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Current status of testosterone replacement therapy in men.

Winters SJ Department of Medicine, University of Pittsburgh Medical Center, Pa., USA. winters@med1.dept-med.pitt.edu Arch Fam Med 1999 May-Jun;8(3):257-63

Testosterone plays an essential role in the development of the normal male and in the maintenance of many male characteristics, including muscle mass and strength, bone mass, libido, potency, and spermatogenesis. Androgen deficiency occurs with disorders that damage the testes, including traumatic or surgical castration (primary testicular failure) or disorders in which the gonadotropin stimulation of the testes is reduced (hypogonadotropic hypogonadism). The clinical manifestations of androgen deficiency depend on the age at onset and the severity and duration of the deficiency. In adult males, these manifestations may include reduced body hair, decreased muscle mass and strength, increased fat mass, decreased hematocrit, decreased libido, erectile dysfunction, infertility, osteoporosis, and depressed mood. The forms of androgen replacement currently available in the United States are intramuscular depot injections of testosterone esters, oral tablets of testosterone derivatives, and transdermal patches. For most patients, androgen replacement therapy with testosterone is a safe, effective treatment for testosterone deficiency.

Direct effects of estrogens on the endocrine function of the mammalian testis.

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.

Direct inhibitory effect of estrogen on the human testis in vitro.

Arch Androl 1988;20(2):131-5 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.

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.

The acute effect of estrogens on testosterone production appears not to be mediated by testicular estrogen receptors

Damber J E; 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.

The effect of testosterone aromatization on high-density lipoprotein cholesterol level and postheparin lipolytic activity.

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)

Effects of estradiol administration in vivo on testosterone production in two populations of rat Leydig cells

Keel B.A.; Abney T.O. Dep. Endocrinol., Med. Coll. Georgia, Augusta, GA 30912 United States Biochemical and Biophysical Research Communications ( Biochem. Biophys. Res. Commun. ) (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.

Tetrahydroisoquinoline alkaloids mimic direct but not receptor-mediated inhibitory effects of estrogens and phytoestrogens on testicular endocrine function. Possible significance for Leydig cell insufficiency in alcohol addiction.

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

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.

Fat tissue a steroid reservoir and site of steroid metabolism

Deslypere J P; Verdonck L; Vermeulen A Dep. of Endocrinology, Academic Hospital, Univ. of Ghent, B-9000 Ghent, Belgium. J Clin Endocrinol Metab 61 (3). 1985. 564-570.

Sex steroid concentrations and 17.beta.-hydroxysteroid dehydrogenase and aromatase activities were determined in fat tissue removed at surgery or, to allow comparisons in different sites, postmortem. Except for dehydroepiandrosterone (DHEA) sulfate (DHEAS), there existed a positive tissue/plasma gradient for all steroids studied (testosterone, androstenedione, DHEA, androstenediol, estrone and estradiol), suggesting androgen uptake and estrogen synthesis in situ. Androgen concentrations did not vary according to site of origin of fat tissue, except that the DHEAS concentration was significantly lower in abdominal s.c. and omental fat than in breast, pericardial, or sc pubic fat. Tissue androgen concentrations were positively correlated with their plasma concentrations, but tissue and plasma estrogen concentrations were not correlated. All tissue steroid concentrations, with the exception of estradiol in men, decreased with age. Aromatase activity [androstenedione .fwdarw. estrone; mean maximum velocity, 7.4 .+-. 3.7 (.+-. SD) fmol estrone/mg protein.cntdot.h] did not vary between sexes or with site of origin of fat tissue. 17.beta.-Hydroxysteroid dehydrogenase activity (estradiol .fwdarw. estrone, mean maximum velocity 9.8 .+-. 5.4 pmol/mg protein.cntdot.h) was higher in fat from women than in that from men, higher in premenopausal than in postmenopausal women, and higher in omental than in s.c. fat. Its activity was noncompetively inhibited in vitro by DHEA and DHEAS in near-physiological concentrations, and the enzyme activity was inversely correlated (P < 0.001) with the tissue DHEA and DHEAS concentrations. Apparently, fat tissue is an important steroid hormone reservoir; it is the site of active aromatase and 17.beta.-hydroxysteroid dehydrogenase; and tissue DHEA(S) may have a modulating effect on tissue estrogen production.

Treatment of men with idiopathic oligozoospermic infertility using the aromatase inhibitor, testolactone. Results of a double-blinded, randomized, placebo-controlled trial with crossover.

Clark RV, Sherins RJ Section of Internal Medicine, Emory University Clinic, Atlanta, Georgia 30322. Mt Sinai J Med 1997 Jan;64(1):20-5

The hypothesis that increased estradiol production may be the cause of impaired spermatogenesis in infertile men with idiopathic oligozoospermia was tested by administering the aromatase inhibitor, testolactone, and by assessing its effects on sperm output and fertility. Our study was a randomized, placebo-controlled double-blind crossover trial. Subjects (n = 25) with infertility due to unexplained oligozoospermia were given testolactone (2 g/day) or placebo for 8 months followed by crossover to the other treatment for an additional 8 months. Total estradiol and testosterone levels during testolactone exposure did not change from basal and placebo values. However, sex hormone-binding globulin binding capacity consistently decreased (30%, p less than 0.01) and free testosterone levels increased (36%, p less than 0.01). Free estradiol values increased but not significantly. Additionally, LH and FSH serum levels increased by 15% and 20%, respectively (p less than 0.05), and 17 alpha-hydroxyprogesterone values increased by 90% (p less than 0.05) during drug administration. Sperm output and semen quality remained unchanged during either testolactone or placebo treatment, and no pregnancies occurred during the 16-month study. These data suggest that chronic administration of testolactone at this dose fails to maintain aromatase inhibition despite depression of 17,20-desmolase activity with elevated 17 alpha-hydroxyprogesterone and depressed SHBG binding capacity with elevation of free testosterone. Testolactone is not efficacious in the treatment of idiopathic oligozoospermic infertility.

Clinical utility of sex hormone-binding globulin measurement.

Pugeat M, Crave JC, Tourniaire J, Forest MG Hospices Civils de Lyon, Laboratoire de la Clinique Endocrinologique, Hopital de l'Antiquaille, France. Horm Res 1996;45(3-5):148-55

The high-affinity binding of the sex hormone-binding globulin (SHBG) for testosterone and to a lesser extent for estradiol influences the circulating levels of these sex steroid hormones, their biodisposal to target cells as well as their mutual balance. Although the regulation of SHBG is still not completely understood, in vitro studies performed with human hepatocarcinoma (Hep G2) cells have shown that estrogens and thyroxine stimulate SHBG secretion, by increasing the steady state of its mRNA concentrations. These observations are in good agreement with studies showing that SHBG levels increase during oral administration of estrogens as well as in patients with thyrotoxicosis. Interestingly, SHBG levels are normal in syndromes such as the abnormal transport of thyroid hormones and/or the syndrome of thyroid hormone resistance, which can be confused with thyrotoxicosis. By contrast, the effects of androgens are controversial. In many patients with hirsutism, SHBG concentrations are low and correlate negatively with both body mass index and fasting insulin levels. Because of the inhibitory effect of both insulin and insulin-like growth factor-1 on SHBG secretion by Hep G2 cells in vitro, it has been proposed that SHBG levels could be a marker of insulin resistance and/or hyperinsulinism in humans. Furthermore, an increased risk for either noninsulin-dependent diabetes and/or the overall mortality are associated with decreased SHBG levels in postmenopausal women. Finally, in men, SHBG levels are positively correlated with the concentration of high-density lipoprotein cholesterol. Therefore, the measurement of SHBG in clinical practice can be a useful diagnostic tool for: (1) correctly interpretating testosterone and estradiol serum concentrations; (2) investigating androgen-estrogen balance in gonadal and sexual dysfunctions; (3) assessing the peripheral effect of the hormones which regulate SHBG productions, and (4) evaluating insulin resistance and cardiovascular risk.

Sex hormone binding globulin: origin, function and clinical significance.

Selby C Department of Clinical Chemistry, City Hospital, Nottingham, UK. Ann Clin Biochem 1990 Nov;27 ( Pt 6):532-41

Sex hormone binding globulin (SHBG) is a glycoprotein possessing high affinity binding for 17 beta-hydroxysteriod hormones such as testosterone and oestradiol. It is probably synthesized in the liver, plasma concentrations being regulated by, amongst other things, androgen/oestrogen balance, thyroid hormones, insulin and dietary factors, it is involved in transport of sex steroids in plasma and its concentration is a major factor regulating their distribution between the protein-bound and free states. Its detailed role in the delivery of hormones to target tissues is not yet clear. Plasma SHBG concentrations are affected by a number of different diseases, high values being found in hyperthyroidism, hypogonadism, androgen insensitivity and hepatic cirrhosis in men. Low concentrations are found in myxoedema, hyperprolactinaemia and syndromes of excessive androgen activity. Concentrations are also affected by drugs such as androgens, oestrogens, thyroid hormones and anti-convulsants. Measurement of SHBG is useful in the evaluation of mild disorders of androgen metabolism and enables identification of those women with hirsutism who are more likely to respond to oestrogen therapy. Testosterone:SHBG ratios correlate well with both measured and calculated values of free testosterone and help to discriminate subjects with excessive androgen activity from normal individuals.

Androgens, estrogens, and sex hormone-binding globulin in middle-aged men.

Longcope C, Goldfield SR, Brambilla DJ, McKinlay J Department of Obstetrics and Gynecology, University of Massachusetts Medical School, Worcester 01655. J Clin Endocrinol Metab 1990 Dec;71(6):1442-6

Although the administration of estrogens and androgens can affect the concentrations of sex hormone-binding globulin (SHBG) in men, the relationships between endogenous estrogens and androgens and SHBG are uncertain. Therefore, in a randomly selected cohort of 1640 middle-aged men we measured androgen, estrogen, and SHBG concentrations and obtained the subjects' weight, ethanol intake, and smoking histories. The data were analyzed by stepwise multiple regression, with SHBG as the dependent variable, to compare the role of hormones with that of other factors in the control of SHBG levels. Neither estrone or estradiol nor the testosterone/estradiol ratio was predictive of SHBG levels. However, SHBG concentrations were positively correlated with total testosterone and negatively correlated with percent free and percent albumin-bound testosterone. SHBG concentrations were negatively correlated with estrone sulfate, but were positively correlated with the testosterone/estrone sulfate ratio and the concentrations of free and albumin-bound testosterone. In addition, in all models tested age and body mass index (wt/ht2), but not smoking or ethanol, were strong predictors of SHBG concentrations. Thus, when present in physiological amounts in the blood as a result of glandular secretion, there is a positive relationship between SHBG concentrations and testosterone and, to a lesser extent, free- and albumin-bound testosterone, but age and body mass index appear to be more important in predicting the SHBG concentration.

Sex hormone changes in male epileptics.

Toone BK, Wheeler M, Fenwick PB Clin Endocrinol (Oxf) 1980 Apr;12(4):391-5

Mean plasma levels of LH, FSH, PRL, and sex-hormone binding globulin (SHBG) were raised in twenty-seven epileptics on anticonvulsants compared with age matched controls. Sexual activity appeared to be reduced. Anticonvulsant therapy results in raised SHBG levels which may be associated with a lowered free testosterone level as indicated by raised LH levels and lowered sexual activity.

Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study.

Gray A, Feldman HA, McKinlay JB, Longcope C New England Research Institute, Watertown, Massachusetts 02172. J Clin Endocrinol Metab 1991 Nov;73(5):1016-25

To evaluate the hypothesis that endocrine profiles change with aging independently of specific disease states, we examined the age trends of 17 major sex hormones, metabolites, and related serum proteins in 2 large groups of adult males drawn from the Massachusetts Male Aging Study, a population-based cross-sectional survey of men aged 39-70 yr conducted in 1986-89. Group 1 consisted of 415 men who were free of obesity, alcoholism, all prescription medication, prostate problems, and chronic illness (cancer, coronary heart disease, hypertension, diabetes, and ulcer). Group 2 consisted of 1294 men who reported 1 or more of the above conditions. Each age trend was satisfactorily described by a constant percent change per yr between ages 39-70 yr. Free testosterone declined by 1.2%/yr, and albumin-bound testosterone by 1.0%/yr. Sex hormone-binding globulin (SHBG), the major serum carrier of testosterone, increased by 1.2%/yr, with the net effect that total serum testosterone declined more slowly (0.4%/yr) than the free or albumin-bound pools alone. Among the major androgens and metabolites, androstane-3 alpha,17 beta-diol (androstanediol; 0.8%/yr) and androstanediol glucuronide (0.6%/yr) declined less rapidly than free testosterone, while 5 alpha-dihydrotestosterone remained essentially constant between ages 39-70 yr. Androstenedione declined at 1.3%/yr, a rate comparable to that of free testosterone, while the adrenal androgen dehydroepiandrosterone (3.1%/yr) and its sulfate (2.2%/yr) declined 2-3 times more rapidly. The levels of testosterone, SHBG, and several androgen metabolites followed a parallel course in groups 1 and 2, remaining consistently 10-15% lower in group 2 across the age range of the study. Subgroup analyses suggested that obese subjects might be responsible for much of the group difference in androgen level. Serum concentrations of estrogens and cortisol did not change significantly with age or differ between groups. Of the pituitary gonadotropins, FSH increased at 1.9%/yr, LH increased at 1.3%/yr, and PRL declined at 0.4%/yr, with no significant difference between groups 1 and 2.

The influence of age, alcohol consumption, and body build on gonadal function in men.

Sparrow D, Bosse R, Rowe JW J Clin Endocrinol Metab 1980 Sep;51(3):508-12

Basal plasma levels of testosterone, dihydrotestosterone, estradiol, and gonadotropins and testosterone-binding capacity (percent radioactive testosterone bound to protein) were measured in health carefully screened young (31-44 yr old; n = 44) and older (64-88 yr old; n = 42) male participants in the Normative Aging Study of the V.A. There was no statistically significant effect of age on testosterone [younger group, 4.16 +/- 0.27 (SEM) ng/ml; older group, 4.62 +/- 0.32 (SEM) ng/ml] or the free testosterone index [younger group, 2.05 +/- 0.14 (SEM) ng/ml; older group, 1.76 +/- 0.11 (SEM) ng/ml]. The testosterone-binding capacity was higher in the older group (younger group, 50.10 +/- 1.18% (SEM); older group, 60.10 +/- 1.18% (SEM); P less than 0.001). Of the two products of testosterone metabolism studied, estradiol did not change with age, while dihydrotestosterone was lower [young group, 0.25 +/- 0.02 (SEM) ng/ml; older group, 0.20 +/- 0.01 (SEM) ng/ml; P = 0.03] in the older group. FSH levels were increased among the older men [older group, 92.9 +/- 6.0 (SEM) ng/ml; younger group, 61.1 +/- 5.0 (SEM) ng/ml; P less than 0.001]. LH levels were not significantly influenced by age. There was no effect of level of chronic stable alcohol intake on gonadal function, as estimated by testosterone levels and the free testosterone index. Analysis of the relationship between body build and hormone levels indicated that estradiol levels were highest in gynandromorphic men and lowest in mesomorphic men.

Serum testosterone and sex hormone-binding globulin concentrations and the risk of prostate carcinoma: a longitudinal study.

Heikkila R, Aho K, Heliovaara M, Hakama M, Marniemi J, Reunanen A, Knekt P Kanta-Hame Central Hospital, Hameenlinna, Finland. Cancer 1999 Jul 15;86(2):312-5

BACKGROUND: It has been hypothesized that high androgen levels are determinants of prostate carcinoma. METHODS: Serum concentrations of testosterone, sex hormone-binding globulin (SHBG), and androstenedione were analyzed to determine their role as predictors of prostate carcinoma in a longitudinal, population-based, nested case-control study. The serum concentrations of testosterone, SHBG, and androstenedione were determined from serum samples collected by the Finnish Mobile Clinic Health Examination Survey between 1968-1972 and stored at -20 degrees C. During a follow-up period of 24 years, a total of 166 prostate carcinoma cases occurred among men who originally were cancer free. Two controls (matched for age and municipality) were chosen. RESULTS: There was no association between serum testosterone, SHBG, or androstenedione concentrations and the occurrence of subsequent prostate carcinoma in the total study population or in subgroups determined based on age or body mass index. The association was not strengthened by simultaneous adjustment for the hormonal variables. CONCLUSIONS: The results of the current study do not appear to corroborate the hypothesis that serum testosterone, SHBG, or androstenedione are determinants of the subsequent occurrence of prostate carcinoma.

Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age.

Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, Lenrow DA, Holmes JH, Dlewati A, Santanna J, Rosen CJ, Strom BL Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-6087, USA. J Clin Endocrinol Metab 1999 Aug;84(8):2647-53

As men age, serum testosterone concentrations decrease, the percentage of body mass that is fat increases, the percentage of lean body mass decreases, and muscle strength decreases. Because these changes are similar to those that occur in hypogonadal men, we hypothesized that increasing the serum testosterone concentration of men over 65 yr of age to that in young men would decrease their fat mass, increase their lean mass, and increase their muscle strength. We randomized 108 men over 65 yr of age to wear either a testosterone patch or a placebo patch in a double blind study for 36 months. We measured body composition by dual energy x-ray absorptiometry and muscle strength by dynamometer before and during treatment. Ninety-six men completed the entire 36-month protocol. Fat mass decreased (-3.0+/-0.5 kg) in the testosterone-treated men during the 36 months of treatment, which was significantly different (P = 0.001) from the decrease (-0.7+/-0.5 kg) in the placebo-treated men. Lean mass increased (1.9+/-0.3 kg) in the testosterone-treated men, which was significantly different (P < 0.001) from that (0.2+/-0.2 kg) in the placebo-treated men. The decrease in fat mass in the testosterone-treated men was principally in the arms (-0.7+/-0.1 kg; P < 0.001 compared to the placebo group) and legs (-1.1+/-0.2 kg; P < 0.001), and the increase in lean mass was principally in the trunk (1.9+/-0.3 kg; P < 0.001). The change in strength of knee extension and flexion at 60 degrees and 180 degrees angular velocity during treatment, however, was not significantly different between the two groups. We conclude that increasing the serum testosterone concentrations of normal men over 65 yr of age to the midnormal range for young men decreased fat mass, principally in the arms and legs, and increased lean mass, principally in the trunk, but did not increase the strength of knee extension and flexion, as measured by dynamometer.

Approaches to prostatic cancer chemotherapy using the Dunning R3327H prostatic adenocarcinoma.

Padilla GM, Petrow V, Marts SA, Mukherji S Prostate 1985;6(2):129-43

Androgen-responsive cells: To determine if testosterone or dihydrotestosterone is the main trophic hormone of prostatic adenocarcinoma, we have treated Dunning R3327H prostatic adenocarcinoma-bearing rats with 6-methylene progesterone, which blocks conversion of testosterone to dihydrotestosterone. Copenhagen-Fisher rats were treated with steroid (20 mg/Kg daily) immediately following implantation of tumor and thereafter for 117 days. There was a 92% inhibition of growth of tumors and a lesser effect upon prostate and seminal vesicles. Tumor-free body weights remained unchanged. Both treated and untreated tumors had equivalent DNA content on a per weight basis. This result supports the thesis that prostatic adenocarcinoma requires dihydrotestosterone for growth. Androgen-insensitive cells: Advanced prostate cancer does not respond to endocrine therapy but is temporarily controlled by the cytotoxic steroid estramustine. The latter shows significant selective binding to prostatic protein. To develop chemotherapeutic agents that will control androgen-insensitive cells and possess improved selectivity for prostatic protein, we have studied a number of steroids for their ability to displace 3H-labeled estramustine from prostatic cytosolic proteins. Surprisingly, a carbamido substituent at the C17 position was found to confer significant binding affinity for prostatic estramustine-binding protein. Extension of this structural characteristic to the estramustine type of molecule is being studied.

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Endocrine News;1996, Vol 21, No. 3, p-2