Showing papers on "Testosterone published in 2010"

Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor

Abstract: Androgen receptor (AR) splice variants lacking the ligand binding domain (ARVs), originally isolated from prostate cancer cell lines derived from a single patient, are detected in normal and malignant human prostate tissue, with the highest levels observed in late stage, castration-resistant prostate cancer. The most studied variant (called AR-V7 or AR3) activates AR reporter genes in the absence of ligand and therefore, could play a role in castration resistance. To explore the range of potential ARVs, we screened additional human and murine prostate cancer models using conventional and next generation sequencing technologies and detected several structurally diverse AR isoforms. Some, like AR-V7/AR3, display gain of function, whereas others have dominant interfering activity. We also find that ARV expression increases acutely in response to androgen withdrawal, is suppressed by testosterone, and in some models, is coupled to full-length AR (AR-FL) mRNA production. As expected, constitutively active, ligand-independent ARVs such as AR-V7/AR3 are sufficient to confer anchorage-independent (in vitro) and castration-resistant (in vivo) growth. Surprisingly, this growth is blocked by ligand binding domain-targeted antiandrogens, such as MDV3100, or by selective siRNA silencing of AR-FL, indicating that the growth-promoting effects of ARVs are mediated through AR-FL. These data indicate that the increase in ARV expression in castrate-resistant prostate cancer is an acute response to castration rather than clonal expansion of castration or antiandrogen-resistant cells expressing gain of function ARVs, and furthermore, they provide a strategy to overcome ARV function in the clinic.

Prostate volume in testosterone‐treated and untreated hypogonadal men in comparison to age‐matched normal controls

Abstract: OBJECTIVE The potential use of testosterone preparations for substitution therapy for ageing men and for male contraception, in addition to the well established substitution therapy of male hypogonadism, make increased testosterone use likely. However, little clinical information is available on the effect of testosterone therapy on the prostate in hypogonadal men. DESIGN AND MEASUREMENTS In a controlled cross-sectional study, prostate volume measured by transrectal ultrasonography, serum levels of prostate-specific antigen (PSA) and sex hormones, and uroflow parameters were determined. PATIENTS Three groups of age-matched men were enrolled in the study: 47 newly diagnosed hypogonadal men before testosterone treatment, 78 hypogonadal men with at least 6 months of effective testosterone therapy and 75 normal men. RESULTS Regression analysis revealed a significant positive correlation of prostate volume with age in normal men and testosterone-treated hypogonadal men, whereas no significant correlation was detected in untreated hypogonadal men. Prostate volume was significantly lower in untreated hypogonadal men (12.2 (11.0-13.5) ml) (mean (95% confidence limits)) compared to both other groups. However, no significant difference in prostate volume was detected between testosterone-treated hypogonadal men (21.3 (19.9-22.8) ml) and normal men (22.9 (21.4-24.4) ml). Similar results were obtained for PSA with comparable values in the testosterone-treated hypogonadal men (0.98 (0.88-1.10) micrograms/l) and normal men (1.02(0.91-1.14) micrograms/l), and significantly lower concentrations in the untreated hypogonadal men (0.64 (0.55-0.73) micrograms/l). No differences in uroflow parameters were detected between the three study groups. CONCLUSIONS Effective testosterone treatment of hypogonadal men results in prostate volume and prostate-specific antigen levels comparable to age-matched normal men. Therefore, testosterone-induced prostate growth should not preclude hypogonadal men from testosterone substitution therapy.

Elevations in ostensibly anabolic hormones with resistance exercise enhance neither training-induced muscle hypertrophy nor strength of the elbow flexors

Abstract: The aim of our study was to determine whether resistance exercise-induced elevations in endogenous hormones enhance muscle strength and hypertrophy with training. Twelve healthy young men (21.8 +/- 1.2 yr, body mass index = 23.1 +/- 0.6 kg/m(2)) trained their elbow flexors independently for 15 wk on separate days and under different hormonal milieu. In one training condition, participants performed isolated arm curl exercise designed to maintain basal hormone concentrations (low hormone, LH); in the other training condition, participants performed identical arm exercise to the LH condition followed immediately by a high volume of leg resistance exercise to elicit a large increase in endogenous hormones (high hormone, HH). There was no elevation in serum growth hormone (GH), insulin-like growth factor (IGF-1), or testosterone after the LH protocol but significant (P < 0.001) elevations in these hormones immediately and 15 and 30 min after the HH protocol. The hormone responses elicited by each respective exercise protocol late in the training period were similar to the response elicited early in the training period, indicating that a divergent postexercise hormone response was maintained over the training period. Muscle cross-sectional area (CSA) increased by 12% in LH and 10% in HH (P < 0.001) with no difference between conditions (condition x training interaction, P = 0.25). Similarly, type I (P < 0.01) and type II (P < 0.001) muscle fiber CSA increased with training with no effect of hormone elevation in the HH condition. Strength increased in both arms, but the increase was not different between the LH and HH conditions. We conclude that exposure of loaded muscle to acute exercise-induced elevations in endogenous anabolic hormones enhances neither muscle hypertrophy nor strength with resistance training in young men.

Androgen action in the masculinization programming window and development of male reproductive organs.

Abstract: We have shown previously that deficient androgen action within a masculinization programming window (MPW; e15.5-e18.5 in rats) is important in the origin of male reproductive disorders and in programming male reproductive organ size, but that androgen action postnatally may be important to achieve this size. To further investigate importance of the MPW, we used two rat models, in which foetal androgen production or action was impaired during the MPW by exposing in utero to either di(n-butyl) phthalate (DBP) or to flutamide. Reduced anogenital distance (AGD) was used as a monitor of androgen production/action during the MPW. Offspring were evaluated in early puberty (Pnd25) to establish if reproductive organ size was altered. The testes, penis, ventral prostate (VP) and seminal vesicles (SV) were weighed and penis length measured. Both DBP and flutamide exposure in the MPW significantly reduced penis, VP and SV size along with AGD at Pnd25; AGD and organ size were highly correlated. In DBP-, but not flutamide-, exposed animals, testis weight was also reduced and correlated with AGD. Intratesticular testosterone was also measured in control and DBP-exposed males during (e17.5) or after (e21.5) the MPW and related to AGD at e21.5. To evaluate the importance of postnatal androgen action in reproductive organ growth, the effect of combinations of prenatal and postnatal maternal treatments on AGD and penis size at Pnd25 was evaluated. In prenatally DBP-exposed animals, further postnatal exposure to either DBP or flutamide significantly reduced AGD and penis size in comparison with prenatal DBP exposure alone. In comparison, rats exposed postnatally to testosterone propionate after prenatal vehicle-exposure showed considerable increase in these parameters vs. controls. In conclusion, we show that the size of all male reproductive organs is programmed by androgen exposure in the MPW, but that growth towards this size is dependent on androgen action postnatally.

Urinary Bisphenol A Concentrations in Relation to Serum Thyroid and Reproductive Hormone Levels in Men from an Infertility Clinic

Abstract: Human exposure to bisphenol A (BPA) is widespread. Animal studies have demonstrated that BPA can alter endocrine function, but human studies are limited. For the present study, we measured urinary BPA concentrations and serum thyroid and reproductive hormone levels in 167 men recruited through an infertility clinic. BPA was detected in 89% of urine samples with a median (range) of 1.3 (<0.4 - 36.4) ng/mL. In multivariable regression models adjusted for potential confounders, BPA concentrations in urine collected on the same day as a blood sample were inversely associated with serum levels of inhibin B and estradiol:testosterone ratio (E(2):T) and positively associated with follicle-stimulating hormone (FSH) and FSH:inhibin B ratio. Because BPA is metabolized quickly and multiple urine measures may better reflect exposure than a single measure, we also considered among a subset of the men the BPA concentrations in repeated urine samples collected weeks or months following serum sample collection. In these analyses, the effect estimates remained consistent for FSH and E(2):T but were somewhat weakened for inhibin B. In addition, we observed inverse relationships between urinary BPA concentrations and free androgen index (ratio of testosterone to sex hormone binding globulin), estradiol, and thyroid stimulating hormone. Our results suggest that urinary BPA concentrations may be associated with altered hormone levels in men, but these findings need to be substantiated through further research.

Histology of genital tract and breast tissue after long-term testosterone administration in a female-to-male transsexual population

Abstract: Growing evidence indicates that androgens play a positive role in follicle proliferation and growth. Hence, many authors have assumed that androgen supplementation in women with poor ovarian reserve might improve the number of antral follicles available for ovarian stimulation. As androgen administration may become more frequently used in reproductive medicine, this study aimed at describing the histological changes observed in the genital tract and the breast of female-to-male (FTM) transsexuals. A pathological analysis of the genital tract of 112 FTM subjects who were given androgen for at least 6 months before hystero-salpingo-oophorectomy was performed. In addition, 100 bilateral mastectomies were performed, allowing a study of the breast tissue. Mean ovarian volume was increased, with histological characteristics of polycystic ovaries (PCO), defined as >12 antral follicles per ovary, observed in 89 patients (79.5%). Endometrial atrophy was observed in 45%. Breast examination revealed marked reduction of glandular tissue and increase of fibrous connective tissue in 93%, without atypical hyperplasia or carcinoma. The present data confirms and expands the putative associations between long-term androgen administration and abnormalities in ovarian architecture with macroscopic and microscopic characteristics of PCO, increased risk of endometrial atrophy and fibrotic breast tissue with marked glandular reduction.

Evidence of Limited Contributions for Intratumoral Steroidogenesis in Prostate Cancer

Abstract: Androgen-deprivation therapy for prostate cancer (PC) eventually leads to castration-resistant PC (CRPC). Intratumoral androgen production might contribute to tumor progression despite suppressed serum androgen concentrations. In the present study, we investigated whether PC or CRPC tissue may be capable of intratumoral androgen synthesis. Steroidogenic enzyme mRNAs were quantified in hormonally manipulated human PC cell lines and xenografts as well as in human samples of normal prostate, locally confined and advanced PC, local nonmetastatic CRPC, and lymph node metastases. Overall, the majority of samples showed low or absent mRNA expression of steroidogenic enzymes required for de novo steroid synthesis. Simultaneous but low expression of the enzymes CYP17A1 and HSD3B1, essential for the synthesis of androgens from pregnenolone, could be detected in 19 of 88 patient samples. Of 19 CRPC tissues examined, only 5 samples expressed both enzymes. Enzymes that convert androstenedione to testosterone (AKR1C3) and testosterone to dihydrotestosterone (DHT; SRD5A1) were abundantly expressed. AKR1C3 expression was negatively regulated by androgens in the experimental models and was increased in CRPC samples. Expression of SRD5A1 was upregulated in locally advanced cancer, CRPC, and lymph node metastases. We concluded that intratumoral steroid biosynthesis contributes less than circulating adrenal androgens, implying that blocking androgen production and its intraprostatic conversion into DHT, such as via CYP17A1 inhibition, may represent favorable therapeutic options in patients with CRPC.

Alterations in cholesterol regulation contribute to the production of intratumoral androgens during progression to castration-resistant prostate cancer in a mouse xenograft model

Abstract: BACKGROUND Emerging evidence suggests that androgens and the androgen receptor (AR) are important mediators of castration-resistant prostate cancer (CRPC) progression. Increased expression of several enzymes responsible for cholesterol synthesis and conversion into downstream androgens has been documented in human CRPC tumors in comparison to primary tumors. Based on these observations it is hypothesized that cholesterol and its overall regulation within the cell are altered, thus modifying precursor levels for de novo androgen synthesis within the castrate tumoral environment. METHODS Tumoral steroid levels were assessed by LC-MS. Free and esterified cholesterol was quantified by LC-MS and a fluorescent assay. Gene and protein expression were assessed by RT-PCR and immunoblotting. RESULTS Herein, using a prostate cancer xenograft mouse model it is demonstrated by Western blot analysis that proteins responsible for cholesterol regulation (LDL-r, SR-B1, HMG-CoA reductase, ACAT1,2, ABCA1) are altered during disease progression to increase influx and synthesis of cholesterol as well as free cholesterol formation from cholesteryl ester stores. In turn this can provide increased amounts of precursor for intratumoral steroidogenesis after castration. Androgens- testosterone and dihydrotestosterone- coincidently increase at CRPC to physiologically relevant levels leading to the induction of AR expression and PSA production. Furthermore, cellular cholesterol homeostasis is maintained by increased cholesterol efflux at CRPC so that excess free cholesterol does not cause toxicity to the tumor cells. CONCLUSIONS Cellular cholesterol regulation processes are altered during progression to CRPC. Free cholesterol from increased biosynthesis or uptake is likely a precursor for intratumoral de novo androgen synthesis. Prostate 70: 390–400, 2010. © 2009 Wiley-Liss, Inc.

Testosterone supplementation reverses sarcopenia in aging through regulation of myostatin, c-Jun NH2-terminal kinase, Notch, and Akt signaling pathways.

Abstract: Aging in rodents and humans is characterized by loss of muscle mass (sarcopenia). Testosterone supplementation increases muscle mass in healthy older men. Here, using a mouse model, we investigated the molecular mechanisms by which testosterone prevents sarcopenia and promotes muscle growth in aging. Aged mice of 22 months of age received a single sc injection of GnRH antagonist every 2 wk to suppress endogenous testosterone production and were implanted subdermally under anesthesia with 0.5 or 1.0 cm testosterone-filled implants for 2 months (n = 15/group). Young and old mice (n = 15/group), of 2 and 22 months of age, respectively, received empty implants and were used as controls. Compared with young animals, a significant (P < 0.05) increase in muscle cell apoptosis coupled with a decrease in gastrocnemius muscles weight (by 16.7%) and muscle fiber cross-sectional area, of both fast and slow fiber types, was noted in old mice. Importantly, such age-related changes were fully reversed by higher dose (1 cm) of testosterone treatment. Testosterone treatment effectively suppressed age-specific increases in oxidative stress, processed myostatin levels, activation of c-Jun NH(2)-terminal kinase, and cyclin-dependent kinase inhibitor p21 in aged muscles. Furthermore, it restored age-related decreases in glucose-6-phosphate dehydrogenase levels, phospho-Akt, and Notch signaling. These alterations were associated with satellite cell proliferation and differentiation. Collectively these results suggest involvement of multiple signal transduction pathways in sarcopenia. Testosterone reverses sarcopenia through stimulation of cellular metabolism and survival pathway together with inhibition of death pathway.

The intracrine sex steroid biosynthesis pathways.

Abstract: There is an increasing number of differences reported between the steroidogenesis pathways described in the traditional literature related to gonadal steroidogenesis and the more recent observations achieved using new technologies, especially molecular cloning, pangenomic expression studies, precise quantification of mRNA expression using real-time PCR, use of steroidogenic enzymes stably transfected in cells, detailed enzymatic activity analysis in cultured cell lines and mass spectrometry analysis of steroids The objective of this chapter is to present steroidogenesis in the light of new findings that demonstrate pathways of biosynthesis of estradiol (E(2)) and dihydrotestosterone (DHT) from adrenal dehydroepiandrosterone (DHEA) in peripheral intracrine tissues which do not involve testosterone as intermediate as classically found in the testis and ovary Steroidogenic enzymes different from those of the ovary and testis act in a tissue-specific manner to catalyze the transformation of DHEA into active sex steroids These new pathways are especially important in post-menopausal women where all estrogens and practically all androgens are made at their site of action in peripheral tissues from DHEA, the precursor of adrenal origin In men, on the other hand, from 40 to 50% of androgens are made in peripheral tissues from adrenal DHEA, thus indicating the major importance of the intracrine pathways in both men and women We also examine the molecular evolution of steroidogenic enzymes which explains the major differences in steroid metabolism observed between laboratory animals and humans

Mechanisms behind estrogen's beneficial effect on muscle strength in females

Abstract: Muscle weakness ensues when serum testosterone declines with age in men. Testosterone's female counterpart, estrogen, also has been implicated in age-related strength loss, but these results are less conclusive. Our working hypothesis is that estrogens do benefit muscle strength, and that the underlying mechanism involves estrogen receptors to improve muscle quality more so than quantity.

A sex-specific role for androgens in angiogenesis

Abstract: Mounting evidence suggests that in men, serum levels of testosterone are negatively correlated to cardiovascular and all-cause mortality. We studied the role of androgens in angiogenesis, a process critical in cardiovascular repair/regeneration, in males and females. Androgen exposure augmented key angiogenic events in vitro. Strikingly, this occurred in male but not female endothelial cells (ECs). Androgen receptor (AR) antagonism or gene knockdown abrogated these effects in male ECs. Overexpression of AR in female ECs conferred androgen sensitivity with respect to angiogenesis. In vivo, castration dramatically reduced neovascularization of Matrigel plugs. Androgen treatment fully reversed this effect in male mice but had no effect in female mice. Furthermore, orchidectomy impaired blood-flow recovery from hindlimb ischemia, a finding rescued by androgen treatment. Our findings suggest that endogenous androgens modulate angiogenesis in a sex-dependent manner, with implications for the role of androgen replacement in men.

Sex Steroid Hormone Concentrations and Risk of Death in US Men

Abstract: The association of sex hormone levels with mortality over a median of 16 years of follow-up was evaluated in a prospective cohort study. The study included 1,114 US men who participated in phase 1 (1988-1991) of the Third National Health and Nutrition Examination Survey Mortality Study and had no history of cardiovascular disease or cancer at baseline. Multivariable adjusted hazard ratios for all-cause mortality associated with a decrease in hormone concentration equal to the difference between the 90th and 10th percentiles of the sex hormone distributions were estimated by using proportional hazards regression. The hazard ratios associated with low free testosterone and low bioavailable testosterone levels were 1.43 (95% confidence interval (CI): 1.09, 1.87) and 1.52 (95% CI: 1.15, 2.02), respectively, for follow-up between baseline and year 9; they were 0.94 (95% CI: 0.51, 1.72) and 0.98 (95% CI: 0.56, 1.72), respectively, for follow-up between year 9 and year 18. Men with low free and bioavailable testosterone levels may have a higher risk of mortality within 9 years of hormone measurement. Future studies should be conducted to fully characterize the association of low free and bioavailable testosterone concentrations and mortality in men and to describe the mechanism underlying the association.

Guidelines for the management of castrate-resistant prostate cancer

Abstract: Secondary hormonal manipulations In patients who develop CRPC and who are relatively asymptomatic, secondary hormonal treatments may be attempted. Level 2 Evidence, Grade C recommendation To date, no study of secondary hormone treatment has demonstrated benefits in terms of survival, but most trials have been smaller and heavily confounded by the future treatments used. In patients treated with luteinizing-hormonereleasing hormone agonist monotherapy or who have had an orchidectomy, total androgen blockade (TAB) with testosterone antagonists, such as bicalutamide, can offer PSA responses in 30% to 35% of patients. For patients who progress on ADT without evidence of distant metastases, it is suggested to screen them for bone metastases and to monitor them for visceral metastases/progression with abdomen and chest imaging. Exact timing of imaging may be modulated using PSA doubling time. Imaging techniques most commonly used include nuclear bone scans and abdominal computed tomography and chest X-ray. The role of magnetic resonance imaging and positron emission tomography is still unclear. For patients who have undergone TAB, the antiandrogen could be discontinued to exclude an antiandrogen withdrawal response (AAWD). The introduction or changes of an AA or the use of ketoconazole has been reported to have transient PSA reductions in about 30% of patients. 3 Level

Are There Any Sensitive and Specific Sex Steroid Markers for Polycystic Ovary Syndrome

Abstract: Context: Despite the high prevalence of hyperandrogenemia, the principal biochemical abnormality in women with polycystic ovary syndrome (PCOS), a definitive endocrine marker for PCOS has so far not been identified. Objective: To identify a tentative diagnostic marker for PCOS, we compared serum levels of sex steroids, their precursors, and main metabolites in women with PCOS and controls. Design and Methods: In this cross-sectional study of 74 women with PCOS and 31 controls, we used gas and liquid chromatography/mass spectrometry to analyze serum sex steroid precursors, estrogens, androgens, and glucuronidated androgen metabolites; performed immunoassays of SHBG, LH, and FSH; and calculated the LH/FSH ratio. Results: Androgens and estrogens, sex steroid precursors, and glucuronidated androgen metabolites were higher in women with PCOS than in controls. In multivariate logistic regression analyses, estrone and free testosterone were independently associated with PCOS. The odds ratios per sd increase were...

Effect of FSH on testicular morphology and spermatogenesis in gonadotrophin-deficient hypogonadal mice lacking androgen receptors

Abstract: FSH and androgen act to stimulate and maintain spermatogenesis. FSH acts directly on the Sertoli cells to stimulate germ cell number and acts indirectly to increase androgen production by the Leydig cells. In order to differentiate between the direct effects of FSH on spermatogenesis and those mediated indirectly through androgen action, we have crossed hypogonadal (hpg) mice, which lack gonadotrophins, with mice lacking androgen receptors (AR) either ubiquitously (ARKO) or specifically on the Sertoli cells (SCARKO). These hpg.ARKO and hpg.SCARKO mice were treated with recombinant FSH for 7 days and testicular morphology and cell numbers were assessed. In untreated hpg and hpg.SCARKO mice, germ cell development was limited and did not progress beyond the pachytene stage. In hpg.ARKO mice, testes were smaller with fewer Sertoli cells and germ cells compared to hpg mice. Treatment with FSH had no effect on Sertoli cell number but significantly increased germ cell numbers in all groups. In hpg mice, FSH increased the numbers of spermatogonia and spermatocytes, and induced round spermatid formation. In hpg.SCARKO and hpg.ARKO mice, in contrast, only spermatogonial and spermatocyte numbers were increased with no formation of spermatids. Leydig cell numbers were increased by FSH in hpg and hpg.SCARKO mice but not in hpg.ARKO mice. Results show that in rodents 1) FSH acts to stimulate spermatogenesis through an increase in spermatogonial number and subsequent entry of these cells into meiosis, 2) FSH has no direct effect on the completion of meiosis and 3) FSH effects on Leydig cell number are mediated through interstitial ARs.

Hypothesis: Kisspeptin Mediates Male Hypogonadism in Obesity and Type 2 Diabetes

Abstract: Hypogonadism occurs commonly in men with type 2 diabetes (T2DM) and severe obesity. Current evidence points to a decreased secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus and thereby decreased secretion of gonadotropins from the pituitary gland as a central feature of the pathophysiology in these men. Hyperglycaemia, inflammation, leptin and oestrogen-related feedback have been proposed to make aetiological contributions to the hypogonadotropic hypogonadism of T2DM. However, the neuroendocrine signals that link these factors with modulation of GnRH neurons have yet to be identified. Kisspeptins play a central role in the modulation of GnRH secretion and, thus, downstream regulation of gonadotropins and testosterone secretion in men. Inactivating mutations of the kisspeptin receptor have been shown to cause hypogonadotropic hypogonadism in man, whilst an activating mutation is associated with precocious puberty. Data from studies in experimental animals link kisspeptin expression with individual factors known to regulate GnRH secretion, including hyperglycaemia, inflammation, leptin and oestrogen. We therefore hypothesise that decreased endogenous kisspeptin secretion is the common central pathway that links metabolic and endocrine factors in the pathology of testosterone deficiency seen in men with obesity and T2DM. We propose that the kisspeptin system plays a central role in integrating a range of metabolic inputs, thus constituting the link between energy status with the hypothalamic-pituitary-gonadal axis, and put forward potential clinical studies to test the hypothesis.

Anabolic Processes in Human Skeletal Muscle: Restoring the Identities of Growth Hormone and Testosterone

Abstract: Testosterone supplementation acts via numerous mechanisms as a highly potent anabolic agent to skeletal muscle. Although growth hormone (GH) strongly affects collagen synthesis and lipolysis, as well as increasing lean body mass, it is not anabolic toward the contractile (ie, myofibrillar) muscle tissue in healthy individuals. However, there is a persistent belief (both in scientific literature and among recreational weightlifters) that exercise-induced release of GH and testosterone underpins muscular hypertrophy with resistance training. This is a premature assumption because although pharmacological GH supplementation can increase muscle strength or size in individuals with clinical GH deficiency, there is no evidence that transient exercise-induced changes in GH have the same effects in individuals with normal GH levels. Exercise paradigms are designed based on the assumption (not necessarily evidenced-based mechanisms) that GH and testosterone facilitate anabolic processes that lead to skeletal muscle protein accretion and hypertrophy. Our recent work disputes this assumption. Instead, our data indicate that exercise-induced hormonal elevations do not enhance intracellular markers of anabolic signaling or the acute postexercise elevation of myofibrillar protein synthesis. Furthermore, data from our training study demonstrate that exercise-induced increases in GH and testosterone availability are not necessary for and do not enhance strength and hypertrophy adaptations. Instead, our data lead us to conclude that local mechanisms that are intrinsic to the skeletal muscle tissue performing the resistive contractions (ie, weightlifting) are predominant in stimulating anabolism. The purpose of this article is 1) to provide a brief overview of the mechanisms of action of testosterone and GH; 2) to discuss the inability of physiological exercise-induced elevations in these hormones to have a measurable impact on skeletal muscle anabolism; and 3) to describe factors that we believe are more important for stimulating hypertrophy in human skeletal muscle. Clarifying both the role of hormones in regulating muscle mass as well as the underlying basis for adaptation of skeletal muscle to resistance exercise will hopefully enhance and support the prescription of resistance exercise as an integral component of a healthy lifestyle.