William J. Bremner

Advances in Male Contraception

Despite significant advances in contraceptive options for women over the last 50 yr, world population continues to grow rapidly. Scientists and activists alike point to the devastating environmental impacts that population pressures have caused, including global warming from the developed world and hunger and disease in less developed areas. Moreover, almost half of all pregnancies are still unwanted or unplanned. Clearly, there is a need for expanded, reversible, contraceptive options. Multicultural surveys demonstrate the willingness of men to participate in contraception and their female partners to trust them to do so. Notwithstanding their paucity of options, male methods including vasectomy and condoms account for almost one third of contraceptive use in the United States and other countries. Recent international clinical research efforts have demonstrated high efficacy rates (90-95%) for hormonally based male contraceptives. Current barriers to expanded use include limited delivery methods and perceived regulatory obstacles, which stymie introduction to the marketplace. However, advances in oral and injectable androgen delivery are cause for optimism that these hurdles may be overcome. Nonhormonal methods, such as compounds that target sperm motility, are attractive in their theoretical promise of specificity for the reproductive tract. Gene and protein array technologies continue to identify potential targets for this approach. Such nonhormonal agents will likely reach clinical trials in the near future. Great strides have been made in understanding male reproductive physiology; the combined efforts of scientists, clinicians, industry and governmental funding agencies could make an effective, reversible, male contraceptive an option for family planning over the next decade.

Bone mineral content of amenorrheic and eumenorrheic athletes

This study was designed to determine whether the hypoestrogenic status of 14 amenorrheic athletes was associated with a decrease in regional bone mass relative to that of 14 of their eumenorrheic peers. The two groups of athletes were matched for age, height, weight, sport, and training regimens. Bone mass was measured by dual-photon and single-photon absorptiometry at the lumbar vertebrae (L1 to L4) and at two sites on the radius. Vertebral mineral density was significantly lower in the amenorrheic group (mean, 1.12 g per square centimeter) than in the eumenorrheic group (mean, 1.30 g per square centimeter). There was no significant difference at either radial site. Radioimmunoassay confirmed a lower mean estradiol concentration (amenorrheic group, 38.58 pg per milliliter; eumenorrheic group, 106.99 pg per milliliter) and progesterone peak (amenorrheic group, 1.25 ng per milliliter; eumenorrheic group, 12.75 ng per milliliter) in the amenorrheic women, in four venous samples drawn at seven-day intervals. A three-day dietary history showed no significant differences in nutritional intake, including calcium with and without supplements. The two groups were similar in percentage of body fat, age at menarche, years of athletic participation, and frequency and duration of training but differed in number of miles run per week (amenorrheic group, 41.8 miles [67.3 km]; eumenorrheic group, 24.9 miles [40.1 km]). We conclude that the amenorrhea that is observed in female athletes may be accompanied by a decrease in mineral density of the lumbar vertebrae.

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

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

Testosterone supplementation improves spatial and verbal memory in healthy older men

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.

Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment.

Objective: To determine the efficacy of testosterone (T) supplementation on cognition in a sample of men with Alzheimer disease (AD) or mild cognitive impairment (MCI). Methods: Fifteen patients with AD and 17 patients with MCI aged 63 to 85 years completed a randomized, double-blind, placebo-controlled study. Nineteen participants received weekly intramuscular (IM) injections of 100 mg T enanthate and 13 participants received weekly injections of placebo (saline) for 6 weeks. Cognitive evaluations using a battery of neuropsychological tests were conducted at baseline, week 3, and week 6 of treatment and again after 6 weeks of washout. Results: Peak serum total T levels were raised from baseline an average of 295% in the active treatment group. Improvements in spatial memory (p < 0.05) and constructional abilities (p < 0.05) and verbal memory were evident in the T group. No changes were noted for selective and divided attention or language. Prostate specific antigen did not significantly change during this brief treatment. Conclusion: Testosterone supplementation may benefit selective cognitive functions in men with Alzheimer disease and mild cognitive impairment.

TESTOSTERONE REPLACEMENT IN HYPOGONADAL MEN: EFFECTS ON OBSTRUCTIVE SLEEP APNOEA, RESPIRATORY DRIVES, AND SLEEP

The obstructive sleep apnoea syndrome occurs predominantly in men. To determine the effect of testosterone on ventilatory function and whether testosterone may play a role in the development of obstructive apnoea, we performed waking ventilatory drive studies and sleep studies in five hypogonadal men. These androgen‐deficient subjects were studied both while receiving no treatment and after six weeks of testosterone replacement therapy (testosterone oenanthate 200 mg i.m. every 2 weeks). Hypoxic ventilatory drive decreased significantly, from 158 · 39 (mean · SEM) off testosterone to 88 · 19 on testosterone therapy (P < 0.05). Hypercapnoeic ventilatory drive did not change significantly on testosterone. Obstructive sleep apnoea developed in one man and markedly worsened in another man in association with testosterone administration. Both of these subjects also exhibited marked decreases in oxygen saturation with the development of cardiac dysrhythmias during sleep and large increases in haematocrit. The remaining three hypogonadal men did not demonstrate significant sleep apnoea either on or off testosterone. The percentage of sleep time spent in REM sleep increased from 14 · 3% to 22 · 2% when the men were receiving testosterone (P < 0.01), but the episodes of sleep apnoea tended to occur during non‐REM sleep. We conclude that in some hypogonadal men, replacement dosages of testosterone may affect ventilatory drives and induce or worsen obstructive sleep apnoea. The obstructive sleep apnoea syndrome is a potential complication of testosterone therapy. These results suggest that androgen levels present in normal man may play an important role in the pathogenesis of obstructive sleep apnoea.

The role of aromatization in testosterone supplementation: Effects on cognition in older 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.

Testicular control of follicle-stimulating hormone secretion.

Publisher Summary This chapter provides an overview of the testicular control of follicle-stimulating hormone (FSH) secretion. Castration is followed by an increase in circulating levels of FSH than of luteinizing hormone (LH). This suggests the possibility that the mechanisms of gonadotropin secretion either have different thresholds to steroid hormones or a feedback influence associated with the germinal epithelium. The chapter analyzes the factors that control the secretion of gonadotropins in the male and the effect of testicular disorders on the secretion. These disorders are frequently associated with characteristic abnormalities of gonadotropin secretion, observations that are valuable both in diagnosis and treatment of patients with problems of hypogonadism or infertility. All the work reported in the chapter is concerned with the testicular effects on the gonadotropins. The possibility that ovaries can produce a similar or identical substance stems from the fact that postmenopausal FSH levels are raised disproportionately, i.e., more than LH levels and there are many analogies between the functions of the testis and the ovary. There is a significant inverse correlation between the absence of ovarian follicles and the plasma levels of FSH in women with primary or secondary amenorrhea. One compelling stimulus in this field is the possibility of obtaining a substance for contraceptive use that could selectively suppress the secretion of FSH while preserving libido and potency in the male.

Obstructive sleep apnea syndrome induced by testosterone administration.

The obstructive sleep apnea syndrome is a recently described clinical disorder that results from repetitive episodes of upper-airway occlusion during sleep.1 Since the syndrome occurs much more fre...

Physiologic testosterone levels in normal men suppress high-density lipoprotein cholesterol levels.

OBJECTIVE To investigate the role of physiologic levels of testosterone in the control of lipoproteins in healthy men. DESIGN A double-blind, randomized study. SETTING A university community. PARTICIPANTS Fifteen healthy men, ages 20 to 36 years. INTERVENTION We induced acute, reversible hypogonadism in five normal men by administering daily subcutaneous injections of the gonadotropin-releasing-hormone (GnRH) antagonist, Nal-Glu, for 6 weeks. Another group of five normal men received Nal-Glu plus weekly injections of testosterone enanthate, 100 mg/wk, thereby maintaining normal serum testosterone levels. Five additional men received placebo injections. MEASUREMENTS Plasma lipids, including high-density lipoprotein (HDL) subfractions HDL2 and HDL3, apoprotein A1, and serum levels of gonadotropins, estradiol, and testosterone were measured before, during, and after treatment. RESULTS At the end of the treatment period, HDL cholesterol levels in men receiving Nal-Glu increased by 26% (95% CI, 18% to 34%; P less than 0.05). Levels of HDL2, HDL3, and apoprotein A1 increased by 63% (CI, 16% to 110%), 17% (CI, 3% to 31%), and 17% (CI, 5% to 29%), respectively (P less than 0.05 for each parameter). Total cholesterol increased by 12% (CI, 2% to 22%). Low-density lipoprotein (LDL) cholesterol and triglyceride concentrations did not change. No statistically significant changes occurred in any lipid measurement in men receiving Nal-Glu plus androgen replacement or placebo (P greater than 0.05). CONCLUSIONS Experimental hypogonadism induced by administration of a GnRH antagonist results in a statistically significant increase in HDL cholesterol, including HDL2 and HDL3. These effects are most likely due to decreased androgen levels because they are reversed by administration of antagonist together with testosterone. Our results imply that androgen levels in the normal adult male range have a suppressive effect on HDL cholesterol concentration and may contribute to the increased risk for coronary artery disease in men.