MALE HORMONE MODULATION
(Page 9)

Kley HK, Edelmann P, Kruskemper HL
Metabolism 1980 Oct;29(11):1041-5

Relationships between plasma sex hormones and different parameters of obesity (weight, ideal body weight [IBW], overweight, fat mass, and body surface) were investigated in 70 healthy nonobese and obese males, 20-40 yr of age and with a body weight of 85%-245% of IBW. Plasma sex hormones remained unaffected by weight up to approximately 160% of the IBW. Only in the massively obese subjects was plasma testosterone decreased to 40% of controls (from 6.2 to 2.5 ng/ml), whereas free testosterone remained almost constant. On the other hand, plasma estrone and estradiol exhibited significant increases in obese subjects, ranging from 31.5 +/- 52.3 +/- 5.8 pg/ml for estrone, and 25.4 +/- 5.4 increasing to 44.7 +/0 5.0 pg/ml for estradiol. Similarly, free estradiol was shown to significantly increase with obesity in men from 505 +/- 118 to 991 +/- 123 fg/ml (p < 0.001). The ratios of testosterone/androstenedione, as well as of estradiol/estrone, were not affected by obesity, suggesting that reduction of the 17-oxo-group of the steroids is not influenced by the amount of fat tissue. A significant (p < 0.001) correlation was found between IBW and estrone (r = 0.80) and estradiol (r = 0.75), as well as the ratios of estrone/androstenedione (r = 0.62) and estradiol/testosterone (r = 0.86). This is consistent in its evidence indicating that fat tissue may be able to aromatize androgens. In the obese subjects, there were significant correlations between plasma sex hormones (testosterone, estrone, estradiol, and free estradiol) and the parameters of obesity used. Among these, correlations were best with IBW, overweight, and fat mass (r = 0.74-0.89; p < 0.001); body weight and body surface were less favorable.

Killinger DW; Perel E; Daniilescu D; Kharlip L; Lindsay WR
Department of Medicine, University of Toronto, Canada.
Steroids (United States) Jul-Sep 1987, 50 (1-3) p61-72

The metabolism of androstenedione (A) to estrone (E1) and 5 alpha-reduced androgens was studied in stromal cells derived from human adipose tissue from different body sites. The tissue was obtained from non-obese patients undergoing cosmetic liposuction or at the time of surgery for reduction mammoplasty. The conversion of A to E1 per 1x 10(6) cells was between 6- and 30-fold greater in the upper thigh, buttock, and flank than in the abdomen. These differences were present in primary culture and persisted to at least the third subculture. Estrogen formation in breast adipose tissue was similar to that found in cells from abdominal fat. The formation of 5 alpha-reduced metabolites (5 alpha-androstenedione, androsterone, and dihydrotestosterone) varied from patient to patient but was similar in cells from different body sites. These studies show that the regional distribution of fat may influence the metabolism of androgens in adipose tissue, with upper body fat tending to form a lower ratio of estrogens to 5 alpha-reduced androgens than lower body fat.

Meikle AW, Stringham JD, Woodward MG, McMurry MP
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City.
Metabolism 1990 Sep;39(9):943-6

The effect of a fat-containing meal on plasma sex steroid concentrations was investigated in normal men. After an overnight fast on two separate occasions, subjects ingested a liquid meal containing either a nonnutritive sweetener (control), or isocaloric meals of mixed calorie sources with either high-fat content or mixed carbohydrate and protein with minimal fat. The order of the meals was alternated. Blood samples were collected at 15-minute intervals and pooled each hour. Sampling began at 7:00 AM and the test meal was ingested at 8:00 AM. Sex steroids, including estrone, estradiol, testosterone, and dihydrotestosterone (DHT), sex hormone-binding globulin (SHBG) capacity, free testosterone concentration, and luteinizing hormone (LH) were determined by either specific radioimmunoassay or dialysis. The fat-containing meal, but not the nonnutritive or mixed carbohydrate and protein meal, resulted in a significant (P less than .01) reduction in total and free testosterone. Estrogens and luteinizing hormone were unaffected by either meal. This is the first documentation, to our knowledge, of the acute effect of a fat-containing meal on sex steroid concentrations in blood. Our observations suggest that a fat-containing meal reduces testosterone concentrations without affecting luteinizing hormone. This might indicate that fatty acids modulate testosterone production by the testes.

Awad Atif B(a); Hartati Maria Sri; Find Carol S
15 Farber Hall, Univ. Buffalo, Buffalo, NY 14214-3000, USA
Journal of Nutritional Biochemistry 9 ( 12 ): p 712-717 Dec., 1998

The objective of the present study was to examine the metabolism of testosterone in rat tissues as influenced by dietary phytosterols. Testosterone metabolism includes reductions to more active metabolites or aromatization to estrogen . Both higher levels of androgens and estrogens are implicated as risk factors in the development of prostate cancer. Tissues studied included liver, testis, and prostate. Feeding 2% phytosterols with 0.2% cholic acid to rats for 22 days resulted in a 33% reduction in serum testosterone compared with controls, which received only 0.2% cholic acid in the diet. 5-alpha-Reductase was reduced by 41 to 44% and 33% in the liver and prostate, respectively. No effect of phytosterols was observed in the testis. Only aromatase activity of the prostate was reduced by 55% upon feeding phytosterols. It was concluded that dietary phytosterols may reduce the risk of prostate cancer by lowering the activities of the enzymes of testosterone metabolism.

Large D M; Anderson D C
Dep. Med., Hope Hosp., Salford M6 8HD, Lancas., Engl., UK.
Clin Endocrinology 11 (5). 1979. 505-522.

The possible mechanisms involved in the development of transient gynecomastia during male puberty were investigated by studying 24 h profiles of circulating androstenedione (Ao) and testosterone (T) and their estrogen pairs estrone (E1) and estradiol (E2), in 8 boys with simple delayed puberty, 11 boys with pubertal gynecomastia (3 of whom were re-tested after its spontaneous resolution) and 2 normal adult men. No differences were observed between the 24 h T and Ao profiles of pubertal boys with or without gynecomastia; the initial T rise was nocturnal, associated with sleep. Late in puberty daytime T levels also rise. A small rise in 24 h Ao was seen, but this was not closely related to the stage of puberty. The major new finding was that E2 and to a lesser extent E1 levels are high relative to T for prolonged periods of the afternoon and evening (when T levels are lowest) in male puberty. A frequent finding, seen only in boys with gynecomastia and one who later developed it, was of elevated and markedly fluctuating levels of plasma E2, and an absolute increase in the area under the 24 h E2 profile and between the E2 and T profiles. These fell towards normal in 3 boys who were re-tested after resolution of gynecomastia. In a minority of subjects T and E2 were quite closely correlated, suggesting that in them rapid aromatization of T was occurring within or outside the testis. Normal male puberty is associated with relative estrogen dominance particularly in the daytime. In boys with gynecomastia there is an addition often an absolute elevation of E2 with or without E1, while 24 h T levels are submaximal. Normal men probably require sustained adult circulating T levels to prevent their estrogens from stimulating breast development.

Gavaler JS; Van Thiel DH
Department of Medicine, University of Pittsburgh School of Medicine, PA 15213.
Alcohol Clin Exp Res (United States) Feb 1992, 16 (1) p87-92

The major source of endogenous estrogens in postmenopausal women is the aromatization of androgens to estrogens; because alcohol is known to increase aromatization, the relationship between moderate alcoholic beverage consumption and serum estradiol levels was evaluated in 128 normal postmenopausal women. Alcohol intake was based on a composite of self-report and food record information. Among the 78.8% of women reporting alcohol use, weekly intake was 4.8 +/- 0.6 drinks. Among abstainers, estradiol levels were 100.8 +/- 12.1 pmol/liter, significantly lower than in alcohol users, 162.6 +/- 11.9 pmol/liter. Significant bivariate correlations were found between the logarithm of estradiol and total weekly drinks. In multiple linear regression analyses inclusion of alcohol as a variable increased the amount of explained variation in estradiol. Similar findings were demonstrable when the crude estimator of aromatization, the estradiol:testosterone ratio logarithm was the dependent variable. Together, these findings suggest that moderate alcohol use is an important factor for postmenopausal estrogen status and may offer a partial explanation for the reported protective effect of moderate alcohol consumption with respect to postmenopausal cardiovascular disease risk. ( 51 Refs.)

Om Ae-Son; Chung Kyung-Won(a)
Dep. Anatomical Sci., Univ. Oklahoma Coll. Med., Oklahoma City, OK 73104, USA
Journal of Nutrition 126 ( 4 ): p 842-848 1996

We studied the effects of zinc deficiency on hepatic androgen metabolism and aromatization, androgen and estrogen receptor binding, and circulating levels of reproductive hormones in freely fed, pair-fed and zinc-deficient rats. Hepatic conversion of testosterone to dihydrotestosterone was significantly less, but formation of estradiol from testosterone was significantly greater in rats fed the zinc-deficient diet compared with freely fed and pair-fed control rats. There were significantly lower serum concentrations of luteinizing hormone, estradiol and testosterone in rats fed the zinc-deficient diet. No difference in the concentration of serum follicle-stimulating hormone was observed between the zinc-deficient group and either control group. Scatchard analyses of the receptor binding data showed a significantly higher level of estrogen receptor in zinc-deficient rats (36.6 +- 3.4 fmol/mg protein) than in pair-fed controls (23.3 +- 2.2 fmol/mg protein) and a significantly lower level of androgen binding sites in rats fed the zinc-deficient diet (6.7 +- 0.7 fmol/mg protein) than in pair-fed control rats (11.3 +- 1.2 fmol/mg protein). There were no differences in hepatic androgen and estrogen receptor levels between freely fed and pair-fed controls. These findings indicate that zinc deficiency reduces circulating luteinizing hormone and testosterone concentrations, alters hepatic steroid metabolism, and modifies sex steroid hormone receptor levels, thereby contributing to the pathogenesis of male reproductive dysfunction.

Bjorntorp P
Department of Medicine I, Sahlgren's Hospital, University of Goteborg, Sweden.
Nutrition (United States) Mar-Apr 1990, 6 (2) p131-7

The relation between obesity and noninsulin-dependent diabetes mellitus is established. The weak association between obesity and cardiovascular disease or stroke might be attributable to a risk present only in a subgroup of obesity patients. Recent prospective studies have shown such a group to be characterized by abdominal localization of adipose tissue, reviving old empiric observations of such links. The sex-linked adipose tissue distribution is probably dependent on a balance between glucocorticoids and sex steroid hormones. The former are active mainly on intraabdominal adipose tissues through the high density of a specific receptor expressing lipoprotein lipase activity. This effect is counteracted by female sex steroid hormones, mainly progesterone, which promote fat deposition in the gluteal-femoral regions, utilized mainly during pregnancy and lactation. Testosterone stimulates lipid mobilization through transcriptional expression of beta-adrenergic receptors via a specific androgen receptor and also inhibits lipoprotein lipase activity. Intraabdominal adipose tissues, drained by the portal vein, have a very sensitive lipolytic system in men, based on an increased beta-adrenoceptor activity. This is probably a testosterone effect via the mechanisms mentioned. With testosterone deficiency, these mechanisms are less active, permitting accumulation of fat that can be reversed by testosterone substitution. Abdominal distribution of fat in men thus is probably a sign of relative testosterone deficiency.

Slemenda CW, Longcope C, Zhou L, Hui SL, Peacock M, Johnston CC
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
J Clin Invest 1997 Oct 1;100(7):1755-9

The purpose of this study was to determine whether bone density in older men was associated with serum sex steroids or sex hormone binding globulin (SHBG). Bone density and sex steroids were measured in men over age 65 at 6-mo intervals for an average of 2.1 yr. Bone density was significantly positively associated with greater serum E2 concentrations (+0.21 < r < +0.35; 0.01 < P < 0.05) at all skeletal sites. There were weak negative correlations between serum testosterone and bone density (-0.20 < r < -0.28; 0.03 < P < 0.10) at the spine and hip. SHBG was negatively associated only with bone density in the greater trochanter (r = -0.26, P < 0.05). Greater body weight was associated with lower serum testosterone and SHBG, and greater E2. Because of these associations, regression models which adjusted for age, body weight, and serum sex steroids were constructed; these accounted for 10-30% of the variability in bone density, and showed consistent, significant positive associations between bone density and serum E2 concentrations in men, even after adjustments for weight and SHBG. These data suggest that estrogens may play an important role in the development or maintenance of the male skeleton, much as is the case for the female skeleton. These data also indicate that, within the normal range, lower serum testosterone concentrations are not associated with low bone density in men.

Arlt W, Haas J, Callies F, Reincke M, Hubler D, Oettel M, Ernst M, Schulte HM, Allolio B
Department of Endocrinology, Medical University Hospital Wuerzburg, Germany.
J Clin Endocrinol Metab 1999 Jun;84(6):2170-6

The most abundant human steroids, dehydroepiandrosterone (DHEA) and its sulfate ester DHEAS, may have a multitude of beneficial effects, but decline with age. DHEA possibly prevents immunosenescence, and as a neuroactive steroid it may influence processes of cognition and memory. Epidemiological studies revealed an inverse correlation between DHEAS levels and the incidence of cardiovascular disease in men, but not in women. To define a suitable dose for DHEA substitution in elderly men we studied pharmacokinetics and biotransformation of orally administered DHEA in 14 healthy male volunteers (mean age, 58.8 +/- 5.1 yr; mean body mass index, 25.5 +/- 1.5 kg/m2) with serum DHEAS concentrations below 4.1 micromol/L (1500 ng/mL). Diurnal blood sampling was performed on 3 occasions in a single dose, randomized, cross-over design (oral administration of placebo, 50 mg DHEA, or 100 mg DHEA). The intake of 50 mg DHEA led to an increase in serum DHEAS to mean levels of young adult men, whereas 100 mg DHEA induced supraphysiological concentrations [placebo vs. 50 mg DHEA vs. 100 mg DHEA; area under the curve (AUC) 0-12 h (mean +/- SD) for DHEA, 108 +/- 22 vs. 252 +/- 45 vs. 349 +/- 72 nmol/L x h; AUC 0-12 h for DHEAS, 33 +/- 9 vs. 114 +/- 19 vs. 164 +/- 36 micromol/L x h]. Serum testosterone and dihydrotestosterone remained unchanged after DHEA administration. In contrast, 17beta-estradiol and estrone significantly increased in a dose-dependent manner to concentrations still within the upper normal range for men [placebo vs. 50 mg DHEA vs. 100 mg DHEA; AUC 0-12 h for 17beta-estradiol, 510 +/- 198 vs. 635 +/- 156 vs. 700 +/- 209 pmol/L x h (P < 0.0001); AUC 0-12 h for estrone, 1443 +/- 269 vs. 2537 +/- 434 vs. 3254 +/- 671 pmol/L x h (P < 0.0001)]. In conclusion, 50 mg DHEA seems to be a suitable substitution dose in elderly men, as it leads to serum DHEAS concentrations usually measured in young healthy adults. The DHEA-induced increase in circulating estrogens may contribute to beneficial effects of DHEA in men.

Schottner M, Gansser D, Spiteller G
Lehrstuhl Organische Chemie I, Universitat Bayreuth, Germany.
Planta Med 1997 Dec;63(6):529-32

Polar extracts of the stinging nettle (Urtica dioica L.) roots contain the ligans (+)-neoolivil, (-)-secoisolariciresinol, dehydrodiconiferyl alcohol, isolariciresinol, pinoresinol, and 3,4-divanillyltetrahydrofuran. These compounds were either isolated from Urtica roots, or obtained semisynthetically. Their affinity to human sex hormone binding globulin (SHBG) was tested in an in vitro assay. In addition, the main intestinal transformation products of plant lignans in humans, enterodiol and enterolactone, together with enterofuran were checked for their activity. All lignans except (-)-pinoresinol developed a binding affinity to SHBG in the in vitro assay. The affinity of (-)-3,4-divanillyltetrahydrofuran was outstandingly high. These findings are discussed with respect to potential beneficial effects of plant lignans on benign prostatic hyperplasia (BPH).

Gansser D, Spiteller G
Lehrstuhl Organische Chemie I, Universitat Bayreuth, Bundesrepublik, Deutschland.
Z Naturforsch [C] 1995 Jan-Feb;50(1-2):98-104

A test system is described, which allows the search for compounds interfering with human sex hormone-binding globulin (SHBG) even in complex plant extracts. The method has been evaluated and applied to Urtica dioica root extracts. The lignan secoisolariciresinol (5) as well as a mixture of isomeric (11 E)-9,10,13-trihydroxy-11-octadecenoic and (10 E)-9,12,13-trihydroxy-10-octadecenoic acids (3 and 4, resp.) were demonstrated to reduce binding activity of human SHBG. Methylation of the mixture of 3 and 4 increased its activity about 10-fold.

Delos S; Carsol JL; Ghazarossian E; Raynaud JP; Martin PM
Laboratoire de Cancerologie Experimentale, Faculte de Medecine Secteur Nord, Marseille, France.
J Steroid Biochem Mol Biol (England) Dec 1995, 55 (3-4) p375-83

We compare testosterone (T) metabolism in primary cultures of epithelial cells and fibroblasts separated from benign prostate hypertrophy (BPH) and prostate cancer tissues. In all cultures, androstenedione (delta 4) formed by oxidation of T by 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) represented 80% of the metabolites recovered. The amounts of 5 alpha-dihydrotestosterone (DHT), formed by reduction of T by 5 alpha-reductase (5 alpha-R), were small: 5 and 2% (BPH) and 8 and 15% (adenocarcinoma) for epithelial cells and fibroblasts, respectively. Northern blot analysis of total RNA from epithelial cells (BPH or adenocarcinoma) attributed the reductive activity to the 5 alpha-reductase type 1 isozyme and oxidative activity to the 17 beta-HSD type 2. In cancer fibroblasts, only little 17 beta-HSD type 2 mRNA was detected. The 5 alpha-reductase inhibitors, 4-MA (17 beta-(N,N-diethyl)carbamoyl-4-methyl-4 -aza-5 alpha-androstan-3-one) and finasteride, inhibited DHT formation with a preferential action of 4-MA on epithelial cells (BPH or adenocarcinoma) and of finasteride on fibroblasts from adenocarcinoma. Neither inhibitor acted on delta 4 formation. On the other hand, the lipido-sterol extract of Serenoa repens (LSESr, Permixon) inhibited the formation of all the T metabolites studied [IC50 S = 40 and 200 micrograms/ml (BPH) and 90 and 70 micrograms/ml (adenocarcinoma) in epithelial cells and fibroblasts, respectively]. These results have important therapeutic implications when selecting appropriate treatment options for BPH.

Cooper CS, Perry PJ, Sparks AE, MacIndoe JH, Yates WR, Williams RD
Department of Urology, The University of Iowa, Iowa City, USA.
J Urol 1998 Feb;159(2):441-3

PURPOSE: We investigate and define the effects of exogenous testosterone on the normal prostate.

MATERIALS AND METHODS: A total of 31 healthy volunteers 21 to 39 years old were randomized to receive either 100, 250 or 500 mg. testosterone via intramuscular injection once a week for 15 weeks. Baseline measurements of serum testosterone, free testosterone and prostate specific antigen (PSA) were taken at week 1. Semen samples were also collected for PSA content and prostate volumes were determined by transrectal ultrasound before testosterone injection. Blood was then drawn every other week before each testosterone injection for the 15 weeks, every other week thereafter until week 28 and again at week 40. After the first 15 weeks semen samples were again collected, and prostate volumes were determined by repeat transrectal ultrasound.

RESULTS: Free and total serum testosterone levels increased significantly in the 250 and 500 mg. dose groups. No significant change occurred in the prostate volume or serum PSA levels at any dose of exogenous testosterone. Total semen PSA levels decreased following administration of testosterone but did not reach statistical significance.

CONCLUSIONS: Despite significant elevations in serum total and free testosterone, healthy young men do not demonstrate increased serum or semen PSA levels, or increased prostate volume in response to exogenous testosterone injections.

Cooper CS, MacIndoe JH, Perry PJ, Yates WR, Williams RD
Department of Urology, University of Iowa, Iowa City, USA.
J Urol 1996 Aug;156(2 Pt 1):438-41; discussion 441-2

PURPOSE: We evaluated the effect of exogenous testosterone administration on serum total and free prostate specific antigen (PSA) in healthy young men.

MATERIALS AND METHODS: Nine volunteers received either 100, 250 or 500 mg. testosterone by intramuscular injection each week for 15 weeks. Blood was drawn every other week for 28 weeks and at week 40. Serum total and free PSA, and total and free testosterone were measured and compared to baseline values.

RESULTS: Significant elevations in total and free testosterone occurred but no significant change in serum total and free PSA was detected.

CONCLUSIONS: Serum PSA is not responsive to elevated serum testosterone levels in healthy young men. PSA metabolism in the normal prostate is unclear but our findings may have implications for differentiation of pathological conditions of the human prostate.

Wallace EM, Pye SD, Wild SR, Wu FC
MRC Reproductive Biology Unit, Edinburgh, Scotland, U.K.
Int J Androl 1993 Feb;16(1):35-40

Steroid regimens containing androgens are being evaluated currently as hormonal contraceptives for men. The possible non-reproductive effects of such treatment were assessed during an efficacy trial using a prototype regime of 200 mg testosterone enanthate i.m. weekly. Prostatic function and size were monitored by regular rectal examination, blood levels of prostate-specific androgen (PSA) were measured in 30 men and prostatic size was measured by trans-rectal ultrasound imaging in a representative subgroup of five subjects for 12 months and for a further 6 months after discontinuation. Despite the sustained rise in serum levels of testosterone, oestradiol and dihydrotestosterone during treatment, there was no detectable increase in prostatic size on rectal examination or any significant change in blood concentrations of PSA. A small but significant increase (14.3 +/- 2.0%) in maximal prostate transverse area was observed in four men while the remaining one showed no change. Our preliminary data demonstrate the feasibility and importance of monitoring prostatic function in the development of androgen-containing male hormonal contraceptives.

Meikle AW, Arver S, Dobs AS, Adolfsson J, Sanders SW, Middleton RG, Stephenson RA, Hoover DR, Rajaram L, Mazer NA
Department of Medicine, University of Utah, Salt Lake City 84132, USA.
Urology 1997 Feb;49(2):191-6

OBJECTIVES: This study examined the effects of testosterone replacement using a nonscrotal testosterone transdermal (TTD) system on prostate size and prostate-specific antigen (PSA) levels in hypogonadal men.

METHODS: As part of an open-label, multicenter study, prostate volume as measured by transrectal ultrasound and PSA were assessed in 29 hypogonadal men during treatment with intramuscular testosterone enanthate (+TE), followed by 8 weeks of androgen withdrawal (-T), and then during 1 year of therapy with Androderm Testosterone Transdermal System, a nonscrotal permeation-enhanced TTD system (+TTD).

RESULTS: Mean prostate volume decreased significantly from the +TE period (17 g) compared with the -T period (14 g) (P < 0.001). Prostate volume increased significantly from the -T period compared with the +TTD period (18 g) (P < 0.001). Maximum prostate size, comparable to that measured during +TE (P = 0.125), was reached by month 3 of +TTD therapy; prostate volume did not increase further during the remaining 9 months of +TTD therapy. Prostate volume correlated with age (P < 0.01) during all three periods of observation (+TE: r = 0.69; -T: r = 0.64; and +TTD: r = 0.55). No patient developed symptomatic benign prostatic hyperplasia during the treatment period. PSA levels decreased during androgen withdrawal compared with levels measured during +TE treatment (P < 0.001) and rose with resumption of androgen therapy with TTD (P < 0.006). However, PSA levels during +TTD replacement remained significantly lower (P < 0.001) than during +TE replacement.

CONCLUSIONS: Physiologic testosterone replacement in hypogonadal men was achieved using the TTD system. Prostate size during therapy with TTD was comparable to that reported for normal men. In these men treated with TTD, PSA levels were also within the normal range.

King DS, Sharp RL, Vukovich MD, Brown GA, Reifenrath TA, Uhl NL, Parsons KA
Department of Health and Human Performance, Iowa State University, Ames 50011, USA.
dsking@iastate.edu
JAMA 1999 Jun 2;281(21):2020-8

CONTEXT: Androstenedione, a precursor to testosterone, is marketed to increase blood testosterone concentrations as a natural alternative to anabolic steroid use. However, whether androstenedione actually increases blood testosterone levels or produces anabolic androgenic effects is not known.

OBJECTIVES: To determine if short- and long-term oral androstenedione supplementation in men increases serum testosterone levels and skeletal muscle fiber size and strength and to examine its effect on blood lipids and markers of liver function.

DESIGN AND SETTING: Eight-week randomized controlled trial conducted between February and June 1998.

PARTICIPANTS: Thirty healthy, normotestosterogenic men (aged 19-29 years) not taking any nutritional supplements or androgenic-anabolic steroids or engaged in resistance training.

INTERVENTIONS: Twenty subjects performed 8 weeks of whole-body resistance training. During weeks 1, 2, 4, 5, 7, and 8, the men were randomized to either androstenedione, 300 mg/d (n = 10), or placebo (n = 10). The effect of a single 100-mg androstenedione dose on serum testosterone and estrogen concentrations was determined in 10 men.

MAIN OUTCOME MEASURES: Changes in serum testosterone and estrogen concentrations, muscle strength, muscle fiber cross-sectional area, body composition, blood lipids, and liver transaminase activities based on assessments before and after short- and long-term androstenedione administration.

RESULTS: Serum free and total testosterone concentrations were not affected by short- or long-term androstenedione administration. Serum estradiol concentration (mean [SEM]) was higher (P<.05) in the androstenedione group after 2 (310 [20] pmol/L), 5 (300 [30] pmol/L), and 8 (280 [20] pmol/L) weeks compared with resupplementation values (220 [20] pmol/L). The serum estrone concentration was significantly higher (P<.05) after 2 (153 [12] pmol/L) and 5 (142 [15] pmol/L) weeks of androstenedione supplementation compared with baseline (106 [11] pmol/L). Knee extension strength increased significantly (P<.05) and similarly in the placebo (770 [55] N vs 1095 [52] N) and androstenedione (717 [46] N vs 1024 [57] N) groups. The increase of the mean cross-sectional area of type 2 muscle fibers was also similar in androstenedione (4703 [471] vs 5307 [604] mm2; P<.05) and placebo (5271 [485] vs 5728 [451] mm2; P<.05) groups. The significant (P<.05) increases in lean body mass and decreases in fat mass were also not different in the androstenedione and placebo groups. In the androstenedione group, the serum high-density lipoprotein cholesterol concentration was reduced after 2 weeks (1.09 [0.08] mmol/L [42 (3) mg/dL] vs 0.96 [0.08] mmol/L [37 (3) mg/dL]; P<.05) and remained low after 5 and 8 weeks of training and supplementation.

CONCLUSIONS: Androstenedione supplementation does not increase serum testosterone concentrations or enhance skeletal muscle adaptations to resistance training in normotestosterogenic young men and may result in adverse health consequences.

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.

Chute CG, Baron JA, Plymate SR, Kiel DP, Pavia AT, Lozner EC, O'Keefe T, MacDonald GJ
Department of Medicine, Dartmouth-Hitchcock Medical Center, Hanover, New Hampshire 03756.
Am J Med 1987 Nov;83(5):853-9
Published erratum appears in Am J Med 1988 Jul;85(1):129

Previous investigators have found an increased risk of coronary heart disease in men with high levels of circulating estrogens. To elucidate further this relationship, a case-control study of atherosclerotic coronary artery disease (ASCAD) and sex hormones was undertaken in male patients. Hormone levels in men with severe ASCAD documented at angiography were compared with those in men found to be virtually free from disease and with those in a group of control subjects without signs or symptoms of ASCAD. Significantly lower total testosterone levels were observed among men with severe ASCAD compared with either control group; the free testosterone level was significantly lower than in angiographically disease-free control subjects. The same pattern of hormone levels persisted after control of covariates. Epidemiologic analysis demonstrated a fivefold decrease in risk for severe ASCAD between the lowest and the highest quartile of total testosterone. No overall pattern of association was seen between ASCAD and free or total estrogens.

Klaiber EL, Broverman DM, Haffajee CI, Hochman JS, Sacks GM, Dalen JE
Am J Med 1982 Dec;73(6):872-81

Serum estradiol and serum estrone levels were assessed in 29 men in 14 men in whom myocardial infarction was ruled out; in 12 men without apparent coronary heart disease but hospitalized in an intensive care unit; and in 28 men who were not hospitalized and who acted as control subjects. (The 12 men who were hospitalized but who did not have coronary heart disease were included to control for physical and emotional stress of a severe medical illness.) Ages ranged from 21 to 56 years. Age, height, and weight did not differ significantly among groups. Blood samples were obtained in the patient groups on each of the first three days of hospitalization. The serum estrone level was significantly elevated in all four patient groups when compared with that in the control group. Estrone level, then, did not differentiate patients with and without coronary heart disease. Serum estradiol levels were significantly elevated in the groups with myocardial infarction, unstable angina, and in the group in whom myocardial infarction was ruled out. However, estradiol levels were not significantly elevated in the group in the intensive care unit without coronary heart disease when compared to the level in the normal control group. Serum estradiol levels, then, were elevated in men with confirmed or suspected coronary heart disease but were not elevated in men without coronary heart disease even under the stressful conditions found in an intensive care unit. Serum estradiol levels were significantly and positively correlated (p less than 0.03) with serum total creatine phosphokinase levels in the patients with myocardial infarction. The five patients with myocardial infarction who died within 10 days of admission had markedly elevated serum estradiol levels. The potential significance of these serum estradiol elevations is discussed in terms of estradiol's ability to enhance adrenergic neural activity and the resultant increase in myocardial oxygen demand.

Lindholm J, Eldrup E, Winkel P
Department of Internal Medicine and Endocrinology, Herlev University Hospital, Copenhagen.
Dan Med Bull 1990 Dec;37(6):552-6

Several studies have reported high levels of oestrogens--especially oestradiol--in plasma in men surviving an acute myocardial infarction (AMI). We have measured plasma levels of the two major oestrogens, oestrone and oestradiol, for three days during the acute AMI and at three months after discharge. Patients admitted to a coronary care unit with ischaemic heart disease without proof of an infarction and patients without evidence of heart disease served as controls. We found significantly higher oestrone levels during the acute infarction than at three months afterwards and also higher than in men without AMI. Men who died shortly after admission had grossly elevated plasma oestrone concentrations. As oestrone levels were correlated to excretion of catecholamines and cardiac enzyme levels in plasma and as circulating levels of oestrone are influenced by ACTH, the hyperoestronaemia may reflect stress-induced increased adrenocortical activity. Plasma oestradiol concentrations in men with AMI decreased significantly during the first three days after admission. In men given no medication oestradiol concentrations did not differ significantly from those in the control groups. Three months after the infarction, the median plasma oestradiol (but not oestrone) concentrations were significantly elevated, but not if only data from men given no medication were considered.

Marques-Vidal P, Sie P, Cambou JP, Chap H, Perret B
MONICA-Observatoire Regional de la Sante de Midi-Pyrenees, INSERM U326, C.H.U. Purpan, Toulouse, France.
J Clin Endocrinol Metab 1995 Jun;80(6):1794-8

The relationships between plasminogen activator inhibitor (PAi) activity and lipoprotein(a) [Lp(a)] and insulin, testosterone, 17 beta-estradiol, and testosterone binding globulin (TEBG) were assessed in 42 myocardial infarction male patients and 74 healthy controls. Patients had higher levels of insulin than did controls (87 +/- 30 vs. 75 +/- 28 pmol/L, respectively; P < 0.04), and no differences were found in levels of PAi activity, testosterone, 17 beta-estradiol, and TEBG. Lp(a) levels greater than 0.3 g/L were more frequent in patients than in controls (P < 0.002). In all subjects, PAi activity levels were significantly and positively correlated with body mass index (r = 0.20, P < 0.05), triglycerides (r = 0.38, P < 0.0001), and insulin (r = 0.27, P < 0.005) and were negatively correlated with testosterone (r = -0.28, P < 0.005) and TEBG (r = -0.42, P < 0.001). Stepwise multiple regression analysis showed triglyceride, insulin, and TEBG levels to be significantly related to PAi activity. No significant correlations were found between Lp(a) levels and all hormonal variables studied and between Lp(a) and PAi activity (r = -0.06, P < 0.58). These results suggest that TEBG is significantly and independently related to PAi levels.

Lichtenstein MJ, Yarnell JW, Elwood PC, Beswick AD, Sweetnam PM, Marks V, Teale D, Riad-Fahmy D
Am J Epidemiol 1987 Oct;126(4):647-57

The relations between estradiol, testosterone, insulin, lipids, and prevalent ischemic heart disease were examined using the cross-sectional data from the Caerphilly Heart Disease Study, a cohort of 2,512 men (aged 45-59 years) surveyed between 1978 and 1982. Endogenous levels of estradiol were associated directly with high density lipoprotein (HDL) cholesterol (r = 0.106, p less than 0.001), but this relation was removed after adjustment for testosterone and insulin levels. Estradiol was not associated with prevalent ischemic heart disease. Endogenous levels of testosterone were associated directly with HDL cholesterol (r = 0.148, p less than 0.001) and inversely with triglyceride (r = -0.217, p less than 0.001). Persons with prevalent ischemic heart disease had significantly lower testosterone levels than persons without ischemic heart disease (mean levels 20.9 vs. 22.0 nmol/liter, p less than 0.01). These relations were confounded by associations with insulin. The associations between testosterone and the lipids persist after adjusting for body mass index, age, and insulin. The association between testosterone and prevalent ischemic heart disease was reduced after adjusting for insulin and/or triglyceride levels. The results suggest that insulin and testosterone may have an interdependent regulatory effect on lipid metabolism. The effect of testosterone on ischemic heart disease appears to be primarily mediated through its association with insulin. Future work on sex hormones and ischemic heart disease will need to account for the effects of insulin.

Aksut SV, Aksut G, Karamehmetoglu A, Oram E
Jpn Heart J 1986 Nov;27(6):825-37

The levels of serum estradiol, testosterone and progesterone were determined in 13 cases of acute myocardial infarction. Thirteen intensive care patients without coronary, hepatic or renal disease, 13 cases of unstable angina and 15 normal subjects. The patients were males ranging from 24 to 56 years of age, the average being 40.4 years. The levels of serum estradiol in the acute myocardial infarction and unstable angina groups were significantly higher than in the normal group, and no difference was found between the normal and intensive care patient. The testosterone levels were significantly lower in the acute myocardial infarction and unstable angina groups than in the normal group. Progesterone levels increased in acute myocardial infarction patients. The estradiol: testosterone ratio was considerably elevated in the acute phase of myocardial infarction, and in unstable angina patients. No difference was found between the intensive care patient and normal groups.

Tripathi Y, Hegde BM
Department of Physiology, Kasturba Medical College, Mangalore.
Indian J Physiol Pharmacol 1998 Apr;42(2):291-4

The present study examined serum testosterone and estradiol levels on the day of admission, 5th and on 10th day following acute myocardial infarction in men. Controls were matched for age and body mass index. Testosterone levels were low on the day of admission and remained statistically unchanged on 5th and 10th day as compared to controls. On the contrary, estradiol levels were significantly higher on the day of admission. A significant decrease in estradiol concentration in comparison to the levels on the day of admission was observed on 10th day post myocardial infarction. However, the estradiol levels on 10th day were significantly higher than control subjects. The results of the study suggest that in acute myocardial infarction, hyperestrogenemia is associated with hypotestosteronemia.

Small M, MacRury S, Beastall GH, MacCuish AC
University Department of Medicine, Royal Infirmary, Glasgow.
Q J Med 1987 Jul;64(243):617-23

Elevated oestradiol levels have been found in men with a previous myocardial infarction and it has been suggested that hyperoestrogenaemia may explain partly the increased risk of coronary heart disease in diabetes mellitus. Therefore we have measured concentrations of oestradiol and testosterone (the main substrate for oestradiol) in a group of diabetic men with a previous myocardial infarction (n = 15), a matched group of diabetic men without overt cardiovascular disease (n = 13) and a group of healthy, non-diabetic men (n = 15). The diabetics had elevated oestradiol levels (p less than 0.03) despite lower testosterone levels (p less than 0.02) compared with control subjects. In the diabetic patients, a correlation between oestradiol and testosterone was found (r = 0.55, p less than 0.02) which suggested that the elevated oestradiol levels were only partly derived from the aromatization of testosterone. There were no differences in oestradiol or testosterone levels between the two diabetic groups. This study has shown that endogenous hyperoestrogenaemia is a consistent finding in diabetic men, irrespective of whether they have or have not sustained a previous myocardial infarction. The source of the raised oestradiol levels is uncertain. It is unclear whether hyperoestrogenaemia can be regarded as a risk for myocardial infarction in diabetic men.

Phillips GB, Jing TY, Resnick LM, Barbagallo M, Laragh JH, Sealey JE
Department of Medicine, Columbia University College of Physicians and Surgeons, St Luke's-Roosevelt Hospital Center, New York, New York.
J Hypertens 1993 Jul;11(7):699-702

OBJECTIVE AND DESIGN: It has been hypothesized that risk factors for coronary heart disease in men are linked and that the underlying factor linking them may be an alteration in the sex hormone milieu. As a test of this hypothesis, sex hormones and fibrinogen, factor VII and plasminogen activator inhibitor (PAI-1), hemostatic factors recently shown to be risk factors for myocardial infarction, were measured in men with hypertension and in healthy control subjects.

RESULTS: The fasting serum testosterone and free testosterone levels were decreased and the plasma factor VII and PAI-1 levels increased in the men with hypertension.

CONCLUSION: These findings are consistent with the stated hypothesis.

Geisthovel W, Perschke B, von zur Muhlen A, Klein H
Z Kardiol 1979 Nov;68(11):776-83

In 18 males (age 49--79 yrs) without endocrine diseases, testosterone, free testosterone fraction, LH, FSH and cortisol (as indicator for stress) were determined in the early stage of an acute myocardia infarction. Blood was taken on admission as well as every 4 hours up to meanly 43 hours. The patients were separated in 2 groups for proving whether alterations of the parameters may depend on the severity of the myocardial infarction (group A=severe infarction; group B=not severe infarction). Testosterone showed a rapid decrease in the first 11 hours after admission, which continued less striking to the end of the investigation. Testosterone was significantly decreased in group A in comparison to group B. LH and FSH in both groups together were remarkably reduced during the whole time. Whereas group A demonstrated a tendency to decreased values in comparison to group B for LH, there were not any essential differences between the two groups for FSH. The free testosterone fraction was not altered. Cortisol in group A was twice as high as in group B during the entire investigation. The systolic pressure in group A was generally lower than in group B during the whole time. The results demonstrate an important reduction of the secretion of testosterone, LH and FSH during the early stage of the acute myocardial infarction. The testosterone suppression seems to be dependent on the severity of the myocardial infarction. These alterations may be caused by a general impaired perfusion as a consequence of myocardial infarction and a suppressive effect of increased cortisol values on testosterone levels.

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