Daily Oral Administration of the Novel Androgen 11ß-MNTDC Markedly Suppresses Serum Gonadotropins in Healthy Men.

BACKGROUND: 11ß-methyl-19-nortestosterone (11ß-MNT) is a modified testosterone (T) with androgenic and progestational activity. A single oral dose of the prodrug, 11ß-MNT dodecylcarbonate (11ß-MNTDC), was well tolerated in healthy men. METHODS: We conducted a randomized, double-blind study at 2 academic medical centers. 42 healthy men (18-50 years) were randomized to receive oral placebo or 11ß-MNTDC, 200 or 400 mg daily, for 28 consecutive days. Primary outcome (safety and tolerability) measures were assessed twice per week. Subjects underwent serial blood sampling over 24 hours on days 1 and 28 to assess secondary outcomes: pharmacokinetics (serum drug concentrations); pharmacodynamics of 11ß-MNTDC (serum sex steroids and gonadotropins); and mood and sexual function (via validated questionnaires). RESULTS: There were no serious adverse events. No participants discontinued because of an adverse event or laboratory test abnormality. 11ß-MNTDC resulted in a dose-related increase in serum 11ß-MNTDC and 11ß-MNT concentrations sustained over 24 hours. Administration of 11ß-MNTDC resulted in a marked suppression of serum gonadotropins, T, calculated free T, estradiol, and SHBG over the treatment period (P < 0.01). Adverse effects that may be related to 11ß-MNTDC included weight gain, acne, headaches, fatigue, and mild mood changes, with 5 men reporting decreased libido and 3 decreased erectile/ejaculatory function. Serum low-density lipoprotein cholesterol, weight (~2 kg), hematocrit, and hemoglobin increased and serum high-density lipoprotein cholesterol decreased in both 11ß-MNTDC groups. CONCLUSION: Daily oral 11ß-MNTDC for 28 days in healthy men markedly suppressed serum gonadotropin and T concentrations without serious adverse effects. These results warrant further evaluation of 11ß-MNTDC as a potential male oral contraceptive.

Testicular fine-needle aspiration for the assessment of intratesticular hormone concentrations.

Measurement of intratesticular sex steroid concentrations in men informs both the development of male hormonal contraceptives and the understanding of male infertility. Given the challenges of using invasive techniques to measure testicular hormone physiology, our group has used a minimally-invasive fine-needle aspiration technique to measure intratesticular hormones in normal healthy men. Herein, we present a post-hoc analysis of the safety and efficacy of testicular fine-needle aspiration (FNA) completed as part of six clinical trials. From 2001 through 2011, a total of 404 procedures were conducted among 163 research volunteers, 85.9% of which were successful in obtaining sufficient fluid for the measurement of intratesticular steroid concentrations. Pain was the most common side effect, with 36.8% of procedures associated with moderate procedural pain and 4.7% with severe procedural pain. Postprocedural pain was uncommon and abated within a few days. Mild local bruising occurred with 14.9% of procedures. Two serious adverse events (0.5%) required surgical intervention. The risk of an adverse event was not associated with age, body mass index, testicular size, or the volume of fluid aspirated. Testicular FNA to obtain fluid for measurement of intratesticular steroid concentrations frequently causes mild to moderate procedural pain, but serious adverse events occur rarely. Testicular FNA has been instrumental for defining human intratesticular hormone physiology and is a minimally-invasive, safe, effective method for obtaining fluid for research on testicular physiology and pathology.

Serum insulin-like factor 3 is highly correlated with intratesticular testosterone in normal men with acute, experimental gonadotropin deficiency stimulated with low-dose human chorionic gonadotropin: a randomized, controlled trial.

OBJECTIVE: To study the potential role for using serum biomarkers, including insulin-like factor 3 (INSL3), 17α-hydroxyprogesterone, antimüllerian hormone, and inhibin B, as correlates of intratesticular T (IT-T) concentrations in men. DESIGN: Prospective, randomized, controlled trial. SETTING: University-based medical center. PATIENT(S): Thirty-seven healthy men aged 18-50 years. INTERVENTION(S): All men received the GnRH antagonist acyline, plus very low doses of hCG (0 IU, 15 IU, 60 IU, or 125 IU) SC every other day or 7.5 g T gel daily (75 mg delivered). The IT-T concentrations obtained by percutaneous testicular aspiration with simultaneous serum protein and steroid concentrations were measured at baseline and after 10 days of treatment. MAIN OUTCOME MEASURE(S): Intratesticular and serum hormone and gonadotropin concentrations. RESULT(S): After 10 days of gonadotropin suppression, serum INSL3 decreased by more than 90% and correlated highly with IT-T concentrations. In contrast, serum inhibin B, antimüllerian hormone, and 17α-hydroxyprogesterone did not correlate with IT-T. Serum INSL3 increased with the dose of hCG administered and returned to baseline after treatment. CONCLUSION(S): Serum INSL3 correlates highly with IT-T and serum T concentrations during acute gonadotropin suppression in men. Human chorionic gonadotropin stimulates dose-dependent increases in INSL3 and IT-T in healthy men and might be a useful biomarker of IT-T concentration in some clinical settings. CLINICAL TRIAL REGISTRATION NUMBER: NCT# 00839319.

Impact of male hormonal contraception on prostate androgens and androgen action in healthy men: a randomized, controlled trial.

CONTEXT: Male hormonal contraception (MHC) combines hypothalamic-pituitary-gonadal axis blockade with exogenous androgen delivery to maintain extragonadal androgen end-organ effects. Concern exists that MHC may adversely impact prostate health. OBJECTIVE: The objective of the study was to determine the molecular impact of MHC on intraprostatic androgen concentrations and androgen action. DESIGN: This was a single-blind, randomized, placebo-controlled study. SETTING: The study was conducted at an academic medical center. PARTICIPANTS: 32 healthy men aged 25-55 yr participated in the study. INTERVENTION: Interventions included placebo, daily transdermal testosterone (T) (T-gel), T-gel + depomedroxyprogesterone acetate (T+DMPA), or T-gel + dutasteride daily (T+D) for 12 wk, and prostate biopsy during treatment wk 10. MAIN OUTCOME MEASURES: Serum and prostate androgen concentrations and prostate epithelial-cell gene expression were measured. RESULTS: Thirty men completed the study. Serum T levels were significantly increased in T-gel and T+D groups compared with baseline (P < 0.05) but were decreased with the addition of DMPA. Intraprostatic androgens were no different from placebo with T-gel treatment. Addition of DMPA to T resulted in 40% lower intraprostatic dihydrotestosterone (DHT) concentration (P = 0.0273 vs. placebo), whereas combining dutasteride with T resulted in a 90% decrease in intraprostatic DHT (P = 0.0012), 11-fold increased intraprostatic T (P = 0.0011), and 7-fold increased intraprostatic androstenedione (P = 0.0011). Significant differences in global or androgen-regulated prostate epithelial-cell gene expression were not observed. Androgen-regulated gene expression correlated with epithelial-cell androgen receptor and prostatic DHT in placebo, T-gel, and T+DMPA arms and with T and androstenedione levels in the T+D arm. CONCLUSIONS: MHC regimens do not markedly alter gene expression in benign prostate epithelium, suggesting they may not alter risk of prostate disease. Longer-term studies examining the impact of MHC on prostate health are needed.

Pharmacokinetics of modified slow-release oral testosterone over 9 days in normal men with experimental hypogonadism.

Oral administration of testosterone has potential use for the treatment of hypogonadism. We have recently demonstrated that a novel formulation of oral testosterone transiently normalized serum testosterone in a single-dose pharmacokinetic study. In this report, we present the steady-state pharmacokinetics of this formulation. Twelve healthy young men were rendered hypogonadal with the gonadotropin-releasing hormone antagonist acyline (300 µg/kg subcutaneously) and administered 300 mg of oral testosterone 3 times daily for 9 days. Serum testosterone, dihydrotestosterone (DHT), estradiol, and sex hormone-binding globulin (SHBG) were measured before and 1, 2, 4, 5, 6, 8, 10, 11, 12, 14, 16, and 24 hours on the first and ninth day of dosing. Before testosterone administration, all men had serum testosterone under 75 ng/dL. Over day 1, the 24-hour average (geometric mean [%CV]) serum total testosterone was 378 (45) ng/dL. This decreased to 315 (41) ng/dL after 9 days of continuous treatment (P = .1 compared with day 1). The 24-hour average serum SHBG was 27 (46) nmol/L on day 1 and was significantly reduced to 19 (47) nmol/L by day 9 (P < .01). As a result, the calculated free testosterone values were similar between day 1 and day 9: 8.7 (43) and 8.3 (37) ng/dL, respectively. DHT was in the reference range and estradiol was slightly below on day 9. Oral testosterone (300 mg) dosed 3 times daily normalized serum testosterone in men with experimentally induced hypogonadism after 9 days of dosing and significantly suppressed SHBG. This formulation of oral testosterone may have efficacy for the treatment of testosterone deficiency.

Pharmacokinetics of 2 novel formulations of modified-release oral testosterone alone and with finasteride in normal men with experimental hypogonadism.

Oral administration of testosterone might be useful for the treatment of testosterone deficiency. However, current "immediate-release" formulations of oral testosterone exhibit suboptimal pharmacokinetics, with supraphysiologic peaks of testosterone and its metabolite, dihydrotestosterone (DHT), immediately after dosing. To dampen these peaks, we have developed 2 novel modified-release formulations of oral testosterone designed to slow absorption from the gut and improve hormone delivery. We studied these testosterone formulations in 16 normal young men enrolled in a 2-arm, open-label clinical trial. Three hundred-mg and 600-mg doses of immediate-release and modified fast-release or slow-release formulations were administered sequentially to 8 normal men rendered hypogonadal by the administration of the gonadotropin-releasing hormone antagonist acyline. Blood for measurement of serum testosterone, DHT, and estradiol was obtained before and 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after each dose. A second group of 8 men was studied with the coadministration of 1 mg of the 5α-reductase inhibitor finasteride daily throughout the treatment period. Serum testosterone was increased with all formulations of oral testosterone. The modified slow-release formulation significantly delayed the postdose peaks of serum testosterone and reduced peak concentrations of serum DHT compared with the immediate-release formulation. The addition of finasteride further increased serum testosterone and decreased serum DHT. We conclude that the oral modified slow-release testosterone formulation exhibits superior pharmacokinetics compared with immediate-release oral testosterone both alone and in combination with finasteride. This formulation might have efficacy for the treatment of testosterone deficiency.

Oral administration of the GnRH antagonist acyline, in a GIPET-enhanced tablet form, acutely suppresses serum testosterone in normal men: single-dose pharmacokinetics and pharmacodynamics.

PURPOSE: GnRH analogs are useful for the treatment of prostate cancer, but require parenteral administration. The peptide GnRH antagonist acyline potently suppresses luteinizing hormone (LH) and testosterone in man; however, its clinical utility is limited by the requirement for frequent injections. The use of a proprietary enhancer system called GIPET, which is based on medium-chain fatty acids, facilitates the oral bioavailability of peptides. We hypothesized that GIPET enhancement would allow for the safe oral dosing of acyline for the treatment of prostate cancer. METHODS: We enrolled eight healthy young men in a pharmacokinetic and pharmacodynamic study of 10, 20 and 40 mg doses of GIPET-enhanced oral acyline. Blood for measurement of serum LH, FSH, testosterone and acyline was obtained prior to each dose of GIPET-enhanced oral acyline and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 48 h after dosing. RESULTS: Serum LH, FSH and serum testosterone were significantly suppressed by all doses of GIPET-enhanced oral acyline after 6 h, with suppression reaching a nadir 12 h after dosing. In addition, the 20 and 40 mg doses demonstrated sustained suppression of testosterone for 12-24 h. All hormone concentrations returned to normal 48 h after administration. There were no treatment-related serious adverse events, and laboratory assessments, including liver function tests and creatinine, were unaffected by treatment. CONCLUSIONS: Oral administration of GIPET-enhanced acyline significantly suppresses testosterone and gonadotropins in normal men without untoward side effects and might have utility in the management of prostate cancer.

Combined transdermal testosterone gel and the progestin nestorone suppresses serum gonadotropins in men.

CONTEXT: Testosterone (T) plus progestin combinations are the most promising hormonal male contraceptives. Nestorone (NES), a progestin without estrogenic or androgenic activity, when combined with T may be an excellent candidate for male contraception. OBJECTIVE: Our objective was to determine the effect of transdermal NES gel alone or with T gel on gonadotropin suppression. DESIGN AND SETTING: The randomized, unblinded clinical trial was conducted at two academic medical centers. PARTICIPANTS: A total of 140 healthy male volunteers participated. INTERVENTIONS: One hundred subjects were randomized initially (20 per group) to apply NES gel 2 or 4 mg, T gel 10 g, or T gel 10 g plus NES gel 2 or 4 mg daily for 20 d. Because only about half of the subjects in T plus NES 4 mg group suppressed serum gonadotropins to 0.5 IU/liter or less (suboptimal suppression), two additional groups of 20 men were randomized to apply daily T gel 10 g plus NES gel 6 or 8 mg. MAIN OUTCOME VARIABLE: Suppression of serum LH and FSH concentrations to 0.5 IU/liter or less after treatment was the main outcome variable. RESULTS: A total of 119 subjects were compliant with gel applications with few study-related adverse events. NES alone reduced gonadotropins significantly but less than T gel alone. Combined T gel 10g plus NES gel 6 or 8 mg suppressed both serum gonadotropins to 0.5 IU/liter or less in significantly more men than either gel alone. CONCLUSION: Transdermal NES gel alone had gonadotropin suppression activity. Combined transdermal NES (6 or 8 mg) plus T gel demonstrated safe and effective suppression of gonadotropins, justifying a longer-term study of this combination for suppression of spermatogenesis.

The effect of 5alpha-reductase inhibition with dutasteride and finasteride on bone mineral density, serum lipoproteins, hemoglobin, prostate specific antigen and sexual function in healthy young men.

PURPOSE: Dutasteride and finasteride are 5alpha-reductase inhibitors that dramatically decrease serum levels of dihydrotestosterone. Because androgens affect bone, lipids, hematopoiesis, prostate and sexual function, we determined the impact of 5alpha-reductase inhibitors on these end points. MATERIALS AND METHODS: We conducted a randomized, double-blinded, placebo controlled trial of 99 men 18 to 55 years old randomly assigned to receive 0.5 mg dutasteride (33), 5 mg finasteride (34) or placebo (32) daily for 1 year. Bone mineral density was measured at baseline, after 1 year of treatment and 6 months after drug discontinuation. In addition, markers of bone turnover, fasting serum lipoprotein concentrations, hemoglobin and prostate specific antigen were measured at baseline, after 26 and 52 weeks of treatment, and again 24 weeks after drug discontinuation. Sexual function was assessed at these points by a validated questionnaire. RESULTS: Significant suppression of circulating dihydrotestosterone levels with the administration of dutasteride or finasteride did not significantly affect bone mineral density or markers of bone metabolism. Similarly serum lipoproteins and hemoglobin were unaffected. Serum prostate specific antigen and self-assessed sexual function decreased slightly during treatment with both 5alpha-reductase inhibitors but returned to baseline during followup. CONCLUSIONS: Profound suppression of circulating serum dihydrotestosterone induced by 5alpha-reductase inhibitors during 1 year does not adversely impact bone, serum lipoproteins or hemoglobin, and has a minimal, reversible effect on serum prostate specific antigen and sexual function in normal men. Circulating dihydrotestosterone does not appear to have a clinically significant role in modulating bone mass, hematopoiesis or lipid metabolism in normal men.

Serum 17-hydroxyprogesterone strongly correlates with intratesticular testosterone in gonadotropin-suppressed normal men receiving various dosages of human chorionic gonadotropin.

OBJECTIVE: To determine if serum concentrations of testosterone precursors would correlate with intratesticular testosterone (ITT) concentration measured directly by testicular aspiration and allow for a less invasive means of inferring ITT. DESIGN: Controlled clinical study. SETTING: Healthy volunteers in an academic research environment. PATIENT(S): Twenty-nine normal men. INTERVENTION(S): We determined ITT concentration by testicular aspiration before and after treatment in men receiving exogenous T to block endogenous gonadotropin production and randomly assigned to one of four doses of hCG (0, 125 IU, 250 IU, or 500 IU every other day) for 3 weeks. MAIN OUTCOME MEASURE(S): The association between serum 17-hydroxyprogesterone (17OH-P), androstenedione, and DHEA and ITT. RESULT(S): With T administration alone, serum 17OH-P decreased significantly and increased significantly when 500 IU hCG was administered. End-of-treatment ITT strongly correlated with serum 17OH-P. Moreover, serum 17OH-P, but not androstenedione or DHEA, was independently associated with end-of-treatment ITT by multivariate linear regression. CONCLUSION(S): Serum 17OH-P is highly correlated with ITT in gonadotropin-suppressed normal men receiving T and stimulated with hCG. Serum 17OH-P is a surrogate biomarker of ITT and may be useful in research and in men receiving gonadotropin therapy for infertility.

Sex steroids and all-cause and cause-specific mortality in men.

BACKGROUND: Sex steroid levels are related to metabolic outcomes that could convey higher risk of premature death. METHODS: We examined whether total or free testosterone, dihydrotestosterone, and sex hormone-binding globulin levels are related to all-cause or cause-specific mortality in men. Data were obtained from the Massachusetts Male Aging Study, a population-based cohort study of 1709 men aged 40 to 70 years. Men were followed up for all-cause and cause-specific mortality. RESULTS: Complete data were available for 1686 men, with 395 deaths occurring during 15.3 years of follow-up. With age adjustment, dihydrotestosterone and sex hormone-binding globulin levels were associated with ischemic heart disease mortality, and free testosterone level was associated with respiratory mortality. In multivariate-adjusted models, higher free testosterone (P=.02) and lower dihydrotestosterone (P=.04) levels were significantly associated with ischemic heart disease mortality, although the latter association was not robust to differences in model selection. The relative risk of death from ischemic heart disease per 1-SD lower free testosterone level was 0.80 (95% confidence interval, 0.64-0.99). Free testosterone level was significantly associated with respiratory mortality (P=.002), with a multivariate-adjusted relative risk per 1-SD lower free testosterone level of 1.90 (95% confidence interval, 1.24-2.92). Total testosterone level was unrelated to mortality, and sex hormone-binding globulin was not significantly associated with mortality after multivariate adjustment. CONCLUSIONS: In men, endogenous sex steroid levels seem to have relatively weak associations with mortality. These data provide little support for the hypothesis that endogenous sex steroid levels are associated with risk of premature death but suggest that further investigation of the relationship between sex steroids and mortality from ischemic heart disease and respiratory disease may be warranted.

Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer.

Androgen deprivation therapy (ADT) remains the primary treatment for advanced prostate cancer. The efficacy of ADT has not been rigorously evaluated by demonstrating suppression of prostatic androgen activity at the target tissue and molecular level. We determined the efficacy and consistency of medical castration in suppressing prostatic androgen levels and androgen-regulated gene expression. Androgen levels and androgen-regulated gene expression (by microarray profiling, quantitative reverse transcription-PCR, and immunohistochemistry) were measured in prostate samples from a clinical trial of short-term castration (1 month) using the gonadotropin-releasing hormone antagonist, Acyline, versus placebo in healthy men. To assess the effects of long-term ADT, gene expression measurements were evaluated at baseline and after 3, 6, and 9 months of neoadjuvant ADT in prostatectomy samples from men with localized prostate cancer. Medical castration reduced tissue androgens by 75% and reduced the expression of several androgen-regulated genes (NDRG1, FKBP5, and TMPRSS2). However, many androgen-responsive genes, including the androgen receptor (AR) and prostate-specific antigen (PSA), were not suppressed after short-term castration or after 9 months of neoadjuvant ADT. Significant heterogeneity in PSA and AR protein expression was observed in prostate cancer samples at each time point of ADT. Medical castration based on serum testosterone levels cannot be equated with androgen ablation in the prostate microenvironment. Standard androgen deprivation does not consistently suppress androgen-dependent gene expression. Suboptimal suppression of tumoral androgen activity may lead to adaptive cellular changes allowing prostate cancer cell survival in a low androgen environment. Optimal clinical efficacy will require testing of novel approaches targeting complete suppression of systemic and intracrine contributions to the prostatic androgen microenvironment.

Persistent intraprostatic androgen concentrations after medical castration in healthy men.

CONTEXT: The impact of serum androgen manipulation on prostate tissue hormone levels in normal men is unknown. Studies of men with prostate cancer have suggested that prostatic androgens are preserved in the setting of castration. Tissue androgens might stimulate prostate growth, producing adverse clinical consequences. OBJECTIVE: The objective of the study was to determine the effect of serum androgen manipulation on intraprostatic androgens in normal men. DESIGN: Thirteen male volunteers ages 35-55 yr (prostate-specific antigen < 2.0 ng/ml; normal transrectal ultrasound) were randomly assigned to: 1) a long-acting GnRH-antagonist, acyline, every 2 wk; 2) acyline plus testosterone (T) gel (10 mg/d); or 3) placebo for 28 d. Serum hormones were assessed weekly. Prostate biopsies were obtained on d 28. Extracted androgens were measured by RIA, and immunohistochemistry for androgen-regulated proteins was performed. RESULTS: The mean decrease in serum T was 94%, whereas prostatic T and dihydrotestosterone levels were 70 and 80% lower, respectively, in subjects receiving acyline alone compared with controls (P < 0.05). Despite this decrease in prostate androgens, there were no detectable differences in prostate epithelial proliferation, apoptosis, prostate-specific antigen, and androgen receptor expression. CONCLUSION: In this small study of healthy subjects, despite a 94% decrease in serum T with medical castration, intraprostatic T and dihydrotestosterone levels remained 20-30% of control values, and prostate cell proliferation, apoptosis, and androgen-regulated protein expression were unaffected. Our data highlight the importance of assessing tissue hormone levels. The source of persistent prostate androgens associated with medical castration and their potential role in supporting prostate metabolism deserves further study.

Drug insight: Recent advances in male hormonal contraception.

As there are limitations to current methods of male contraception, research has been undertaken to develop hormonal contraceptives for men, analogous to the methods for women based on estrogen and progestogens. When testosterone is administered to a man, it functions as a contraceptive by suppressing the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland. Since these hormones are the main stimulatory signals for spermatogenesis, low levels of LH and FSH markedly impair sperm production. After 3-4 months of testosterone treatment, 60-70% of men no longer have sperm in their ejaculate, and most other men exhibit markedly diminished sperm counts. Male hormonal contraception is well tolerated, free of serious adverse side effects, and 95% effective in the prevention of pregnancy. Importantly, male hormonal contraception is reversible, with sperm counts usually recovering within 4 months of the discontinuation of hormone treatment. Because exogenous testosterone administration alone does not completely suppress sperm production in all men, researchers have combined testosterone with second agents, such as progestogens or gonadotropin-releasing-hormone antagonists, to further suppress secretion of LH and FSH and improve suppression of spermatogenesis. Recent trials have used combinations of long-acting injectable or implantable forms of testosterone with progestogens, which can be administered orally, by injection or by a long-acting implant. Such combinations suppress spermatogenesis to zero without severe side effects in 80-90% of men, with near-complete suppression in the remainder of individuals. One of these testosterone and progestogen combination regimens might soon bring the promise of male hormonal contraception to fruition.

Testosterone gel combined with depomedroxyprogesterone acetate is an effective male hormonal contraceptive regimen and is not enhanced by the addition of a GnRH antagonist.

INTRODUCTION: Exogenous androgens plus progestins can be used to suppress spermatogenesis, resulting in effective male hormonal contraception; however, induction of azoospermia can require 3-6 months, and these methods require injectable or implantable androgens. We hypothesized that testosterone (T) transdermal gel (T gel) could be combined with a depot formulation of the progestin, depomedroxyprogesterone acetate (DMPA), with or without the potent GnRH antagonist, acyline, to suppress spermatogenesis conveniently, rapidly, and reversibly. OBJECTIVES: The objectives of the study were: 1) to determine the rate of severe oligospermia (< or = 1 million sperm/ml) using T gel+DMPA; and 2) to determine whether the addition of acyline to T gel+DMPA during the first 12 wk of the regimen would accelerate and improve suppression of spermatogenesis. METHODS: Forty-four healthy men, ages 18-55 yr, were randomized to T gel (100 mg daily)+DMPA (300 mg/3 months) or acyline (300 microg/kg.2 wk x 12 wk)+T gel+DMPA. Thirty-eight men completed the 24-wk treatment protocol. RESULTS: All men had dramatic suppression of spermatogenesis; 90% of the subjects became severely oligospermic, a rate comparable to implantable and injectable T+progestin combinations. The addition of acyline did not significantly accelerate spermatogenic suppression or improve rates of severe oligospermia. There were no serious adverse events, and there were minimal changes in weight, serum lipids, and prostate-specific antigen. CONCLUSIONS: The combination of T gel+DMPA is a promising new regimen in male contraception. The addition of the GnRH antagonist acyline, as part of an induction phase in a male contraception regimen, has limited clinical utility. Additional studies using T gel for male contraception are warranted.

Oral testosterone in oil: pharmacokinetic effects of 5alpha reduction by finasteride or dutasteride and food intake in men.

Oral administration of 400 mg of testosterone (T) in oil, when combined with the 5alpha reductase inhibitor dutasteride (D), elevates serum T in medically castrated men to the normal range. In this study, we sought to determine the impact of 1) finasteride (F) and 2) food intake on the serum T and dihydrotestosterone (DHT) levels observed after the oral administration of T in oil. Therefore, we conducted a pharmacokinetic study of oral T in oil, alone or with D or F, in the fasting and fed states in normal men whose endogenous T production was suppressed by the GnRH antagonist acyline. After acyline administration, 7 healthy men (mean age 31 +/- 8 years) were sequentially administered five 400-mg doses of oral T in sesame oil once daily. The first dose of oral T (T-alone) in oil was given while fasting without F or D. The second (fasting) and third (fed) doses were administered after pretreatment with F (T + F). Four days later, the fourth (fasting) and fifth (fed) doses were administered after pretreatment with D (T + D). Blood samples for measurement of serum T and DHT were obtained before T dosing and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours after each administration. In the fasting state, 24-hour area-under-the-curve of serum T after oral T administration was significantly greater with coadministration of either D or F compared with T-alone (126 +/- 36 nmol-h/L [T-alone] vs 287 +/- 98 nmol-h/L [T + F] vs 236 +/- 82 nmol-h/L [T + D]; P < .05 for T + F and T + D vs T-alone). Administration of the T with food nonsignificantly decreased serum T levels compared with fasting administration. The administration of oral T in oil combined with either F or D results in serum T levels adequate to treat men with testicular failure. Additional studies of the combination of oral T in oil with 5alpha-reductase inhibitors as a novel form of oral T therapy are warranted.

Low sex hormone-binding globulin, total testosterone, and symptomatic androgen deficiency are associated with development of the metabolic syndrome in nonobese men.

BACKGROUND: The metabolic syndrome (MetS), characterized by central obesity, lipid and insulin dysregulation, and hypertension, is a precursor state for cardiovascular disease. The purpose of this analysis was to determine whether low serum sex hormone levels or clinical androgen deficiency (AD) predict the development of MetS. METHODS: Data were obtained from the Massachusetts Male Aging Study, a population-based prospective cohort of 1709 men observed at three time points (T1, 1987-1989; T2, 1995-1997; T3, 2002-2004). MetS was defined using a modification of the ATP III guidelines. Clinical AD was defined using a combination of testosterone levels and clinical signs and symptoms. The association between MetS and sex hormone levels or clinical AD was assessed using relative risks (RR), and 95% confidence intervals (95% CI) were estimated using Poisson regression models. RESULTS: Analysis was conducted in 950 men without MetS at T1. Lower levels of total testosterone and SHBG were predictive of MetS, particularly among men with a body mass index (BMI) below 25 kg/m2 with adjusted RRs for a decrease in 1 sd of 1.41 (95% CI, 1.06-1.87) and 1.65 (95% CI, 1.12-2.42). Results were similar for the AD and MetS association, with RRs of 2.51 (95% CI, 1.12-5.65) among men with a BMI less than 25 compared with an RR of 1.22 (95% CI, 0.66-2.24) in men with a BMI of 25 or greater. CONCLUSIONS: Low serum SHBG, low total testosterone, and clinical AD are associated with increased risk of developing MetS over time, particularly in nonoverweight, middle-aged men (BMI, <25). Together, these results suggest that low SHBG and/or AD may provide early warning signs for cardiovascular risk and an opportunity for early intervention in nonobese men.

Transdermal androgen therapy to augment EPO in the treatment of anemia of chronic renal disease.

BACKGROUND: Hypogonadism and anemia are common comorbid conditions in dialysis patients. Testosterone replacement may improve such clinical parameters as anemia, sarcopenia, and low libido. Additionally, by increasing hemoglobin levels, testosterone replacement may allow for a dose reduction in recombinant human erythropoietin (rHuEPO), thereby reducing cost. METHODS: This phase IV, single-center, placebo-controlled, double-blind study assessed the effect of transdermal testosterone on serum testosterone levels, rHuEPO dose required to maintain hemoglobin level, bone mineral content, lean body mass and fat content, cholesterol level, sexual function, and mood. Forty hypogonadal male hemodialysis patients who were administered rHuEPO were randomly assigned to 100 mg of topical 1% testosterone gel (Testim; Auxilium Pharmaceuticals, Norristown, PA) or placebo, applied daily for 6 months. RESULTS: Forty men with a mean age of 56 years and baseline serum testosterone level less than 300 ng/dL (< 10.4 nmol/L) participated in this trial. In men assigned to administration of transdermal testosterone, there was an increase beyond that in the placebo group in mean serum testosterone (77.1 ng/dL [2.7 nmol/L]), dihydrotestosterone (DHT; 0.8 nmol/L), and estradiol levels (6.3 pg/mL [23.0 pmol/L]) and a decrease in mean serum luteinizing hormone levels (-3.1 IU/L). Compared with subjects administered placebo, participants on testosterone replacement therapy did not show an appreciable change in rHuEPO dose (mean difference adjusted for baseline values, 12.6 U/kg/wk; P = 0.73), bone mineral density, lean body mass or fat content, cholesterol level, sexual function, or mood. CONCLUSION: Daily administration of 100 mg of topical 1% testosterone gel for 6 months failed to significantly increase serum testosterone or DHT levels in hypogonadal men with end-stage renal disease. Treatment with transdermal testosterone did not impact on rHuEPO requirement or clinical parameters in this small placebo-controlled study. Greater serum testosterone levels may be required to show clinical benefit in men with end-stage renal disease.

Effect of medical castration on CD4+ CD25+ T cells, CD8+ T cell IFN-gamma expression, and NK cells: a physiological role for testosterone and/or its metabolites.

The higher prevalence of autoimmune disease among women compared with men suggests that steroids impact immune regulation. To investigate how sex steroids modulate cellular immune function, we conducted a randomized trial in 12 healthy men aged 35-55 yr treated for 28 days with placebo, a GnRH antagonist, acyline to induce medical castration, or acyline plus daily testosterone (T) gel to replace serum T, followed by a 28-day recovery period. Serum hormones were measured weekly and peripheral blood lymphocytes (PBLs) were collected biweekly for analyses of thymus-derived lymphocyte (T cell) subtypes and natural killer (NK) cells. Compared with the other groups and to baseline throughout the drug exposure period, men receiving acyline alone had significant reductions in serum T (near or below castrate levels), dihydrotestosterone, and estradiol (P < 0.05). Medical castration significantly reduced the percentage of CD4+ CD25+ T cells (P < 0.05), decreased mitogen-induced CD8+ T cell IFN-gamma expression, and increased the percentage of NK cells without affecting the ratio of CD4+ to CD8+ T cells and the expression of NK cell-activating receptor NKG2D or homing receptor CXCR1. No changes in immune composition were observed in subjects receiving placebo or acyline with replacement T. These data suggest that T and/or its metabolites may help maintain the physiological balance of autoimmunity and protective immunity by preserving the number of regulatory T cells and the activation of CD8+ T cells. In addition, sex steroids suppress NK cell proliferation. This study supports a complex physiological role for T and/or its metabolites in immune regulation.

Effects of testosterone and levonorgestrel combined with a 5alpha-reductase inhibitor or gonadotropin-releasing hormone antagonist on spermatogenesis and intratesticular steroid levels in normal men.

CONTEXT: Combination of a GnRH antagonist (acyline), types I and II, 5alpha-reductase inhibitor (dutasteride) or levonorgestrel (LNG) with testosterone (T) treatment may augment the suppression of spermatogenesis and intratesticular (iT) steroids. OBJECTIVE: The objective of this study was to assess the effects of combined hormonal contraceptive regimens on germ cell populations and iT steroids. DESIGN, SETTING, AND PARTICIPANTS: Twenty-nine normal health men enrolled in this prospective, randomized, 14-wk study at the University of Washington. INTERVENTION(S): Twenty-two men (n = 5-6/group) received 8 wk of T enanthate (TE; 100 mg, i.m., weekly) combined with 1) 125 microg LNG daily, orally; 2) 125 microg LNG plus 0.5 mg dutasteride daily, orally; 3) 300 microg/kg acyline twice weekly, s.c.; or 4) 125 microg LNG daily, orally, plus 300 microg/kg acyline twice weekly, s.c. Subjects then underwent a vasectomy and testicular biopsy. Control men (n = 7) proceeded directly to surgery. MAIN OUTCOME MEASURE(S): The main outcome measures were germ cells and iT steroids [T, dihydrotestosterone, 3alpha- and beta-androstanediol (Adiol), and estradiol (E2)]. RESULTS: High iT levels of all androgens (6- to 123-fold serum levels) and E2 (407-fold serum levels) were found in control men. iTT (1.9-2.6% control; P < 0.001) and iT3betaAdiol (16-34% control; P < 0.05) levels decreased with all treatments. iT dihydrotestosterone (13-29% control; P < 0.05) and iT3alphaAdiol (44-47% control; P < 0.05) levels decreased with all but the TE plus LNG treatment. iTE2 levels decreased only in the TE plus acyline group (28% control; P = 0.01). Germ cells from type B spermatogonia onward were suppressed, with no differences between groups found. Variable sites of impairment of germ cell progression were evident between men (spermagonial maturation, meiosis 1 entry, and spermiation). Other than a negative correlation between iT3alphaAdiol and haploid germ cell number (P < 0.006), no correlations between germ cell number and gonadotropins, sperm concentration, or iT steroids were found. CONCLUSIONS: A similar high testicular:serum gradient exists for E2 and T in normal men, and 8 wk of gonadotropin suppression markedly reduces iTT, with 5alpha-reduced androgens and E2 levels decreasing to a much lesser degree. The heterogeneity of the germ cell response, regardless of treatment, gonadotropins or iT steroids, points to the individual sensitivity of sites in germ cell development, which is worthy of additional exploration.