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.     

Daily testosterone and gonadotropin levels are similar in azoospermic and nonazoospermic normal men administered weekly testosterone: implications for male contraceptive development.

Weekly intramuscular administration of testosterone esters such as testosterone enanthate (TE) suppresses gonadotropins and spermatogenesis and has been studied as a male contraceptive. 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 testosterone 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 fluoroimmunoreactive follicle-stimulating hormone (FSH) and luteinizing hormone (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 gonadotropin levels between men achieving azoospermia and those with persistent spermatogenesis. This study, therefore, demonstrates that neither monthly nor daily differences in serum testosterone, 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 testicle's ability to maintain spermatogenesis in a low-gonadotropin environment may explain persistent spermatogenesis in some men treated with androgen-based contraceptive regimens.     

Effects of ether anesthesia and surface-induced hypothermia on regional blood flow.

Regional blood flow and distribution of cardiac output (CO) were evaluated by the radioactive microsphere technique in seven rhesus monkeys prior to anesthesia, following the induction of deep ether anesthesia and throughout the cooling course during surface-induced hypothermia to temperatures of 20 degrees C. As given, deep ether anesthesia alone significantly decreased CO 10% to 15% and output fraction (Qt) was decreased to the carcass, increased to the splanchnic circulation (although not statistically significant), and unchanged to other organs, while total vascular (TVR) and organ resistances were reduced. With the addition of cooling, CO progressively decreased. Individual organ Qt's, however, did not change from anesthetized normothermic values; thus organ flows decreased parallel to the reduction of CO as cooling progressed. TVR and organ vascular resistances increased to levels in excess of 150% of anesthetized precooling values, apparently as the result of viscosity rather than vascular changes.     

A single dose of the potent gonadotropin-releasing hormone antagonist acyline suppresses gonadotropins and testosterone for 2 weeks in healthy young men

Acyline is a novel GnRH antagonist that reliably inhibits gonadotropins and testosterone (T) levels in men for 48 h after a single dose up to 75 microg/kg. In this study we examined gonadotropin and T levels in 28 healthy young men administered acyline as single doses of 150 or 300 microg/kg or serial injections of 75 microg/kg. A single 300 microg/kg dose of acyline suppressed gonadotropins and T to castrate levels for 15 d (baseline, 21.1 +/- 3.1; nadir, 1.95 +/- 0.4 nmol/liter; mean +/- sem; P < 0.05). Serum acyline levels peaked 90 min after the injection of 300 microg/kg acyline to a maximum concentration of 112.4 +/- 18 ng/ml (n = 7; t(1/2) = 4.9 d). Injections of 75 microg/kg acyline every 2 d for five doses suppressed gonadotropins for more than 20 d (nadir T, 1.06 +/- 0.17 nmol/liter; P < 0.05 compared with baseline). Adverse events were mild and included erythema and pruritus at the injection site. Acyline, therefore, is one of the most potent peptide GnRH antagonists studied to date with minimal adverse events. A twice monthly injection of acyline could be used as a potent suppressor of the GnRH axis to advance the development of a hormonal male contraceptive or for treatment of hormonally dependent disease.     

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.     

The Classic: A Study in Hospital Efficiency: As Demonstrated by the Case Report of First Five Years of Private Hospital

This is an abridged version of the Classic Article by E.A. Codman, A Study in Hospital Efficiency: As Demonstrated by the Case Report of the First Five Years of a Private Hospital. The full article is available as supplemental material for the abridged version in the online version of CORR®. An accompanying biographical sketch of E.A. Codman is available at DOI 10.1007/s11999-012-2750-4. The Classic Article is © 1918 and is reprinted courtesy of Thomas Todd Co. from E.A. Codman. A Study in Hospital Efficiency: As Demonstrated by the Case Report of the First Five Years of a Private Hospital. Boston: Thomas Todd Co.; 1918: 4–10,108,162.     

Acceptability of a transdermal gel-based male hormonal contraceptive in a randomized controlled trial

Objective

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.

Study Design

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.

Results

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).

Conclusions

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.

Implications

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.     

Serum Osteocalcin and CTX‐MMP Concentration in Young Exercising Thoroughbred Racehorses

Bone responds to exercise with changes in bone (re‐)modelling, which might be monitored non‐invasively with biochemical bone markers. The aim of this study was to evaluate the influence of exercise on serum osteocalcin and serum carboxy‐terminal cross‐linked telopeptide of type I collagen generated by matrix metalloproteinases (CTX‐MMP) concentration in young racehorses. Seventy‐one 2 to 4‐year‐old Thoroughbreds were included in this prospective infield study. Blood sampling was performed six times (i.e. six sampling cycles) during a 9‐month period. Serum samples were analysed with commercial osteocalcin and CTX‐MMP radioimmunoassays. Two‐year‐old racehorses had higher serum osteocalcin and CTX‐MMP values than 3‐year‐old horses. Gender and training amplitude did not significantly influence serum osteocalcin and CTX‐MMP values. Two‐year‐old horses showed an increase in osteocalcin values between cycles 2 and 3 and an increase in serum CTX‐MMP values between cycles 1 and 2. Serum osteocalcin and CTX‐MMP concentrations decreased between cycles 4 and 5, and 5 and 6. Three‐year‐old horses showed an increase in serum osteocalcin levels between cycles 3 and 4 and an increase in serum CTX‐MMP concentrations between cycles 1 and 2, and 3 and 4. Serum osteocalcin levels decreased between cycles 5 and 6, whereas serum CTX‐MMP levels decreased between cycles 4 and 5, and 5 and 6. Two‐ and three‐year‐old horses showed a decreased osteocalcin/CTX‐MMP ratio between cycles 1 and 2. Moreover, 2‐year‐old horses showed an increase in the osteocalcin/CTX‐MMP ratio between cycles 2 and 3. Sore shin formation did not significantly influence serum osteocalcin and CTX‐MMP values. Serum osteocalcin and CTX‐MMP are promising bone markers for monitoring exercise induced changes in equine bone metabolism.