[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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