) as the metabolic parameters; and (4) free testosterone (FT), dehydroepiandrosterone sulfate (DHEAS), and sex hormone-binding globulin (SHBG) serum levels as the parameters of androgenicity. Body fat distribution was evaluated by the waist to hip ratio (WHR). In OO and non-obese subjects taken together, plasma levels of PAI-1 antigen, fibrinogen, and FVII were inversely associated with FT (r = .255, P < .05, r = -3.14, P < .05, and r = -.278, P <.05, respectively), and the negative relationships of both fibrinogen and FVII with FT were maintained after stepwise multiple regression analysis. Plasma concentrations of PAI-1 antigen and PAI-1 activity were also negatively correlated with SHBG (r = -.315, P < .05 and r = -.362, P < .01, respectively), and these associations held irrespective of the other parameters investigated. None of the antithrombotic and fibrinolytic factors were independently related to serum androgen levels. Subjects with a BMI higher than 25 kg/m2 had higher plasma concentrations of PAI-1 antigen, PAI-1 activity, and fibrinogen as compared with non-obese controls (P < .001, P < .001, and P < .01, respectively). In addition, in OO and control subjects as a whole, multiple stepwise regression analysis showed that the associations of BMI with PAI-1 activity, fibrinogen, vWF antigen, and vWF activity were independent of any other metabolic and hormonal parameters. Plasma concentrations of PAI-1 antigen, PAI-1 activity, and fibrinogen were also directly correlated with WHR in all subjects taken together, irrespective of the other parameters investigated. Evaluation of antithrombotic factors showed that OO subjects had higher TPA plasma concentrations than non-obese controls (P < .001), whereas protein C and antithrombin III did not differ in the two groups. TPA was also directly correlated with BMI (r = .415, P < .001) and WHR (r = .393, P < .001) in all subjects. The results of this study indicate that (1) men with lower FT serum levels have higher fibrinogen and FVII plasma concentrations, and those with lower SHBG serum levels also have higher levels of PAI-1 antigen and activity; (2) irrespective of other factors, obesity per se may account for higher concentrations of PAI-1, fibrinogen, and vWF; (3) plasma levels of PAI-1 (antigen and activity) and fibrinogen correlate independently with WHR; and (4) among the investigated antithrombotic factors (TPA antigen, protein C, antithrombin III), only TPA antigen plasma concentrations are higher in men with abdominal obesity. Thus, because of the increase in several prothrombotic factors, men with central obesity, particularly those with lower androgenicity, seem to be at greater risk for coronary heart disease (CHD). Apparently, this risk is not counteracted by a parallel increase in plasma concentrations of antithrombotic factors.

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Glueck CJ, Glueck HI, Stroop D, Speirs J, Hamer T, Tracy T
Department of Pathology, University of Cincinnati College of Medicine.
J Lab Clin Med 1993 Oct;122(4):412-20

To assess relationships of endogenous testosterone with fibrinolysis and coronary heart disease risk factors in 55 newly referred hyperlipidemic men, we studied the relationships of testosterone to basal fibrinolytic activity, lipids, lipoproteins, and apolipoproteins. Testosterone correlated positively with the major stimulator of fibrinolysis, tissue plasminogen activator activity (r = 0.30; p = 0.02) and correlated inversely with two independent coronary heart disease risk factors, plasminogen activator inhibitor activity, the major fibrinolysis inhibitor (r = -0.33; p = 0.01), and fibrinogen (r = -0.39; p = 0.004). Testosterone correlated inversely with plasma triglycerides (r = -0.33; p = 0.01). Stepwise multiple regression was done with fibrinolytic activities as the dependent variables, and age, Quetelet Index (relative ponderosity), apolipoprotein A-I, apolipoprotein B, triglyceride, testosterone, time of blood sampling, and lipoprotein (a) as explanatory variables. Testosterone was an inverse, independent predictor of fibrinogen (p = 0.002); 53% of the variance of fibrinogen could be accounted for by age and triglyceride level (positive; p = 0.001, p = 0.01), and by apolipoprotein A-I and testosterone (negative; p = 0.02, p = 0.002). Testosterone was an independent inverse predictor of tissue plasminogen activator antigen (p = 0.0008), with tissue plasminogen activator antigen correlating inversely with tissue plasminogen activator activity. Quetelet index and apolipoprotein B wereindependent negative predictors of tissue plasminogen activator activity (p =0.02, p = 0.03); Quetelet index and triglycerides were independent positive predictors of plasminogen activator inhibitor activity (p = .0001, p = .0001) and alpha 2-antiplasmin (p = 0.0003, p = 0.009).

Winkler UH
Zentrum fur Frauenheilkunde, Universitatsklinikum Essen, Germany.
Maturitas 1996 Jul;24(3):147-55

Androgen deficiency is associated with an increased incidence of cardiovascular disease. There is evidence that thromboembolic disease as well as myocardial ifarction in hypogonadic males are mediated by low baseline fibrinolytic activity. Hypogonadism in males is associated with an enhancement of fibrinolytic inhibition via increased synthesis of the plasminogen activator inhibitor PAI 1. On the other hand, stanozolol and danazol reduce PAI 1 and are associated with increased fibrinolytic activity. However, in male abusers of anabolic steroids the net effect on the haemostatic system may change from anti- to prothrombotic; there appears to be an individual threshold dose above which thrombogenic effects on platelets and vasomotion may overcome the profibrinolytic effects on PAI 1. There are numerous reports on weight-lifters dying of atherothrombotic ischemic heart disease while abusing anabolic steroids. Androgens are known to have profound effects on carbohydrate and lipid metabolism. In fact, much of the individual inconsistency of the effects of androgens on fibrinolytic and haemostatic activity appears to be based on the close interrelationship of these metabolic systems. Androgens may have unfavourable effects on the HDL/LDL cholesterol ratio, on triglyceride levels and on the insulin/insulin-like growth factor 1 (IGF 1) system. Hypertriglyceridemia as well as insulin resistance are both associated with low fibrinolytic activity and increased PAI 1 levels. On the other hand, lipoprotein(a), a recently acknowledged independent risk factor of CVD was shown to respond favourable to androgen treatment, in men as well as in women. In women, agonistic as well as antagonistic effects of estrogens and progestins need to be taken into account. In fact, estradiol may modulate testosterone effects on haemostasis. Androgen medication in premenopausal women, such asdanazol, was found to reduce PAI 1 suggesting an improvement of the fibrinolytic activity. Also, in hormone replacement therapy (HRT) androgenic progestins or complex compounds with androgenic effects are associated with a marked reduction of PAI 1 and an improvement of fibrinolytic activity. Further improvement of fibrinolytic activity may be associated with the marked decrease of lipoprotein (a) (Lp(a)) in women on androgenic HRT. However, little is known on the interrelationship of estrogens, 19-nortestosterone or progesterone derivatives and testosterone. an interrelationship that may have substantial impact on the metabolic and particularly haemostatic net effects of a preparation. In summary, information on the effects of androgens on haemostasis is limited and may be particularly incomplete due to the fact that interaction with other sex steroids appears to be an important confounder. In any case, there are numerous effects of synthetic androgens on the synthesis and release of haemostatic factors, namely an increase of the inhibitors of coagulation and a decrease of the inhibitor of the fibrinolytic system. However, the use of androgens in patients with congenital deficiencies of these coagulation factors or previous events of cardiovascular disease has yielded disappointing results. On the other hand, particularly the reduction of fibrinolytic inhibition (PAI 1) and Lp(a) were considered favourable effects of androgens with regard to the risk of cardiovascular disease. Differences between preparations withpronounced androgenic versus antiandrogenic effects and the effect of combined preparations need to be studied in much more detail. The profibrinolytic effects of androgens may be of particular interest with regard to favourable effects of HRT on cardiovascular disease.

Caron P, Bennet A, Camare R, Louvet JP, Boneu B, Sie P
Service d'Endocrinologie, Hopital Purpan, Toulouse, France.
Metabolism 1989 Oct;38(10):1010-5

Low plasma testosterone and high levels of the rapid inhibitor of plasminogen activator (PA-I) have been proposed as risk factors for myocardial infarction. In this study, the relationship between testosterone and PA-I activity levels in middle-aged men without thrombotic antecedent was investigated. In 54 normogonadic men (testosterone, 7.3 to 29.1 nmol/L), PA-I was related positively to body mass index (BMI) and triglycerides and negatively to testosterone. When these variables were controlled, the relation between PA-I and testosterone remained significant (P less than .01). In the 41 normogonadic men with BMI less than 25, testosterone was the only variable to influence PA-I. Fibrinolytic activity was evaluated by the euglobulin lysis plate method and the specific measurement of functional tissue plasminogen activator. The basal fibrinolytic activity and the response to venous occlusion were essentially controlled by PA-I but were not significantly related to testosterone. In 17 men with severe hypogonadotrophinic hypogonadism (testosterone less than 3 nmol/L), PA-I was significantly increased (18.5 +/- 1.8 AU/mL, mean +/- SE) compared with 9.5 +/- 0.8 AU/mL in 41 normogonadic men of normal weight (P less than .001). However, 14 hypogonadic men had a hypertriglyceridemia or a BMI greater than 25, which could explain high PA-I levels. This study shows that the level of the inhibitor of plasminogen activator is partly dependent on hormonal status in men and provides a link between independently established epidemiologic data.

Ajayi AA; Mathur R; Halushka PV
Department of Pharmacology, Medical University of South Carolina, Charleston 29425-2251, USA.
Circulation (United States) Jun 1 1995, 91 (11) p2742-7

BACKGROUND: The incidence of thrombotic cardiovascular disease is greater in men than in premenopausal women. Testosterone has been implicated as a significant risk factor for cardiovascular disease and for acutemyocardial infarctions and strokes in young male athletes who abuse anabolic steroids. Thromboxane A2 (TXA2) is a vasoconstrictor and platelet proaggregatory agent that has been implicated in the pathogenesis of cardiovascular disease. We therefore tested the hypothesis that testosterone regulates the expression of human platelet TXA2 receptors.

METHODS AND RESULTS: In a double-blind, placebo-controlled, randomized, parallel-group study, we determined the effects of testosterone cypionate 200 mg IM given twice, 2 weeks apart, or saline placebo in 16 healthy men. Platelet TXA2 receptor density (Bmax) and dissociation constant (Kd) were measured by use of the TXA2 mimetic 125I-BOP. Platelet aggregation responses to I-BOP and to thrombin and plasma testosterone concentrations were measured before treatment (pretreatment phase), at 2 and 4 weeks (active phase), and again at 8 weeks (recovery phase). Treatment with testosterone was associated with an increase in the Bmax value from 0.95 +/- 0.13 to 2.10 +/- 0.4 pmol/mg protein (n = 9), with a peak effect at 4 weeks (P = .001), returning to baseline by 8 weeks. There was no significant change in Bmax values in the saline-treated group. The Kd values were unchanged. Testosterone treatment was associated with a significant increase in the maximum platelet aggregation response to I-BOP (P < .001) at 4 weeks and returned to baseline at 8 weeks. The EC50 values were not significantly changed. Platelet TXA2 receptor density was positively correlated (r = .56, P < .001, n = 32 measurements) with pretreatment (endogenous) plasma testosterone levels (range, 215 to 883 ng/dL) but not Kd.

CONCLUSIONS: Testosterone regulates the expression of platelet TXA2 receptors in humans. This may contribute to the thrombogenicity of androgenic steroids.

Suzuki K, Ito K, Ichinose Y, Kurokawa K, Suzuki T, Imai K, Yamanaka H, Honma S
Department of Urology, School of Medicine, Gunma University, Japan.
Scand J Urol Nephrol 1995 Mar;29(1):65-8

Estrogen plays an important role in the development of benign prostatic hyperplasia (BPH), as has been shown in both experimental and clinical studies. T determine the endocrine environment of BPH, serum total testosterone (Total-T), free testosterone (Free-T), and estradiol (E2) conceptions were measured, and the relationship between these levels and prostate size and volume was analyzed. Blood samples were collected from subjects who attended the mass screening for prostate disease performed by our institute. No significant correlations were found between Total-T levels, Free-T levels, and prostate size, as determined by digital rectal examination. However, E2 levels and the ratios for E2 levels and the ratios for E2/Total-T and E2/Free-T were significantly correlated with prostate size. To confirm these relationships, prostate volume was calculated from transrectal ultrasonographic images. E2 levels and these two ratios were, indeed, highly correlated with prostate volume. These results suggest that an estrogen-dominant environment plays an important role in the development of BPH.

Gann PH, Hennekens CH, Longcope C, Verhoek-Oftedahl W, Grodstein F, Stampfer MJ
Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Prostate 1995 Jan;26(1):40-9

We assessed the relation of plasma hormone levels and nonhormonal factors with subsequent occurrence of surgical treatment for benign prostatic hyperplasia (BPH) among participants in the Physicians' Health Study. Frozen plasma samples, collected at the study onset, were available for 320 men who developed surgically treated BPH up to 9 years later and for 320 age-matched controls. Plasma testosterone (T), dihydrotestosterone (DHT), androstenedione, estradiol (E2), and estrone (E1) were measured for each case-control pair. In unadjusted analyses, none of the hormones or hormone ratios were associated with BPH; for example, for T and E2 the odds ratios (OR) comparing the highest quintile (Q5) with the lowest (Q1) were 0.74 (95% CI = 0.42, 1.30) and 1.07 (95% CI = 0.51, 2.22), respectively. However, in multivariate analyses controlling diastolic blood pressure, exercise, alcohol, E1, and DHT:T ratio, we observed a strong trend for increasing risk across quintiles for E2 (Q5 vs. Q1 OR = 3.56, P trend = 0.009), and a weak inverse trend for E1 (Q5 vs Q1 OR = 0.51, P trend = 0.07). The excess risk associated with E2 was confined to men with relatively low androgen levels. Three nonhormonal factors previously suspected as risk factors were independently associated with surgical BPH in these data. The OR for a 1-mm Hg difference in diastolic blood pressure was 1.04 (95% CI = 1.01, 1.07). Alcohol use and infrequent exercise were inversely associated with risk of BPH surgery; however, risk estimates were not consistent across categories of exercise and alcohol frequency. Our results indicate that normal variation in circulating androgen levels does not influence development of BPH, but that variation in estrogen levels might be important.

Stone NN, Fair WR, Fishman J
Prostate 1986;9(4):311-8

Prostatic tissue removed at the time of cystoprostatectomy was separated into periurethral and peripheral zones. Homogenized tissue was incubated with [1,2,6,7(3)H] androstenedione in the presence or absence of an aromatase inhibitor, 4-hydroxyandrostenedione (4-OHAD) and a 5 alpha-reductase inhibitor 4-MA (N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane 17 beta-carboxamide). Estrogen formation was determined by reverse isotope dilution of [3H] estrone and [3H] estradiol and crystallization to constant specific activity. Control incubations were carried out in parallel utilizing heated prostatic tissue. Total estrogens produced in the periurethral zone in patients with benign prostatic hyperplasia (BPH) was 223 fmol/mg protein/hr (SE +/- 57) compared to 102 fmol (SE +/- 17) in patients without BPH. Estrogen formation in the peripheral zone was 175 fmol (SE +/- 69) and 105 fmol (SE +/- 26) in patients with and without BPH, respectively. The prostatic aromatase exhibits Michaelis-Menton kinetics with an apparent Km of 90 nM. 4-OHAD inhibited aromatization in the prostatic tissue by 57-93%. Aromatization was also strongly inhibited by 4-MA, indicating that 4-MA is a potent aromatase as well as a 5 alpha-reductase inhibitor in this tissue. These results suggest that aromatization of androgens to estrogens in the human prostate proceeds at a substantial rate and that local estrogen formation could preexist and be a factor in the etiology of BPH and prostatic cancer.

Ehara H; Koji T; Deguchi T; Yoshii A; Nakano M; Nakane PK; Kawada Y
Department of Urology, Gifu University School of Medicine, Japan.
Prostate 1995 Dec;27(6):304-13

To understand the role of estrogen in the pathogenesis of benign prostatic hyperplasia, expressions of estrogen receptor (ER) mRNA and ER protein by in situ hybridization and by immunohistochemistry, respectively, were investigated in human prostatic tissues. In non-malignant region, ER mRNA and ER protein were found in cytoplasm and nucleus, respectively, of stromal cells, but not in glandular epithelial and basal cells. In benign regions, ER mRNA/ER protein positive cells were found in fibromyoadenomatous and myoadenomatous hyperplasia, but not in adenomatous hyperplasia. A striking feature was periacinar arrangement of ER mRNA/ER protein positive stromal cells in all prostate carcinoma treated with androgen withdrawal. The ER mRNA/ER protein positive cells were immunohistochemically identified as fibroblasts, myoblasts, and smooth muscle cells. These results indicate that stromal cells are the primary target of estrogen in prostate, and that androgen withdrawal upregulates the expression of ER gene.

Farnsworth WE
Department of Urology, Northwestern University Medical School, Chicago, Illinois, USA.
Prostate 1996 Jan;28(1):17-23

Heretofore, the function of estrogen in the prostate, other than as an antiandrogen, has been unclear. In this review of a growing fund of knowledge about both estrogen and the plasma protein, sex hormone-binding globulin (SHBG), or testosterone-estradiol binding globulin (TeBG), the hypothesis is proposed that estrogen, mediated by SHBG, participates with androgen in setting the pace of prostatic growth and function. It is suggested that the estrogen not only directs stromal proliferation and secretion, but also, through IGF-I, conditions the response of the epithelium to androgen.

[Article in German]
Voigt KD, Bartsch W
Universitatskrankenhaus Eppendorf, Abteilung fur klinische Chemie, Hamburg.
Urologe [A] 1987 Nov;26(6):349-57

This paper presents a large body of data relating to benign prostatic hyperplasia, which have been derived from fundamental endocrinological research. For the urologist, the data open up interesting aspects of the pathomorphology of prostatic hyperplasia. The most interesting findings can be summed up as follows: 1. Testosterone is the circulating androgenic prohormone that mediates the intracellular message leading to androgen secretion, though by way of its metabolite dihydrotestosterone, which is really the active substance. 2. This metabolic conversion is catalyzed by 5 alpha-reductase, which is predominantly a stromal enzyme. 3. The estrogen metabolism in the stromal cells of the prostate may be associated with the abnormal growth of the prostate. 4. In the presence of benign prostatic hyperplasia dihydrotestosterone and 17 beta-estradiol accumulate in the nuclei of the stromal cells. 5. Adrenal androgens are also metabolized in the human prostate, yielding some substances with androgenic and some with estrogenic potency. 6. Changes in sex hormone binding globulins (SHBG) are found with age whether benign prostatic hyperplasia is present or not. It is therefore questionable whether it has any influence on the development of prostatic hyperplasia. 7. Although in some cases it is not yet possible to determine whether the findings presented in this paper have any causal significance, the data can be used as a rational basis for hormonal treatment of prostatic disease.

Nakhla AM; Khan MS; Romas NP; Rosner W
Department of Medicine, St. Luke's/Roosevelt Hospital Center, New York, NY 10019.
Proc Natl Acad Sci U S A 1994 Jun 7;91(12):5402-5

Androgens are widely acknowledged to be central to the pathogenesis of benign prostatic hypertrophy (BPH). However, BPH increases in prevalence as men age, at precisely the stage of life when plasma androgens are decreasing. The decrease in total plasma androgens is amplified by an age-related increase in plasma sex hormone-binding globulin (SHBG) that results in a relatively greater decrease in free androgens than in total androgens. In addition, estrogens have long been suspected to be important in BPH, but a direct effect on the human prostate has never been demonstrated. We present data that are consistent with a role for estradiol, and for a decrease in androgens and an increase in SHBG, in the pathogenesis of BPH. We show that estradiol, but not dihydrotestosterone, acts in concert with SHBG to produce an 8-fold increase in intracellular cAMP in human BPH tissue. This increase is not blocked by an antiestrogen and is not provoked by an estrogen (diethylstilbestrol) that does not bind to SHBG, thus excluding the classic estrogen receptor as being operative in these events. Conversely, dihydrotestosterone, which blocks the binding of estradiol to SHBG, completely negates the effect of estradiol. Finally, we demonstrate that the SHBG-steroid-responsive second-messenger system is primarily localized to the prostatic stromal cells and not to the prostatic epithelial cells. Thus, we have shown a cell-specific, powerful, nontranscriptional effect of estradiol on the human prostate.

Hryb DJ, Khan MS, Romas NA, Rosner W
Department of Medicine, St. Luke's/Roosevelt Hospital Center, New York, N.Y. 10019.
Planta Med 1995 Feb;61(1):31-2

Extracts from the roots of the stinging nettle (Urtica dioica) are used in the treatment of benign prostatic hyperplasia. The mechanisms underlying this treatment have not been elucidated. We set out to determine whether specific extracts from U. dioica had the ability to modulate the binding of sex hormone-binding globulin to its receptor on human prostatic membranes. Four substances contained in U. dioica were examined: an aqueous extract; an alcoholic extract; U. dioica agglutinin, and stigmasta-4-en-3-one. Of these, only the aqueous extract was active. It inhibited the binding of 125I-SHBG to its receptor. The inhibition was dose related, starting at about 0.6 mg/ml and completely inhibited binding at 10 mg/ml.

Hirano T, Homma M, Oka K
Department of Clinical Pharmacology, Tokyo College of Pharmacy, Japan.
Planta Med 1994 Feb;60(1):30-3

The effects of organic-solvent extracts of Urtica dioica (Urticaceae) on the Na+,K(+)-ATPase of the tissue of benign prostatic hyperplasia (BPH) were investigated. The membrane Na+,K(+)-ATPase fraction was prepared from a patient with BPH by a differential centrifugation of the tissue homogenate. The enzyme activity was inhibited by 10(-4)-10(-5) M of ouabain. The hexane extract, the ether extract, the ethyl acetate extract, and the butanol extract of the roots caused 27.6-81.5% inhibition of the enzyme activity at 0.1 mg/ml. In addition, a column extraction of stinging nettle roots using benzene as an eluent afforded efficient enzyme inhibiting activity. Steroidal components in stinging nettle roots, such as stigmast-4-en-3-one, stigmasterol, and campesterol inhibited the enzyme activity by 23.0-67.0% at concentrations ranging from 10(-3)-10(-6) M. These results suggest that some hydrophobic constituents such as steroids in the stinging nettle roots inhibited the membrane Na+,K(+)-ATPase activity of the prostate, which may subsequently suppress prostate-cell metabolism and growth.

Lichius JJ, Muth C
Institut fur Pharmazeutische Biologie, Philipps-Universitat, Marburg, Germany.
Planta Med 1997 Aug;63(4):307-10

Extracts of stinging nettle roots (Urtica dioica L. Urticaceae) are used in the treatment of benign prostatic hyperplasia (BPH). We established a BPH-model by directly implanting an urogenital sinus (UGS) into the ventral prostate gland of an adult mouse. Five differently prepared stinging nettle root extracts were tested in this model. The 20% methanolic extract was the most effective with a 51.4% inhibition of induced growth.

Blum I; Marilus R; Barasch E; Sztern M; Bruhis S; Kaufman H
Department of Medicine C, Rokach (Hadassah) Hospital, Tel-Aviv, Israel.
Int J Obes (ENGLAND) 1988, 12 (3) p185-9

A 45-year-old man, was admitted for investigation of severe sexual impairment. During 20 years of marriage, he had had no normal sexual intercourse and the couple was childless. Physical examination disclosed a severely obese man (weight 300 kg, height 1.75 m), with a relatively small and invaginated penis and small (5 ml) soft testes. Laboratory examinations disclosed the following: low serum testosterone (1 ng/ml), with a reduced response to HCG (3.8 ng/ml). Sex hormone binding globulin was at the lower limit of normal (0.38 microgram/dl), serum free testosterone was low (0.98% of total testosterone) as well as non-SHBG bound testosterone (22% of total testosterone). Daily total urinary estrogen excretion was increased (107 micrograms), the plasma estrone (78 pg/ml) and estradiol (74 pg/ml) were elevated. The gonadotropins were normal and responded adequately to LRH. Plasma growth hormone was decreased, prolactin, T4 and adrenal steroids were normal and responded normally to stimuli and inhibitors. Chromosomal constitution was 46XY. Thus, in this man the marked obesity produced a significant increase in estrogens which subsequently induced a severe decrease in testosterone and its free counterpart in excessive impairment of sexual function.

Shippen and Fryer
1998 M. Evans and Company New York, NY

No abstract.

Gooren LJ
Department of Endocrinology, Hospital of the Vrije Universiteit, Amsterdam, The Netherlands.
lgooren@inter.nl.net
Mol Cell Endocrinol 1998 Oct 25;145(1-2):153-9

There is a statistical decline of testosterone levels in ageing men, most manifest in free testosterone. While this fall is only moderate, ageing men show clinical signs of hypogonadism (loss of muscle mass/strength, reduction in bone mass and an increase in visceral fat). This might represent not only a fall but (also) an impairment of the biological action of androgens in target organs. The first small scale studies of androgen supplement administration in ageing men were not disappointing. Anticipated risks lie with the prostate and the cardiovascular system. The risks with regard to prostate disease are often over-rated. The question remains how the segment of the ageing male population possibly benefiting from androgen supplements, can be identified. For the treatment of postmenopausal women 'designer oestrogens' are being developed; similarly, designer androgens retaining beneficial anabolic effects with elimination of harmful effects on the prostate and cardiovascular system, could be devised.

Kley HK; Nieschlag E; Wiegelmann W; Kruskemper HL
Aktuelle Gerontol (Germany, West) Feb 1976, 6 (2) p61-7

Alterations of sexual hormones in plasma of ageing males occur between the 50th and 60th year of life with individual variations: 1. Decreased values of testosterone in plasma and a poor response to gonadotrophins demonstrate a diminished synthesizing capacity of the testes in old men. 2. The decreased testosterone plasma values are followed by an increase in LH. The response of the anterior pituitary gland to LH-RH stimulation in old men is normal. 3. Under basal conditions estrone as well as estradiol plasma concentrations increase significantly with age because of increased conversion from androgens. 4. Parallel to estrogen plasma values an increased concentration of the sexual hormone binding globulin (SHBG) is found, resulting in a steep decrease of the free (= active) testosterone fraction. 5. Decreased testosterone, which is more strongly bound to SHBG and increased estrone and estradiol plasma values result in an androgen/estrogen imbalance in old men. (25 Refs.)

Moger WH
Can J Physiol Pharmacol 1980 Sep;58(9):1011-22

This article reviews literature relevant to the view that estradiol (E2) synthesized in the testis acts locally to modify testosterone secretion. Despite a lack of convincing evidence from in vitro experiments, in vivo experiments with intact and hypophysectomized animals have demonstrated that estrogens can inhibit testosterone secretion by acting directly on the testis. Reduced testosterone production in estrogen-treated animals probably results from reduced 17 alpha-hydroxylase and (or) C17-C20 lyase activity. Estrogen-inhibited steroidogenesis may result from estrogen binding to high affinity--low capacity estrogen receptors. Besides being an estrogen target tissue, the testis produces E2; the cellular site of testicular E2 synthesis remains controversial. Recent studies indicate that E2 is synthesized primarily in the Sertoli cells of neonatal rats and in the Leydig cells of older rats. Follicle-stimulating hormone and human chorionic gonadotropin (hCG) increase testicular aromatase activity and E2 concentrations in neonatal and older rats, respectively. An increase in testicular E2 concentrations, following hCG administration, may be one mechanism by which testosterone synthesis becomes desensitized to subsequent hCG stimulation. However, whether gonadotropin-stimulated testicular E2 synthesis is part of a physiologically relevant "short" feedback loop that participates in the regulation of testosterone synthesis remains to be determined.

Namiki M, Kitamura M, Nonomura N, Sugao H, Nakamura M, Okuyama A, Utsunomiya M, Itatani H, Matsumoto K, Sonoda T
Department of Urology, Osaka University Medical School, Japan.
Arch Androl 1988;20(2):131-5

The direct inhibitory effects of estrogens on human testicular functions were investigated with a testicular organ culture technique. 125I-labeled human chorionic gonadotropin (125I-hCG) bindings in testes cultured in media containing diethylstilbestrol diphosphate (DESDP) began to dose-relatedly decrease a day after the start of the culture, and this decrease remained relatively constant during the 5-day culture. On the other hand, testosterone produced by the cultured testes time-relatedly decreased during the 5-day culture. From the above results it may be concluded that the direct inhibitory effect of estrogens on human testicular androgen production consists of not only the loss of testicular hCG receptors but also of other mechanisms at a distal step from hCG receptor activation.

Damber JE; Bergh A, Daehlin L, Ekholm C, Selstam G, Sodergard R
Department of Physiology, University of Umea, 90187, Umea.
Mol Cell Endocr 31 (1). 1983. 105-116.

Scatchard binding analysis was performed to measure the cytoplasmic estrogen receptor in the testis of rats. After treatment of rats with the antiestrogen tamoxifen no estrogen receptor binding was found in testicular low speed supernatant between 12 and 96 h after treatment. Such tamoxifen-treated rats were used to study the acute effect of estrogens on testosterone secretion, both in vivo and in vitro. Injection of estradiol benzoate (50 .mu.g, 24 h prior to experiment) resulted in a significant depression of basal and LH[lutropin]-stimulated plasma testosterone levels in control rats and this effect was unchanged in tamoxifen-pretreated rats. In vitro, estradiol-17.beta. also inhibited the LH-induced rise in testosterone secretion by isolated testicular interstitial cells. This inhibition was not affected if the rats had been pretreated with tamoxifen. The inhibitory effects of exogenous estrogens on testicular testosterone production are probably not mediated by the estrogen receptor.

Zmuda JM; Fahrenbach MC; Younkin BT; Bausserman LL; Terry RB; Catlin DH; Thompson PD
Department of Medicine, Miriam Hospital, Providence, RI.
Metabolism (United States) Apr 1993, 42 (4) p446-50,

Stanozolol, an oral 17 alpha-alkylated androgen, increases hepatic triglyceride lipase activity (HTGLA) and decreases high-density lipoprotein cholesterol (HDL-C) levels, whereas intramuscular testosterone has comparatively little effect. In the present study, we tested the hypothesis that aromatization of androgen to estrogen blunts the lipid and lipase effects of exogenous testosterone. Fourteen male weightlifters received testosterone enanthate (200 mg/wk intramuscularly), the aromatase inhibitor testolactone (250 mg four times per day), or both drugs together in a randomized cross-over design. Serum testosterone level increased during all three drug treatments, whereas estradiol level increased only with testosterone alone (+47%, P < .05), demonstrating that testolactone effectively inhibited testosterone aromatization. Testosterone decreased HDL-C(-16%, P < .05), HDL2-C(-23%, NS), and apoprotein (apo) A-I (-12%, P < .05) levels, effects that were consistently but not significantly greater with simultaneous testosterone and testolactone administration (HDL-C, -20%; HDL2-C, -30%; apo A-I, -15%; P < .05 for all). In contrast, both testosterone regimens decreased HDL3-C levels by 13% (P < .05 for both). HTGLA increased 21% during testosterone treatment and 38% during combined testosterone and testolactone treatment (P < .01 for both). Lipoprotein lipase activity (LPLA) increased only during combined testosterone and testolactone treatment (+31%, P < .01), suggesting that estrogen production may counteract the effects of testosterone on LPLA. Testolactone alone had little effect on any lipid, lipoprotein, apoprotein, or lipase concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Keel B.A.; Abney T.O.
Dep. Endocrinol., Med. Coll. Georgia, Augusta, GA 30912 United States
Biochemical and Biophysical Research Communications (United States) 1982, 107/4 (1340-1348)

The effects of in vivo administration of estradiol on isolated rat testicular Leydig cells were investigated. Adult intact rats were injected s.c. with 50 mug/100 g B.W. of 17beta-estradiol or vehicle twice daily for 2 days. Twelve hours after the last injection, collagenase dispersed interstitial cells were obtained and Leydig cells were subsequently isolated on metrizamide gradients. Two distinct peaks of specific sup 1sup 2sup 5I-hCG binding corresponding to population I and II Leydig cells were observed. The hCG binding profile was unaltered as a result of estradiol treatment. Although twice as much testosterone was produced in population II, the responsiveness of the two populations to hCG or dbcAMP in vitro was identical (11- to 13-fold increase). Estradiol administration in vivo resulted in a 33-48% decrease in basal and stimulated testosterone production in both populations. These data indicate for the first time that both population I and II Leydig cells are sensitive to the direct inhibitory effects of estrogens on testosterone production. This inhibitory effect was not associated with an alternation in hCG binding capacity in either population. Therefore, we conclude that no functional difference exists between the two populations of Leydig cells with respect to the action of estrogens.

Stammel W, Thomas H, Staib W, Kuhn-Velten WN
Abteilung Physiologische Chemie, Universitat Ulm, F.R. Germany.
Life Sci 1991;49(18):1319-29

Possible effects of various tetrahydroisoquinolines (TIQs) on rat testicular endocrine function were tested in vitro in order to prove whether these compounds, some of which have been claimed to accumulate in alcoholics, may be mediators of the development of Leydig cell insufficiency, a well-known side-effect of ethanol ingestion. TIQ effects on different levels of regulation of testis function were compared in vitro with estrogen effects, since both classes of compounds have structural similarities. Gonadotropin-stimulated testosterone production by testicular Leydig cells was inhibited by tetrahydropapaveroline and isosalsoline, the IC50 values (30 microM) being comparable to those of estradiol (3 microM), 2-hydroxyestradiol (10 microM), and the phytoestrogens, coumestrol (15 microM) and genistein (7 microM); salsolinol (85 microM) and salsoline (240 microM) were less effective, and salsolidine was ineffective. None of these TIQs interacted significantly with testicular estrogen receptor as analyzed by estradiol displacement. However, tetrahydropapaveroline, isosalsoline and salsolinol competitively inhibited (Ki 130-150 microM) substrate binding to cytochrome P450XVII, one key enzyme of androgen biosynthesis, with similar efficiency as the estrogens did (Ki 50-110 microM); salsoline and salsolidine were again much less effective. Since the efficient TIQ concentrations in this system are identical with those reported to generate central-nervous effects, it is concluded that certain TIQs may amplify peripheral inhibitory effects of ethanol on testicular endocrine function by their interaction with at least one enzyme of the androgen biosynthetic pathway.

Misao R, Nakanishi Y, Fujimoto J, Iwagaki S, Tamaya T
Department of Obstetrics and Gynecology, Gifu University School of Medicine, Japan.
[Medline record in process]
Gynecol Endocrinol 1999 Apr;13(2):82-8

To understand regulation of the function of human ovarian corpus luteum by sex steroid-binding proteins, the levels of luteal intracellular sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) mRNAs and serum steroid hormones were simultaneously determined. The expression of SHBG and CBG mRNAs was detected in all samples analyzed. SHBG mRNA level was positively correlated with serum estradiol-17 beta level (p < 0.05), but not with serum progesterone level. There was a positive correlation between SHBG mRNA level and serum estradiol-17 beta/progesterone ratio (p < 0.01). On the other hand, CBG mRNA level was positively correlated with serum estradiol-17 beta and progesterone level (p < 0.01 and p < 0.01, respectively). There was no correlation between CBG mRNA level and serum estradiol-17 beta/progesterone ratio. SHBG and CBG mRNA levels were not correlated with the levels of serum testosterone, free testosterone or cortisol. These findings suggest that the synthesis of luteal SHBG and CBG is complexly regulated by estrogen and progesterone, and that SHBG and CBG interact with estrogen and progesterone, respectively, for luteal steroidal activity.

Van Look PF, Frolich M
Clin Endocrinol (Oxf) 1981 Mar;14(3):237-43

Daily measurements of plasma FSH, LH, prolactin, testosterone, 17 beta-oestradiol and sex hormone binding globulin (SHBG) activity were made in eight healthy, normal men during treatment with oral ethinyloestradiol (EE2) in a dose of 30 micrograms/day for 5 days following a 5-day control period. No significant changes in plasma levels of FSH and prolactin during oestrogen treatment occurred. In contrast, plasma concentrations of both LH and testosterone showed a biphasic pattern. Following an initial suppression during the first 3 days of oestrogen treatment both LH and testosterone increased again to baseline values despite continuation of oestrogen administration. The secondary rise of both hormones was associated with (and probably resulted from) a nearly 100% increase in the plasma concentration of SHBG binding activity, and hence reduction of free testosterone index (FTI). Unlike testosterone, plasma 17 beta-oestradiol during EE2 administration did not show a biphasic pattern, but a progressive decline that was positively correlated with the fall in FTI. The rapidity of onset and magnitude of the observed rise in SHBG levels emphasizes the need for measurement of this binding protein (or the free testosterone fraction) in studies on feedback regulation of gonadotrophins employing exogenous EE2 in human males. The observed increase of SHBG to supraphysiological values suggests that currently employed EE2 doses in such studies may be less 'physiologic' than is often assumed.

Bricout VA; Germain PS; Serrurier BD; Guezennec CY
IMASSA-CERMA, Departement de Physiologie Systemique, Bretigny sur Orge, France.
Cell Mol Biol (Noisy-le-grand) 1994 May;40(3):291-4

From results obtained in physiological investigations carried out on various tissues sensitive to androgens, it seems that the hormonal receptivity can reflect changes in the endocrine status and specific response of a tissue. The purpose of the present investigation was to test whether an androgen treatment could modify the receptivity to testosterone of the skeletal muscle and myocardium of endurance trained rats. The experiment extended over 8 weeks, and animals received injections of delayed testosterone heptylate every seven days. The myocardium and two skeletal muscles with opposed functions and typology were examined: the extensorum digitorum longus (EDL), and the soleus (SOL). Results obtained using techniques based upon the radio-competition principles provided information on the testosterone-receptor binding. The binding curves were plotted up to the saturating concentration of tritiated mibolerone, a synthetic androgen specific of androgen receptors. The quantity of receptors, calculated at the specific saturation plateau is expressed in fmol/mg protein. Results show that contractile muscular activity always increased the quantity of receptors whereas the steroid treatment decreased it. Thus for EDL and SOL of control trained rats the quantity of receptors was 0.78 and 0.82 fmol/mg protein, respectively, compared to 0.23 and 0.43 fmol/mg protein for sedentary testosterone-treated rats. The same "contractile activity" effect was observed on the myocardium but enhanced with values of 1.63 fmol/mg protein for control trained rats versus 0.30 fmol/mg protein for sedentary testosterone-treated rats. The receptivity to testosterone of the skeletal muscle and myocardium changes under the effect of an androgen treatment.

Jones KJ
Department of Biological Chemistry and Structure, University of Health Sciences, Chicago Medical School, Illinois 60064.
Metab Brain Dis (United States) Mar 1988, 3 (1) p1-18

Current data on the neurotrophic effects of steroid hormones suggest that, in brain and spinal cord regions containing receptor systems, steroids act at the level of RNA and protein synthesis to effect metabolic changes associated with nerve-cell survival, elaboration/maintenance of dendritic and axonal processes, synaptogenesis, and neurotransmission. While many of these effects appear to be associated with the neuroanatomical systems involved in the endocrine and behavioral aspects of reproduction, evidence does exist for similar neurotrophic effects outside the reproductive sphere. Both estrogens and androgens appear to exert this stimulatory, growthlike effect on target neurons. The effects of progesterone are not discussed in this review because relatively little information is available regarding the independent effects of progesterone on the brain . We have just completed a study (Jones et al., 1987b) which suggests that progesterone may act independently in the brain to affect protein synthesis. A number of conclusions concerning the mechanism of steroid action in producing trophic effects on neurons can be drawn. First, the time course of hormone action is similar to that found in nonneural target tissue, such as the uterus. Second, steroid hormones act on neurons through receptor-mediated genomic activation. Third, this effect on the genome appears to be at the level of both transcription and translation. Fourth, there is brain -region specificity in the gene products resulting from steroid hormone administration. Finally, short-term exposure to estrogens or androgens generally results in an anabolic response within target neurons. The brain and spinal cord, injured either by disease or by experimentally induced trauma , is responsive in a reparative manner to exogenous and/or endogenous gonadal steroid hormones. The mechanism underlying this therapeutic role of steroids on damaged neurons is not known but has been postulated to involve direct action of steroid hormones or target neurons. It has been hypothesized that two diseases, Alzheimer's and ALS, may be related to steroid hormone/receptor deficiencies. In this regard, Appel (1981) has suggested that putative "neurotrophic hormones" acting at the synapse may be critical in maintaining the neural networks affected in ALS, Alzheimer's disease, and parkinsonism. Extending that hypothesis to include direct action of such putative hormones within the cell body and at the level of the genome, the evidence presented in this discussion would argue that possible candidates could be gonadal steroids.

Swerdloff RS, Wang C
Department of Medicine, University of California, Los Angeles, School of Medicine.
West J Med 1993 Nov;159(5):579-85

Androgen levels decrease with age in men. Androgen deficiency in men older than 65 years leads to asthenia, a decrease in muscle mass, osteoporosis, and a decrease in sexual activity. Androgen deficiency has been reported to cause changes in mood and cognitive function. The combination of these factors results in impaired quality of life in older men. Androgen replacement therapy in hypogonadal men increases bone and muscle mass, enhances muscle and cardiovascular function, and improves sexual function and general well-being; whether elderly men experience benefits of androgen replacement is not known. These benefits have to be weighed against the possible adverse effects of prostate and cardiovascular diseases. Careful long-term studies are needed to assess the risk-to-reward ratios of androgen or other hormone replacement therapy before treatment strategies similar to estrogen therapy for postmenopausal women are implemented.

Swerdloff RS, Wang C
Division of Endocrinology, Harbor-UCLA Medical Center, Torrance 90509.
Exp Gerontol 1993 Jul-Oct;28(4-5):435-46

Androgen levels decrease with aging in men. Androgen deficiency in elderly men may lead to asthenia, decrease in muscle mass, osteoporosis, decrease in sexual activity, and, in some cases, changes in mood and cognitive function. Combination of these factors may result in impaired quality of life in the elderly male. Androgen replacement therapy may increase bone and muscle mass, enhance muscle and cardiovascular function, and improve sexual function and general well-being. These potential benefits of androgens have to be weighed against the possible adverse effects on prostate and cardiovascular diseases. Careful long-term studies will be required to assess the risk-to-reward ratios of androgen or other hormone replacement therapy before the development of treatment strategies similar to estrogen and progestagen substitution therapy for the postmenopausal female.

Continued on the next page...

de Lignieres B
Departement d'endocrinologie et medecine de la reproduction, Hopital Necker, Paris, France.
Ann Med 1993 Jun;25(3):235-41

Male ageing coincides on average with progressive impairment of testicular function. The most striking plasma changes are an increase in sex hormone binding globulin (SHBG) and a decrease in non SHBG-bound testosterone, which is the only testosterone subfraction effectively bioavailable for target tissues. In healthy subjects the bioavailable testosterone declines by approximately 1% per year between 40 and 70 years but a more pronounced decline has been observed in non-healthy groups, especially in high cardiovascular risks groups. Relative androgen deficiency is likely to have unfavourable consequences on muscle, adipose tissue, bone, haematopoiesis, fibrinolysis, insulin sensitivity, central nervous system, mood and sexual function and might be treated by an appropriate androgen supplementation. The potential risk for prostate has been the main reason for limiting indications of such treatment. Testosterone (T) and dihydrotestosterone (DHT) are two potent androgens which have opposite effects regarding aromatase activity, an enzyme present in prostate stroma and suspected to have a pathogenic influence through local oestradiol synthesis. T is the main substrate for aromatase and oestradiol synthesis while DHT is not aromatizable and, at sufficient concentration, decreases T and oestradiol levels. A 1.8 years survey of 37 men aged 55-70 years treated with daily percutaneous DHT treatment suggested that high plasma levels of DHT (> 8.5 nmol/l) effectively induced clinical benefits while slightly but significantly reducing prostate size. Early stages of prostate hypertrophy require synergic stimulation by both DHT and oestradiol, and suppressing oestradiol instead of DHT seems easier and better adapted to the specific situation of aged hypogonadic men.

Velazquez E, Bellabarba Arata G
Department of Medicine, Medical School, University of the Andes, Merida, Venezuela.
Arch Androl 1998 Sep-Oct;41(2):79-90

The benefits conferred by testosterone replacement therapy are substantial, both in the short term for the eradication of symptoms of androgen deficiency, and in the long term for the prevention of osteoporosis. As with any long-term treatment there are risks that must be considered, but overall the benefits achieved far outweigh potential risk. Ideally, androgen replacement therapy should provide physiological serum testosterone levels, as well as DHT and estradiol levels, and correct the clinical symptoms of androgen deficiency in hypogonadal men. This goal is difficult to achieve because the dose dependency of androgen-dependent physiological processes is not known. Androgen preparations that are currently available do not fulfill all criteria for an ideal androgen replacement therapy. Parenteral testosterone esters are effective, safe, practical, and inexpensive. The transdermal testosterone systems provide an alternative to testosterone esters in selected patients but these preparations are expensive. Ongoing studies are showing the benefits of testosterone replacement therapy in aging men, but there is concern about side effects on cardiovascular system and prostate. Thus, clinical decision regarding testosterone therapy in older men should be better defined.

Swerdloff RS, Wang C, Hines M, Gorski R
Harbor-UCLA Medical Center, Torrance 90502.
Psychoneuroendocrinology 1992 Aug;17(4):375-83

Androgens have important biological effects on accessory sexual organs and have a broad range of effects on metabolic processes. Male hormones have been shown to have important organizational and activational effects on morphological, behavioral, and cognitive activity in experimental animals. Sexual dimorphic effects on cognitive and behavioral activities in animals have been linked to androgens during the fetal period. The effects of testosterone on sexual drive are well established in humans, although the threshold for such activity appears to be lower than that required for many of the other and organic effects of testosterone. There are suggestive data to link fetal androgen levels to cognitive and behavioral activities in children and adults, but the behavioral activities may be modified by social and other learning processes. Androgen levels fall in older men at a time when impaired sexual function, osteopenia, and decreased muscle mass can be identified. The relative importance of androgen deficiency in these disorders requires further study, since they are likely to be multifactorial in pathogenesis. Replacement therapy of elderly men who have lowered testosterone levels has been proposed to decrease bone and muscle loss as well as to improve sexual function and general well-being. Careful studies will be required to assess the risk-to-reward ratio of such treatment, since theoretical adverse effects on prostate and cardiovascular diseases may occur. While conservation in management has its virtues, we should be reminded that several decades ago estrogen replacement of postmenopausal women was highly criticized until data supporting its favorable therapeutic ratio were demonstrated.

Greendale GA, Edelstein S, Barrett-Connor E
Division of Geriatrics, UCLA School of Medicine, USA.
J Bone Miner Res 1997 Nov;12(11):1833-43

This study examines the associations between endogenous sex steroids and bone mineral density (BMD), using data from a geographically defined cohort in Rancho Bernardo, California. Participants were community-dwelling women and men aged 50-89 years who took part in a study of endogenous sex steroid measurement between 1984-1987 and who had BMD measured in 1988-1991. Those taking corticosteroids or estrogen at the time of sex steroid determination were excluded. The main study outcomes were BMD of the ultradistal radius, midshaft radius, lumbar spine, and total hip by sex steroid level, adjusted for age, body mass index, cigarette smoking, alcohol consumption, leisure exercise, use of thiazides, thyroid hormones, and former estrogen use (women only). At the time of the hormone measurements, the mean age of the 457 women was 72.1 years and that of the 534 men was 68.6 years. A statistically significant positive relation was seen between bioavailable estradiol and BMD at all sites in women and men. Total estradiol was significantly associated with BMD at all sites in women and at all but the ultradistal radius in men. Estrone had a global effect on BMD in women and was not measured in men. Higher bioavailable (but not total) testosterone levels were associated with higher BMD of the ultradistal radius, spine, and hip in men and the ultradistal radius in women. Dehydroepiandrosterone was positively associated with BMD of the midradius, spine, and hip in women and was not associated with BMD at any site in men. Of the sex steroids tested, bioavailable estrogen was most strongly associated with BMD in both women and men. We conclude that endogenous sex steroid levels are significantly related to bone density in older women and men. Individual variation in age-related bone loss may be partially accounted for by alterations in sex steroid levels with aging. Further study to elucidate safe environmental and medical methods to maintain optimal sex steroid levels in old age is needed.

Gooren LJ
Department of Endocrinology, Hospital of the Vrije Universiteit, Amsterdam, The Netherlands.
lgooren@inter.nl.net
Mol Cell Endocrinol 1998 Oct 25;145(1-2):153-9

There is a statistical decline of testosterone levels in ageing men, most manifest in free testosterone. While this fall is only moderate, ageing men show clinical signs of hypogonadism (loss of muscle mass/strength, reduction in bone mass and an increase in visceral fat). This might represent not only a fall but (also) an impairment of the biological action of androgens in target organs. The first small scale studies of androgen supplement administration in ageing men were not disappointing. Anticipated risks lie with the prostate and the cardiovascular system. The risks with regard to prostate disease are often over-rated. The question remains how the segment of the ageing male population possibly benefiting from androgen supplements, can be identified. For the treatment of postmenopausal women 'designer oestrogens' are being developed; similarly, designer androgens retaining beneficial anabolic effects with elimination of harmful effects on the prostate and cardiovascular system, could be devised.

Marin P, Holmang S, Jonsson L, Sjostrom L, Kvist H, Holm G, Lindstedt G, Bjorntorp P
Department of Medicine I, Sahlgren's Hospital, University of Goteborg, Sweden.
Int J Obes Relat Metab Disord 1992 Dec;16(12):991-7

Twenty-three middle-aged abdominally obese men were treated for eight months with testosterone or with placebo. Testosterone treatment was followed by a decrease of visceral fat mass, measured by computerized tomography, without a change in body mass, subcutaneous fat mass or lean body mass. Insulin resistance, measured by the euglycemic/hyperinsulinemic glucose clamp method, improved and blood glucose, diastolic blood pressure and serum cholesterol decreased with testosterone treatment. A small increase in prostate volume was noted, but serum prostate specific antigen concentrations were unchanged and no adverse functional side-effects were found. Insulin sensitivity improved more in men with relatively low testosterone values at the outset. The mechanisms involved in these changes might act either via effects on visceral fat accumulation, followed by metabolic improvements, and/or via direct effects on muscle insulin sensitivity, as suggested by results of other recent studies. It is concluded that testosterone treatment of middle-aged abdominally obese men gives beneficial effects on well-being and the cardiovascular and diabetes risk profile, results similar to those observed after hormonal replacement therapy in postmenopausal women.

Tenover JS
Division of Gerontology and Geriatric Medicine, University of Washington, Seattle 98104.
J Clin Endocrinol Metab 1992 Oct;75(4):1092-8

Serum androgen levels decline with aging in normal males, such that a significant number of men over 60 yr of age will have a mean serum total testosterone (T) level near the low end of the normal adult range. It is not known whether lower T levels in older men have an effect on androgen-responsive organ systems, such as muscle, bone, bone marrow, and prostate, nor are there data to evaluate the relative benefits and risks of T supplementation in older men. We assessed the physiological and biochemical effects of T therapy in 13 healthy men, 57-76 yr old, who had low or borderline low serum T levels (< or = 13.9 nmol/L). Intramuscular testosterone enanthate (TE; 100 mg weekly) and placebo injections were given for 3 months each. Before treatment and at the end of both 3-month treatment regimens, lean body mass, body fat, biochemical parameters of bone turnover, hematological parameters, lipoprotein profiles, and prostate parameters [such as prostate-specific antigen (PSA)] were evaluated. Serum T levels rose in all subjects with TE treatment, such that the lowest level of T during a week's period was 19.7 +/- 0.7 nmol/L (mean +/- SE). After 3 months of TE treatment, lean body mass was significantly increased, and urinary hydroxyproline excretion was significantly depressed. With TE treatment, there was a significant increase in hematocrit, a decline in total cholesterol and low density lipoprotein cholesterol, and a sustained increase in serum PSA levels. Placebo treatment led to no significant changes in any of these parameters. We conclude that short term (3 months) TE supplementation to healthy older men who have serum T levels near or below the lower limit of normal for young adult men results in an increase in lean body mass and possibly a decline in bone resorption, as assessed by urinary hydroxyproline excretion, with some effect on serum lipoproteins, hematological parameters, and PSA. The sustained stimulation of PSA and the increase in hematocrit that occur with physiological TE supplementation suggest that older men should be screened carefully and followed periodically throughout T therapy.

Baumgartner RN, Waters DL, Gallagher D, Morley JE, Garry PJ
Clinical Nutrition Program, The University of New Mexico School of Medicine, Albuquerque, USA.
Mech Ageing Dev 1999 Mar 1;107(2):123-36

BACKGROUND: Elderly men and women lose muscle mass and strength with increasing age. Decreased physical activity, hormones, malnutrition and chronic disease have been identified as factors contributing to this loss. There are few data, however, for their multivariate associations with muscle mass and strength. This study analyzes these associations in a cross-sectional sample of elderly people from the New Mexico Aging Process Study.

METHODS: Data collected in 1994 for 121 male and 180 female volunteers aged 65-97 years of age enrolled in The New Mexico Aging Process Study were analyzed. Body composition was measured using dual energy X-ray absorptiometry; dietary intake from 3 day food records; usual physical activity by questionnaire; health status from annual physical examinations; and serum testosterone, estrone, sex-hormone binding globulin (SHBG), and insulin-like growth factor (IGF1) from radioimmunoassays of fasting blood samples. Statistical analyses included partial correlation and stepwise multiple regression.

RESULTS: The muscle mass and strength (adjusted for knee height) decreased with increasing age in both sexes. The muscle mass was significantly associated with serum free-testosterone, physical activity, cardiovascular disease, and IGF1 in the men. In the women, the muscle mass was significantly associated with total fat mass and physical activity. Age was not associated significantly with muscle mass after controlling for these variables. Grip strength was associated with age independent of muscle mass in both sexes. Estrogen (endogenous and exogenous) was not associated with muscle mass or strength in women.

CONCLUSIONS: Age-related loss of muscle mass and strength occurs in relatively healthy, well-nourished elderly men and women and has a multifactorial basis. Sex hormone status is an important factor in men but not in women. Physical activity is an important predictor of muscle mass in both sexes.

Ferrando AA; Tipton KD; Doyle D; Phillips SM; Cortiella J; Wolfe RR
Department of Surgery, University of Texas Medical Branch, Galveston, Texas 77550, USA.
Am J Physiol 1998 Nov;275(5 Pt 1):E864-71

Testosterone administration (T) increases lean body mass and muscle protein synthesis. We investigated the effects of short-term T on leg muscle protein kinetics and transport of selected amino acids by use of a model based on arteriovenous sampling and muscle biopsy. Fractional synthesis (FSR) and breakdown (FBR) rates of skeletal muscle protein were also directly calculated. Seven healthy men were studied before and 5 days after intramuscular injection of 200 mg of testosterone enanthate. Protein synthesis increased twofold after injection (P < 0.05), whereas protein breakdown was unchanged. FSR and FBR calculations were in accordance, because FSR increased twofold (P < 0.05) without a concomitant change in FBR. Net balance between synthesis and breakdown became more positive with both methodologies (P < 0.05) and was not different from zero. T injection increased arteriovenous essential and nonessential nitrogen balance across the leg (P < 0.05) in the fasted state, without increasing amino acid transport. Thus T administration leads to an increased net protein synthesis and reutilization of intracellular amino acids in skeletal muscle.

Urban RJ; Bodenburg YH; Gilkison C; Foxworth J; Coggan AR; Wolfe RR; Ferrando A
Department of Internal Medicine, University of Texas Medical Branch Galveston 77555-1060, USA.
Am J Physiol 1995 Nov;269(5 Pt 1):E820-6

Aging men develop a significant loss of muscle strength that occurs in conjunction with a decline in serum testosterone concentrations. We investigated the effects of testosterone administration to six healthy men [67 +/- 2 (SE) yr] on skeletal muscle protein synthesis, strength, and the intramuscular insulin-like growth factor I (IGF-I) system. Elderly men with serum testosterone concentrations of 480 ng/dl or less were given testosterone injections for 4 wk to produce serum concentrations equal to those of younger men. During testosterone administration muscle strength (isokinetic dynamometer) increased in both right and left hamstring and quadricep muscles as did the fractional synthetic rate of muscle protein (stable-isotope infusion). Ribonuclease protection assays done on total RNA from muscle showed that testosterone administration increased mRNA concentrations of IGF-I and decreased mRNA concentrations of insulin-like growth factor binding protein-4. We conclude that increasing testosterone concentrations in elderly men increases skeletal muscle protein synthesis and strength. This increase may be mediated by stimulation of the intramuscular IGF-I system.

Mauras N; Hayes V; Welch S; Rini A; Helgeson K; Dokler M; Veldhuis JD; Urban RJ
Nemours Children's Clinic, Jacksonville, Florida 32207, USA.
nmauras@nemours.org.
J Clin Endocrinol Metab 1998 Jun;83(6):1886-92

To investigate specific effects of androgens on whole body metabolism, we studied six healthy lean men (mean +/- SEM age, 23.2 +/- 0.5 yr) before and after gonadal steroid suppression with a GnRH analog (Lupron), given twice, 3 weeks apart. Primed infusions of [13C]leucine, indirect calorimetry, isokinetic dynamometry, growth factor measurements, and percutaneous muscle biopsies were performed at baseline (D1) and after 10 weeks of treatment (D2); each subject served as his own control. Testosterone concentrations were markedly suppressed after 10 weeks of treatment (D1, 535 +/- 141 ng/dL; D2, 31 +/- 9). Leucine's rate of appearance (index of proteolysis) was markedly suppressed after 10 weeks of hypogonadism (-13%; P = 0.01) as well as the nonoxidative leucine disposal, an index of whole body protein synthesis (-13%; P = 0.01) without any changes in plasma amino acid concentrations. All subjects studied after 10 weeks showed a decrease in fat-free mass, as measured by skinfold calipers and dual emission x-ray absortiometry scans (D1, 56.5 +/- 2.9 kg; D2, 54.4 +/- 2.5; P = 0.005), and an increase in percent fat mass (D1, 19.2 +/- 2.5%; D2, 22.2 +/- 2.5; P = 0.001). Rates of lipid oxidation decreased (-31%; P = 0.05) after treatment, with parallel changes in resting energy expenditure (-9%; P = 0.05). Mean and peak GH concentrations (measured every 10 min for 6 h) and GH production rates did not decrease after testosterone deficiency, with an actual increase in basal secretion (P < 0.02). Plasma insulin-like growth factor I (IGF-I) concentrations did not change significantly after 10 weeks of treatment (D1, 227 +/- 44 micrograms/L; D2, 291 +/- 60; P = 0.08). Isokinetic dynamometry of leg extensors at 60 degrees and 180 degrees/s was also decreased after 10 weeks of hypogonadism. Total ribonucleic acid (RNA) was isolated from muscle biopsy samples, and ribonuclease protection assays were performed using human complementary DNA clones for IGF-I, IGF-binding protein-4, myosin, and actin. Ten weeks after Lupron treatment, messenger RNA (mRNA) concentrations of IGF-I decreased significantly, whereas there was a trend toward higher IGF-binding protein-4 concentrations, with no change in myosin or actin mRNA concentrations. In conclusion, testosterone deficiency in young men is associated with a marked decrease in measures of whole body protein anabolism, decreased strength, decreased fat oxidation, and increased adiposity. These effects of testosterone deficiency are independent of changes in peripheral GH production and IGF-I concentrations, even though im IGF-I mRNA concentrations decrease. These data suggest a direct effect of androgens on whole body lipid and protein metabolism.

Tenover JS
Division of Gerontology and Geriatric Medicine, Emory University School of Medicine, Atlanta, Georgia.
Endocrinol Metab Clin North Am 1994 Dec;23(4):877-92

Normal aging in men frequently is associated with a decline in serum testosterone levels below the normal range for young adult men. These changes in serum testosterone with age may impact negatively on androgen target organs such as bone, muscle, and psychosexual functioning. Androgen replacement therapy may be of benefit in certain older men, but the potential benefits must be balanced with the potential risks.

Mol Cell Endocrinol 1998 Oct 25;145(1-2):153-9
Gooren LJ
Department of Endocrinology, Hospital of the Vrije Universiteit, Amsterdam, The Netherlands.
lgooren@inter.nl.net

There is a statistical decline of testosterone levels in ageing men, most manifest in free testosterone. While this fall is only moderate, ageing men show clinical signs of hypogonadism (loss of muscle mass/strength, reduction in bone mass and an increase in visceral fat). This might represent not only a fall but (also) an impairment of the biological action of androgens in target organs. The first small scale studies of androgen supplement administration in ageing men were not disappointing. Anticipated risks lie with the prostate and the cardiovascular system. The risks with regard to prostate disease are often over-rated. The question remains how the segment of the ageing male population possibly benefiting from androgen supplements, can be identified. For the treatment of postmenopausal women 'designer oestrogens' are being developed; similarly, designer androgens retaining beneficial anabolic effects with elimination of harmful effects on the prostate and cardiovascular system, could be devised.

Katznelson L
Harvard Medical School, Massachusetts General Hospital, Boston, USA.
Baillieres Clin Endocrinol Metab 1998 Oct;12(3):453-70

There has been much recent interest in the relationship between androgens and bone mineralization in men. Increases in serum androgens during puberty allow for skeletal maturation and the attainment of peak bone mass, and the persistence of normal testosterone secretion during adulthood is important for the maintenance of bone density. Testosterone deficiency is associated with heightened bone turnover and is a major risk factor for osteoporosis in men. The administration of testosterone to androgen-deficient men leads to an increase in bone mass, particularly in the trabecular bone compartment, and a reduction in levels of surrogate markers of bone turnover, suggesting that androgens have a dampening effect on bone remodelling. In addition, the administration of androgens to eugonadal men with idiopathic osteoporosis, with resulting supraphysiological testosterone concentrations, may lead to increases in bone mineral density. The risk of osteopenia due to androgen deficiency and the benefits of testosterone substitution therapy or supraphysiological administration on bone will be reviewed.

De Sanctis V, Vullo C, Urso L, Rigolin F, Cavallini A, Caramelli K, Daugherty C, Mazer N
Department of Pediatrics, Hospital S. Anna, Ferrara, Italy.
J Pediatr Endocrinol Metab 1998;11 Suppl 3:891-900

beta-Thalassemia major is associated with a high prevalence of hypogonadotropic hypogonadism affecting adolescents and young men with this disease. The pharmacokinetics of Androderm, a non-scrotal permeation-enhanced testosterone transdermal system, was previously studied in this population using three application regimens designed to mimic the nocturnal secretion and circadian patterns of testosterone production characteristics of puberty and young adulthood. In regimen I, designed for prepubertal 14 to 16 year-olds, a single Androderm patch (2.5 mg/day nominal delivery rate) is applied at night and removed 12 hours later in the morning. In regimen II, designed for partially virilized 17 to 19 year-olds, a single Androderm patch is applied nightly for 24 hours. In regimen III, intended for virilized men aged 20 years and older, two Androderm patches (total dose of 5 mg/day) are applied nightly for 24 hours. This report presents the results of a 12-month open label study using these three Androderm regimens to treat nine hypogonadal males with beta-thalassemia (ages 16.8 to 31.8 yr). Our data show that Androderm produced physiologically appropriate testosterone levels, lowered SHBG levels, promoted growth and virilization, increased bone mineral density, and was generally well tolerated in this population of hypogonadal adolescents and young men with beta-thalassemia.

Haffner SM, Karhapaa P, Mykkanen L, Laakso M
Department of Medicine, University of Texas Health Science Center, San Antonio 78284-7873.
Diabetes 1994 Feb;43(2):212-9

Although many studies have suggested that increased androgenicity is associated with insulin resistance and hyperinsulinemia in both pre- and postmenopausal women, relatively few data are available on this relationship in men. We examined the association of body mass index (BMI), waist-to-hip ratio (WHR), sex hormone-binding globulin (SHBG), total and free testosterone, dehydroepiandrosterone sulfate (DHEA-SO4), and estradiol with insulin concentrations and whole-body glucose disposal in 87 men from a population-based study in Kuopio, Finland. BMI was significantly correlated with fasting insulin (r = 0.46), total whole-body glucose disposal (r = -0.30), glucose oxidation (r = -0.21), and nonoxidative glucose disposal (r = -0.25). WHR also was significantly associated with fasting insulin (r = 0.61), total whole-body glucose disposal (r = -0.54), glucose oxidation (r = -0.23), and nonoxidative whole-body glucose disposal (r = -0.50). SHBG and total and free testosterone were significantly associated with insulin concentrations and total and nonoxidative glucose disposal but not with glucose oxidation. DHEA-SO4 and estradiol were not associated with insulin, glucose concentrations, or whole-body glucose disposal in univariate analysis. In multivariate analysis, total whole-body glucose disposal was associated negatively with WHR and positively associated with total testosterone and SHBG; nonoxidative whole-body glucose disposal was associated negatively with WHR and positively associated with total and free testosterone. Glucose oxidation was significantly associated only with WHR. In conclusion, higher WHR and lower testosterone were strongly associated with a decrease in total and nonoxidative whole-body glucose disposal in men.

Haffner SM, Valdez RA, Mykkanen L, Stern MP, Katz MS
Department of Medicine, University of Texas Health Science Center, San Antonio 78284.
Metabolism 1994 May;43(5):599-603

Although many studies indicate that increased androgenicity is associated with insulin resistance and hyperinsulinemia in both premenopausal and postmenopausal women, relatively few data are available on this relationship in men. We examined the association of sex hormone-binding globulin (SHBG), total and free testosterone, dehydroepiandrosterone sulfate (DHEA-SO4), and estradiol to glucose and insulin concentrations before and during an oral glucose tolerance test in 178 men from the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Total and free testosterone and DHEA-SO4 were significantly inversely associated with insulin concentrations. Free testosterone and DHEA-SO4 were also significantly inversely correlated with glucose concentrations. SHBG was weakly positively associated with glucose concentrations. Estradiol was not related to glucose or insulin concentrations. After adjustment for age, obesity, and body fat distribution, insulin concentrations remained significantly inversely correlated with free testosterone (r = -.23), total testosterone (r = -.21), and DHEA-SO4 (r = -.21; all P < .01). In conclusion, we observed that increased testosterone and DHEA-SO4 are associated with lower insulin concentrations in men. This is in striking contrast to women, where increased androgenicity is associated with insulin resistance and hyperinsulinemia.

Pasquali R, Macor C, Vicennati V, Novo F, De lasio R, Mesini P, Boschi S, Casimirri F, Vettor R
Dipartimento di Medicina Interna e Gastroenterologia, and Istituto di Farmacologia Clinica, University Alma Mater, Bologna, Italy.
Metabolism 1997 May;46(5):526-9

In a previous study performed in adult obese and normal-weight male subjects, we found that suppression of insulin levels by diazoxide reduced testosterone and increased sex hormone-binding globulin (SHBG) blood concentrations. These and other data suggested that insulin may have a regulatory capacity in testosterone secretion and/or metabolism in men, similar to what has already been demonstrated in women. In this study, we investigated the effects of acute hyperinsulinemia on major androgen levels, including testosterone, in two groups of normal-weight in = 11) and obese (n = 9) men. Acute hyperinsulinemia was obtained by the euglycemic-hyperinsulinemic clamp technique. Relationships between the degree of insulin resistance (ie, total glucose disposal [M value]) and testosterone levels were also evaluated. Basal testosterone levels in obese subjects (10.40 +/- 3.02 nmol/L) were significantly lower than in normal-weight controls (15.50 +/- 4.65 nmol/L, P <.01), whereas no difference was present in androstenedione and dehydroepiandrosterone sulfate (DHEA-S) concentrations. During the clamp study, testosterone was significantly increased in the obese group (11.79 +/- 3.64 nmol/L, P < .05) but not in the control group (15.81 +/- 4.54 nmol/L, P = NS). The other two androgens did not significantly change in either the obese or control group. There was a highly significant correlation between baseline testosterone concentrations, with M values suggesting a relationship between impaired peripheral insulin sensitivity and reduced plasma testosterone concentrations. It should be pointed out that there was a certain discrepancy in the testosterone variations, particularly in the control group, in which two thirds of the subjects had no change or some decrease in testosterone levels, whereas in the remainder testosterone increased over the values of the assay variation coefficient. These findings are consistent with the hypothesis that insulin may regulate testosterone blood levels also in male subjects. Whether these effects are primarily due to increased hormone secretion or reduced clearance needs to be investigated.

Marin P
Department of Heart and Lung Diseases, Sahlgrenska University Hospital, Goteborg, Sweden.
Obes Res 1995 Nov;3 Suppl 4:609S-612S

The effects of testosterone treatment of abdominally obese men have been assessed by evaluating the following parameters: The metabolic activity of different adipose tissue regions in vivo (using lipid label as a tracer) and in vitro (measuring lipoprotein lipase (LPL) activity), the total and visceral adipose tissue mass, insulin sensitivity, fasting blood glucose, blood lipids, and blood pressure as well as prostate volume. Middle-aged men with abdominal obesity were treated with transdermal administration of testosterone (T), dihydrotestosterone (DHT) or placebo (P) during 9 months. The study was double-blind. Treatment with T was followed by an inhibited uptake of lipid label in adipose tissue triglycerides, a decreased LPL-activity and an increased turn-over rate of lipid label in the abdominal adipose tissue region in comparisons with the DHT and P groups. These effects on adipose tissue metabolism were not detected in the femoral adipose tissue region in any of the groups. T treatment was also followed by a specific decrease of visceral fat mass (measured by CT-scan), by increased insulin sensitivity (measured with the euglycemic glucose clamp), by a decrease in fasting blood glucose, plasma cholesterol and triglycerides as well as a decrease in diastolic blood pressure. In the DHT group an increased visceral mass was detected. No other changes in these variables were found in the DHT and P groups. There were no detectable changes in prostate volume (measured by ultra-sound), prostate specific antigen concentration, genito-urinary history or urinary flow measurements in any of the groups. It is suggested that T substitution to a selected group of men results in general metabolic and circulatory improvements. The prostate area needs further careful attention.

Marin P, Krotkiewski M, Bjorntorp P
Department of Medicine I, Sahlgren's Hospital, University of Goteborg, Sweden.
Eur J Med 1992 Oct;1(6):329-36

OBJECTIVES: This pilot investigation was conducted to explore the relationship between androgens and glucose tolerance in obese men and to select an optimal mode for androgen treatment.

METHODS: For exploratory purposes, testosterone (T) or dihydrotestosterone (DHT) were given in different doses and preparations for different periods of time to obese, middle-aged men. The administration forms were selected in order to by-pass the liver. In the first two studies T was given as a single intramuscular injection of 250 or 500 mg and the results evaluated after 1 week. In two subsequent studies testosterone was administered in moderate doses either as oral T undecanoate or a T and DHT in preparations applied on the skin for transdermal absorption for 6 weeks and 3 months respectively. Before and after treatment the following examinations were performed: glucose tolerance tests with insulin determinations or euglycemic clamps at submaximal insulin levels. Anthropometric measurements including the waist/hip circumference ratio and estimations of body fat and lean body mass (from measurements of whole body potassium content) were performed. Plasma triglyceride and cholesterol concentrations, liver function tests and blood pressure were followed. Physical examination including the prostate was performed before and after study. Muscle function, glycogen synthase and morphology were examined in the 3-month study.

RESULTS: Administration of T was followed by moderate increases of circulating T concentrations in all studies, except after injection of 500 mg, where large increases were seen. Follicle stimulating hormone and luteinizing hormone levels decreased consistently. Injection of 500 mg T resulted in a decreased glucose tolerance. In the other treatment groups, plasma insulin decreased or glucose disappearance rate increased in clamp measurements, suggesting improved insulin sensitivity. This was most pronounced in men with relative hypogonadism from the outset. In the study of 3 months duration, a decrease in the waist/hip ratio, without a change in body fat mass, was also seen. Plasma lipids, liver function tests and blood pressure did not change. Muscle strength, the fractional velocity of glycogen synthase as well as the percentage and diameter of type IIB fibres increased after T treatment. No adverse effects were seen. 17 -beta oestradiol concentrations were unaltered and DHT administration was less effective than T, suggesting that T rather than derivatives of this hormone was mainly responsible for the effects observed.

CONCLUSION: The results suggest that T administration to middle-aged, obese man may have beneficial effects.

Gelfand MM, Wiita B
Department of Obstetrics and Gynecology, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.
Clin Ther 1997 May-Jun;19(3):383-404; discussion 367-8

The endocrine physiology of the climacteric supports a rationale for the concomitant replacement of androgen and estrogen following menopause. Clinical and research experience with estrogen-androgen hormone replacement therapy, as well as androgen-only therapy, suggests that the health benefit offered by androgen replacement exceeds the potential risk when treatment is properly managed. In this review, we concentrate on the effects of oral alkylated androgens. The virilizing effects (e.g., hirsutism, acne, voice change, and alopecia) of oral androgens are typically dose and duration dependent; androgen replacement at doses < or = 10 mg once daily administered for prolonged periods (> 6 months) produces masculinization effects that generally abate with dose reduction or discontinuation of treatment. No clinical sequelae or irreversible pathophysiologic effects have been associated with any virilization that may occur. Changes in lipoprotein metabolism associated with oral estrogen-androgen use include reduced total cholesterol levels and reduced high-density lipoprotein cholesterol levels which may reduce the long-term risk of cardiovascular disease. No clinically identifiable risk with respect to other cardiovascular variables, such as blood pressure, has been associated with the longterm administration of low doses of oral androgen. With regard to liver toxicity, reports of jaundice, peliosis hepatis, and hepatocellular carcinoma are extremely rare at the dose levels of androgen used in hormone replacement therapy, although individual sensitivity to the potential hepatotoxic effects of oral alkylated and nonalkylated androgen may vary considerably. Daily dosing with oral alkylated androgen in combination with estrogen is well tolerated. Retrospective and prospective studies involving the use of androgens alone and in combination with estrogens demonstrate that concerns about the adverse effects of androgen use associated with supraphysiologic, self-escalated doses in men do not apply to the much lower doses combined with estrogens for hormone replacement in postmenopausal women.

Catanzano-Troutaud D; Ardail D; Deschaux PA
Laboratory of General and Comparative Immunophysiology, Limoges, France.
Int J Immunopharmacol (ENGLAND) Feb 1992, 14 (2) p263-8

The purpose of the present investigation was to examine the in vivo influence of testosterone on the immune properties of a thymic factor (thymosin fraction 5, TF5) a partially purified thymic preparation in male Swiss IOPS/OF1 mice (5-10 weeks old). Testosterone administration (100 micrograms/ml) significantly inhibited the enhanced anti-sheep red blood cell antibody response induced by TF5 (100 micrograms/ml); this inhibition was only observed on the secondary antibody response and not on the primary. These results suggest that gonadal steroids can affect the immune response by modulating the activity of thymic factors.

Kanda N; Tsuchida T; Tamaki K
Department of Dermatology, Faculty of Medicine, University of Tokyo, Japan.
Clin Exp Immunol (ENGLAND) Nov 1996, 106 (2) p410-5

We studied the in vitro effect of testosterone on spontaneous immunoglobulin production by human peripheral blood mononuclear cells (PBMC). Testosterone inhibited IgG and IgM production by PBMC both from males and females. The inhibitory effect of testosterone was revealed at doses more than 1 nM, increased dose-dependently, and reached a plateau at 100 nM. At doses < 1000 nM, testosterone did not reduce cell viability. Testosterone treatment reduced IgG production by 59.0% and that of IgM by 61.3% compared with control. Immunoglobulin production by B cells was also suppressed by testosterone, though the magnitude of the suppressive effect on B cells was lower than that on whole PBMC; testosterone-induced decrease of IgG production compared with control was 26.9% and that of IgM was 24.9%. Exogenous IL-6 partially restored the impaired immunoglobulin production of testosterone-treated PBMC; IgG production in testosterone culture was increased by IL-6 from 35.6% to 66.5% of control and that of IgM was also increased from 38.9% to 71.2%, respectively. Testosterone treatment reduced IL-6 production of monocytes by 78.4% compared with control, but neither affected that of T cells or B cells. These results suggest that testosterone may suppress immunoglobulin production of human PBMC directly by inhibiting B cell activity and indirectly by reducing IL-6 production of monocytes. It is thus indicated that this hormone may have protective and therapeutic effects on human autoimmune diseases.

Murphy S, Khaw KT, Cassidy A, Compston JE
Clinical Gerontology Unit, Addenbrooke's Hospital, Cambridge, UK.
Bone Miner 1993 Feb;20(2):133-40

The aim of this study was to determine the relationships between sex hormones and bone mineral density (BMD) in older men. Community-dwelling men (n = 134, mean age (SD) 69.5 (3.1) years) were recruited from two general practices in Cambridge, UK. Plasma total testosterone and sex hormone binding globulin (SHBG) were assayed and a free androgen index (FAI) was derived as the ratio of total testosterone to SHBG (x 100). Spine and hip BMD were measured by dual energy x-ray absorptiometry using the Hologic QDR-1000. After adjusting for age and body mass index (BMI), the FAI correlated with femoral neck (r = 0.20, P = 0 0.03), intertrochanteric, trochanteric and Ward's Triangle BMD (r = 0.22, P = 0.01). Analysis of variance, with adjustment for age and BMI, showed a progressive upward trend of hip BMD with increasing quartiles of FAI. The findings suggest that free testosterone plays a role in determining bone mineral density in older men.

Stanley HL, Schmitt BP, Poses RM, Deiss WP
Division of Geriatric Medicine, McGuire VAMC, Richmond, VA 23249.
J Am Geriatr Soc 1991 Aug;39(8):766-71

The risk of MTHF in hypogonadal elderly men was investigated with a case-control model. Cases and controls were selected from males age 65 years and older residing in the 120-bed McGuire Veterans Affairs Medical Center Nursing Home Care Unit over a 5-day interval. Historical data and serum free testosterone (fTe) were available on 17 subjects with MTHF and 61 controls. When groups were compared for differences in age, race, alcohol abuse, cigarette abuse, and diseases or drugs that may be associated with MTHF, only race was significantly different. Although 25.6% of residents were black, 100% of MTHF subjects were white (P = 0.004). Hypogonadism was defined as a random fTe less than 9 pg/mL (normal 9 to 46 pg/mL) and was found in 21 subjects (26.9%). Of cases with a MTHF, 58.8% were hypogonadal compared with only 18.0% of controls. Utilizing logistic regression, a highly significant association was found between hypogonadism and MTHF (P = 0.008), and using the odds ratio, subjects with hypogonadism were 6.5 times more likely to have a MTHF (95% CI 2.0 to 20.6). To adjust for race, the odds ratio was repeated excluding black subjects, and the results remained highly significant (4.6, 95% CI 1.3 to 16.2). We conclude that hypogonadal elderly white men may be at increased risk for MTHF.

Rudman D, Drinka PJ, Wilson CR, Mattson DE, Scherman F, Cuisinier MC, Schultz S
Department of Medicine, Medical College of Wisconsin, Milwaukee 53295-1000.
Clin Endocrinol (Oxf) 1994 May;40(5):653-61

OBJECTIVE: It has been proposed that declining activities of the somatotrophic or gonadotrophic axes, or sedentary life style, are partial causes for geriatric losses of bone mineral density (BMD) and of lean body mass (LBM). The present study tested these hypotheses by determining, in both free-living and institutionalized elderly men, the correlations of bone mineral density (BMD), total body bone mineral content (TBBMC) and lean body mass (LBM) with the following predictor variables: age, body mass index, body weight, serum insulin-like growth factor I (IGF-I), serum testosterone, habitual physical activity and mobility.

SUBJECTS: Forty-nine independent, community-dwelling older men, and 49 men of similar age residing in two Veterans Administration extended care facilities. The age range was 58-95 years.

MEASUREMENTS: Serum IGF-I and testosterone were measured by radioimmunoassay. Habitual physical activity in the independent men and mobility in the institutionalized men were estimated by standard instruments. LBM and bone status at nine skeletal sites were determined by dual X-ray absorptiometry.

RESULTS: The BMD and TBBMC values of the free living men were 4-20% higher than those of the institutionalized men. In the independent old men, serum testosterone was the strongest predictor of BMD and TBBMC, while age was the only predictor of LBM. In the chronically institutionalized men, age, body weight and immobility were the strongest predictors of body composition, and testosterone was correlated only with femoral neck BMD.

CONCLUSIONS: In aging independent men, low levels of testosterone are associated with demineralization of the skeleton. Immobility and under-weight are associated with the osteopenia of old men residing in nursing homes. In this cross-sectional study of elderly men, there was no evidence of a relation of the

Tobin C, Pecot-Dechavassine M
Eur J Cell Biol 1982 Feb;26(2):284-8

The levator ani (L. A.) muscle, part of the genital apparatus of rodents, atrophies after castration. Changes in end-plate structure in the L. A. muscle of castrated male rats were examined with correlated light and electron microscopic methods. Four months after castration acetylcholinesterase staining reveals, in some muscle fibres, the presence of subneural gutters composed of a succession of cuplets whereas the subneural gutters are continuous and ramified in control muscles. Six months after castration most of the end-plates are further modified. Their terminal arborization, as revealed by silver nitrate staining, is more tortuous and irregular than in controls. At the ultrastructural level, reduced sole-plate and superimposed axonal endings are seen in some end-plates three months after castration. Our findings demonstrate that the changes (reduction of muscular activity and atrophy of muscle) are accompanied by adaptations of the neuromuscular junctions. As receptors for testosterone are known to be present in these motoneurons and muscle fibres, the observed morphological changes might be under the control of testosterone acting on both muscle and motoneurons.

Vyskocil F, Gutmann E
Pflugers Arch 1977 Mar 11;368(1-2):105-9

Electrical and contractile properties of the levator ani muscle were studied in normal rats, in castrated rats and in castrated rats treated with testosterone. 2. No significant changes in the frequency of miniature end-plate potentials were found 6 months after castration. The frequency increased already 6 h after testosterone treatment; an increase of about 100% was observed after 7 days of testosterone treatment. 3. Castration led to a 2-fold increase of the input resistance of the muscle fibres. After 7 days of testosterone treatment the input resistance was only slightly higher than normal. 4. The weight of the muscle was decreased to 18% of the control value after 6 months castration. It increased to 46% after 7 days of testosterone treatment. 5. The muscles of castrated animals revealed a prolongation of contraction time and marked changes in maximal rate of tension development and half relaxation time. Partial recovery of these parameters was found after 7 days of testosterone treatment. 6. Long-term castration did not induce any denervation-like changes of action potential parameters, and no tetrodotoxin resistance was found in spite of marked muscle atrophy.

Souccar C, Lapa AJ, do Valle JRU
Muscle Nerve 1982 Mar;5(3):232-7

The influence of testosterone on neuromuscular transmission was studied in levator ani (LA) and extensor digitorum longus (EDL) muscles taken from normal rats, castrated rats, and castrated rats treated with testosterone. Thirty days after castration LA muscle weights were reduced by 60%, but the frequency and amplitude of the miniature end-plate potentials (mepps) were increased by 40% and 50%, respectively. The weights and mepp frequencies of the EDL muscles were not altered after castration, but the mepp amplitudes increased by 30%. The quantal content of the endplate potentials was not affected in either muscle. Administration of testosterone to the castrated rats prevented such changes in the LA muscles. The results indicate that castration of adult rats affects the spontaneous transmitter release in both muscles, but the changes are more pronounced in the levator ani, which is a target muscle for testosterone.

Sachs BD
J Reprod Fertil 1982 Nov;66(2):433-43

In 4 experiments, various striated penile muscles of the rat were excised. Without the ischiocavernosus (IC) muscles no dorsiflexions ('flips') of the glans penis occurred during ex copula reflex tests, but erections were unaffected. In attempted copulation, males lacking the IC muscles rarely gained intromission, apparently because dorsiflexion of the glans penis is necessary for penetration of the vagina. Nonetheless some males lacking the IC muscles displayed the gross motor pattern of intromission and ejaculated, but rarely within the vagina. Males lacking the bulbocavernosus (BC) and levator ani (LA) muscles were incapable of developing intense erections ('cups') in ex copula tests, but they did have lesser erections, probably due to vascular action. Males with excised BC and LA muscles displayed normal copulatory behaviour, including intromission and intravaginal ejaculation, but only 1/15 females mated to these males became pregnant. The infertility of the males was attributed in part to their inability to form the penile cup, which caused them to withdraw a larger portion of the seminal plug from the vagina and, presumably, prevented the plug from being tightly lodged against the cervix. In male rats copulation apparently requires co-ordination of the penile vasculature with the contraction of separate groups of striated penile muscles, each having a distinct contribution to the integrated pattern of copulation and, ultimately, to the male's fertility.

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Stephen B. Strum
Culver City, & Whittier, California

Over 75% of patients with prostate cancer receiving combination hormonal blockade (CHB) with an LHRH agonist + Eulexin develop a moderate anemia with hematocrits ranging from 30-36%. In patients with underlying heart disease, in physically active patients or in those travelling to areas of high altitude, this anemia may become clinically significant. Hematologic findings in these patients are those of a normochromic and normocytic anemia that are not related to bone metastases nor to renal insufficiency. The anemia is temporally related to the administration of CHB and is apparent 3 months after the start of CHB and disappears within 2 to 3 months after the termination of CHB. In a pilot study, Epogen was administered at a dose of 4000 units sq 3 times per week. Within 2 months hematocrits returned to normal. Most patients were titrated down to doses of 2000 units sq twice each week while maintaining hematocrits slightly lower, in the 38-40% range. In those patients in whom the Epogen was stopped, the hematocrits dropped to pretreatment values(30-36%) within 2 months. No patients had evidence of phlebitis or thrombosis after starting Epogen. We conclude that the anemia of androgen deprivation is: 1] a common finding in patients receiving CHB & 2] highly responsive to low dose erythropoietin. Studies have begun to evaluate erythropoietin levels obtained prior to CHB, during CHB and during CHB + exogenous erythropoietin.

Strum SB; McDermed JE; Scholz MC; Johnson H; Tisman G
Daniel Freeman Marina Medical Centre, Marina del Rey, California, USA.
Br J Urol (ENGLAND) Jun 1997 , 79 (6) p933-41

OBJECTIVE: To describe the incidence, time to onset and extent of anaemia occurring in patients with prostate cancer receiving combined hormone blockade (CHB) and the timing and extent of recovery from anaemia in those patients where CHB was discontinued.

PATIENTS AND METHODS: Patients with prostate cancer were evaluated prospectively by physical examination and laboratory tests at baseline and at routine intervals while receiving CHB. Of 142 patients who received CHB, 133 were evaluable for the assessment of anaemia; CHB was discontinued in 76 patients, of whom 64 were assessable for recovery from their anaemia.

RESULTS: Haemoglobin levels declined significantly in all patients from a mean baseline of 149 g/L to means of 139 g/L, 132 g/L and 131 g/L at 1, 2 and 3 months, respectively. Haemoglobin levels continued to decline during CHB to a mean nadir of 123 g/L at a mean of 5.6 months of CHB, representing a mean absolute haemoglobin decline at nadir of 25.4 g/L. In 120 of the 133 (90%) patients, the relative decline in haemoglobin at nadir was > or = 10% and was > or = 25% in 17 (13%) others, representing a mean absolute haemoglobin decline in this subset of 42.7 g/L. Significant symptoms related to anaemia occurred in 17 patients (13%). Anaemia and symptoms in these patients were easily corrected with the subcutaneous administration of recombinant human erythropoietin.

CONCLUSIONS: The anaemia associated with androgen deprivation is significant and occurs routinely in men receiving CHB. It is normochromic, normocytic, temporally-related to the initiation of androgen blockade and usually resolves after CHB is discontinued. We suggest that patients receiving CHB undergo haematological testing at baseline, 1-2 months after initiating CHB and periodically thereafter. Patients developing anaemia should be questioned about symptoms reflecting physiological compromise (e.g. angina , dyspnoea on exertion). In the absence of other causes, CHB should be suspected in the development of anaemia in patients receiving this treatment.

[Article in Polish]
Rabijewski M, Adamkiewicz M, Zgliczynski S
Klinika Endokrynologii Centrum Medycznego Ksztalcenia Podyplomowego, Szpital Bielanski.
Pol Arch Med Wewn 1998 Sep;100(3):212-21

The aim of this study was to determine the influence of testosterone replacement therapy in elderly men on mood, bone mineral density, and lipids. We investigated thirty men (mean +/- SD; age 61.1 +/- 5.6 yr) with testosterone concentrations (mean +/- SEM) 2.1 +/- 0.2 ng/ml. Testosterone deficiency was replacement by intramuscular injections of testosterone enanthate 200 mg every second week from 1.5 to 6 yr. (mean +/- SD; 3.35 +/- 1.6 yr.). During the treatment serum testosterone increased reaching normal levels (mean +/- SEM; 6.6 +/- 0.2 ng/ml). This was associated with significant increase in positive mood parameters and a decrease in negative mood parameters. Also self assessment of libido, potence and dream were improved. Bone mineral density (BMD) of lumbar spine increased. We noticed significant decrease in total cholesterol, and LDL-cholesterol. Hematocrit was increased. Prostate-specific antigen concentration statistically increased from 0.65 +/- 0.1 to 1.35 +/- 0.1 ng/ml (mean +/- SEM), but in the cases of its levels were in normal range. Patients with coronary heart disease demonstrated decreasing symptoms of angina pectoris and nitrate requirement. In summary, long-term testosterone replacement therapy in elderly men may have beneficial effects on well-being, libido, potence, dream, bone mineral density, lipids, blood cell count and body mass (BMI). This therapy appears to be safe and there is no adverse effection on prostate.

Seidman SN, Walsh BT
Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Am J Geriatr Psychiatry 1999 Winter;7(1):18-33

In men, testosterone secretion affects neurobehavioral functions such as sexual arousal, aggression, emotional tone, and cognition. Beginning at approximately age 50, men secrete progressively lower amounts of testosterone; about 20% of men over age 60 have lower-than-normal levels. The psychiatric sequelae are poorly understood, yet there is evidence of an association with depressive symptoms. The authors reviewed 1) the physiology of the hypothalamic-pituitary-gonadal axis and its changes with age in men; and 2) the evidence linking testosterone level and major depression in men. Data on this relationship are derived from two types of studies: observational studies comparing testosterone levels and secretory patterns in depressed and non-depressed men, and treatment studies using exogenous androgens for male depression. The data suggest that some depressed older men may have state-dependent low testosterone levels and that some depressed men may improve with androgen treatment.

Barrett-Connor E, Von Muhlen DG, Kritz-Silverstein D
Department of Family and Preventive Medicine, School of Medicine, University of California, San Diego, La Jolla 92093-0607, USA.
J Clin Endocrinol Metab 1999 Feb;84(2):573-7

A cross-sectional population-based study examined the association between endogenous sex hormones and depressed mood in community-dwelling older men. Participants included 856 men, ages 50-89 yr, who attended a clinic visit between 1984-87. Total and bioavailable testosterone, total and bioavailable estradiol, and dihydrotestosterone levels were measured by radioimmunoassay in an endocrinology research laboratory. Depressed mood was assessed with the Beck Depression Inventory (BDI). Levels of bioavailable testosterone and bioavailable estradiol decreased with age, but total testosterone, dihydrotestosterone, and total estradiol did not. BDI scores increased with age. Low bioavailable testosterone levels and high BDI scores were associated with weight loss and lack of physical activity, but not with cigarette smoking or alcohol intake. By linear regression or quartile analysis the BDI score was significantly and inversely associated with bioavailable testosterone (both Ps = 0.007), independent of age, weight change, and physical activity; similar associations were seen for dihydrotestosterone (P = 0.048 and P = 0.09, respectively). Bioavailable testosterone levels were 17% lower for the 25 men with categorically defined depression than levels observed in all other men (P = 0.01). Neither total nor bioavailable estradiol was associated with depressed mood. These results suggest that testosterone treatment might improve depressed mood in older men who have low levels of bioavailable testosterone. A clinical trial is necessary to test this hypothesis.

Schweiger U, Deuschle M, Weber B, Korner A, Lammers CH, Schmider J, Gotthardt U, Heuser I
Max-Planck-Institute of Psychiatry, Clinical Institute, Munich, Germany.
schweiger.u@psychiatry.mu-Luebeck.de
Psychosom Med 1999 May-Jun;61(3):292-6

OBJECTIVE: Previous studies of sex hormone concentrations in depression yielded inconsistent results. However, the activation of the hypothalamic-pituitary-adrenal system seen in depression may negatively affect gonadal function at every level of regulation. The objective of this study was to explore whether major depressive episodes are indeed associated with an alteration of gonadal function. METHODS: Testosterone, pulsatile LH secretion, FSH, and cortisol were assessed using frequent sampling during a 24-hour period in 15 male inpatients with major depression of moderate to high severity and in 22 healthy comparison subjects (age range 22-85 years).

RESULTS: An analysis of covariance model showed that after adjustment for age only, daytime testosterone (p < .01), nighttime testosterone (p < .05), and 24-hour mean testosterone secretion (p < .01) were significantly lower in the depressed male inpatients. There was also a trend for a decreased LH pulse frequency in the depressed patients (p < .08).

CONCLUSIONS: Gonadal function may be disturbed in men with a depressive episode of moderate to high severity.

Rabkin JG; Wagner GJ; Rabkin R
New York State Psychiatric Institute and Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York 10032, USA.
jgr1@columbia.edu
J Clin Psychopharmacol (UNITED STATES) Feb 1999, 19 (1) p19-27

This study was designed to evaluate the safety and effectiveness of testosterone therapy for clinical symptoms of hypogonadism (low libido, low mood, low energy, loss of appetite/weight) in human immunodeficiency virus-positive men with CD4 cell counts less than 400 cells/mm3 and deficient or low normal serum testosterone levels. The trial consisted of 8 weeks of open treatment with 400 mg of intramuscular testosterone cypionate biweekly. Responders were maintained at this dosage for another 4 weeks and then were randomized in a double-blind, placebo-controlled, 6-week discontinuation trial. Of the 112 men who completed at least 8 weeks of treatment, 102 (91%) were rated as responders on a global assessment of sexual desire/function. Of the 34 study completers with major depressive disorder and/or dysthymia, 79% reported significant improvement in mood at week 8. Average weight change was a gain of 3.7 pounds, with 45% gaining more than 5 pounds. Eighty-four men entered and 77 completed the double-blind phase; of these, 78% of completers randomized to testosterone and 13% randomized to placebo maintained their response. No significant medical or immunologic adverse effects were identified. Testosterone therapy was well tolerated and effective in ameliorating symptoms of clinical hypogonadism, and equally so for men with and without testosterone deficiency. For patients with major depression and/or dysthymia, improvement was equal to that achieved with standard antidepressants.

Mooradian AD, Morley JE, Korenman SG
Endocr Rev 1987 Feb;8(1):1-28

Though unnecessary for life itself, androgens are essential for the propagation of the species and for establishment and maintenance of the quality of life of males through their support of sexual behavior and function, muscle strength, and sense of well-being. In carrying out its many functions, T acts both as hormone and prohormone. It is an outstanding example of the diverse evolutionary utilization of a primitive informational molecule both among and within species. Not only does T act through the androgen receptor both unchanged and via 5 alpha-reduction, but it acts in tissues with a high aromatase level as an estrogen via the estrogen receptor. Furthermore, DHT, binding to the estrogen receptor, can act as an inhibitor of estrogen action. The products of androgen metabolism may also play active regulatory roles in hematopoiesis and in the regulation of certain hepatic enzymes. Table 3 summarizes the actions of secreted T in males indicating the probable effector hormone. While gross hypogonadism is uncommon, mild androgen insufficiency may be much more frequent, especially in older men, and in those receiving treatment for chronic medical conditions. It is quite possible that such individuals would benefit from appropriate androgen therapy were it available, but the current forms of replacement therapy are not very satisfactory. Better approaches are required. With the exception of a small number of secreted proteins, the products of transcription induced by androgens are not, as yet, known. When the androgen receptor gene is cloned it will be possible to identify androgen-regulated genes and their products. It will then be possible to design agents selectively producing specific desired androgenic effects.

Anderson RA, Bancroft J, Wu FC
Medical Research Council Reproductive Biology Unit, Centre for Reproductive Biology, Edinburgh, Scotland.
J Clin Endocrinol Metab 1992 Dec;75(6):1503-7

The effects of supraphysiological levels of testosterone, used for male contraception, on sexual behavior and mood were studied in a single-blind, placebo-controlled manner in a group of 31 normal men. After 4 weeks of baseline observations, the men were randomized into two groups: one group received 200 mg testosterone enanthate (TE) weekly by im injection for 8 weeks (Testosterone Only group), the other received placebo injections once weekly for the first 4 weeks followed by TE 200 mg weekly for the following 4 weeks (Placebo/Testosterone group). The testosterone administration increased trough plasma testosterone levels by 80%, compatible with peak testosterone levels 400-500% above baseline. Various aspects of sexuality were assessed using sexuality experience scales (SES) questionnaires at the end of each 4-week period while sexual activity and mood states were recorded by daily dairies and self-rating scales. In both groups there was a significant increase in scores in the Psychosexual Stimulation Scale of the SES (i.e. SES 2) following testosterone administration, but not with placebo. There were no changes in SES 3, which measures aspects of sexual interaction with the partner. In both groups there were no changes in frequency of sexual intercourse, masturbation, or penile erection on waking nor in any of the moods reported. The Placebo/Testosterone group showed an increase in self-reported interest in sex during testosterone treatment but not with placebo. The SES 2 results suggest that sexual awareness and arousability can be increased by supraphysiological levels of testosterone. However, these changes are not reflected in modifications of overt sexual behavior, which in eugonadal men may be more determined by sexual relationship factors. This contrasts with hypogonadal men, in whom testosterone replacement clearly stimulates sexual behavior. There was no evidence to suggest an alteration in any of the mood states studied, in particular those associated with increased aggression. We conclude that supraphysiological levels of testosterone maintained for up to 2 months can promote some aspects of sexual arousability without stimulating sexual activity in eugonadal men within stable heterosexual relationships. Raising testosterone does not increase self-reported ratings of aggressive feelings.

Davidson JM, Kwan M, Greenleaf WJ
Clin Endocrinol Metab 1982 Nov;11(3):599-623

Only in the last few years has the scientific study of hormonal replacement therapy for hyposexuality begun in earnest with the advent of appropriately controlled experiment studies. Dose-response relationships can be demonstrated between testosterone (T) and sexual measures, but these have not yet been investigated in detail. Some aspects of sexual function are maintained in the presence of androgen levels well below the normal range, but preliminary evidence suggests that within a normal population high levels of T are correlated with more vigorous responses to visual erotic stimuli. Though T (and to a greater extent free T) declines with aging in parallel with the decline of sexual function, these hormonal changes contribute only to a minor extent to the behavioural change. Some non-aromatizable androgens may be less effective in stimulating sexual behaviour than T, but initial data on effects of dihydrotestosterone suggests that the capacity of an androgen to be aromatized (converted to oestrogen) is not a requirement for its sexual action. While T apparently increases the incidence of all types of male sexual activity, recent data contradict the belief that it directly facilitates the erectile mechanism in men, even though erection frequency is greatly reduced in untreated hypogonadal men. At the present juncture, it appears that the initial action of T may be on libido factors which lead in turn to the stimulation of other aspects of sexuality. Specifically, we propose that androgen acts through stimulating genital sensations and/or other pleasurable awareness of sexual response rather than directly through cognitive processes such as sexual imagery.

Tenover J.L.
Dr. J.L. Tenover, Wesley Woods Geriatric Hospital, 1821 Clifton Road NE, Atlanta, GA 30329-5102 United States
Endocrinology and Metabolism Clinics of North America (United States) 1998, 27/4 (969-987)

Adult onset male hypogonadism and the testosterone deficiency of the aging male often are under-recognized entities. The etiologies, presentation, and diagnosis of hypogonadism and andropause in the adult male are presented. The expected therapeutic goals, potential treatment risks, and management of androgen replacement therapy for the adult man are reviewed. The advantages and disadvantages of the various androgen delivery systems currently available and under investigation are discussed.

Ahmed SR, Boucher AE, Manni A, Santen RJ, Bartholomew M, Demers LM
Department of Medicine, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey 17033.
J Clin Endocrinol Metab 1988 Mar;66(3):546-51

Five hypogonadal men were treated with transdermal testosterone therapy, using a testosterone patch applied to the scrotal skin. Daily application of the patch, which contained 10 mg testosterone, produced an increase in serum testosterone concentrations from a pretreatment value of 45 +/- 12 (+/- SE; 1.5 +/- 0.4) to 436 +/- 80 ng/dL (15.1 +/- 2.8 nmol/L; P less than 0.001) after 4 weeks of treatment. Normal serum testosterone concentrations were achieved in all men after 6-8 weeks of therapy and were maintained during continued long term therapy for 9-12 months with a patch containing 15 mg testosterone. All men reported a subjective increase in libido and sexual function during therapy, and three men preferred it to testosterone injections. The serum testosterone and estradiol levels did not rise above the normal adult male range at any time during therapy. However, elevated serum dihydrotestosterone (DHT) concentrations occurred during treatment; the pretreatment DHT concentration was 95 +/- 3 ng/dL (3.3 +/- 0.1 nmol/L), and it increased to 228 +/- 40 ng/dL (7.8 +/- 1.4 nmol/L) after 4 weeks of treatment and remained elevated thereafter. The individual mean DHT to testosterone ratio increased from a pretreatment value of 0.2 (range, 0.1-0.3) to 0.6 (range, 0.4-0.7) after 2 weeks of therapy and remained high thereafter. Comparison of the serum DHT levels in patients during therapy with those in normal men who had similar testosterone concentrations [531 +/- 62 vs. 566 +/- 72 ng/dL (18.4 +/- 2.1 vs. 19.6 +/- 2.5 nmol/L); P greater than 0.05] revealed that the mean serum DHT concentration was significantly higher in the patients [315 +/- 69 vs. 87 +/- 6 ng/dL (10.8 +/- 2.4 vs. 2.9 +/- 0.2 nmol/L); P less than 0.001], as was the mean DHT to testosterone ratio [0.6 (range, 0.25- 1.1) vs. 0.16 (range, 0.09- 0.24); P less than 0.001]. The high serum DHT levels presumably were due to increased metabolism of testosterone to DHT by the 5 alpha-reductase in the scrotal skin. Serum 3 alpha-androstanediol glucuronide levels were not elevated in the patients. We conclude that transdermal testosterone therapy is an effective long term treatment for hypogonadism in men. It is, however, associated with high serum DHT levels, whose potential long term effects on the prostate and other tissues need to be investigated.

Phillips GB
Am J Med 1984 Jun;76(6):1041-8

The previous findings of hyperestrogenemia in men with myocardial infarction and of a correlation between the ratio of serum estradiol to testosterone and the glucose-insulin-lipid defect have led to the hypothesis that hyperestrogenemia may be responsible for the increased incidence of atherosclerosis and its complications in patients with diabetes. The hypothesis predicts that the mean serum level of estradiol and the ratio of serum estradiol to testosterone are elevated in patients with diabetes. To test this hypothesis, the serum levels of estradiol and testosterone were measured in 21 nonobese men with diabetes and in 19 apparently healthy men of similar age and weight. A higher mean serum estradiol level (p less than 0.001) and estradiol-to-testosterone ratio (p less than 0.005) were observed in the patients with diabetes, whereas the mean serum testosterone level was not significantly different. The findings are consistent with the hypothesis.

Sewdarsen M, Vythilingum S, Jialal I, Desai RK, Becker P
Department of Medicine, R.K. Khan Hospital, Durban, South Africa.
Atherosclerosis 1990 Aug;83(2-3):111-7

The relation between sex hormone levels and myocardial infarction was studied in a case-control study among 117 Indian men with myocardial infarction aged 30-60 years and in 107 healthy Indian male controls. The patients and controls were further divided into subsets defined by age in decades. In the total patient population, testosterone concentration was significantly lower than in the controls (P less than 0.01), whilst oestradiol (P less than 0.0005) and the oestradiol to testosterone ratio (P less than 0.0005) were significantly higher. Multivariate stepwise logistic regression analyses demonstrated that free testosterone index, the free oestradiol index, and the oestradiol to testosterone ratio were significantly associated with myocardial infarction, and that this association was independent of age, body mass index, smoking and serum lipids. Further analyses according to age subsets revealed that compared to respective control groups, patients in the 4th decade had both significant hypotestosteronaemia and hyperoestrogenaemia, whereas in patients of the 5th decade significant differences in total and in the calculated free oestradiol index were noted, and in the 6th decade a significant difference was detected only in the free oestradiol index. Hence, we conclude that aberrations in endogenous sex hormones are significantly associated with myocardial infarction, and that this association appears to be strongest in young men and diminishes with age, suggesting that these disturbances in sex hormones may be associated with premature manifestation of coronary artery disease.

Phillips GB
Proc Natl Acad Sci U S A 1977 Apr;74(4):1729-33

Fifteen patients who had had a myocardial infarction before the age of 43 were compared with thirteen age-matched normal subjects. Twelve of the patients and three of the controls had a delayed glucose and insulin peak in the glucose and insulin areas than normal curves. When the measurements of the four patients with the largest areas under the glucose tolerance curve were separated, significant correlations were observed in the remaining patients and controls. The ratio in serum of the concentrations of estradiol-17beta to testosterone (E/T) correlated with serum glucose area (r equals + 0.69, P is less than 0.001), insulin area (r equals + 0.80, P is less than 0.001), and the ratio of insulin area to glucose area (I/G) (r equals + 0.64, P is less than 0.005) in the glucose tolerance test. Serum cholesterol concentration correlated with E/T, insulin area, and I/G, and serum triglyceride concentration correlated with glucose area, I/G, and serum cholesterol concentration. The hypothesis is presented (i) that in men who have had a myocardial infarction, an abnormality in glucose tolerance and insulin response and elevation in serum cholesterol and triglyceride concentrations are all part of the same defect (glucose-insulin-lipid defect), (ii) that this glucose-insulin-lipid defect when glucose intolerance is present is the "mild diabetes" commonly associated with myocardial infarction but is based on a mechanism different from that of classical diabetes, (iii) that this glucose-insulin-lipid defect is secondary to an elevation in E/T, and (iv) that an alteration in the sex hormone milieu is the major predisposing factor for myocardial infarction.

Luria MH, Johnson MW, Pego R, Seuc CA, Manubens SJ, Wieland MR, Wieland RG
Arch Intern Med 1982 Jan;142(1):42-4

An alteration in sex hormones has been considered a risk factor for myocardial infarction. In this study, estradiol (E2) and testosterone (T) levels were evaluated in healthy firefighters, patients with myocardial infarction acutely and during their convalescence, patients with no evidence of occlusive coronary artery disease on arteriography, and patients with chronic angina pectoris in whom there was at least one vessel that indicated 50% occlusive coronary artery disease. Although T levels were similar in all groups, E2 levels were substantially higher in patients with myocardial infarction and in patients with chronic angina pectoris. These results support the hypothesis that elevated estrogen levels may be a risk factor for myocardial infarction and coronary artery disease, possibly by promoting clotting or coronary spasm.

Mendoza SG, Zerpa A, Carrasco H, Colmenares O, Rangel A, Gartside PS, Kashyap ML
Artery 1983;12(1):1-23

A series of thirty-three Venezuelan men with premature myocardial infarction (mean age (M +/- SEM) 45 +/- 1.5 yrs) and with greater than 50% occlusion of at least 2 coronary arteries, and 19 weight matched control men (age 44 +/- 2 yrs) with normal coronary arteries on coronary angiography were studied. The percentages of significantly abnormal (greater than +/- 2 S.D. of controls) serum or plasma concentrations of various measurements (in decreasing order) were: estradiol (33%), total apolipoprotein (apo)B (24%), estradiol/testosterone ratio (21%), low density lipoprotein (LDL) apo B (19%), apo AI (17%), apo AI/total plasma apo B ratio (17%), total cholesterol (17%), and LDL-cholesterol (LDL-C) (11%). In addition, a multivariate discriminant function analysis showed that only estradiol, apo AI, LDL-C, estradiol/testosterone ratio and total cholesterol were statistically significant independent markers of myocardial infarction with occlusive coronary disease in these patients. Both serum estradiol and estradiol/testosterone ratio correlated positively with plasma apo B and LDL apo B, and inversely with apo AI; serum testosterone correlated inversely with plasma apo B (p less than 0.05). The data suggest that circulating sex hormones (estrogens, testosterone) are not only independent markers of coronary disease but may be pathogenetically linked to apo B and apo AI metabolism.

Phillips GB, Pinkernell BH, Jing TY
Department of Medicine, Columbia University College of Physicians and Surgeons, St. Luke's-Roosevelt Hospital Center, New York, NY.
Arterioscler Thromb 1994 May;14(5):701-6

Hyperestrogenemia and hypotestosteronemia have been observed in association with myocardial infarction (MI) and its risk factors. To determine whether these abnormalities may be prospective for MI, estradiol and testosterone, as well as risk factors for MI, were measured in 55 men undergoing angiography who had not previously had an MI. Testosterone (r = -.36, P = .008) and free testosterone (r = -.49, P < .001) correlated negatively with the degree of coronary artery disease after controlling for age and body mass index. When the patient group was successively reduced to a final study group of 34 men by excluding the patients with other major disorders, the testosterone and free testosterone correlations persisted (r = -.43, P < .02 and r = -.62, P < .001, respectively). Neither estradiol nor the risk factors, except for high-density lipoprotein cholesterol, correlated with the degree of coronary artery disease in the final group. Testosterone correlated negatively with the risk factors fibrinogen, plasminogen activator inhibitor-1, and insulin and positively with high-density lipoprotein cholesterol. The correlations found in this study between testosterone and the degree of coronary artery disease and between testosterone and other risk factors for MI raise the possibility that in men hypotestosteronemia may be a risk factor for coronary atherosclerosis.

Chou TM, Sudhir K, Hutchison SJ, Ko E, Amidon TM, Collins P, Chatterjee K
Cardiovascular Research Institute, University of California at San Francisco 94143-0124, USA.
chou@cardio.ucsf.edu
Circulation 1996 Nov 15;94(10):2614-9

BACKGROUND: Although estrogens have been shown to be vasoactive hormones, the vascular effects of testosterone are not well defined. Like estrogen, testosterone causes relaxation of isolated rabbit coronary arterial segments. We examined the vasodilator effects of testosterone in vivo in the coronary circulation and the potential mechanisms of its actions.

METHODS AND RESULTS: Using simultaneous intravascular two-dimensional and Doppler ultrasound, we examined the effect of intracoronary testosterone in coronary conductance and resistance arteries in 10 anesthetized dogs (5 male, 5 female). We also assessed the contribution of NO, prostaglandins, ATP-sensitive K+ channels, and classic estrogen receptors to testosterone-induced vasodilation. Testosterone induced a significant increase in cross-sectional area, average coronary peak flow velocity, and calculated volumetric coronary blood flow at the 0.1 and 1 mumol/L concentrations. This effect was independent of sex. Pretreatment with N omega-nitro-L-arginine methyl ester to block NO synthesis decreased testosterone-induced increase in cross-sectional area, average coronary peak flow velocity, and coronary blood flow. Pretreatment with glybenclamide to assess the role of ATP-sensitive K+ channels did not influence testosterone-induced dilation in epicardial arteries but did attenuate its effect in the microcirculation. Pretreatment with indomethacin or the classic estrogen-receptor antagonist ICI 182,780 did not alter testosterone-induced changes.

CONCLUSIONS: Short-term administration of testosterone induces a sex-independent vasodilation in coronary conductance and resistance arteries in vivo. Acute testosterone-induced coronary vasodilation of epicardial and resistance vessels is mediated in part by endothelium-derived NO. ATP-sensitive K+ channels appear to play a role in the vasodilatory effect of testosterone in resistance arteries.

Costarella CE, Stallone JN, Rutecki GW, Whittier FC
Department of Physiology, Northeastern Ohio Universities College of Medicine, Rootstown, USA.
J Pharmacol Exp Ther 1996 Apr;277(1):34-9

Several recent studies have provided evidence that gonadal steroid hormones can exert acute (nongenomic) effects on both neural and vascular tissues. This study examines the acute effects of testosterone (T) on vascular reactivity of the rat thoracic aorta. Aortic rings from male Sprague-Dawley (SD) rats with (+ENDO) and without (-ENDO) endothelium were prepared for isometric tension recording. In (+ENDO) male aortae precontracted with phenylephrine (PE), T produced dose-dependent relaxation from 25 microM (30.3 +/- 7.1%) to 300 microM (99.4 +/- 0.4%), whereas T vehicle (< or = 0.5% ethanol) had no effect. Pretreatment of (+ENDO) aortae with T (50 microM; 10 min) attenuated subsequent contractile responses to PE. Both maximal contraction and sensitivity to PE were reduced by T. Pretreatment of (+ENDO) aortae with both T and N omega-nitro-L-arginine methyl ester (250 microM) reversed in part the attenuating effects of T alone; however, both maximal response and sensitivity to PE were still reduced compared to control rings (without T or N omega-nitro-L-arginine methyl ester). Pretreatment of (-ENDO) aortae with T reduced sensitivity to PE, but had no effect on maximal contraction. T pretreatment (50 microM; 10 min) of both (+ENDO) female SD aortae and (+ENDO) male testicular-feminized rat aortae reduced maximal contraction and sensitivity to PE in both groups to a similar extent as in (+ENDO) male SD aortae. These data suggest that T has a direct vasodilating effect on the rat aorta, which involves endothelium-dependent (enhanced NO release) and Bindependent mechanisms and is gender- and intracellular androgen receptor-independent.

Yue P, Chatterjee K, Beale C, Poole-Wilson PA, Collins P
Department of Cardiac Medicine, National Heart and Lung Institute, London, UK.
Circulation 1995 Feb 15;91(4):1154-60

BACKGROUND: Until menopause, women appear to be protected from coronary heart disease. Evidence suggests that estrogen may play a role in the protection of the cardiovascular system by exerting a beneficial effect on risk factors such as cholesterol metabolism and by a direct effect on the coronary arteries. To date there has been no evidence linking testosterone with the occurrence of coronary heart disease. Testosterone may affect the cardiovascular system directly, thus partially explaining the difference in the incidence of coronary artery disease in men and premenopausal women. The purpose of this study was to assess the direct effect of testosterone and a number of testosterone analogues on rabbit coronary arteries and aorta in vitro. METHODS AND RESULTS: Rings of coronary artery and aorta of adult male or nonpregnant female New Zealand White rabbits were suspended in organ baths containing Krebs solution; isometric tension then was measured. The response to testosterone was investigated in prostaglandin F2 alpha (PGF 2 alpha)- and KCl-contracted rings. The effects of endothelium and nitric oxide synthase, prostaglandin synthetase, and guanylate cyclase inhibition on testosterone-induced relaxation were investigated. The effects of ATP-sensitive potassium channels and potassium conductance were also assessed. Relaxing responses in the presence of aromatase inhibition and testosterone receptor blockade were performed. The relaxing responses to the testosterone analogues etiocholan-3 beta-ol-17-one, epiandrosterone, 17 beta-hydroxy-5 alpha-androst-1-en-3-one, androst-16-en-3-ol, and testosterone enanthanate were measured. Testosterone relaxed rabbit coronary arteries and aorta. There was no significant difference between the relaxation effect of testosterone with or without endothelium. Similar results were obtained from male and nonpregnant female rabbits. The relaxing response of testosterone in the coronary artery was significantly greater than in the aorta. The relaxing response of testosterone in the coronary artery was significantly reduced by the potassium channel inhibitor barium chloride but not by the ATP-sensitive potassium channel inhibitor glibenclamide. The relaxing response to testosterone was greater in PGF 2 alpha-contracted rings compared with KCl-contracted rings. Inhibitors of nitric oxide synthase, prostaglandin synthetase, and guanylate cyclase did not affect relaxation induced by testosterone. Inhibition of aromatase and testosterone receptors did not affect relaxation. Testosterone did not shift the rabbit coronary arterial calcium concentration-dependent contraction curves, whereas verapamil did. There were, however, significant differences in the relaxing response to testosterone compared with testosterone analogues. Testosterone was the most potent relaxing agent, suggesting that there may be a structure-function relation in the relaxing response. CONCLUSIONS: Testosterone induces endothelium-independent relaxation in isolated rabbit coronary artery and aorta, which is neither mediated by prostaglandin I2 or cyclic GMP. Potassium conductance and potassium channels but not ATP-sensitive potassium channels may be involved partially in the mechanism of testosterone-induced relaxation. The in vitro relaxation is independent of sex and of a classic receptor. The coronary artery is significantly more sensitive to relaxation by testosterone than the aorta. Testosterone is a more potent relaxing agent of rabbit coronary artery than other testosterone analogues.

Webb CM, Adamson DL, de Zeigler D, Collins P
Cardiac Medicine, National Heart & Lung Institute, Imperial College School of Medicine, and Royal Brompton Hospital, London, United Kingdom.
Am J Cardiol 1999 Feb 1;83(3):437-9, A9

The effect of acute testosterone administration on exercise-induced myocardial ischemia was assessed in 14 men with coronary artery disease and low plasma testosterone concentrations in a study of randomized, double-blind, crossover design. Testosterone increased time to 1-mm ST-segment depression compared with placebo by 66 (15 to 117) seconds (p = 0.016), suggesting a beneficial effect of testosterone on myocardial ischemia in these patients.

Rosano GM, Leonardo F, Pagnotta P, Pelliccia F, Panina G, Cerquetani E, della Monica PL, Bonfigli B, Volpe M, Chierchia SL
Department of Cardiology, Istituto H. San Raffaele, Roma and Milano, Italy.
rosanog@roma.hsr.it
Circulation 1999 Apr 6;99(13):1666-70

BACKGROUND: The role of testosterone on the development of coronary artery disease in men is controversial. The evidence that men have a greater incidence of coronary artery disease than women of a similar age suggests a possible causal role of testosterone. Conversely, recent studies have shown that the hormone improves endothelium-dependent relaxation of coronary arteries in men. Accordingly, the aim of the present study was to evaluate the effect of acute administration of testosterone on exercise-induced myocardial ischemia in men.

METHODS AND RESULTS: After withdrawal of antianginal therapy, 14 men (mean age, 58+/-4 years) with coronary artery disease underwent 3 exercise tests according to the modified Bruce protocol on 3 different days (baseline and either testosterone or placebo given in a random order). The exercise tests were performed 30 minutes after administration of testosterone (2.5 mg IV in 5 minutes) or placebo. All patients showed at least 1-mm ST-segment depression during the baseline exercise test and after placebo, whereas only 10 patients had a positive exercise test after testosterone. Chest pain during exercise was reported by 12 patients during baseline and placebo exercise tests and by 8 patients after testosterone. Compared with placebo, testosterone increased time to 1-mm ST-segment depression (579+/-204 versus 471+/-210 seconds; P<0. 01) and total exercise time (631+/-180 versus 541+/-204 seconds; P<0. 01). Testosterone significantly increased heart rate at the onset of 1-mm ST-segment depression (135+/-12 versus 123+/-14 bpm; P<0.01) and at peak exercise (140+/-12 versus 132+/-12 bpm; P<0.01) and the rate-pressure product at the onset of 1-mm ST-segment depression (24 213+/-3750 versus 21 619+/-3542 mm Hgxbpm; P<0.05) and at peak exercise (26 746+/-3109 versus 22 527+/-5443 mm Hgxbpm; P<0.05).

CONCLUSIONS: Short-term administration of testosterone induces a beneficial effect on exercise-induced myocardial ischemia in men with coronary artery disease. This effect may be related to a direct coronary-relaxing effect.

Zgliczynski S, Ossowski M, Slowinska-Srzednicka J, Brzezinska A, Zgliczynski W, Soszynski P, Chotkowska E, Srzednicki M, Sadowski Z
Department of Endocrinology, Bielanski Hospital, Warszawa, Poland.
Atherosclerosis 1996 Mar;121(1):35-43

We investigated the effects of long-term testosterone replacement in hypogonadal and elderly men on lipids and lipoproteins. Twenty-two men with initial serum testosterone concentrations below 3.5 ng/ml took part in the study: 11 with hypopituitarism (1st group) and 11 otherwise healthy elderly men with low testosterone levels (2nd group). Testosterone deficiency was replaced by intramuscular injections of testosterone enanthate 200 mg every second week. Plasma levels of sex hormones, gonadotropins, SHBG, lipids and lipoproteins were determined before the treatment and after 3, 6 and 12 months of treatment. During the treatment serum testosterone and estradiol increased significantly, reaching normal levels. This was associated with a decrease in total cholesterol (from 225 +/- 16.9 mg/dl to 202 +/- 13.6 mg/dl after 6 months and 198 +/- 12.8 mg/dl after 1 year of testosterone administration, P < 0.0001 in men with hypoandrogenism associated with aging and from 255 +/- 12.1 mg/dl to 214 +/- 10.6 mg/dl after 6 months and 206 +/- 9 mg/dl after 1 year of treatment, P < 0.0001 in men with hypopituitarism) and LDL-cholesterol concentrations (from 139 +/- 12.5 mg/dl to 126 +/- 10.7 mg/dl after 6 months and 118 +/- 9.8 mg/dl after 1 year of testosterone administration, P < 0.0001 in men with hypoandrogenism associated with aging and from 178 +/- 10.3 mg/dl to 149 +/- 10.2 mg/dl after 6 months and 140 +/- 7.3 mg/dl after 1 year of treatment, P < 0.001 in men with hypopituitarism). However, no significant decrease in HDL-cholesterol levels or HDL2- and HDL3-cholesterol subfractions was observed. The effects of testosterone replacement therapy on lipids and lipoproteins were similar in both groups with different aetiology of hypogonadism. No side effects on the prostate were observed. The results of this study indicate that testosterone replacement therapy in hypogonadal and elderly men may have a beneficial effect on lipid metabolism through decreasing total cholesterol and atherogenic fraction of LDL-cholesterol without significant alterations in HDL-cholesterol levels or its subfractions HDL2-C and HDL3-C.

Wu S, Weng X
Beijing Red Cross Chaoyang Hospital.
Chin Med Sci J 1993 Dec;8(4):207-9

Several recent observations suggest that atrial natriuretic peptides (ANP) can modulate steroidogenesis in isolated rat Leydig cells and in young men. Other observations suggest that catechol estrogen can inhibit prostaglandin (PGI2) release in the endothelium, and we had found that androgen can relieve angina pectoris and improve myocardial ischemia in elderly men with coronary heart disease (CHD), possibly through relieving coronary artery smooth muscle spasm. Because ANP and PGI2 are vasoactive peptides which regulate vasomotion, there must be an interaction between steroidogenesis hormones and vasoactive peptides. We evaluated the effects of androgen (Sustanon 250) administration on plasma ANP, PGI2 and thromboxane (TXA2) levels in elderly men with CHD. Thirty 60-75-year-old men with CHD received 250 mg (1 ml) Sustanon 250 injection, and 30 age- and sex-matched CHD patients received 1 ml saline. Plasma ANP, PGI2, TXA2, estradiol (E2) and testosterone (T) were determined before injection and 3 weeks thereafter. The results showed that Sustanon 250 administration increased plasma ANP levels, decreased TXA2 and increased PGI2 levels significantly, and thereby improved the TXA2/PGI2 imbalance in CHD patients (all P < 0.01). Meanwhile, serum T levels rose (P < 0.01), but E2 levels remained unchanged, and thus the E2/T ratio decreased (P < 0.05). Our findings demonstrate that androgen exerts its regulatory role by altering plasma ANP levels and the TXA2/PGI2 ratio.

[Article in Chinese]
Wu SZ, Weng XZ, Yao XX
Department of Internal Medicine, Beijing Red-Cross Chaoyang Hospital.
Chung Hua Nei Ko Tsa Chih 1993 Mar;32(4):235-8

Sixty-two elderly men with coronary heart disease (CHD), 54 of them also suffering from hyperlipidemia, were treated with a new oral androgenic preparation (Andriol) through crossover study. The results showed that after oral Andriol administration for one month, serum estradiol/testosterone (E2/T) ratio was reduced, (P < 0.05) symptom of angina pectoris was relieved (total effective rate, 77.4%), signs of myocardial ischemia in ECG and Holter monitoring were improved (total effective rate, 68.8% and 75% respectively), serum total cholesterol (TC) and triglyceride (TG) levels were reduced dramatically (both P < 0.001) and the serum level of high density lipoprotein cholesterol (HDL-ch) was increased (P < 0.05), but the blood levels of apolipoprotein-AI (APO-AI) and B (APO-B) remained unchanged. No significant side effect of Andriol was observed.

Stone NN, Laudone VP, Fair WR, Fishman J
Urol Res 1987;15(3):165-7

Human prostatic tissue and expressed prostatic secretions (EPS) from patients with benign prostatic hyperplasia (BPH) and prostate cancer were incubated with (1 beta 3H) androstenedione. The extent of aromatization was determined by measuring the transfer of 3H from the 1 beta position into water. The amount of 3H2O recovered corresponds to the estrogens formed. Tissue from 5 patients with BPH yielded 2.13 (+/- 1.05) pmol/mg protein/h while the EPS from the same patients yielded 727 fmol/mg protein/h. In patients with prostate cancer the mean formation of estrogens was 388 fmol/mg protein/h (+/- 75). 4-hydroxy-androstenedione, an aromatase inhibitor, successfully inhibited aromatization in BPH and prostate cancer 53-98%.

Ekman P
Department of Urology, Karolinska Hospital, Stockholm, Sweden.
J Urol (Paris) 1995;101(1):22-5

Endocrine therapy by means of castration for benign prostatic hyperplasia was introduced already in the middle of the 19th century. The technique was never popularized and was abandoned following the introduction of safe surgical techniques. In the second half of this century, small series of various endocrine treatments have been reported, mainly using progestational agents. The hormone dependency of the prostate is unique, since testosterone itself is not very active on the prostate cells but has to be converted to 5 alpha-dihydrotestosterone, which is almost ten times as effective an androgen in the prostate cell. By blocking this conversion, highly specific antiandrogenic effect will be obtained in the prostate but not in other organs of the body. The first 5 alpha-reductase inhibitor, finasteride, has proven effective in reducing prostate DHT. In large clinical trials, it has shown to reduce prostate size, improve urinary flow and reduce symptom score, statistically significantly better than placebo. The effect is sustained over at least 3 years. In a double-blind, randomized, placebo-controlled study over 2 years, patients were similarly improved in the finasteride group, whereas they deteriorated in the placebo group. This indicates that finasteride is able to halt the progression of the natural course of benign prostatic hyperplasia. Benign prostatic hyperplasia, generally believed to be a stromal disease, is potentially dependent on estrogens for its development. By blocking aromatization of testosterone to estrogen in the prostate cells, a hypothetical beneficial effect on the disease process should be gained. Results from phase II-studies have been promising. However, in placebo-controlled studies, aromatase inhibitors did not perform better than placebo.

[Article in French]
Sole-Balcells F
Instituto de Urologia, Nefrologia y Andrologia, Fundacion Puigvert Escuela de Post-Graduados, Universidad Autonoma de Barcelona, Espagne.
J Urol (Paris) 1993;99(6):303-6

The hypothesis of the etiopathogenesis of Benign Prostatic Hypertrophy (BPH) on the basis of stroma-epithelium interaction is presented. The fetal prostate has its origin in the urogenital sinus depending on the dehydrotestosterone stimulating the stromal cells having androgenic receptors. This stroma hyperplasia is considered to be the initial factor in the BPH formation. The inequality in growth factors is also relevant for its formation. Stimulating factors, especially the epidermal growth factor (EGF) prevail on involution factors. The stromal cell has estrogenic receptors. The estrogens from the testosterone aromatization are the first stimulus on the prostatic stroma on the transitional and periurethral area stimulating the glandular epithelium causing BPH. The knowledge of BPH etiopathogenesis will make its rational medical treatment possible, and eventually slow or stop its growth when therapy in its early evolutive stages is prescribed.

Chang WY, Prins GS
Department of Urology, University of Illinois College of Medicine, Chicago 60612, USA.
Prostate 1999 Jul 1;40(2):115-24

Estrogens can have profound effects on prostate growth and differentiation. These effects were thought to be mediated by the classical estrogen receptor; however, the discovery of a second estrogen receptor has redefined the estrogen signaling pathway and may have broad implications on estrogen-responsive tissues, including the prostate. The new estrogen receptor, named estrogen receptor-beta (ERbeta), is preferentially expressed in the prostate and maintains some characteristics that are different from ERalpha. Establishing the distribution and function of ERbeta in the various estrogen-responsive tissues is critical to defining its pharmacological and physiological impact. Differential expression of ERbeta may facilitate development of tissue-specific estrogen agonists and antagonists, a goal in the treatment of diseases in estrogen-sensitive tissues such as breast cancer. This article reviews the current knowledge on ERbeta and its potential impact on the prostate.

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Albert C, Vallee M, Beaudry G, Belanger A, Hum DW
Laboratory of Molecular Endocrinology, CHUL Research Center, Laval University, Quebec, Canada.
[Medline record in process]
Endocrinology 1999 Jul;140(7):3292-302

Considering the physiologic importance of the steroid response, which is regulated in part by steroid levels in a given tissue, relatively little is known about steroid glucuronidation, which is widely accepted as a major pathway involved in the catabolism and elimination of steroid hormones from the human body. In a previous study, it was ascertained that the monkey may be the most appropriate model in which to examine the role of steroid glucuronidation. Northern blot analysis of simian RNA, hybridized with human UGT complementary DNA (cDNA) probes demonstrate the similarity of the transcripts. The simian UGT1A09 cDNA isolated from a liver library is 2396 bp and contains an open reading frame encoding 530 amino acids. The predicted primary structure is most homologous to the human UGT1A9 (hUGT1A9) enzyme, which share 93% identity. Stable transfection of the monkey UGT1A09 (monUGT1A09) cDNA into HK293 cells, expresses a microsomal protein with an apparent molecular mass of 55 kDa. Of the more than 30 endogenous substrates tested, both proteins show the highest activity on 4-hydroxyestradiol and 4-hydroxyestrone, followed by 2-hydroxyestradiol and estradiol. RT-PCR analysis demonstrate that UGT1A9 transcript is expressed in several tissues, which include the prostate, testis, breast, ovary, and skin of the monkey and humans. The expression of UGT1A9 in extrahepatic estrogen-responsive tissues, and its high activity on estrogens is consistent with this enzyme having a role in estrogen metabolism.

Singh J, Handelsman DJ
Department of Medicine, DO2, University of Sydney, Sydney, New South Wales 2006, Australia.
[Record supplied by publisher]
Biol Reprod 1999 Jul;61(1):200-208

Perinatal sex-steroid exposure may result in permanent modifications in the structure and function of the prostate gland. The mechanism of such long-range alterations in hormonal sensitivity is not known. This study aimed to define the molecular requirements for neonatal sex-steroid imprinting and to investigate whether combined administration of neonatal androgens and estrogens had synergistic effects upon the mature mouse prostate. Since the interaction between endogenous and exogenous sex steroids in normal mice makes it difficult to dissociate direct from indirect effects, we used the hypogonadal (hpg) mouse, characterized by congenital androgen deficiency yet still fully responsive to exogenous androgens. Newborn mice (Days 1-2) were administered a single s.c. injection of androgens alone or in combination with an estrogen followed by testosterone-induced maximal prostate growth at maturity. The final effects were determined in 7-wk-old mice through study of ductal architecture in microdissected ventral prostates (VP) and quantitation of volume densities and diameters of prostate tissue components. A single neonatal dose of androgens, but not of estrogen, increased branching morphogenesis and VP weights at adulthood. These effects did not differ significantly between various androgens; in addition, combined androgen and estrogen treatment failed to demonstrate any synergistic effects on the prostate. We conclude that neonatal androgens induce long-range effects upon the mature VP structure as well as its secretory function and that this imprinting occurs via the androgen receptor without requiring aromatization of androgens. However, these conclusions, based on a specific treatment protocol, are confined only to the distal segment of VP, and effects of neonatal sex-steroid exposure in other regions

Abreu-Martin MT, Chari A, Palladino AA, Craft NA, Sawyers CL
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90095, USA.
Mol Cell Biol 1999 Jul;19(7):5143-54

Mitogen-activated protein (MAP) kinases phosphorylate the estrogen receptor and activate transcription from estrogen receptor-regulated genes. Here we examine potential interactions between the MAP kinase cascade and androgen receptor-mediated gene regulation. Specifically, we have studied the biological effects of mitogen-activated protein kinase kinase kinase 1 (MEKK1) expression in prostate cancer cells. Our findings demonstrate that expression of constitutively active MEKK1 induces apoptosis in androgen receptor-positive but not in androgen receptor-negative prostate cancer cells. Reconstitution of the androgen receptor signaling pathway in androgen receptor-negative prostate cancer cells restores MEKK1-induced apoptosis. MEKK1 also stimulates the transcriptional activity of the androgen receptor in the presence or absence of ligand, whereas a dominant negative mutant of MEKK1 impairs activation of the androgen receptor by androgen. These studies demonstrate an unanticipated link between MEKK1 and hormone receptor signaling and have implications for the molecular basis of hormone-independent prostate cancer growth.

Chang WY, Birch L, Woodham C, Gold LI, Prins GS
Department of Urology, University of Illinois College of Medicine, Chicago 60612, USA.
Endocrinology 1999 Jun;140(6):2801-13

Exposure of male rats to estrogens during the neonatal period retards prostate branching morphogenesis, blocks epithelial differentiation, and predisposes the adult prostate to hyperplasia and dysplasia. The mechanism of neonatal estrogenization is not well understood. The present study evaluated transforming growth factor-beta (TGFbeta) in the neonatally estrogenized ventral prostate to determine whether this paracrine/autocrine factor may in part mediate the effects ofestrogen on the developing prostate gland. Immunocytochemistry using antibodies against active TGFbeta1 and its latency-associated peptide localized this molecule to the periductal smooth muscle cells in the developing prostate. Although neonatal estrogenization increased the accumulation of total and active TGFbeta1 in the smooth muscle layer as early as day 6 of life, it was physically separated from the epithelial ducts by a proliferating layer of fibroblasts surrounding the basement membrane. RT-PCR demonstrated that alterations in TGFbeta1 levels were not due to alterations in TGFbeta1 transcription. TGFbeta2 and TGFbeta3 were primarily immunolocalized to differentiating epithelial cells in developing prostates, and this was markedly dampened between days 10-30 after neonatal estrogen exposure. Immunocytochemistry for TGFbeta signaling components revealed that neonatal estrogenization transiently reduced TGFbeta type I receptor levels in the prostate epithelium, but not in stroma, between days 6-15, whereas there was no effect on TGFbeta type II receptor. Levels of the intracellular signal Smad2 (52 kDa) were detected in epithelial cells but were not altered after estrogenization. To analyze the functional status of the TGFbeta signaling pathway, immunocytochemistry was performed for p21(cip-1/waf-1), a cyclin-dependent kinase inhibitor that is inducible by TGFbeta1 in the prostate. Transient nuclear localization of p21(cip-1/waf-1) was normally observed in epithelial cells between days 6-15 and was associated with entry of cells into a terminal differentiation pathway. Neonatal estrogenization prevented this transient expression of p21(cip-1/waf-1). The present findings demonstrate that the TGFbeta signaling system is perturbed at several levels in the estrogenized prostate, which may in part account for the epithelial cell differentiation blockade as well as the proliferation of periductal fibroblasts in this model.

Konishi N, Nakaoka S, Matsumoto K, Nakamura M, Kuwashima S, Hiasa Y, Cho M, Uemura H, Hirao Y
Second Department of Pathology, Nara Medical University, Kashihara, Japan.
nkonishi@naramed-u.ac.jp
Pathol Int 1999 Mar;49(3):203-7

The expression of pepsinogen II (PG II), an aspartyl proteinase usually involved in the digestion of proteins in the stomach, was immunohistochemically investigated in conjunction with androgen (AR) and estrogen receptor (ER) status in prostate adenocarcinomas. Of a total of 38 samples obtained from radical prostatectomies, 23 tumors (60.5%) were positive for PG II and there was a significant positive correlation to the expression of AR but not to ER. Cells positive for PG II were localized mainly to the peripheral zones of tumorous glands which, in normal prostate, are negative, and in areas also expressing AR. In addition, a significant correlation between AR and ER was detected in the prostate carcinomas examined, which suggests a hormone-dependent status. On the basis of these results, PG II expression might be closely related to hormonal alterations associated with the development of prostate tumors

Wang LG, Liu XM, Kreis W, Budman DR
Department of Medicine, New York University School of Medicine, North Shore University Hospital, Manhasset, New York, 11030, USA.
Biochem Biophys Res Commun 1999 May 27;259(1):21-8

Protein phosphorylation/dephosphorylation is an important posttranslational modification that plays a critical role in signal transduction. The androgen receptor (AR) is under such control. We demonstrate that androgen receptor phosphorylation determines whether or not AR ligands perform as agonists or antagonists in LNCaP cells. Androgen receptor ligands (such as dihydrotestosterone and beta-estradiol) stimulate receptor expression and phosphorylation and, as a result, they act as agonists or partial agonists. In contrast, agents such as bicalutamide and estramustine inhibit the receptor phosphorylation and act as antagonists. This model is supported by gene expression and transactivation assays. Significant increases in levels of both mRNA and protein of prostate-specific antigen (PSA), a natural AR target gene, occur following the treatment of LNCaP cells with DHT, beta-estradiol, or hydroxyflutamide. In contrast, exposure of LNCaP cells to bicalutamide or estramustine results in a sharp decrease of PSA expression. Agonistic or antagonistic effect of these compounds on PSA expression parallels the level of phosphorylated, but not dephosphorylated androgen receptors. These agonistic or antagonistic effects are also observed in HeLa cells transfected with wild-type AR expression plasmid (pAR0) and AR-driven luciferase expression plasmid GRE-tk-LUC in the presence of different groups of AR blockers. Our data indicate that the functional status of androgen receptors is strongly correlated with the phosphorylation status of the receptors, and that the phosphorylated androgen receptor is the form of the receptor transcriptionally active in regulation. Thus the androgen receptor phosphorylation/dephosphorylation

Kuiper GG, Shughrue PJ, Merchenthaler I, Gustafsson JA
Department of Medical Nutrition, Karolinska Institute, Novum, Huddinge, S-14157, Sweden.
george.kuiper@cbt.ki.se
Front Neuroendocrinol 1998 Oct;19(4):253-86

The recent discovery that an additional estrogen receptor (ERbeta) subtype is present in many rat, mouse, and human tissues has advanced our understanding of the mechanisms underlying estrogen signalling. Ligand-binding experiments have shown specific binding of 17beta-estradiol by ERbeta with an affinity similar to that of ERalpha. The rat tissue distribution and/or the relative level of ERalpha and ERbeta expression seems to be quite different, i.e., moderate to high expression in uterus, testis, pituitary, ovary, kidney, epididymis, and adrenal for ERalpha and prostate, ovary, lung, bladder, brain, bone, uterus, and testis for ERbeta. Within the same organ it often appears that the ER subtypes are expressed in different cell types, supporting the hypothesis that the ER's may have different biological functions. The cell type-specific expression of ERalpha and ERbeta in rat prostate, testis, uterus, ovary, and brain and the distribution of ERbeta mRNA in the ERalpha knock-out mouse brain are discussed. The discovery of ERbeta suggests the existence of two previously unrecognized pathways of estrogen signalling; via the ERbeta subtype in tissues exclusively expressing this subtype and via the formation of heterodimers in tissues expressing both ER subtypes. The existence of two ER subtypes, their differential expression pattern, and different actions on certain response elements could provide explanations for the striking species-, cell-, and promoter-specific actions of estrogens and antiestrogens. The challenge for the future is to unravel the detailed physiological role of each subtype and to use this knowledge to develop the next generation of ER-targeted drugs with improved therapeutic profiles in the treatment or prevention of osteoporosis, cardiovascular system disorders, Alzheimer's disease, breast cancer, and disorders of the urogenital tract.

Kuiper GG, Gustafsson JA
Center for Biotechnology and Department of Medical Nutrition, Karolinska Institute, NOVUM, Huddinge, Sweden.
george.kuiper@cbt.ki.se
FEBS Lett 1997 Jun 23;410(1):87-90

The recent discovery that an additional estrogen receptor (ER) subtype is present in various rat, mouse and human tissues has advanced our understanding of the mechanisms underlying estrogen signalling. The discovery of a second ER subtype (ERbeta) suggests the existence of two previously unrecognised pathways of estrogen signalling: via the ERbeta subtype in tissues exclusively expressing this subtype and via the formation of heterodimers in tissues expressing both ER subtypes. Various models have been suggested as explanations for the striking cell- and promoter-specific effects of estrogens and anti-estrogens, all on the basis of the assumption that only a single ER gene

Chu S, Fuller PJ
Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia.
Mol Cell Endocrinol 1997 Sep 19;132(1-2):195-9

Recently a second estrogen receptor termed estrogen receptor beta (ERbeta) has been cloned and characterized, and shown to be expressed at the highest levels in ovarian granulosa cells and prostatic epithelium. In the course of amplifying a region of the ligand-binding domain of the rat ERbeta cDNA we identified a second, larger transcript which appears to arise through differential splicing. The second isoform has 54 nucleotides inserted after position 1372 encoding 18 additional amino acids. Both isoforms are expressed at similar relative abundance in a range of tissues.

Gustafsson JA
Department of Medical Nutrition, Karolinska Institute, Novum, Huddinge, Sweden.
Curr Opin Chem Biol 1998 Aug;2(4):508-11

The hormone estradiol has effects on many tissues in both males and females. Some of these effects, such as inhibition of cancer growth and modulation of the devastating effects of aging on bone, brain, skin and bladder, are good. Others, such as the effect on the breast and endometrium, are undesirable. The task of designing drugs that would have only the good effects of estradiol has, until recently, seemed almost impossible because it was thought that there was only one estrogen receptor and that an estrogenic agent was definitively categorized as an estrogen agonist or an antagonist. More recently we have learnt that there are two estrogen receptors which, under certain conditions, have opposite effects on gene transcription. In addition, it is now understood that agents cannot be described as agonists or antagonists because a single agent can be an agonist in one tissue and an antagonist in another. The term 'selective' estrogen receptor modulator' was designed to incorporate this. The idea of estrogen receptor modulators has raised new hope that tissue specific estrogens or anti-estrogens can be designed.

Donnelly BJ, Lakey WH, McBlain WA
J Urol 1983 Jul;130(1):183-7

Estrogens have been proposed as a major etiological factor in the pathogenesis of benign prostatic hyperplasia in man. The presence of estrogen receptor in benign prostatic hyperplasia would support this concept. Using the receptor stabilizer, sodium molybdate, and a hydroxylapatite assay we assayed human benign prostatic hyperplasia for the presence of cytosolic estrogen receptor. For comparison, we assayed estrogen receptor in cytosols of prostatic cancer and normal tissue, and we also measured androgen receptor and progesterone receptor concentrations in the 3 tissue types. Estrogen receptor was present in 8 of 15 benign prostatic hyperplasia specimens at a mean concentration of 9.2 fmol./mg. protein for the estrogen-receptor-positive samples. Sucrose gradient analysis of the estrogen receptor of benign prostatic hyperplasia revealed that it sedimented in the region of 8S, and steroid specificity studies confirmed that the binding to estrogen receptor was estrogen-specific. Estrogen receptor was also found in normal (3 of 3) and malignant (4 of 6) tissues, and all tissues were positive for androgen receptor. The presence of estrogen receptor in human benign prostatic hyperplasia supports the proposal that circulating estrogens may have a role in the pathogenesis of this disorder.

Ekman P, Barrack ER, Greene GL, Jensen EV, Walsh PC
J Clin Endocrinol Metab 1983 Jul;57(1):166-76

The existence of estrogen receptors in the human prostate has long been a controversial issue. This may be explained partly by the apparent heterogeneity of estrogen-binding sites in prostatic tissue. We herein report on multiple binding sites for estrogens in cytosol as well as nuclear preparations of human prostatic tissues. One class of binding sites corresponds to the classical, high affinity estrogen receptor; the Kd for [3H]estradiol binding to the receptor was approximately 0.10 nM and the binding was specific for estrogens. The second class of binding sites appeared to have a Kd for [3H]estradiol in the range of 5-10 nM. This second, lower affinity class of binding sites markedly influenced studies of the classical receptor even at low ligand concentrations. Saturation analysis should be performed over a wide range of ligand concentrations (0.05-10 nM) to allow separation of the two binding components. Quantitation of estrogen receptor by a single point assay cannot be carried out accurately unless the low affinity binding component can be blocked. Multiple binding sites for estradiol were observed in the cytosol as well as in the nuclear salt extractable and salt-resistant compartments of normal, benign hyperplastic, and cancerous human prostates. Normal peripheral and cancerous prostates contained significantly (P less than 0.01) higher amounts of cytosol estrogen receptor compared to benign hyperplastic tissue.

Khalid BA, Nurshireen A, Rashidah M, Zainal BY, Roslan BA, Mahamooth Z
Department of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur.
Med J Malaya 1990 Jun;45(2):148-53

One hundred and six prostatic tissue samples obtained from transurethral resection were analysed for androgen and estrogen receptors. In 62 of these, progesterone and glucocorticoid receptors were also assayed. Steroid receptors were assayed using single saturation dose 3H-labelled ligand assays. Ninety percent of the 97 prostatic hyperplasia tissues and six of the nine prostatic carcinoma tissues were positive for androgen receptors. Estrogen receptors were only present in 19% and 33% respectively. Progesterone receptors were present in 70% of the tissues, but glucocorticoid receptors were present in only 16% of prostatic hyperplasia and none in prostatic carcinoma.

Pontes JE, Karr JP, Kirdani RY, Murphy GP, Sandberg AA
Urology 1982 Apr;19(4):399-403

Measurement of estrogen binding in human prostate using high-pressure liquid chromatography (HPLC) revealed the presence of cytosolic estrogen receptors (ER) both in benign prostatic hyperplasia (BPH) and adenocarcinoma. Receptor concentrations correlated with several histopathologic features in the specimens analyzed. Estrogen receptor levels generally were higher in BPH than in cancer specimens although there was a subgroup of patients with poorly differentiated carcinoma with levels higher than those of BPH, HPLC can be used for measuring ER in 50 microliters of cytosol, and thus needle biopsy specimens will be analyzed routinely for ER with this micromethod.

Redman C, Scott JA, Baines AT, Basye JL, Clark LC, Calley C, Roe D, Payne CM, Nelson MA
Pharmacology/Toxicology Department, The University of Arizona, Tucson 85724, USA.
Cancer Lett 1998 Mar 13;125(1-2):103-10

Selenium supplementation has been shown for many years to work as an anticarcinogenic agent both in epidemiology and in in vitro studies. Selenium supplementation has recently been shown to decrease total cancer incidence. However, the mechanism of action of selenium as an anticarcinogenic agent has yet to be elucidated. Selenomethionine was the predominant form of selenium in the dietary supplement in the study by Clark et al. (Clark, L.C., Combs, G.F., Turnbull, W.B., Slate, E.H., Chalker, D.K., Chow, J., Davis, L.S., Glover, R.A., Graham, G.F., Gross, E.G., Krongrad, A., Lesher, J.L., Park, H.K., Sanders, B.B., Smith, C.L., Taylor, J.R. and The Nutritional Prevention of Cancer Study Group (1996) Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin: a randomized controlled trial. J. Am. Med. Assoc., 276 (24), 1957-1963) and therefore we evaluated the growth inhibitory effects of selenomethionine against human tumor cells. Selenomethionine was tested against each of three human tumor cell lines (MCF-7/S breast carcinoma, DU-145 prostate cancer cells and UACC-375 melanoma) and against normal human diploid fibroblasts. All cell lines demonstrated a dose-dependent manner of growth inhibition by selenomethionine. Selenomethionine inhibited the growth of all of the human tumor cell lines in the micromolar (microM) range (ranging from 45 to 130 microM) while growth inhibition of normal diploid fibroblasts required 1 mM selenomethionine, approximately 1000-fold higher than for the cancer cell lines. In short, normal diploid fibroblasts were less sensitive than the cancer cell lines to the growth inhibitory effects of selenomethionine. Furthermore, we show that selenomethionine administration to these cancer cell lines results in apoptotic cell death and aberrant mitoses. These results demonstrate the differential sensitivity of tumor cells and normal cells to selenomethionine.

Gey KF
Department of Biochemistry and Molecular Biology, University of Berne, Switzerland.
Biofactors 1998;7(1-2):113-74

Antioxidants are crucial components of fruit/vegetable rich diets preventing cardiovascular disease (CVD) and cancer: plasma vitamins C, E, carotenoids from diet correlate prevalence of CVD and cancer inversely, low levels predict an increased risk of individuals which is potentiated by combined inadequacy (e.g., vitamins C + E, C + carotene, A + carotene); self-prescribed rectification of vitamins C and E at adequacy of other micronutrients reduce forthcoming CVD, of vitamins A, C, E, carotene and conutrients also cancer; randomized exclusive supplementation of beta-carotene +/- vitamin A or E lack benefits except prostate cancer reduction by vitamin E, and overall cancer reduction by selenium; randomized intervention with synchronous rectification of vitamins A + C + E + B + minerals reduces CVD and counteracts precancerous lesions; high vitamin E supplements reveal potentials in secondary CVD prevention. Plasma values desirable for primary prevention: > or = 30 mumol/l lipid-standardized vitamin E (alpha-tocopherol/cholesterol > or = 5.0 mumol/mmol); > or = 50 mumol/l vitamin C aiming at vitamin C/vitamin E ratio > 1.3-1.5; > or = 0.4 mumol/l beta- (> or = 0.5 mumol/l alpha+ beta-) carotene. CONCLUSIONS: In CVD vitamin E acts as first risk discriminator, vitamin C as second one; optimal health requires synchronously optimized vitamins C + E, A, carotenoids and vegetable conutrients.

Rao AV, Fleshner N, Agarwal S
Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, ON, Canada.
v.rao@utoronto.ca
Nutr Cancer 1999;33(2):159-64

Dietary intake of tomatoes and tomato products containing lycopene, an antioxidant carotenoid, has been shown in recent studies to reduce the risk of cancer. This study was conducted to investigate the serum and prostate tissue lycopene and other major carotenoid concentrations in cancer patients and their controls. Serum lipid and protein oxidation was also measured. Twelve prostate cancer patients and 12 age-matched subjects were used in the study. Significantly lower serum and tissue lycopene levels (44%, p = 0.04; 78%, p = 0.050, respectively) were observed in the cancer patients than in their controls. Serum and tissue beta-carotene and other major carotenoids did not differ between the two groups (p = 0.395 and p = 0.280, respectively). Although there was no difference (p = 0.760) in serum lipid peroxidation between cancer patients and their controls (7.09 +/- 0.74 and 6.81 +/- 0.56 mumol/l, respectively), serum protein thiol levels were significantly lower among the cancer patients (p = 0.026). This study demonstrates that the status of lycopene but not other carotenoids in prostate cancer patients is different from controls. The role of dietary lycopene in preventing oxidative damage of biomolecules and thereby reducing the risk of prostate cancer needs to be evaluated in future studies.

Brawer Michael K(a); Ellis William J
Seattle VA Med., Cent., 112 UR, 1660 South Columbian Way, Seattle, WA 98108, USA
Cancer (Philadelphia) 75 (7 Suppl.):p1783-1789 1995

With prostate cancer representing the most common male cancer and the second most common cause of cancer-related death in men in the United States, increasing attention is being directed at providing early detection, as well as improvement in therapy. The third option to decrease cancer-related deaths, decreasing the incidence, has only recently gained attention. If tumor promoters can be removed from the patient environment and/or agents administered that inhibit cancer progression, we may indeed be able to decrease the incidence of this most common neoplasm. The prostate is a suitable site for chemoprevention strategies. High-risk populations, including those men with a strong family history of prostate cancer, black men, and/or men with prostatic intraepithelial neoplasia, a putative premalignant change identified on prostate biopsy or simple prostatectomy, represent useful target populations. If a chemopreventive strategy could be developed that was free of toxicity and also simple, inexpensive, and readily administered, indeed all men could be targeted. Several potential agents are available for chemoprevention in the prostate. The retinoids moderate differentiation and proliferation in several prostate cell lines. Severe toxicity, however, may preclude their widespread application. Difluoromethylornithine has also been investigated. A chemopreventive trial directed against lung cancer showed that alpha-tocopherol is associated with a decreasing incidence of prostate cancer. The greatest interest in the chemopreventive strategies for prostate cancer, however, has focused on decreasing the male androgens. Although most agents, such as luteinizing hormone-releasing hormone agonists and antiandrogens, have severe toxicity, the 5-alpha reductase inhibitors, because they do not, are thought to be excellent agents for a chemopreventive trial. The dependence of prostate epithelial differentiation and maintenance of transformed cells on circulating androgens is widely acknowledged. This is the impetus for the hypothesis that reduction of circulating androgens or blockage of testosterone to the more active metabolite dihydrotestosterone by agents such as finasteride or epristeride will reduce the incidence of prostate cancer. The National Cancer Institute Intergroup Prostate Cancer Prevention Trial, now underway, will randomize 18,000 men to receive 5 mg finasteride or a placebo daily for 7 years in a chemopreventive strategy. Entry requirements include a normal result of digital rectal examination and a serum prostate-specific antigen result less than 3.0 ng/ml. Abnormalities on digital rectal examination results or prostate-specific antigen level greater than 4.0 ng/ml on annual evaluation indicate the need for biopsies in the men receiving the placebo. An equal number of men will undergo biopsy in the active arm of the study. At the end of the 7-year study, all men will have biopsies. Although the primary endpoint is a reduction in prostate cancer incidence, additional benefits include long-term follow-up of the patients receiving finasteride, with potential salutary benefits with regard to symptoms of benign prostatic hyperplasia. This trial, which already has accrued more than 75% of the required participants, should resolve the issue of whether reduction in effective androgen level will prevent the development of prostate cancer.

Kelloff GJ, Lieberman R, Steele VE, Boone CW, Lubet RA, Kopelovitch L, Malone WA, Crowell JA, Sigman CC
National Cancer Institute, Division of Cancer Prevention, Chemoprevention Branch, Bethesda, Md., USA.
Eur Urol 1999;35(5-6):342-50

Chemoprevention is the administration of agents to prevent induction and inhibit or delay progression of cancers. For prostate, as for other cancer targets, successful chemopreventive strategies require well-characterized agents, suitable cohorts, and reliable intermediate biomarkers of cancer for evaluating chemopreventive efficacy. Agent requirements are experimental or epidemiological data showing chemopreventive efficacy, safety on chronic administration, and a mechanistic rationale for the observed chemopreventive activity. On this basis, promising chemopreventive drugs in prostate include retinoids, antiandrogens, antiestrogens, steroid aromatase inhibitors, 5alpha-reductase inhibitors, vitamins D and E, selenium, lycopene, and 2-difluoromethylornithine. Phase II trials are critical for evaluating chemopreventive efficacy. Cohorts in these trials should be suitable for measuring the chemopreventive activity of the agent and the intermediate biomarkers chosen as endpoints. Many cohorts proposed for phase II trials are patients with previous cancers or premalignant lesions. For such patients, trials should be conducted within the context of standard treatment. Two cohorts currently used in phase II prostate cancer chemoprevention trials are patients with PIN and patients scheduled for prostate cancer surgery. Biomarkers should fit expected biological mechanisms, be assayed reliably and quantitatively, measured easily, and correlate to decreased cancer incidence. Protocols for adequately sampling tissue are essential. Changes in PIN provide prostate biomarkers with the ability to be quantified and a high correlation to cancer. PIN measurements include nuclear polymorphism, nucleolar size and number of nucleoli/nuclei, and DNA ploidy. Other potentially useful biomarkers are associated with cellular proliferation kinetics (e.g. PCNA and apoptosis), differentiation (e.g. blood group antigens, vimentin), genetic damage (e.g. LOH on chromosome 8), signal transduction (e.g. TGFalpha, TGFbeta, IGF-I, c-erbB-2 expression), angiogenesis, and biochemical changes (e.g. PSA levels).

Thomas JA
Department of Pharmacology, University of Texas Health Science Center, San Antonio, USA.
Nutr Rev 1999 Apr;57(4):95-103

Diseases of the prostate gland, particularly adenocarcinoma and benign prostatic hyperplasia (BPH), are age-related. Prostate cancer is the most commonly occurring tumor in U.S. men. Differences in the incidence of this disease among ethnic populations are not due solely to genetic differences. Many efforts have been devoted to studying associations between nutrition and prostate cancer. The strongest association appears to be related to total fat intake and increased risk of this malignancy. Evidence also exists to suggest a role for certain micronutrients, such as zinc, selenium, vitamin E, lycopene, phytoestrogens, and phytosterols, although the role of nutrition and micronutrients in protection against prostate cancer is less convincing. Further research is necessary.

Gann PH, Ma J, Giovannucci E, Willett W, Sacks FM, Hennekens CH, Stampfer MJ
Department of Preventive Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA.
pgann@nwu.edu
Cancer Res 1999 Mar 15;59(6):1225-30

Dietary consumption of the carotenoid lycopene (mostly from tomato products) has been associated with a lower risk of prostate cancer. Evidence relating other carotenoids, tocopherols, and retinol to prostate cancer risk has been equivocal. This prospective study was designed to examine the relationship between plasma concentrations of several major antioxidants and risk of prostate cancer. We conducted a nested case-control study using plasma samples obtained in 1982 from healthy men enrolled in the Physicians' Health Study, a randomized, placebo-controlled trial of aspirin and beta-carotene. Subjects included 578 men who developed prostate cancer within 13 years of follow-up and 1294 age- and smoking status-matched controls. We quantified the five major plasma carotenoid peaks (alpha- and beta-carotene, beta-cryptoxanthin, lutein, and lycopene) plus alpha- and gamma-tocopherol and retinol using high-performance liquid chromatography. Results for plasma beta-carotene are reported separately. Odds ratios (ORs), 95% confidence intervals (Cls), and Ps for trend were calculated for each quintile of plasma antioxidant using logistic regression models that allowed for adjustment of potential confounders and estimation of effect modification by assignment to either active beta-carotene or placebo in the trial. Lycopene was the only antioxidant found at significantly lower mean levels in cases than in matched controls (P = 0.04 for all cases). The ORs for all prostate cancers declined slightly with increasing quintile of plasma lycopene (5th quintile OR = 0.75, 95% CI = 0.54-1.06; P, trend = 0.12); there was a stronger inverse association for aggressive prostate cancers (5th quintile OR = 0.56, 95% CI = 0.34-0.91; P, trend = 0.05). In the placebo group, plasma lycopene was very strongly related to lower prostate cancer risk (5th quintile OR = 0.40; P, trend = 0.006 for aggressive cancer), whereas there was no evidence for a trend among those assigned to beta-carotene supplements. However, in the beta-carotene group, prostate cancer risk was reduced in each lycopene quintile relative to men with low lycopene and placebo. The only other notable association was a reduced risk of aggressive cancer with higher alpha-tocopherol levels that was not statistically significant. None of the associations for lycopene were confounded by age, smoking, body mass index, exercise, alcohol, multivitamin use, or plasma total cholesterol level. These results concur with a recent prospective dietary analysis, which identified lycopene as the carotenoid with the clearest inverse relation to the development of prostate cancer. The inverse association was particularly apparent for aggressive cancer and for men not consuming beta-carotene supplements. For men with low lycopene, beta-carotene supplements were associated with risk reductions comparable to those observed with high lycopene. These data provide further evidence that increased consumption of tomato products and other lycopene-containing foods might reduce the occurrence or progression of prostate cancer.

Pastori M, Pfander H, Boscoboinik D, Azzi A
Institute for Biochemistry and Molecular Biology, University of Bern, Bern, CH-3012, Switzerland.
Biochem Biophys Res Commun 1998 Sep 29;250(3):582-5

The effect of lycopene alone or in association with other antioxidants was studied on the growth of two different human prostate carcinoma cell lines (the androgen insensitive DU-145 and PC-3). It was found that lycopene alone was not a potent inhibitor of prostate carcinoma cell proliferation. However, the simultaneous addition of lycopene together with alpha-tocopherol, at physiological concentrations (less than 1 microM and 50 microM, respectively), resulted in a strong inhibitory effect of prostate carcinoma cell proliferation, which reached values close to 90 %. The effect of lycopene with alpha-tocopherol was synergistic and was not shared by beta-tocopherol, ascorbic acid and probucol.

Yoshizawa K, Willett WC, Morris SJ, Stampfer MJ, Spiegelman D, Rimm EB, Giovannucci E
Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
J Natl Cancer Inst 1998 Aug 19;90(16):1219-24

BACKGROUND: In a recent randomized intervention trial, the risk of prostate cancer for men receiving a daily supplement of 200 microg selenium was one third of that for men receiving placebo. By use of a nested case-control design within a prospective study, i.e., the Health Professionals Follow-Up Study, we investigated the association between risk of prostate cancer and prediagnostic level of selenium in toenails, a measure of long-term selenium intake.

METHODS: In 1986, 51,529 male health professionals aged 40-75 years responded to a mailed questionnaire to form the prospective study. In 1987, 33,737 cohort members provided toenail clippings. In 1988, 1990, 1992, and 1994, follow-up questionnaires were mailed. From 1989 through 1994, 181 new cases of advanced prostate cancer were reported. Case and control subjects were matched by age, smoking status, and month of toenail return. Selenium levels were determined by neutron activation. All P values are two-sided.

RESULTS: The selenium level in toenails varied substantially among men, with quintile medians ranging from 0.66 to 1.14 microg/g for control subjects. When matched case-control data were analyzed, higher selenium levels were associated with a reduced risk of advanced prostate cancer (odds ratio [OR] for comparison of highest to lowest quintile = 0.49; 95% confidence interval [CI] = 0.25-0.96; P for trend = .11). After additionally controlling for family history of prostate cancer, body mass index, calcium intake, lycopene intake, saturated fat intake, vasectomy, and geographical region, the OR was 0.35 (95% CI = 0.16-0.78; P for trend = .03).

CONCLUSIONS: Our results support earlier findings that higher selenium intakes may reduce the risk of prostate cancer. Further prospective studies and randomized trials of this relationship should be conducted.

Thompson Ian M(a); Coltman Charles A Jr; Crowley John
Dep. Surg., Brooke Army Med. Cent., 3851 Roger Brooke Dr., San Antonio, TX 78234-6200, USA
Prostate 33 (3):p217-221 Nov. 1, 1997

Background: A variety of innovative approaches to the prevention of prostate cancer are now available, including selenium, alpha tocopherol, dietary interventions, and vitamin D. Perhaps the most promising opportunity is based upon considerable evidence that cumulative androgen exposure of the prostate contributes to the age-related risk of prostate cancer.

Methods: The Prostate Cancer Prevention Trial has completed randomization of over 18,000 healthy men to either finasteride or placebo.

Conclusions: While the primary objective of this study is to determine whether finasteride can reduce the period prevalence of prostate cancer over a 7-year period, the biologic and data resources of this study will provide multiple opportunities to better understand this most common cancer in U.S. men.

Paubert-Braquet M; Cousse H; Raynaud JP; Mencia-Huerta JM; Braquet P
Bio-Inova Euro Lab Research Laboratories, Plaisir, France.
Eur Urol 1998;33(3):340-7

OBJECTIVE: To assess the effect of the lipidosterolic extract of Serenoa repens (LSESr) on in vitro cell proliferation in biopsies of human prostate

MATERIAL AND METHODS: Cell proliferation was assessed by incorporation of [3H]thymidine followed by historadiography.

RESULTS: Basic fibroblast growth factor (b-FGF) induced a considerable increase in human prostate cell proliferation (from +100 to +250%); the glandular epithelium was mainly affected, minimal labeling being recorded in the other regions of the prostate. Similar results were observed with epidermal growth factor (EGF), although the increase in cell proliferation was not recorded in some cases. Lovastatin, an inhibitor of hydroxymethylglutaryl coenzyme A, antagonized both the basal proliferation and the growth factor-stimulated proliferation of human prostate epithelium (EGF, mean inhibition approximately 80-95%; b-FGF, mean inhibition approximately 40-90%). Geraniol, a precursor of both farnesyl pyrophosphate and geranylgeranyl pyrophosphate, and farnesol, the precursor of farnesyl pyrophosphate, increased cell proliferation only in some prostate specimens, this effect being antagonized by lovastatin. LSESr did not affect basal prostate cell proliferation, with the exception of two prostate specimens in which a significant inhibition of basal proliferation was observed with the highest concentration of LSESr (30 micrograms/ ml). In contrast, LSESr inhibited b-FGF-induced proliferation of human prostate cell cultures; this effect was significant for the highest concentration of LSESr (30 micrograms/ml). In some prostate samples, a similar inhibition was also noted with lower concentrations. Unsaturated fatty acids (UFA), in the range 1-30 ng/ml), did not affect the basal prostate cell proliferation, only a slight increase in cell proliferation was noted in 1 prostate specimen. UFA (1, 10 or 30 micrograms/ml) markedly inhibited the b-FGF-induced cell proliferation down to the basal value. Lupenone, hexacosanol and the unsaponified fraction of LSESr markedly inhibited the b-FGF-induced cell proliferation, whereas a minimal effect on basal cell proliferation was noted.

CONCLUSIONS: Despite the large variability in the response of the prostate samples to b-FGF, these results indicate that LSESr and its components affect the proliferative response of prostate cells to b-FGF more than their basal proliferation.

Breza J; Dzurny O; Borowka A; Hanus T; Petrik R; Blane G; Chadha-Boreham H
Department of Urology, University Hospital, Bratislava, Slovak Republic.
Curr Med Res Opin (ENGLAND) 1998, 14 (3) p127-39

Pygeum africanum extract is available as Tadenan in many countries, including those in central and eastern Europe, for the treatment of mild to moderate BPH. Its efficacy and acceptability have been demonstrated in numerous open and placebo-controlled studies in large populations. The present open three-centre efficacy and safety study was conducted according to common protocol at urology clinics in the Czech and Slovak Republics and in Poland, in order to confirm the therapeutic profile of Pygeum africanum in conditions of daily practice, using International Prostate Symptom Score (IPSS) and flowmetry assessments. Men aged 50-75 years and in compliance with the selection criteria (including IPSS > or = 12, quality of life (QoL) score > or = 3, and maximum urinary flow < or = 15 ml/s) were first examined then recalled after two weeks during which no treatment was provided (washout and check of stability). If still compliant, they were entered at this point into a two-month period of treatment with Pygeum africanum extract 50 mg twice daily. There followed a further one-month period without treatment, the objective being to evaluate the persistence of any effects observed during the previous two months of Pygeum africanum administration. The primary efficacy parameter investigated was IPSS; the other efficacy parameters were QoL, nocturnal frequency, maximum urinary flow, average urinary flow, post-voiding residual volume and prostatic volume, after one and two months of Pygeum africanum treatment and one month after stopping treatment. A total of 85 patients were evenly distributed between the three centres and completed the entire study. At inclusion their mean IPSS was 16.17, QoL was 3.60 and nocturia was 2.6 times per night. The changes in subjective scores, IPSS and QoL after the two-month treatment period were highly statistically significant with mean improvements of 40% and 31%, respectively. Nocturnal frequency was reduced by 32% and the mean reduction was again highly statistically significant. Mean maximum urinary flow, average urinary flow and urine volume were also statistically significantly improved, but the modest improvement in post-voiding volume did not reach statistical significance. The improvements, which exceeded those observed with placebo in earlier studies, were maintained after one month without treatment indicating an interesting persistence of clinically useful activity. Prostatic volume and quality of sexual life remained unchanged throughout. No treatment-related adverse effects were observed. In conclusion, under conditions of daily practice, Pygeum africanum extract induces significant improvement in IPSS and uroflowmetry parameters. These positive effects are accompanied by a very satisfactory safety profile with the overall result of a substantial improvement in QoL.

Lowe F.C.; Dreikorn K.; Borkowski A.; Braeckman J.; Denis L.; Ferrari P.; Gerber G.; Levin R.; Perrin P.; Senge T.
Dr. F.C. Lowe, Department of Urology., St. Luke's/Roosevelt Hospital, 425 West 59th St., 3A, New York, NY 10019 United States
Prostate (United States) 1998, 37/3 (187-193)

BACKGROUND. In order to assess the efficacy of phytotherapeutic agents for the treatment of benign prostatic hyperplasia (BPH), a review of recently published double-blind placebo-controlled trials was undertaken.

METHODS. Only those studies reviewed by the Other Medical Therapies Committee of the Fourth International Consultation on BPH were included.

RESULTS. These studies suggest a possible benefit for the use of phytotherapeutic preparations in the treatment of BPH.

CONCLUSIONS. These studies need to be confirmed in larger long-term placebo-controlled studies in order to ascertain the true efficacy of these agents.

Desgrandchamps F.
Dr. F. Desgrandchamps, Department of Urology, Hopital Saint-Louis, 1 avenue Claude Vellefaux, F-75475 Paris Cedex 10 France
European Urology (EUR. UROL.) (Switzerland) 1997, 32/SUPPL. 1 (28-31)

Changing demography and expectations about maintaining quality of life mean that an increasing number of men will require treatment for benign prostatic hyperplasia (BPH). Many growth factors have a role in the development of BPH. Consequently growth factor antagonists offer an attractive therapeutic option. In double-blind randomised trials Tadenan(R), a drug known to have growth factor antagonist activity, conferred significant improvement of urinary symptoms, maximum flow rate and residual volume, with no serious side-effects. Therapeutic outcome could be enhanced in a number of ways including matching patients with particular cell type overgrowth for treatment with a growth factor antagonist specific for that cell type. Full exploitation of this approach awaits the development of less invasive means of determining the cell type affected.

Levin R.M.; Levin S.S.; Zhao Y.; Buttyan R.
Prof. R.M. Levin, Albany College of Pharmacy, Albany Medical College, Stratton VA Medical Center, 106 New Scotland Avenue, Albany, NY 12208-3492 United States
European Urology (Switzerland) 1997, 32/Suppl. 1 (15-21)

Bladder dysfunction secondary to benign prostatic hyperplasia (BPH) is a major affliction associated with ageing. As the disease slowly progresses, the bladder changes from a state of compensation to decompensation, in which there are severe, irreversible alterations in bladder function. Using a rabbit model of partial outlet obstruction we have identified three major cellular changes in the bladder which result from such obstruction. These include progressive denervation, mitochondrial dysfunction and disturbances of calcium storage and release from the sarcoplasmic reticulum. Our hypothesis is that outlet obstruction results in bladder hypertrophy which induces ischaemia. This leads to a release of intracellular calcium, leading to activation of specific enzymes and generation of free radicals. These then attack the membranes of nerves, sarcoplasmic reticulum and mitochondria. We have demonstrated that pretreatment of rabbits with Pygeum africanum extract (Tadenan(R)) significantly reduced the severity of both the contractile and metabolic dysfunctions induced by partial outlet obstruction. Our current hypothesis is that Tadenan(R) may either prevent the activation of degradative enzymes (or generation of free radicals), or protect the intracellular membranes against the destructive effects of free radicals or degredative enzymes. In conclusion, identifying cellular mechanisms responsible for bladder dysfunction induced by partial outlet obstruction provides new possibilities for non-surgical treatment of BPH. Our studies on Tadenan(R) support this concept that the bladder provides a novel target for therapeutic intervention.

Odenthal K.P.
K.P. Odenthal, Dept. Exp. Biology, Pharmacology, MADAUS AG, Ostmerheimerstr. 198, D-51109 Cologne Germany
Phytotherapy Research (United Kingdom) 1996, 10/Suppl. 1 (S141-S143)

The enlargement of prostate (BPH) is accompanied by urge, reduced urinary flow and increased residual urine volume. The etiology is not yet clear, though many results speak for hormonal imbalance. Several herbal drugs have been applied traditionally in the therapy of BPH, i.e., preparations of Cucurbita, Hypoxis, Pygeum, Urtica and from Sabal serrulata. Among the discussed mechanisms, phytosterols are considered as active and have been found in experimental as well as in clinical investigations to interfere with either reduction of testosterone to dihydrotestosterone, sexual hormone binding globulin, aromatization of testosterone or growth factors like EGF. Additional effects have been documented in experiments speaking for immunomodulation and anti-inflammatory qualities. We demonstrate that smooth muscle contraction of rat deferential duct, guinea-pig ileum and bladder is reduced by lipophilic extract of Sabal. Both noradrenaline-induced contractions of rat deferential duct as well as contractions elicited by electrical stimulation could be reduced concentration-dependently following addition of <= 0.33 mg/ml of lipophilic Sabal serrulata extract into the bath medium. Cumulative dosing of <= 0.15 mg/ml of Sabal extract antagonized in guinea-pig ileum and bladder smooth muscular tissue contracted in KCl salt solution. Sabal extract, in concentrations identical to those published for the so-called anti-androgenic and anti-inflammatory effects, is therefore characterized by alpha-adrenoceptor antagonistic as well as calcium blocking activities. Furthermore, these findings could explain the clinically demonstrated symptomatic relief or so called release of dynamic component of BPH.

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Andro M.-C.; Riffaud J.-P.
Laboratoires DEBAT, Medical Department, 153, Rue de Buzenval,92380 Garches France
Current Therapeutic Research - Clinical and Experimental (United States) 1995, 56/8 (796-817)

Pygeum africanum bark extract has been used to treat mild and moderate symptomatic benign prostatic hyperplasia (BPH) in France since 1969. The extract has several potentially relevant pharmacologic properties: modulation of age-related hypercontractility of the bladder detrusor muscle; anti-inflammatory activity, including inhibition of chemotactic activity of leukotrienes; inhibition of fibroblast proliferation; and improvement of prostatic histology and secretion. The constituents of the extract have a safe toxicologic profile, and some of them have anticarcinogenic and antimutagenic properties. Published clinical experience includes 2262 patients, of whom 452 received the active product in comparative studies. Global outcome scores are rated as good or better in at least half the patients in most studies. Objective parameters were measured in some open-label and all comparative studies and included maximum flow rate, voided volume, residual volume, nocturia, daytime frequency, and other symptoms. The placebo effect on these parameters was often large. Nonetheless, the majority of placebo-controlled studies, which compared changes from baseline in patients who received placebo versus patients who received P africanum extract, showed a statistically significant advantage for most objective parameters with the active compound. This finding was particularly true of more recent and larger studies. Clinical tolerability of the extract was excellent, with most studies reporting the complete absence of any adverse effects. Thus published clinical data from 2262 patients during the last 25 years show that P africanum bark extract is an effective and exceptionally well-tolerated treatment for mild and moderate symptomatic BPH. P africanum extract has a pharmacologic profile distinct from other classes of drugs now being proposed for BPH treatment (alpha-adrenoceptor antagonists and 5-alpha-reductase inhibitors). The recent resurgence of interest in nonsurgical treatments for this condition should prompt a reappraisal of P africanum extract, perhaps in comparative trials with these other drug classes.

Paubert-Braquet M.; Monboisse J.C.; Servent-Saez N.; Serikoff A.; Cave A. ; Hocquemiller R.; Dupont Ch.; Fourneau C.; Borel J.P.
Bio-Inova, Laboratoire de Recherche, 48-52, rue de la Gare,78370 Plaisir France
Biomedicine and Pharmacotherapy (France) 1994, 48/Suppl. 1 (43S-47S)

An extract of Pygeum africanum bark (Tadenan(R)) is prescribed for older men suffering from micturitional difficulties due to benign prostatic hyperplasia (BPH). Its mechanism of action is not completely understood. Basic fibroblast growth factor (bFGF) probably plays a role in the development of BPH. We have examined the effects of P africanum extract on basal cell proliferation and on the proliferation induced by bFGF, epidermal growth factor (EGF) and insulin-like growth factor-1 (IGF-1). The proliferation of 3T3 fibroblasts was measured by the incorporation of tritiated methylthymidine and staining nuclei with crystal violet. P africanum extract slightly inhibited the basal growth of fibroblasts. However, it had a much larger inhibitory effect on cell proliferation induced by bFGF with 0.5 mug/ml, and the effect was significant at 1 mug/ml. Pygeum africanum extract also inhibited cell proliferation induced with EGF, but to a lesser extent. This suggests that the therapeutic effect of P africanum extract may be partly due to inhibition of cell growth induced by certain growth factors.

Dutkiewicz S.; Kalczak M.
Department of Urology, Ministry of Internal Affairs, Central Clinical Hospital,Warsaw Poland
International Urology and Nephrology (Hungary) 1994, 26/4 (455-460)

Transvesical adenectomy was done in 60 men with prostatic adenomas, including 40 pretreated medically (20 with prazosin, 20 with Tadenan). The resected material was sampled for histologic examination. Glandular, smooth muscle and fibrotic tissues as well as inflammatory foci were assessed quantitatively by planimetry . No adenomas consisting solely of glandular hyperplasia were found. In adenomas from patients pretreated with prazosin smooth muscle tissue was predominant and postinflammatory lesions were the least frequently observed. In Tadenan-pretreated patients quantitative predominance of glandular and fibrotic tissues was found and smooth muscle constituted the smallest pair of the adenomas. Patients who had undergone surgery only had adenomas in which focal inflammation predominated.

Paubert-Braquet M.; Cave A.; Hocquemiller R.; Delacroix D.; Dupont C.; Hedef N.; Borgeat P.
BIO-INOVA Research Laboratories, 48-52 Rue de la Gare,F 78370 Plaisir France
Journal of Lipid Mediators and Cell Signalling (Netherlands) 1994, 9/3 (285-290)

Pygeum africanum extract has been used for more than 20 years in France in patients suffering from benign prostatic hypertrophy (BPH). The extract displays anti-inflammatory activity and inhibits bladder hyperreactivity during the above conditions. However, the mechanism of action of P. africanum extract has never been clearly resolved. It has been recently demonstrated that infiltration by inflammatory cells may be involved in the development of BPH. Certain of these cell types, such as macrophages, are known to produce chemotactic mediators including leukotrienes, and thus may contribute to the development of the disease. In order to investigate the potential effect of P. africanum extract on arachidonate metabolism, we examined its effect in vitro on leukotriene (LT) synthesis in human polymorphonuclear cells stimulated with the calcium ionophore A23187. Two formulations of the extract were tested, one dissolved in DMSO and one aqueous solution obtained after alkalinization (0.1 N; NaOH/acidification (0.1 N; HCl). Neither formulation had any effect on cell viability which was above 95% in both cases. P. africanum extract dissolved in DMSO significantly inhibited the production of 5-lipoxygenase metabolites (5-HETE, 20-COOH LTBinf 4, LTB4 and 20-OH LTBinf 4) at concentrations as low as 3 mug/ml (p < 0.01), while the same extract dissolved in NaOH/HCl only exhibited an inhibitory effect at 10 mug/ml (p < 0.01). This difference apparently reflects the greater solubility of the active components in the extract in DMSO. The ability of P. africanum to antagonize 5-lipoxygenase metabolite production may contribute, at least in part, to its therapeutic activity in inflammatory component of BPH.

Krzeski T.; Kazon M.; Borkowski A.; Witeska A.; Kuczera J.
Warsaw School of Medicine,Warsaw Poland
Clinical Therapeutics (United States) 1993, 15/6 (1011-1020)

The 134 patients (aged 53 to 84 years) with symptoms of benign prostatic hyperplasia were drawn from two medical centers in Warsaw. The patients were randomly assigned to receive two capsules of the standard dose of an urtica/pygeum preparation (300 mg of Urtica dioica root extract combined with 25 mg of Pygeum africanum bark extract) or two capsules containing half the standard dose twice daily for 8 weeks. After 28 days' treatment, urine flow, residual urine, and nycturia were significantly reduced in both treatment groups. After 56 days' treatment, further significant decreases were found in residual urine (half-dose group) and in nycturia (both groups). There were no between-group differences in these measures of efficacy. Five patients reported adverse effects of treatment; treatment was not discontinued in any patient because of side effects. It is concluded that half doses of the urtica/pygeum extract are as safe and effective as the recommended full doses.

Barlet A.; Albrecht J.; Aubert A.; Fischer M.; Grof F.; Grothuesmann H.G. ; Masson J.-C.; Mazeman E.; Mermon R.; Reichelt H.; Schonmetzler F.; Suhler A.
Laboratoires Debat, 60 Rue de Monceau,F-75008 Paris France
Wiener Klinische Wochenschrift (Austria) 1990, 102/22 (667-673)

The efficacy of an extract of Pygeum africanum in the treatment of micturitional disorders due to benign prostatic hyperplasia was tested in a multicentre double-blind trial versus placebo. Capsules containing 50 mg of Pygeum africanum extract or placebo were administered at a dosage of 1 capsule in the morning and 1 capsule in the evening over aperiod of 60 days. 263 patients were included in this study, which was carried out in 8 centres in Germany, France, and Austria. Evaluation was mainly based on quantitative parameters such as residual urine, uroflowmetry and the precise monitoring of diurnal and nocturnal pollakiuria. Treatment with the Pygeum africanum extract led to a marked clinical improvement: a comparison of the quantitative parameters showed a significant difference between the Pygeum africanum group and the placebo group with respect to therapeutic response. The characteristic subjective symptoms of micturitional disorders, which were evaluated by the patients in a qualitative manner, were also significantly improved by administration of Pygeum africanum extract. Overall assessment at the end of therapy, showed that micturition improved in 66% of the patients treated with Pygeum africanum extract, as compared with an improvement of 31% in the placebo group. The difference was significant at the statistical level of p < 0.001. During therapy with Pygeum africanum extract, gastrointestinal side effect occurred in 5 patients. Treatment was discontinued in three of those cases.

Carilla E.; Briley M.; Fauran F.; et al.
Centre de Recherches Pierre Fabre, 81106 Castres Cedex France
Journal of Steroid Biochemistry (United Kingdom) 1984, 20/1 (521-523)

The benign hyperplasia of the prostate is a manifestation of aging, involving the accumulation within the gland, of dihydrotestosterone, the probable mediator of the hyperplasia. Binding studies were performed on the cytosolic androgenic receptor of the rat prostate using (sup 3H)methyltrienolone as a ligand. The binding of (sup 3H)methyltrienolone at 5 nM, was inhibited by various drugs, such as methyltrienolone and cyproterone acetate. Permixon, a liposterolic extract of the plant, Serenoa Repens B, inhibits competitively the binding to the cytosolic receptor of the rat prostate. Various vegetable and mineral oils, the plant steroid: beta sitosterol and the antiprostatic drug: Tadenan, were all found to be inactive. The antiprostatic activity of Permixon shown in animal studies and controlled clinical trials, may thus result from a direct action at the cytosolic receptor.

Flamm J.; Kiesswetter H.; Englisch M.
Urol. Abt., Wilhelminenspit., Wien Austria
Wiener Klinische Wochenschrift (Austria) 1979, 91/18 (622-627)

Conservative therapy of benign prostatic hypertrophy comprises the administration of oestrogens, gestagens, androgens and anti-androgens. Phytodrugs, which contain an extract of Sabal serrulatum or Pygeum Africana as active substance are without side effects and are, therefore, being used increasingly. 74 patients with irritable or obstructive bladder symptoms due to benign prostatic hypertrophy were treated with a phytodrug (Sabal serrulatum) or with testosterone throughout a period of three months. In group one (20 patients given phytodrugs and 10 patients given testosterone) clinical symptoms and measurements of residual urine, residual urine quotient, bladder capacity, micturition pressure and maximum urethral closure pressure were recorded at the beginning and at the end of therapy. In group two 28 patients were treated with the phytodrug in the first and third months with an intervening placebo trial lasting four weeks and 16 patients were given testosterone. Clinical symptoms and uroflow and residual urine only were charted in this group. None of the patients in either group showed an improvement in the urodynamic parameters of obstruction, but all patients felt a subjective alleviation of their symptoms.

Goepel M; Hecker U; Krege S; Rubben H; Michel MC
Department of Urology, University of Essen, Germany.
mark.goepel@uni-essen.de
Prostate (United States) Feb 15 1999, 38 (3) p208-15

BACKGROUND: We wanted to test whether phytotherapeutic agents used in the treatment of lower urinary tract symptoms have alpha1-adrenoceptor antagonistic properties in vitro.

METHODS: Preparations of beta-sitosterol and extracts of stinging nettle, medicinal pumpkin, and saw palmetto were obtained from several pharmaceutical companies. They were tested for their ability to inhibit [3H]tamsulosin binding to human prostatic alpha1-adrenoceptors and [3H]prazosin binding to cloned human alpha1A- and alpha1B-adrenoceptors. Inhibition of phenylephrine-stimulated [3H]inositol phosphate formation by cloned receptors was also investigated.

RESULTS: Up to the highest concentration which could be tested, preparations of beta-sitosterol, stinging nettle, and medicinal pumpkin were without consistent inhibitory effect in all assays. In contrast, all tested saw palmetto extracts inhibited radioligand binding to human alpha1-adrenoceptors and agonist-induced [3H]inositol phosphate formation. Saturation binding experiments in the presence of a single saw palmetto extract concentration indicated a noncompetitive antagonism. The relationship between active concentrations in vitro and recommended therapeutic doses for the saw palmetto extracts was slightly lower than that for several chemically defined alpha1-adrenoceptor antagonists.

CONCLUSIONS: Saw palmetto extracts have alpha1-adrenoceptor-inhibitory properties. If bioavailability and other pharmacokinetic properties of these ingredients are similar to those of the chemically defined alpha1-adrenoceptor antagonists, alpha1-adrenoceptor antagonism might be involved in the therapeutic effects of these extracts in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction.

Bombardelli E.; Morazzoni P.
E. Bombardelli, Indena S.p.A., Scientific Department, Viale Ortles 12, 20139 Milan Italy
Fitoterapia (Italy) 1997, 68/5 (387-402)

U. dioica L. was used as medicinal plant since ancient times. Hydroalcoholic extract of the nettle root (Urticae radix) are currently used in the therapy of micturition disorders associated with slight and moderate BPH.

Gansser D.; Spiteller G.
Lehrstuhl Organische Chemie 1, Universitat Bayreuth, NW I,
Universitatsstrasse 30,D-95440 Bayreuth Germany
Planta Medica (Germany) 1995, 61/2 (138-140)

Methanolic extracts of stinging nettle (Urtica dioica L.) roots were investigated for aromatase inhibition. Enzyme inhibition was detected only after appropriate chromatographic separation. Inhibitory effects on aromatase could be demonstrated in vitro for a variety of compounds belonging to different classes. The following compounds developed weak to moderate activity: secoisolariciresinol (1), oleanolic and ursolic acid (2 and 3), (9Z,11E)-13-hydroxy-9,11-octadecadienoic acid (4), and 14-octacosanol (5). Inhibitory effects on aromatase have been known to date neither for pentacyclic triterpenes nor for secondary fatty alcohols. The potential physiological significance of the above findings is discussed. Compound 5 is a previously unknown constituent of plants.

Hirano T.; Homma M.; Oka K.
Dept. of Clinical Pharmacology, Tokyo College of Pharmacy, 1432-1 Horinouchi,Hachioji, Tokyo 192-03 Japan
Planta Medica (Germany) 1994, 60/1 (30-33)

The effects of organic-solvent extracts of Urtica dioica (Urticaceae) on the Nasup +,Ksup +-ATPase of the tissue of benign prostatic hyperplasia (BPH) were investigated. The membrane Nasup +,Ksup +-ATPase fraction was prepared from a patient with BPH by a differential centrifugation of the tissue homogenate. The enzyme activity was inhibited by 10sup -sup 4-10sup -sup 5 M of ouabain. The hexane extract, the ether extract, the ethyl acetate extract, and the butanol extract of the roots caused 27.6-81.5% inhibition of the enzyme activity at 0.1 mg/ml. In addition, a column extraction of stinging nettle roots using benzene as an eluent afforded efficient enzyme inhibiting activiry. Steroidal components in stinging nettle roots, such as stigmast-4-en-3-one, stigmasterol, and campesterol inhibited the enzyme activity by 23.0-67.0% at concentrations ranging from 10sup -sup 3-10sup -sup 6 M. These results suggest that some hydrophobic constituents such as steroids in the stinging nettle roots inhibited the membrane Nasup +,Ksup +-ATPase activity of the prostate, which may subsequently suppress prostate-cell metabolism and growth.

Yablonsky F; Nicolas V; Riffaud JP; Bellamy F
Laboratoires Debat, groupe Fournier, Garches, France.
J Urol; 157(6):2381-7 1997
[published erratum appears in J Urol 1997 Sep;158(3 Pt 1):889]

The effect of a Pygeum africanum extract (Tadenan) (Pa), used in the treatment of micturition disorders associated with BPH, has been examined on the proliferation of rat prostatic stromal cells stimulated by different growth factors. EGF, bFGF, and IGF-I but not KGF are mitogenic for prostatic fibroblasts in culture. Pygeum africanum inhibits both basal and stimulated growth with IC50 values of 4.5, 7.7 and 12.6 micrograms./ml. for EGF, IGF-I and bFGF, respectively, compared to 14.4 micrograms./ml. for untreated cells, the inhibition being stronger towards EGF. Pygeum africanum inhibited the proliferation induced by TPA or PDBu in a concentration-dependent manner with IC50 values of 12.4 and 8.1 micrograms./ml. respectively. The antiproliferative effects of Pa were not ascribed to cytotoxicity. These results show that Pygeum africanum is a potent inhibitor of rat prostatic fibroblast proliferation in response to direct activators of protein kinase C, the defined growth factors bFGF, EGF and IGF-I, and the complex mixture of mitogens in serum depending on the concentration used. PKC activation appears to be an important growth factor-mediated signal transduction for this agent. These data suggest that therapeutic effect of Pygeum africanum may be due at least in part to the inhibition of growth factors responsible for the prostatic overgrowth in man.

Casella G; Barbaro A
Clinica 'Villa S. Anna', Reggio Calabria, Italy
Arch Sci Med (Torino); 135(1):95-98 1978

A Chloroform extract of Pygeum africanum and mepartricin were used to treat 22 patients with prostatic hypertrophy. Both substances were active against urinary symptomatology, and the polyene also induced a significant decrease in prostate size. Excellent results were obtained in 77% of the patients. (6 Refs)

Thieblot L, Grizard G, Boucher D
Therapie (Paris) 32 (1). 1977 99-110.

In castrated rats, an extract of P. africanum (V 1326) stimulates the secretory activity of the prostate and seminals vesicles but it appears as an antagonist of testosterone in these organs. In castrated adrenalectomized rats, V 1326 stimulates the action of testosterone on target organs and increases pituitary gonadotropin content. The action of V 1326 stimulates the adrenals and pituitary.

Moyad MA
Section of Urology, University of Michigan, Ann Arbor 48109-0330, USA.
Semin Urol Oncol 1999 May;17(2):97-102

Population-based studies from around the world support the theory that soy products and their constituents, primarily the isoflavones or phytoestrogens, are partly responsible for the lower rates of certain chronic diseases in different areas of the world. Cardiovascular disease and hormonally induced cancers are just a few of the conditions lower in Asian countries that consume large quantities of soy per average person. Genistein, one of soy's individual phytoestrogens, has been found to inhibit numerous breast and prostate cancer cell lines. A limited amount of clinical evidence also points to a beneficial role of soy in reducing hormonal levels and exhibiting weak estrogen and antiestrogen-like qualities. Other phytoestrogens found in nature, such as lignans, may also have a future role in cancer. Collectively, these phytoestrogens, like genistein, have enough evidence to warrant their use in a number of clinical trials as a potential chemopreventive agent or adjunct to prostate cancer treatment.

Jacobsen BK, Knutsen SF, Fraser GE
Institute of Community Medicine, University of Tromso, Norway.
Cancer Causes Control 1998 Dec;9(6):553-7

OBJECTIVES: Recent experimental studies have suggested that isoflavones (such as genistein and daidzein) found in some soy products may reduce the risk of cancer. The purpose of this study was to evaluate the relationship between soy milk, a beverage containing isoflavones, and prostate cancer incidence.

METHODS: A prospective study with 225 incident cases of prostate cancer in 12,395 California Seventh-Day Adventist men who in 1976 stated how often they drank soy milk.

RESULTS: Frequent consumption (more than once a day) of soy milk was associated with 70 per cent reduction of the risk of prostate cancer (relative risk = 0.3, 95 percent confidence interval 0.1-1.0, p-value for linear trend = 0.03). The association was upheld when extensive adjustments were performed.

CONCLUSIONS: Our study suggests that men with high consumption of soy milk are at reduced risk of prostate cancer. Possible associations between soy bean products, isoflavones and prostate cancer risk should be further investigated.

Dalu A, Haskell JF, Coward L, Lamartiniere CA
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, 35294, USA.
Prostate 1998 Sep 15;37(1):36-43