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BACKGROUND: Novel male-based contraceptives are needed to broaden family planning choices. A progestin, Nestorone® (Nes) gel, plus a testosterone (T) gel suppresses sperm concentrations to levels associated with effective contraception in normal men. However, administration of two gels on different parts of the body daily is impractical. OBJECTIVE: Compare the effectiveness of daily application of a single, combined 8.3 mg Nes-62.5 mg T gel (Nes-T) vs. 62.7 mg T gel to suppress serum FSH and LH concentrations to ≤ 1.0 IU/L (a threshold associated with suppression of sperm concentrations to ≤ 1 million and effective contraception) and to compare the pharmacokinetics of serum Nes and T concentrations between the gel groups. DESIGN: We conducted a 28-day, double-blind, controlled trial of 44 healthy men randomized to daily Nes-T or T gel with measurement of hormones at baseline, treatment and recovery and during 24-hour pharmacokinetic studies on days 1 and 28 of treatment. RESULTS: Of the subjects who met pre-defined inclusion criteria, 84% of the Nes-T group suppressed serum gonadotropin concentrations to ≤ 1.0 IU/L at days 21–28 vs. 16.7% in the T group (p < .001). On day 1, Nes concentrations rose significantly above baseline by two hours and continued to rise up to 24 hours after Nes-T gel application. Nes concentrations were not detectable in the T group. Serum total T concentrations rose and were significantly higher in the T gel group compared to the Nes-T group at 24 hours on day 1 and days 11, 14, and 21 (p < 0.01). There were no serious adverse events in either group. About 80% of the subjects reported satisfaction with both gels. CONCLUSION: Daily Nes-T gel effectively and safely suppresses serum gonadotropins and is acceptable to most men. It should be studied further in efficacy trials of hormonal male contraception.

Dimethandrolone (DMA, 7α,11β-dimethyl-19-nortestosterone) has both androgenic and progestational activities, ideal properties for a male hormonal contraceptive. In vivo, dimethandrolone undecanoate (DMAU) is hydrolyzed to DMA. We showed previously that single oral doses of DMAU powder in capsule taken with food are well tolerated and effective at suppressing both LH and testosterone (T), but absorption was low. We compared the pharmacokinetics and pharmacodynamics of two new formulations of DMAU, in castor oil and in self-emulsifying drug delivery systems (SEDDS), with the previously tested powder formulation. DMAU was dosed orally in healthy adult male volunteers at two academic medical centers. For each formulation tested in this double-blind, placebo-controlled study, 10 men received single, escalating, oral doses of DMAU (100, 200, and 400 mg) and two subjects received placebo. All doses were evaluated for both fasting and with a high fat meal. All three formulations were well tolerated without clinically significant changes in vital signs, blood counts, or serum chemistries. For all formulations, DMA and DMAU showed higher maximum (p

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.

BACKGROUND Testosterone (T)/Nestorone (NES) combination gel is a potential transdermal male contraceptive that suppresses gonadotropins and spermatogenesis. Transfer of transdermal T from men to women can be prevented by washing or covering application sites with clothing. OBJECTIVES We hypothesized that showering or wearing a shirt over gel application sites would prevent secondary exposure of T and NES to a woman after close skin contact. MATERIALS AND METHODS Twelve healthy male and 12 healthy female participants were recruited. Men applied T/NES 62 mg/8 mg gel to their shoulders and upper arms. Two hours after application, female partners rubbed the application site for 15 min. Exposure in the female partner was assessed under three conditions: a shirt covered the application site; the man showered prior to skin contact; or without intervention to reduce transfer. Serum T and NES concentrations were measured by LC-MS/MS in serial blood samples for 24 h after gel exposure. MAIN OUTCOMES Change in female serum T and NES levels as measured by average concentration over 24 h (Cavg ). RESULTS Median female serum T Cavg was 23.9 ng/dL (interquartile range, 19.3, 33.9) with the shirt barrier and 26.7 ng/dL (20.7, 33.9) after showering, which was higher than baseline 20.9 ng/dL (16.7, 25.0), both p

CONTEXT: 11β-Methyl-19-nortestosterone-17β-dodecylcarbonate (11β-MNTDC) is an orally bioavailable prodrug of 11β-methyl-19-nortestosterone (11β-MNT) with androgenic and progestational activity. OBJECTIVES: (i) Quantify 11β-MNT binding to androgen and progesterone receptors. (ii) Evaluate safety, tolerability, and serum gonadotropin and testosterone suppression by 11β-MNTDC in men. DESIGN AND SETTING: (i) In vitro receptor binding and transactivation studies and (ii) randomized, double-blind, placebo-controlled single-dose, dose-escalating phase I study at two academic medical centers. PARTICIPANTS AND INTERVENTION: Twelve healthy male volunteers were randomized (five active, one placebo) to escalating single oral doses (100, 200, 400, and 800 mg) of 11β-MNTDC or placebo given with or without food. MAIN OUTCOME MEASURES: (i) In vitro 11β-MNT/11β-MNTDC human receptor binding and transactivation and (ii) safety and tolerability, pharmacokinetics, and quantification of serum gonadotropin and testosterone concentrations for 24 hours following dosing. RESULTS: 11β-MNT avidly binds and activates human androgen and progesterone receptors, but 11β-MNTDC has minimal activity. Single oral doses of 11β-MNTDC were well tolerated without serious adverse events. Administration of 11β-MNTDC with food markedly increased average 11β-MNTDC and 11β-MNT serum concentrations (P < 0.001 for all doses) compared with fasting with a significant dose-related effect on average serum drug concentrations (P < 0.0001). The 200-, 400-, and 800-mg doses significantly suppressed average serum testosterone concentrations (P < 0.05). CONCLUSIONS: A single, oral dose of 11β-MNTDC up to 800 mg administered with food is safe and well tolerated in healthy men. The active drug 11β-MNT has androgenic and progestational activity, rapidly suppresses serum testosterone, and is a promising candidate for an effective once-daily oral male hormonal contraceptive.

Fifty percent of pregnancies in the United States are unintended despite numerous contraceptive methods available to women. The only male contraceptive methods, vasectomy and condoms, are used by 10% and 16% of couples, respectively. Prior studies have shown efficacy of male hormonal contraceptives in development, but few have evaluated patient acceptability and potential use if commercially available. The objective of this study is to determine if a transdermal gel-based male hormonal contraceptive regimen, containing testosterone and Nestorone® gels, would be acceptable to study participants as a primary contraceptive method.As part of a three-arm, 6-month, double-blind, randomized controlled trial of testosterone and nestorone gels at two academic medical centers, subjects completed a questionnaire to assess the acceptability of the regimen. Of the 99 men randomized, 79 provided data for analysis.Overall, 56% (44/79) of men were satisfied or extremely satisfied with this gel-based method of contraception, and 51% (40/79) reported that they would recommend this method to others. One third of subjects (26/79) reported that they would use this as their primary method of contraception if it were commercially available today. However, men with concerns about sexually transmitted disease were significantly less satisfied than men without such concerns (p=0.03).A majority of the men who volunteered to participate in this trial of an experimental male hormonal contraceptive were satisfied with this transdermal male hormonal contraceptive. If commercially available, a combination of topical nesterone and testosterone gels could provide a reversible, effective method of contraception that is appealing to men.A substantial portion of men report they would use this transdermal male contraceptive regimen if commercially available. This method would provide a novel, reversible method of contraception for men, whose current choices are limited to condoms and vasectomy.

Objective To study the potential role for using serum biomarkers, including insulin-like factor 3 (INSL3), 17α-hydroxyprogesterone, antimullerian 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, antimullerian 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.

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.

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.

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. 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. 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. 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.

Aim: To study the relationship between circulating androgens (total testosterone [TT], free testosterone [fT] and dihydrotestosterone [DHT]) and HDL-C in men with and without CVD. Methods: Cross-sectional analyses included 1 661 baseline samples from the Massachusetts Male Aging Study (MMAS), a population-based cohort of men ages 40–70 years. Serum hormones were measured by radioimmunoassay and HDL-C was determined following precipitation of the lower density lipoproteins. CVD was determined by self-report. Analyses were performed using multiple linear regression. Results: TT and HDL-C were positively correlated in the entire sample (r = 0.11, P = 0.0001). After adjusting for confounders, we found this relationship was mostly limited to the 209 men with CVD. Among men with CVD, TT (P = 0.0004), fT (P = 0.0172) and DHT (P = 0.0128) were all positively correlated with HDL-C, whereas in men without CVD only TT correlated with HDL-C (P = 0.0099). Conclusion: Our results suggest that if androgens contribute to CVD in middle-aged men, the effect is not related to a suppressive effect of endogenous T on HDL-C. (Asian J Androl 2008 Mar; 10: 193–200)

Oral androgen development has been hampered by the rapid metabolism of orally administered testosterone (T) and low bioavailibility. The addition of the 5alpha-reductase inhibitor dutasteride (D) to oral T in oil dramatically improves concentrations of serum T. In this study we evaluate the absorption of oral T+D, comparing nanomilled T (NmT+D) vs T dissolved in oil (Capmul; CpT+D), as nanomilling might offer a simpler, more practical means of oral T administration, given the limited solubility of T in oil. Twelve healthy men were administered leuprolide on Day -14 to suppress endogenous T biosynthesis and were pretreated with D to block 5alpha-reductase. Once hypogonadal, subjects were sequentially administered 200- and 400-mg doses of CpT+D and NmT+D in the fasted and fed states. Serum T and dihydrotestosterone (DHT) were measured: before dose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours after each dose. Two weeks after leuprolide administration, T levels were below the normal range. A 400-mg dose of either formulation of oral T+D increased mean serum T above the lower limit of the normal range for 8-10 hours. Food had a minimal effect on the pharmacokinetic parameters of the NmT+D formulation but decreased the maximum observed concentration after dosing (C(max)) for CpT+D. Serum DHT remained below the normal range throughout the study period with both formulations. No significant changes in liver function tests or other adverse events were observed. A 400-mg dose of either oral T+D formulation normalized serum T for 8-10 hours and suppressed DHT. NmT allows for tablet formulation, and its pharmacokinetics were not affected by food, demonstrating the feasibility of oral nanomilled T as a promising and practical twice-daily therapy for the treatment of male hypogonadism.

Male hormonal contraceptive regimens function by suppressing gonadotropin secretion, resulting in a dramatic decrease in testicular androgen biosynthesis and spermatogenesis. Animal studies suggest that persistent intratesticular (iT)-androgen production has a stimulatory effect on spermatogenesis in the setting of gonadotropin suppression. We hypothesized that men with incompletely suppressed spermatogenesis (>1,000,000 sperm/mL) during male hormonal contraceptive treatment would have higher iT-androgen concentrations than men who achieved severe oligospermia (

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. [Cancer Res 2007;67(10):5033–41]

The administration of testosterone plus a progestogen functions as a male contraceptive by inhibiting the release of pituitary gonadotropins. After 3 to 4 months of treatment, most men are azoospermic or severely oligospermic (< or =1 million sperm/mL). However, 10% to 20% of men have persistent sperm production despite profound gonadotropin suppression. Since insulin-like factor 3 (INSL3) has been shown to prevent germ cell apoptosis in mice, we hypothesized that INSL3 might be higher in men with persistent spermatogenesis during treatment with male hormonal contraceptives. In a retrospective analysis, we measured serum INSL3 in 107 men from 3 recent male hormonal contraceptive studies and determined the relationship between suppression of spermatogenesis and serum INSL3. At the end of treatment 63 men (59%) were azoospermic and 44 men (41%) had detectable sperm in their ejaculates. Baseline INSL3 did not predict azoospermia; however, end of treatment serum INSL3 was significantly higher in nonazoospermic men compared with those with azoospermia (median [interquartile range]: 95 [73-127] pg/mL vs 80 [67-101] pg/mL; P = .03). Furthermore, serum INSL3 was positively correlated with sperm concentration (r = .25; P = .009) at the end of treatment and was significantly associated with nonazoospermia by multivariate logistic regression (P = .03). After 6 months of treatment with a hormonal male contraceptive regimen, higher serum INSL3 concentrations were associated with persistent sperm production. INSL3 may play a role in preventing complete suppression of spermatogenesis in some men on hormonal contraceptive regimens. This finding suggests that INSL3 may be a potential target for male contraceptive development.

Despite numerous contraceptive options available to women, approximately half of all pregnancies in the United States and worldwide are unplanned. Women and men support the development of reversible male contraception strategies, but none have been brought to market. Herein we review the physiologic basis for male hormonal contraception, the history of male hormonal contraception development, currents agents in development, as well as the potential risks and benefits of male hormonal contraception for 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.

We assessed attitudes towards and acceptability of male hormonal contraception among volunteers participating in a clinical trial of a prototype regimen consisting of progestin and testosterone injections. After completing screening eligible men were randomly assigned to the no-treatment group (n = 40) or to receive injections of norethisterone enanthate and testosterone undecanoate or placebo at different intervals (n = 50) according to a blocked randomization list. They underwent self-administered questionnaires. The average age of the participants was approximately 28 years; most were involved in a stable relationship and had no children. Ninety-two percentage of the respondents thought that men and women should share responsibility for contraception and 75% said they would try a hormonal contraceptive if available. At the end of the treatment phase 66% of the participants said that they would use such a method and most rated its acceptability very highly; none reported it to be unacceptable. The injections themselves were indicated as the biggest disadvantage. No significant changes in sexual function or mood states were detected among the men who underwent hormone injections. The contraceptive tested in this study was well accepted by the participants over the course of 1 year. (authors)

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.

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.The objective of this study was to assess the effects of combined hormonal contraceptive regimens on germ cell populations and iT steroids.Twenty-nine normal health men enrolled in this prospective, randomized, 14-wk study at the University of Washington.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.The main outcome measures were germ cells and iT steroids [T, dihydrotestosterone, 3alpha- and beta-androstanediol (Adiol), and estradiol (E2)].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; P0.001) and iT3betaAdiol (16-34% control; P0.05) levels decreased with all treatments. iT dihydrotestosterone (13-29% control; P0.05) and iT3alphaAdiol (44-47% control; P0.05) 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 (P0.006), no correlations between germ cell number and gonadotropins, sperm concentration, or iT steroids were found.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.

The development of a safe, well-tolerated, effective, and reversible male hormonal contraceptive would be a major clin- ical advance for couples planning their family size and for control of population growth. High-dosage parenteral testosterone (T) esters alone or in combination with a progestogen (eg, depot medroxypro- gesterone) have been shown to confer effective and reversible male contraception in clinical trials, but these regimens are associated with weight gain and suppression of serum high-density lipoprotein cholesterol (HDL) levels. We have previously demonstrated that in- tramuscular T enanthate 100 mg weekly plus oral levonorgestrel (LNG) 125, 250, or 500 mg daily suppresses spermatogenesis to levels associated with effective contraception, but there is a LNG- dosage-dependent effect of weight gain and HDL suppression. We hypothesized that intramuscular T enanthate 100 mg weekly plus a very low dosage of oral LNG would effectively suppress spermato- genesis in normal men without inducing weight gain or HDL sup- pression. We conducted a randomized trial comparing 6 months of intramuscular T enanthate (100 mg weekly) plus 31.25 mg of oral LNG daily (T1LNG 31; n 5 20) or 62.5 mg of oral LNG daily (T1LNG 62; n 5 21). The 2 regimens were equally effective in suppressing spermatogenesis to azoospermia, fewer than 1 million sperm/mL and fewer than 3 million sperm/mL (T1LNG 31 (60%, 85%, and 90%) vs T1LNG 62 (62%, 91%, and 95%) for azoospermia, fewer than 1 million and fewer than 3 million, respectively; P 5 NS). The T1LNG 31 group did not gain weight (0.25 6 1.08 kg; P 5 NS compared with baseline), but the T1LNG 62 group gained 2.5 6 0.77 kg (P , .05 compared with baseline). Serum HDL cholesterol levels declined significantly in both groups (percentage decline month 6 of treatment vs baseline: 12.0% 6 2.6% and 15.1% 6 3.0%; P , .05 for T1LNG 31 and 62 respectively). Serum low-den- sity lipoprotein cholesterol levels also declined in both groups (per- centage decline month 6 of treatment vs baseline: 6.9 6 3.9 and 6.0% 6 4.1%; P , .05 for T1LNG 31 and P 5 NS for T1LNG 62). There were no clinically significant adverse events or significant changes in hematology or chemistry profiles in either group during the study. We conclude that 1) intramuscular T plus oral LNG has a very potent synergistic effect in suppressing spermatogenesis at LNG dosages equal to or lower than dosages used in common fe- male oral contraceptive regimens and 2) large, long-term contracep- tive efficacy trials should be conducted with a variety of androgen- progestogen combinations including long-acting T formulations such as depot T pellets or intramuscular T undecanoate plus depot LNG or very low dosage oral LNG.

In previous studies of testicular biopsy tissue from healthy men, intratesticular testosterone (ITT) has been shown to be much higher than serum testosterone (T), suggesting that high ITT is needed relative to serum T for normal spermatogenesis in men. However, the quantitative relationship between ITT and spermatogenesis is not known. To begin to address this issue experimentally, we determined the dose-response relationship between human chorionic gonadotropin (hCG) and ITT to ascertain the minimum dose needed to maintain ITT in the normal range. Twenty-nine men with normal reproductive physiology were randomized to receive 200 mg T enanthate weekly in combination with either saline placebo or 125, 250, or 500 IU hCG every other day for 3 wk. ITT was assessed in testicular fluid obtained by percutaneous fine needle aspiration at baseline and at the end of treatment. Baseline serum T (14.1 nmol/liter) was 1.2% of ITT (1174 nmol/liter). LH and FSH were profoundly suppressed to 5% and 3% of baseline, respectively, and ITT was suppressed by 94% (1234 to 72 nmol/liter) in the T enanthate/placebo group. ITT increased linearly with increasing hCG dose (P < 0.001). Posttreatment ITT was 25% less than baseline in the 125 IU hCG group, 7% less than baseline in the 250 IU hCG group, and 26% greater than baseline in the 500 IU hCG group. These results demonstrate that relatively low dose hCG maintains ITT within the normal range in healthy men with gonadotropin suppression. Extensions of this study will allow determination of the ITT concentration threshold required to maintain spermatogenesis in man.

The goal of this study was to find the most favorable injection interval of norethisterone enanthate (NETE) plus testosterone undecanoate (TU) in terms of gonadotropin, sperm suppression, and prostatic effects. Fifty normal men were randomly assigned to receive NETE 200 mg plus TU 1000 mg every 8 wk (n = 10), every 12 wk (n = 10), every 6 wk for 12 wk and then every 12 wk (n = 10), and every 6 wk for 12 wk and thereafter TU 1000 mg plus placebo every 12 wk (n = 10), and placebo plus placebo every 6 wk for 12 wk and then every 12 wk (n = 10) for 48 wk. Semen analyses, blood drawings, physical examinations, and prostate ultrasounds were performed throughout the study. Of the men in the 8-wk injection group, 90% (nine of 10) achieved azoospermia, compared with 37.5% (three of eight) in the 12-wk injection group (P = 0.019). TU plus placebo injected every 12 wk did not maintain sperm suppression. Prostate volumes did not change significantly in either group. In conclusion, these data suggest that the combined administration of NETE and TU at 8-wk intervals represents an effective hormonal contraceptive regimen.

Testosterone (T) therapy in older men with low serum T levels increases lean body mass and decreases fat mass. These changes might improve physical performance and strength; however, it has not been established whether T therapy improves functional outcome in older men. Moreover, concerns exist about the impact of T therapy on the prostate in older men. The administration of finasteride (F), which partially blocks the conversion of T to the more potent androgen, dihydrotestosterone, attenuates the impact of T replacement on prostate size and prostate-specific antigen. We hypothesized that T replacement in older, hypogonadal men would improve physical function and that the addition of F to this regimen would continue to provide the T-induced improvements in physical performance, strength, and body composition. Seventy men with low serum T (350 ng/dl), age 65 yr and older, were randomly assigned to receive one of three regimens for 36 months: 1) T enanthate, 200 mg im every 2 wk, with placebo pills daily (T-only); 2) T enanthate, 200 mg every 2 wk, with 5 mg F daily (T + F); or 3) placebo injections and pills (placebo). We obtained serial measurements of timed physical performance, grip strength, lower extremity strength, body composition (by dual-energy x-ray absorptiometry), fasting cholesterol profiles, and hormones. Fifty men completed the 36-month protocol. After 36 months, T therapy significantly improved performance in a timed functional test when compared with baseline and placebo [4.3 +/- 1.6% (mean +/- sem, T-only) and 3.8 +/- 1.0% (T + F) vs. -5.6 +/- 1.9% for placebo (P0.002 for both T and T + F vs. placebo)] and increased handgrip strength compared with baseline and placebo (P0.05). T therapy increased lean body mass [3.77 +/- 0.55 kg (T-only) and 3.64 +/- 0.56 kg (T + F) vs. -0.21 +/- 0.55 kg for placebo (P0.0001)], decreased fat mass, and significantly decreased total cholesterol, low-density lipoprotein, and leptin, without affecting high-density lipoprotein, adiponectin, or fasting insulin levels. These results demonstrate that T therapy in older men with low serum T improves physical performance and strength over 36 months, when administered alone or when combined with F, and suggest that high serum levels of dihydrotestosterone are not essential for these beneficial effects of T in men.

Objective: To determine the contribution of conversion of testosterone (T) to estradiol on cognitive processing in a population of healthy older men who received T supplementation. Methods: Sixty healthy, community-dwelling volunteers aged 50 to 90 years completed a randomized, double-blind, placebo-controlled study. Participants were randomized to receive weekly IM injections of 100 mg T enanthate plus daily oral placebo pill (T group, n = 20), 100 mg testosterone enanthate plus 1 mg daily of anastrozole, an aromatase inhibitor (oral pill), to block the conversion of T to estradiol (AT group, n = 19), or saline injection and placebo pill (placebo group, n = 21) for 6 weeks. Cognitive evaluations using a battery of neuropsychological tests were conducted at baseline, week 3 and week 6 of treatment, and after 6 weeks of washout. Results: Circulating total T was increased from baseline an average of 238% in the T and AT treatment groups. Estradiol increased an average of 81% in the T group and decreased 50% in the AT group during treatment. Significant improvements in spatial memory were evident in the AT and T treatment groups. However, only the group with elevated estradiol levels (T group) demonstrated significant verbal memory improvement. Conclusion: In healthy older men, improvement in verbal memory induced by testosterone administration depends on aromatization of testosterone to estradiol, whereas improvement in spatial memory occurs in the absence of increases in estradiol.

We postulated that the addition of a combined types I and II, 5alpha-reductase inhibitor (dutasteride) or long-acting GnRH antagonist (acyline) to combination testosterone plus levonorgestrel treatment may be advantageous in the suppression of spermatogenesis for male contraception. This study aimed to examine effects of novel combination contraceptive regimens on serum gonadotropins and androgens and sperm concentration.This study was divided into three phases: screening (2 wk), treatment (8 wk), and recovery (4 wk). Twenty-two men (n = 5-6/group) received 8 wk of treatment with testosterone enanthate (TE, 100 mg im weekly) combined with one of the following: 1) levonorgestrel (LNG) 125 mug orally daily; 2) LNG 125 microg plus dutasteride 0.5 mg orally daily; 3) acyline 300 microg/kg sc every 2 wk (as a comparator for any additional progestin effects); or 4) LNG 125 microg orally daily plus acyline 300 microg/kg sc every 2 wk. Serum gonadotropin levels were similarly suppressed by all treatments, falling to a nadir between 1.2 and 3.4% and 0.5 and 0.8% baseline for FSH and LH, respectively (P < 0.05). Serum dihydrotestosterone levels were significantly (P < 0.05) decreased in the dutasteride group throughout the treatment period to a nadir of 31% baseline (wk 7). No significant differences in sperm concentrations among treatment groups were seen. Severe oligospermia (0.1-3 million/ml) or azoospermia was seen in none of five and four of five in TE + LNG; two of six and four of six in TE + LNG + dutasteride; two of six and four of six in TE + acyline; and one of five and three of five in TE + LNG + acyline groups, respectively. There was one nonresponder in each of the TE + LNG and TE + LNG + acyline groups.We conclude that the addition of a combined types I and II, 5alpha-reductase inhibitor or long-acting GnRH antagonist to a testosterone plus LNG regimen provides no additional suppression of gonadotropins or sperm concentration over an 8-wk treatment period. However, further evaluation of the effects of these regimens on the testis (including testicular steroid levels and germ cell maturation) and the treatment of larger numbers of men (and for longer periods) may provide data to support their place in contraceptive development.

Monthly injections of testosterone undecanoate (TU) act as a male contraceptive by reversibly suppressing spermatogenesis to azoospermia or severe oligoazoospermia in 95% of Chinese men. In 5% of Chinese men, however, monthly TU administered alone fails to suppress spermatogenesis into contraceptive ranges, or sperm "rebound," leading to occurrences of pregnancy during treatment. Since combinations of progestins and androgens are associated with greater degrees of sperm suppression in white men, we hypothesized that the combination of TU and the progestin levonorgestrel (LNG) would result in improved spermatogenic suppression in Chinese men. Sixty-two healthy Chinese men were randomly assigned to one of the following 3 regimens: group I (n = 21) received 4 LNG rods (75 mg each), which were followed 4 weeks later by 500 mg of TU by intra-muscular (IM) injection every 8 weeks for 24 weeks; group II (n = 20) received 4 LNG implants, which were followed 4 weeks later by 1000 mg of TU by IM injection every 8 weeks for 24 weeks; and group III (n = 21) received TU 1000 mg by IM injection every 8 weeks for 24 weeks. Sperm counts, serum testosterone (T), luteinizing hormone, follicle-stimulating hormone, and LNG were measured every 2 weeks before, during, and after treatment. During treatment, group II demonstrated a trend toward a greater attainment of azoospermia than groups I and III (90% vs 62% [group I] vs 67% [group III]; P =.09). Attainments of either azoospermia or oligozoospermia (sperm density,3 x 10(6)/mL) were 95%, 100%, and 86% for groups I, II, and III, respectively (P.05 for comparisons between groups). Spermatogenesis in all subjects returned to the normal range after the implants were removed. No serious adverse events and no significant changes in serum chemistry occurred during the study. These results demonstrate that the combination of IM injections of high-dose TU every 2 months and LNG implants is associated with marked suppression of spermatogenesis in Chinese men. The combination of high-dose TU every 2 months and LNG implants is a promising candidate for future large-scale efficacy studies of hormonal male contraception in Chinese men.

Author(s): Luderer, Ulrike; Bushley, Abigail; Stover, Bert D; Bremner, William J; Faustman, Elaine M; Takaro, Timothy K; Checkoway, Harvey; Brodkin, Carl Andrew | Abstract: BackgroundLittle is known about the effects of organic solvents on male reproductive health. To assess fertility and reproductive endocrine function in solvent-exposed men, we investigated time-to-pregnancy using a retrospective cohort design and cross-sectionally measured reproductive hormone concentrations in painters and millwrights compared to a reference group of carpenters.MethodsDetailed occupational, exposure, medical, and time-to-pregnancy histories were obtained by telephone interview. Plasma luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone concentrations were determined by immunoassay. Exposure indices, which summarized working life exposure to total solvents, chlorinated solvents, aromatic solvents, and thinners, degreasers, varnishes, and adhesives as a category were calculated from exposure histories.ResultsFSH concentrations increased significantly with increasing exposure indices for all solvents and for chlorinated solvents. There were no significant associations of solvent exposure indices with LH or testosterone levels. LH, FSH, and testosterone concentrations also did not differ by job title. Using Cox regression, time-to-pregnancy was non-significantly longer in the painters and millwrights than the carpenters. There was no significant association between time-to-pregnancy and any of the solvent exposure indices; however, it should be noted that some of the pregnancies occurred more than 20 years previously, potentially reducing the reliability of the retrospectively collected pregnancy and exposure data.ConclusionsThe significant associations between FSH levels and solvent exposure indices suggest the potential for adverse effects of solvent exposures on reproductive function in men.

In this study we evaluated whether testosterone undecanoate (TU), alone or combined with low dose cyproterone acetate (CPA), can maintain spermatogenic suppression induced by higher doses of CPA plus TU. Twenty-four men received for 12 wk 20 mg/d CPA plus 1000 mg/6 wk TU and then 1000 mg/8 wk TU plus 20 mg/d CPA (n = 8), 2 mg/d CPA (n = 8), or plus placebo (n = 8) for 32 wk. Blood samples, physical examinations, hormones, chemistry, hematology, semen analysis, and sexual/behavioral assessments were performed throughout the study. Sperm counts decreased to less than 1 million/ml in all subjects by wk 12, and 54% of them achieved azoospermia. Suppression of sperm counts was maintained until wk 44. Serum LH and FSH levels were suppressed by wk 12 of hormone administration and remained suppressed until wk 44. No significant changes in any biochemical parameters were detected at wk 44 in any group. There was a slight increase in total prostate volume to within the normal range at wk 44 that returned to baseline 1 yr after stopping hormone administration. In conclusion, TU alone or combined with lower doses of CPA maintains sperm suppression induced by higher dose CPA plus TU for 32 wk. This prototype regimen represents a promising male contraceptive regimen.

Development of a safe and effective oral form of testosterone has been inhibited by the rapid hepatic metabolism of nonalkylated androgens. Since triglycerides are absorbed via lymphatics and bypass the liver, we hypothesized that a testosterone-triglyceride conjugate (TTC) might allow for safe and effective oral testosterone therapy. Therefore, we studied the single-dose pharmacokinetics of oral administration of TTC in rabbits. Female New Zealand rabbits were administered 2, 4, or 8 mg/kg of TTC in sesame oil by gastric lavage. Testosterone undecanoate (TU) by gastric lavage was used as a positive control. Blood was sampled from a catheter in the auricular artery at 0, 15, 30, 60, 90, 120, 180, 240, 360, 480, and 600 minutes after drug administration. Samples were assayed for testosterone by a fluoroimmunoassay. Mean serum testosterone, area under the curve (AUC), and terminal half-life were calculated. Oral TTC administration resulted in rapid and marked increases in serum testosterone. Oral TTC resulted in higher maximum serum testosterone concentrations than oral TU at 8 mg/kg (TTC: 28.6 +/- 7.9 nmol/L vs TU: 11.9 +/- 2.1 nmol/L; P

In the adult male, the testes produce both sperm and testosterone. The function of the testicles is directed by the central nervous system and pituitary gland. Precise regulation of testicular function is conferred by an elegant feedback loop in which the secretion of pituitary gonadotropins is stimulated by gonadotropin hormone-releasing hormone (GnRH) from the hypothalamus and modulated by testicular hormones. Testosterone and its metabolites estradiol and dihydrotestosterone (DHT) as well as inhibin B inhibit the secretion of the gonadotropins both directly at the pituitary and centrally at the level of the hypothalamus. In the testes, LH stimulates testosterone synthesis and FSH promotes spermatogenesis, but the exact details of gonadotropin action are incompletely understood. A primary goal of research into understanding the hormonal regulation of testicular function is the development of reversible, safe and effective male hormonal contraceptives. The administration of exogenous testosterone suppresses pituitary gonadotropins and hence spermatogenesis in most, but not all, men. The addition of a second agent such as a progestin or a GnRH antagonist yields more complete gonadotropin suppression; such combination regimens effectively suppress spermatogenesis in almost all men and may soon bring the promise of hormonal male contraception to fruition.

OBJECTIVES: Older patients undergoing knee replacement surgery can recover more slowly than younger patients and require extended rehabilitation. Because administration of supraphysiological testosterone (T) dramatically increases strength, we hypothesized that preoperative T therapy would improve functional recovery and reduce hospital stay in older men undergoing knee replacement surgery. DESIGN: Double-blinded, placebo-controlled pilot trial. SETTING: A Veterans Affairs orthopedics clinic and inpatient postoperative unit. PARTICIPANTS: Twenty-five men, mean age 70, undergoing elective knee replacement. INTERVENTION: Preoperative, supraphysiological T administration (600 mg T enanthate intramuscularly weekly for 4 weeks) or sesame oil placebo. MEASUREMENTS: Length of hospital stay and functional ability by Functional Independence Measure (FIM) score. RESULTS: Mean length of hospital stay ± standard deviation was nonsignificantly reduced in the T group (5.9 ± 2.4 days vs 6.8 ± 2.5 days; P = .15). At postoperative Day 3, there was a significant improvement in ability to stand (mean FIM score 5.2 ± 1.0 vs 4.0 ± 1.1; P = .04) and trends towards improvements in walking and stair climbing in the T group. There were no complications attributable to T therapy. CONCLUSIONS: In older men undergoing knee replacement surgery, preoperative supraphysiological T administration may confer some clinical benefit. Future studies using longer courses of preoperative T administration in larger numbers of older men undergoing knee replacement surgery are warranted.

In this study we compared the effects of high-dose and low-dose testosterone enanthate (TE) administered with the same dose of cyproterone acetate (CPA). Eighteen men aged 21-45 were treated with CPA 5 mg/day and with TE 100 mg/week (n = 9; CPA-5-100) or TE 200 mg/week (n = 9; CPA-5-200) for 16 weeks. Semen analyses were performed every 2 weeks; physical examination and chemistry, hematology, gonadotropin, and testosterone measurements were performed every 4 weeks. At week 16 of treatment, sperm counts were significantly more suppressed in the CPA-5-100 group than in the CPA-5-200 group. Sperm counts returned to baseline in all subjects after hormone administration ceased. No difference in gonadotropin levels was found at any time between the 2 groups. During the treatment phase, testosterone levels were significantly higher in the CPA-5-200 group than in the CPA-5-100 group. The present study confirms that CPA/TE administration induces profound sperm suppression. An increase in the dose of androgen resulted in less profound sperm suppression despite no difference in gonadotropin suppression. These data suggest that high testosterone levels can maintain sperm production in men.

Weekly intramuscular administration of testosterone esters such as testosterone enanthate (TE) suppresses gonadotro- pins and spermatogenesis and has been studied as a male contra- ceptive. For unknown reasons, however, some men fail to achieve azoospermia with such regimens. We hypothesized that either 1) daily circulating serum fluoroimmunoreactive gonadotropins were higher or testosterone levels were lower during the weekly injection interval, or 2) monthly circulating bioactive gonadotropin levels were higher in nonazoospermic men. We therefore analyzed daily testos- terone and fluoroimmunoreactive gonadotropin levels as well as pooled monthly bioactive and fluoroimmunoreactive gonadotropin levels in normal men receiving chronic TE injections and correlated these levels with sperm production. After a 3-month control period, 51 normal men were randomly assigned to receive intramuscular TE at 25 mg (n 10), 50 mg (n 9), 100 mg (n 10), 300 mg (n 10), or placebo (n 12) weekly for 6 months. After 5 months of testosterone administration, morning testosterone and fluoroimmu- noreactive follicle-stimulating hormone (FSH) and luteinizing hor- mone (LH) levels were measured daily for a 1-week period between TE injections. In addition, fluoroimmunoreactive and bioactive FSH and LH levels were measured in pooled monthly blood samples drawn just before the next TE injection. In the 100-mg and 300-mg TE groups, mean monthly fluoroimmunoreactive FSH and LH levels were suppressed by 86%-97%, bioactive FSH and LH levels by 62%-80%, and roughly half the subjects became azoospermic. In the 1-week period of month 6, daily testosterone levels between TE injections were within the normal range in men receiving placebo, or 25 or 50 mg of weekly TE, but were significantly elevated in men receiving 100 or 300 mg of weekly TE. At no point during treatment, however, were there significant differences in daily testosterone or fluoroimmunoreactive gonadotropin levels, or monthly bioactive go- nadotropin levels between men achieving azoospermia and those with persistent spermatogenesis. This study, therefore, demon- strates that neither monthly nor daily differences in serum testoster- one, or fluoroimmunoreactive or bioactive gonadotropins explain why some men fail to completely suppress their sperm counts to zero with weekly TE administration. Innate differences in the testi- cle's ability to maintain spermatogenesis in a low-gonadotropin en- vironment may explain persistent spermatogenesis in some men treated with androgen-based contraceptive regimens.

Objective: To determine the relationship between exogenous testosterone administration and cognitive abilities in a population of healthy older men. Background: Serum levels of total and bioavailable testosterone gradually decrease with age in men and are associated with reductions in muscle mass, osteoporosis, decreased sexual activity, and changes in cognition. Methods: Twenty-five healthy, community-dwelling volunteers, aged 50 to 80 years, completed a randomized, double-blind, placebo-controlled study. Participants received weekly intramuscular injections of either 100 mg testosterone enanthate or placebo (saline) for 6 weeks. Cognitive evaluations were conducted at baseline, week 3, and week 6 of treatment by use of a battery of neuropsychologic tests. Results: Circulating total testosterone was raised an average of 130% from baseline at week 3 and 116% at week 6 in the treatment group. Because of aromatization of testosterone, estradiol increased an average of 77% at week 3 and 73% at week 6 in the treatment group. Significant improvements in cognition were observed for spatial memory (recall of a walking route), spatial ability (block construction), and verbal memory (recall of a short story) in older men treated with testosterone compared with baseline and the placebo group, although improvements were not evident for all measures. Conclusions: The results suggest that short-term testosterone administration enhances cognitive function in healthy older men. However, it remains unclear whether these improvements in cognition are attributable to increased testosterone or estradiol levels, or both. The potential role of testosterone vs its metabolites on cognition requires further research.

Human male hormonal contraceptive regimens do not consistently induce azoospermia, and the basis of this variable response is unclear. This study used nine adult macaque monkeys (Macaca fascicularis) given testosterone (T) implants for 20 weeks to study changes in germ cell populations in relation to sperm output. Germ cell numbers were determined using the optical disector stereological method. Four animals achieved consistent azoospermia (azoo group), whereas five animals did not (nonazoo group). T-induced gonadotropin suppression in all animals decreased A pale (Ap) spermatogonia to 45% of baseline within 2 weeks, leading to decreased B spermatogonia (32--38%) and later germ cells (20--30%) after 14 and 20 weeks. Though the reduction in later germ cell types could be primarily attributed to the loss of spermatogonia, the data suggested that some cells were lost during the spermatocyte and spermatid phase of development. B spermatogonial number was more markedly suppressed in azoospermic animals, compared with the nonazoo group, as was the conversion ratio between Ap and B spermatogonia. Abnormal retention of elongated spermatids (failed spermiation) was also prominent in some animals after long-term T administration. We conclude that: 1) the variable suppression of sperm output is attributed to the degree of inhibition of germ cell development from type B spermatogonia onwards, and this is related to the degree of FSH suppression; and 2) inhibition of Ap and B spermatogonial development and of spermiation are the major defects caused by long-term T administration to monkeys.

This is a pilot dose-finding study of spermatogenic suppression using testosterone undecanoate (TU) injections alone in normal Chinese men. Thirty-two healthy men were recruited. Volunteers underwent pretreatment evaluation, then a treatment period in which group I (n = 13) received 500 mg TU, group II (n = 12) received 1000 mg TU, and group III (n = 7) received placebo, respectively, at monthly intervals during the treatment period (or until azoospermia was achieved). Thereafter, they underwent a recovery period until all parameters returned to pretreatment levels. Eleven of 12 volunteers in the 500-mg TU group, and all volunteers in the 1000-mg TU group became azoospermic. Faster suppression of spermatogenesis was achieved in the 1000-mg TU group. Serum testosterone increased significantly in the higher dose group at weeks 8 and 12, but remained within the normal range. Mean serum LH and FSH were profoundly suppressed by both doses to undetectable levels at week 16. TU injections did not cause a significant change in high density lipoprotein cholesterol levels. No serious side-effects were found. We conclude that both dosages of TU can effectively, safely, and reversibly suppress spermatogenesis in normal Chinese men.

7alpha-Methyl-19-nortestosterone (MENT) is a potent synthetic androgen that cannot be converted to dihydrotestosterone. In this study we determined the relative androgenic, antigonadotropic, and anabolic potencies of testosterone vs. MENT in the nonhuman primate M. fascicularis. In castrated monkeys, dose-response relationships were generated for the effects of testosterone and MENT on gonadotropin levels, prostate growth, body weight, and lipid metabolism. In a pilot study, four monkeys were castrated, and magnetic resonance imaging (MRI) was used to document a 50% loss of prostate volume within 8 weeks, verifying that MRI is a reliable means to measure prostate size in this species. Two additional groups of six monkeys each were then castrated and serially administered four graded dosages of testosterone or MENT via osmotic minipumps over 20 weeks. Complete suppression of LH was achieved with a minimum of 0.3 mg/day MENT, compared to 3.0 mg/day testosterone. MENT supported body weight 10 times more potently than did testosterone. Baseline prostate volumes were maintained with 0.1-0.2 mg/day MENT vs. 0.3 mg/day testosterone. Thus, in monkeys, MENT is 10 times more potent than testosterone with regard to the clinically desirable end points of gonadotropin suppression and anabolism, but only twice as potent at stimulating prostate growth. These results suggest that MENT may have a wider therapeutic index than testosterone for human androgen replacement and male contraception.

Testosterone functions as a contraceptive by suppressing secretion of the pituitary gonadotropins luteinizing hormone and follicle stimulating hormone. Low levels of these hormones decrease endogenous testosterone secretion from the testis and deprive developing sperm of the signals required for normal maturation. Interference with sperm maturation causes a decline in sperm production and can lead to reversible infertility in men, raising the possibility that testosterone could be utilized in a commercially available contraceptive. To this end, testosterone has been studied alone and in combination with either gonadotropin releasing hormone analogues or progestins in efforts to improve its contraceptive efficacy. In this chapter, we will review efforts to use testosterone to create a safe, convenient, efficacious contraceptive method for men.This article reviews efforts promoting the use of testosterone (TE) as a safe, convenient and an efficacious contraceptive method for men. In order to assess the efficacy of a potential male contraceptive, it is important to determine what level of sperm inhibition is necessary to achieve infertility. In efforts to improve its contraceptive efficacy, the following contraceptive trials have been studied: TE alone; TE and gonadotropin releasing hormone (GnRH) analogues; and TE and progestins. TE requires weekly injections, which is a significant drawback. Thus, longer-acting esters, such as 19-nortestosterone and its derivative 7-alpha-methyl-19-nortestosterone, have been evaluated as potential substitutes for TE. Moreover, several advances have been made in understanding estrogen activity at the molecular level. This article concludes that TE is useful as contraceptive in human males; combinations with GnRH antagonists improve the efficacy of TE, although impractical for widespread use; and TE with progestins may also be promising. Furthermore, recent insights into the molecular regulation of transcription by estrogen receptors may point to the existence of a similar complexity in the androgen receptor and may provide new avenues for the generation of a male hormonally-derived contraceptive. A better understanding of the molecular regulation of spermatogenesis will clearly increase the chances of successfully manipulating these systems to create an easily usable, long-term contraceptive for men and to complement the success of the estrogen-progestin pill for women.

Objective: To determine whether immature spermatids increase in semen in response to hormonal contraceptive treatments. Such a finding would support the existence of a defect in spermiogenesis, which in turn may explain the reported variability in sperm output. Design: Semen smears were obtained from healthy men undergoing randomized control trials of T plus progestin contraceptive treatments. Patient(s): Healthy men (21–49 years) with normal semen analyses received T (50–100 mg IM weekly) in combination with either desogestrel (150–300 μg daily, ( n = 5) or levonorgestrel (125–250 μg daily, n = 10) for 24 weeks. Semen smears were made during spermatogenic suppression and recovery. Nine control subjects were also assessed. Main Outcome Measure(s): Semen analyses were performed using World Health Organization criteria. Immature spermatids and white blood cells in semen were identified by immunostaining with monoclonal antibodies to the human intra-acrosomal antigen SP-10 and the ubiquitous white cell CD-45 antigen, respectively. Result(s): In a total of 14 normal ejaculates (9 control and 5 pretreatment) 74 ±14 million/mL sperm (mean ±SEM) were seen together with a few immature spermatids (0.69 ± 0.20 million/mL). During contraceptive treatments, spermatid number decreased in parallel with the sperm concentration and spermatids disappeared in most subjects. No significant changes were seen in either leukocyte or immunonegative round cell concentration (0.41 ± 0.25 and 0.25 ± 0.09 million/mL in controls, respectively) in response to treatments. Conclusion(s): Spermatid sloughing, as assessed by the ejaculation of immature spermatids, is not a feature of T-induced spermatogenic regression in men; rather, the decline in both mature and immature germ cells in the ejaculate probably results from a decline in the number of precursor cells, ultimately resulting in severe oligoor azoospermia. Detailed studies on the sites of spermatogenic interruption are required to understand the variability in responses seen after contraceptive therapies in men.

Most cross-sectional studies and one recent longitudinal study suggest that testosterone levels in healthy men decline slowly and that this decline begins during middle age. The decline in "free" or unbound testosterone is greater than the decline in total testosterone levels. Physiologic sequellae of lower testosterone levels may include a decrease in muscle mass, increase in body fat, decreased bone density, and a variety of changes in sexual function. Long-term studies of androgen replacement are currently in progress. Short-term studies suggest that, for some men, androgen replacement may increase libido and muscle strength and decrease abdominal fat. The available data suggest that androgens do not generally worsen symptoms of prostatic hypertrophy or stimulate the development of prostate cancer. Lipid profiles may be slightly improved during androgen replacement, but the long-term effects of androgens on the cardiovascular system are unknown. Hematocrit and hemoglobin frequently rise in response to ...

Testosterone enanthate (TE) administration is associated with a failure rate (3.4/100 person-years) considerably lower than that of other currently available reversible male contraceptive methods. However acceptability of this regimen is limited by the need for weekly injections the lack of complete azoospermia and the decrease in high-density lipoprotein (HDL)-cholesterol. Under investigation is the concurrent administration of a progestin that can act synergistically with TE in the suppression of gonadotropins. Because of the additive effects the dose of each steroid can be decreased minimizing androgen-related side effects. Third-generation progestins and hybrid progestins seem to offer the most potential for such an approach. In particular the combination of cyproterone acetate (CPA) and TE has been found to result in a rapid profound suppression of spermatogenesis without side effects through its ability to block both the follicle-stimulating hormone and androgen effects at the testis level. The anti-androgenic action of CPA is based on its ability to competitively inhibit the binding of testosterone and dehydrotestosterone to androgen receptors. The block of intratesticular testosterone effect by CPA is presumed to cause a decrease in cell-adhesion molecule concentrations and contribute to the premature sloughing of permatids from the seminiferous epithelium thereby resulting in the early disappearance of spermatozoa from the ejaculate. This regimen did not cause any changes in plasma HDL or other lipoproteins or affect liver function test results.

Development of a male hormonal contraceptive has been challenging ascribable to the failure to adequately suppress spermatogenesis in 5-10% of men. Methods to identify incomplete suppressors early in treatment might identify men most responsive to male hormonal contraceptives. We hypothesized that serum hormone and gonadotropin concentrations after 4 weeks of transdermal treatment with testosterone and Nestorone in a contraceptive trial would be associated with suppression of sperm concentrations to

The concentration of intratesticular testosterone (IT-T) required for human spermatogenesis is unknown because spermatogenesis can persist despite the markedly reduced IT-T concentrations observed with LH suppression. Methods to lower IT-T further are needed to determine the relationship between IT-T and spermatogenesis.The objective of the study was to determine the effect of inhibiting the synthesis and metabolism of testosterone (T) on IT-T in gonadotropin-suppressed human testes.Forty normal men participated in a blinded, placebo-controlled, randomized trial at an academic center. INTERVENTION/OUTCOME MEASURES: All men were first administered the GnRH antagonist acyline to suppress LH. Forty-eight hours after acyline administration, subjects were randomly assigned to placebo, ketoconazole (to inhibit T synthesis) at 400 or 800 mg, dutasteride (to inhibit T metabolism) 2.5 mg, or anastrazole (to inhibit T metabolism) 1 mg, daily for 7 days (n = 8/group). Intratesticular steroid concentrations were measured 48 hours after acyline administration alone and again after 7 days of combination treatment.After 7 days of combination treatment, the median IT-T (25th, 75th percentile) in the placebo group was 14 (8.0, 21.2) ng/mL. IT-T was reduced to 3.7 (2.5, 7.1) ng/mL in the ketoconazole 400 mg group and 1.7 (0.8, 4.0) ng/mL in the ketoconazole 800 mg group (P.001 vs placebo for both comparisons). IT-T concentrations in the dutasteride and anastrazole groups were similar to placebo.Combining inhibition of steroidogenesis with gonadotropin suppression lowers IT-T more than gonadotropin suppression alone. This combination might be useful to determine the minimum IT-T concentration necessary for human spermatogenesis, information essential for developing male hormonal contraceptives.

Studies using high dose testosterone (T) administration in normal men as a male contraceptive have resulted in azoospermia rates of only 50-70%. Previous studies of T and progestogen combinations have shown comparable rates of azoospermia, but have been uncontrolled or used T in doses less than that associated with maximal suppression of sperm production. We conducted a randomized, placebo-controlled, single blind trial comparing 6 months of T enanthate administration (100 mg, im, weekly) with the same dose of T enanthate in conjunction with the progestogen levonorgestrel (LNG; 500 micrograms, orally, daily) in 36 normal men, aged 20-42 yr (n = 18 in each group). The primary end points were induction of azoospermia or severe oligospermia (3 million sperm/mL). The combination of T plus LNG was much more effective in suppressing sperm production than T alone. Sixty-seven percent of the T plus LNG group (12 of 18) and 33% of the T alone group (6 of 18) achieved azoospermia by 6 months (P = 0.06). Severe oligospermia or azoospermia developed in 94% of the T plus LNG (17 of 18) group compared to 61% of the T alone group (11 of 18; P0.05). T plus LNG also suppressed sperm production more rapidly than T alone. Time to azoospermia was 9.9 +/- 1.0 vs. 15.3 +/- 1.9 weeks in the T plus LNG and T alone groups, respectively (mean +/- SEM; P0.05). Serum high density lipoprotein cholesterol decreased 21.7 +/- 3.6% in men given T plus LNG (P0.05), compared to only a 1.8 +/- 3.8% decrease in men in the T alone group. Average weight gain was 5.3 +/- 0.8 kg in the T plus LNG group and 2.3 +/- 0.9 kg in the T alone group (P0.05). Acne and increase in hemoglobin were similar in the two groups. We conclude that combination hormonal therapy with T plus a progestogen might offer a reversible male contraceptive approach with a more rapid onset of action and more reliable induction of both azoospermia and severe oligospermia than T alone.In Washington State, 36 men aged 20-42 years were randomly allocated to either the group receiving intramuscular injection of 100 mg/week testosterone (T) enanthate alone or to the group receiving the same dose T plus oral 500 mcg/day levonorgestrel (LNG). This 6-month, placebo-controlled, single blind trial aimed to compare the effectiveness of both regimes in suppressing sperm production. The combination of T plus LNG was more likely than T alone to achieve severe oligospermia or azoospermia in 6 months (94% vs. 61%; p .05). It also achieved azoospermia more quickly than T alone (9.9 vs. 15.3 weeks; p .05). Men in the T plus LNG group experienced greater reduction in serum high density lipoprotein than those in the T alone group (21.7% vs. 1.8%; p .05). They also gained more weight than those in the T alone group (5.3 vs. 2.3 kg; p .05). The two groups experienced a similar rate for acne and increase in hemoglobin. The increase in hemoglobin was significant for both groups. In conclusion, T plus LNG treatment over a 6-month period is a more effective and quicker acting method than T alone for suppressing sperm production to levels low enough to prevent pregnancy.

The concept that androgen alone can provide an effective male contraceptive has been tested in a multicentre, multiphase trial by the World Health Organization. Results from this trial showed that an ester of testosterone, testosterone enanthate (TE), administered at a dose of 200 mg/week, has a very high contraceptive efficacy, and suggested that, at least in some populations, androgen alone might provide a viable option for the control of male fertility. It has been claimed that testosterone represents one of the gender-related risk factors for coronary artery disease (CAD) in men. Epidemiological and interventional studies have failed to establish a convincing relationship between testosterone and high density lipoprotein cholesterol (HDL-C). Therefore, there is concern about possible negative effects on lipoprotein asset of an androgen-alone male contraceptive. In this study we analysed the effects of long-term (12 months) administration of TE (200 mg/week) in normal healthy men. Blood samples (six men > 10 h fast = Group 1; 30 men > 4 h fast = Group 2) were drawn from 36 men, monthly before the beginning of the injections (control), every 3 months throughout the study period (treatment), and 1 month after stopping TE injections (recovery). Total cholesterol (chol), triglycerides, HDL-C and LDL-C levels were measured in these samples. Biochemical parameters were also monitored. TE administration induced a significant decrease (15-20%) in HDL-C levels that was of comparable magnitude in men from both groups (fasting and non-fasting) and occurred regardless of basal HDL-C levels. No statistically significant effect on other lipoproteins was detected. Considering all men together, HDL-C levels were decreased in 78% of the men by month 3, 83% by month 6, 94% by month 9 and 97% by month 12 of treatment. In all men the HDL-C decrease was reversible within 1 month of stopping TE administration. It is concluded that: (1) injection of 200 mg TE/week causes a 15-20% decrease in HDL-C in normal men with no effect on other lipoproteins, (2) the suppressive effect of TE is maintained throughout the 1-year-injection period, and a direct relationship between the duration of TE administration and the proportion of men showing decreased HDL-C levels, was observed. (3) The HDL-C decrease was reversible within 1 month of stopping TE administration. These data will be important in designing further studies on male contraception, and in interpreting the relationship between testosterone levels, HDL-C levels and potential cardiovascular risk.

Objective To test the hypothesis that over a 4-week treatment period, Nal-Glu GnRH antagonist ([AcD2Nal 1 , D4ClPhe 2 , D3Pal 3 , Arg 5 , DGlu 6 [AA], DAla 10 ] GnRH) at a dose of 200 μ g/kg per day SC would suppress levels of immunologically active and biologically active LH and FSH more completely than a dose of 100 μ g/kg per day. Design Placebo controlled clinical study. Setting A university community. Subjects Thirty normal male volunteers. Interventions We administered Nal-Glu at doses of 0, 100, and 200 μ g/kg body weight per day in combination with T enanthate, 50 mg IM weekly, to separate groups of men (9 or 10 men per group) for 4 weeks. Results Serum levels of immunologically active and biologically active gonadotropins were suppressed similarly in both groups of men who received Nal-Glu; this suppression was significantly greater than in the men who received placebo + T. Local side effects were more severe in the Nal-Glu 200 μ g/kg per day group. Conclusions Administration of Nal-Glu in combination with T suppresses gonadotropins more completely than does T alone, but at doses > 100 μ g/kg, gonadotropins are not suppressed additionally with larger doses of Nal-Glu. Subjects experienced greater local discomfort and side effects with the higher dosage. These findings suggest that dosages of Nal-Glu of >100 μ g/kg per day may have no advantage over the 100- μ g/kg dose in a male contraceptive regimen.

Combinations of testosterone (T) and nestorone (NES; a nonandrogenic progestin) transdermal gels may suppress spermatogenesis and prove appealing to men for contraception.The objective of the study was to determine the effectiveness of T gel alone or combined with NES gel in suppressing spermatogenesis.This was a randomized, double-blind, comparator clinical trial conducted at two academic medical centers.Ninety-nine healthy male volunteers participated in the study.Volunteers were randomized to one of three treatment groups applying daily transdermal gels (group 1: T gel 10 g+NES 0 mg/placebo gel; group 2: T gel 10 g+NES gel 8 mg; group 3: T gel 10 g+NES gel 12 mg).The main outcome variable of the study was the percentage of men whose sperm concentration was suppressed to 1 million/ml or less by 20-24 wk of treatment.Efficacy data analyses were performed on 56 subjects who adhered to the protocol and completed at least 20 wk of treatment. The percentage of men whose sperm concentration was 1 million/ml or less was significantly higher for T+NES 8 mg (89%, P0.0001) and T+NES 12 mg (88%, P=0.0002) compared with T+NES 0 mg group (23%). The median serum total and free T concentrations in all groups were maintained within the adult male range throughout the treatment period. Adverse effects were minimal in all groups.A combination of daily NES+T gels suppressed sperm concentration to 1 million/ml or less in 88.5% of men, with minimal adverse effects, and may be further studied as a male transdermal hormonal contraceptive.

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.The objective of the study was to determine the molecular impact of MHC on intraprostatic androgen concentrations and androgen action.This was a single-blind, randomized, placebo-controlled study.The study was conducted at an academic medical center.32 healthy men aged 25-55 yr participated in the study.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.Serum and prostate androgen concentrations and prostate epithelial-cell gene expression were measured.Thirty men completed the study. Serum T levels were significantly increased in T-gel and T+D groups compared with baseline (P0.05) 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.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.

In addition to their use as replacement therapy for hypogonadal males, androgens, particularly testosterone (T), are being explored as potential hormonal male contraceptive agents, alone or in combination with other compounds. Androgens have regulatory effects on a variety of physiological systems in addition to gonadotropin secretion and spermatogenesis. Therefore, as hormonal contraceptive regiments that alter serum T levels are explored, it is important to evaluate their effects on these aspects of normal male physiology. The effects of exogenous T on suppression of spermatogenesis in 19 healthy men were recently compared, using a T dosage of 200 mg im/week for 20 weeks. Before treatment, the men were evaluated during a 3-month pretreatment period, and after treatment, they were followed for 4-6 months or until their sperm counts normalized. Because of the lack of information regarding the effects of exogenous T on nonreproductive physiology, we examined the effects of high-dose T on plasma lipids, calcium metabolism, and sexual behavior in our subjects. Mean serum T and estradiol levels increased significantly during the treatment period. Plasma high-density lipoprotein (HDL) cholesterol levels decreased significantly within the first month and remained suppressed during the duration of T administration. At the end of the treatment period, mean plasma HDL cholesterol had decreased by 13 +/- 2% (P < 0.05); plasma levels of HDL2, HDL3, and apoprotein AI also decreased significantly; mean levels of low density lipoprotein cholesterol and triglycerides were unchanged. After 1 month of the recovery period, plasma HDL levels had returned to the baseline range. Serum calcium levels decreased slightly during treatment; this decrease was statistically significant. Urinary calcium excretion did not change. Mean levels of serum intact PTH increased by 84 +/- 17% (P < 0.05) during T administration; in contrast, 25-hydroxyvitamin D levels decreased by 16 +/- 4% (P < 0.05), and 1,25-dihydroxyvitamin D levels did not change significantly. All markers of calcium metabolism returned to baseline during the posttreatment period. Little change was found in self-reported sexual and aggressive behaviors during the study. There was a trend toward increased arousal and spontaneous erections during T administration, but this did not reach statistical significance. Frequency of sexual intercourse, masturbation, and kissing and fondling did not change, nor was the subjects' satisfaction in their relationships affected by T administration. Mean body weight increased by 4.0 +/- 0.5 kg. Approximately half the men noted mild acne. Body weight and acne symptoms returned to baseline during the recovery period.(ABSTRACT TRUNCATED AT 400 WORDS)