Issues in testosterone replacement in older men.
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Aged↗
Biomedical subjects
W J Bremner
Publications and source records attributed to W J Bremner.
Suppression of spermatogenesis in man induced by Nal-Glu gonadotropin releasing hormone antagonist and testosterone enanthate (TE) is maintained by TE alone.
GnRH antagonists plus testosterone (T) suppress LH and FSH levels and inhibit spermatogenesis to azoospermia or severe oligozoospermia. High-dose T treatment alone has been shown to be an effective male contraceptive (contraceptive efficacy rate of 1.4 per 100 person yr). Combined GnRH antagonist and T induces azoospermia more rapidly and at a higher incidence than T alone; this combination has therefore been proposed as a prototype male contraceptive. However, because GnRH antagonists are expensive to synthesize and difficult to deliver, it would be desirable to rapidly suppress sperm counts to low levels with GnRH antagonist plus T and maintain azoospermia or severe oligozoospermia with T alone. In this study, 15 healthy men (age 21-41 yr) with normal semen analyses were treated with T enanthate (TE) 100 mg im/week plus 10 mg Nal-Glu GnRH antagonist sc daily for 12 weeks to induce azoospermia or severe oligozoospermia. At 12-16 weeks, 10 of 15 subjects had zero sperm counts, and 14 of 15 had sperm counts less than 3 x 10(6)/mL. The 14 who were suppressed on combined treatment were maintained on TE alone (100 mg/week im) for an additional 20 weeks. Thirteen of 14 subjects in the TE alone phase had sperm counts maintained at less than 3 x 10(6)/mL for 20 weeks. Ten remained persistently azoospermic or had sperm concentration of 0.1 x 10(6)/mL once during maintenance. Mean LH and FSH levels in the subjects were suppressed to 0.4+/-0.2 IU/L and 0.5+/-0.2 IU/L in the induction phase, which was maintained in the maintenance phase. The 1 subject who failed to suppress sperm counts during induction had serum LH and FSH reduced to 0.3 and 0.5 IU/L, respectively. The subject who failed to maintenance had LH and FSH suppressed to 1.0 and 0.2 IU/L, respectively, during the induction phase but these rose to 1.6 and 2.1 IU/L, respectively, during maintenance. Failure to suppress or maintain low sperm counts may be related to incomplete suppression of serum LH and FSH levels. We conclude that sperm counts suppressed with GnRH antagonist plus T can be maintained with relatively low dose TE treatment alone. This concept should be explored further in the development of effective, safe, and affordable hormonal male contraceptives.
Adult↗
Prostate-sparing effects in primates of the potent androgen 7alpha-methyl-19-nortestosterone: a potential alternative to testosterone for androgen replacement and male contraception.
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.
Anabolic Agents↗
An oral regimen of cyproterone acetate and testosterone undecanoate for spermatogenic suppression in men.
OBJECTIVE: To test the effectiveness, safety, and reversibility of the combined administration of cyproterone acetate and T undecanoate. DESIGN: Open clinical trial. SETTING: Healthy volunteers in an academic research environment. PATIENT(S): Eight healthy men, aged 25-42 years were selected. INTERVENTION(S): Cyproterone acetate, 12.5 mg, and T undecanoate, 80 mg, were administered orally twice daily for 16 weeks. MAIN OUTCOME MEASURE(S): Semen analyses every 2 weeks; physical examination, chemistries, hematology, prostatic-specific antigen, gonadotropins and T levels, and a questionnaire on sexual and behavioral function every 4 weeks. RESULT(S): In all subjects a profound suppression of spermatogenesis occurred; one subject became azoospermic, five subjects had sperm counts of < or = 3 x 10(6)/mL, and in two subjects sperm counts were 4 and 6 x 10(6)/mL in week 16. Sperm counts returned to baseline in all men after hormone administration was discontinued. No changes in metabolic parameters and total prostatic-specific antigen were detected. Hemoglobin and hematocrit decreased statistically significantly at week 16 of treatment and returned to baseline by week 12 of recovery. There was no change in sexual function or behavior. CONCLUSION(S): The oral administration of T undecanoate plus cyproterone acetate induces a profound suppression of spermatogenesis with no major adverse effects. These data suggest the feasibility of oral contraception in men.
Adult↗
Clinical review 85: Emerging issues in androgen replacement therapy.
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Androgens↗
Male contraception: ideas for the future.
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Adult↗
Testosterone-induced suppression of lipoprotein(a) in normal men; relation to basal lipoprotein(a) level.
The concentration of lipoprotein(a) [Lp(a)] in human plasma is largely genetically determined and is inversely correlated to the size of apolipoprotein(a) [apo(a)]. Additionally, Lp(a) values are relatively stable within individuals and are only marginally susceptible to therapeutic treatment. The aim of our study was to evaluate the effect of exogenous testosterone on plasma Lp(a) concentration. The study was carried out on 19 healthy men who were receiving weekly intramuscular injections of 200 mg testosterone enanthate. Lp(a) values were determined at multiple time-points by a double monoclonal antibody-based enzyme immunoassay. This method is not sensitive to variation in Lp(a) size and the values are expressed in nmol/l. Apo(a) size isoforms were determined by agarose gel electrophoresis followed by immunoblotting. No correlation was found between the baseline Lp(a) values and the baseline values of testosterone or estradiol. The Lp(a) response to testosterone treatment varied widely among subjects and was dependent upon the pretreatment Lp(a) concentration. For 10 subjects with low Lp(a) values (< 25 nmol/l), no significant decrease in Lp(a) was observed while, for the nine individuals with Lp(a) values > 25 nmol/l, there was a significant and consistent reduction in Lp(a) ranging from 25 to 59%. Lp(a) levels returned to baseline values following cessation of testosterone administration. Apo(a) size polymorphism did not appear to play a role in the determination of Lp(a) response to testosterone.
Adult↗
Androgens in men--uses and abuses.
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Adolescent↗
Annual patterns of luteinizing hormone, follicle stimulating hormone, testosterone and inhibin in normal men.
Reproductive functions in most animals demonstrate seasonal fluctuations that allow young to be born at a time of the year favourable for their survival. Whether there is a seasonal change in the human reproductive system is unclear. In the present study, we measured serum concentrations of luteinizing hormone, follicle stimulating hormone, testosterone and inhibin in the same 16 normal men sampled monthly for 1 year. A statistically significant increase in all four measured hormones was found in June, with a nadir in August. Our findings suggest that a circannual rhythm of gonadotrophins and testicular hormones exists in normal men. The mechanism leading to this rhythm and the importance of the rhythm in human biology are unknown.
Adult↗
Combined administration of levonorgestrel and testosterone induces more rapid and effective suppression of spermatogenesis than testosterone alone: a promising male contraceptive approach.
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; P < 0.05). 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; P < 0.05). Serum high density lipoprotein cholesterol decreased 21.7 +/- 3.6% in men given T plus LNG (P < 0.05), 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 (P < 0.05). 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.
Adult↗
Reproductive aging: accelerated ovarian follicular development associated with a monotropic follicle-stimulating hormone rise in normal older women.
Women experience a decline in fertility that precedes the menopause by several years. Previous studies have demonstrated a monotropic rise in FSH associated with reproductive aging: however, the mechanism of this rise and its role in the aging process are poorly understood. The purpose of this study was to characterize ovarian follicular development and ovarian hormone secretion in older reproductive age women. Sixteen women, aged 40-45 yr, with regular ovulatory cycles were studied. The control group consisted of 12 ovulatory women, aged 20-25 yr. Serum obtained by daily blood sampling was analyzed for FSH, LH, estradiol (E), progesterone, and inhibin (Monash polyclonal assay). Follicle growth and ovulation were documented by transvaginal ultrasound. Older women had significantly higher levels of FSH throughout the menstrual cycle. E, progesterone, LH, and inhibin levels did not differ between the two age groups when compared relative to the day of the LH surge. Ultrasound revealed normal growth, size, and collapse of a dominant follicle in all subjects. Older women had significantly shorter follicular phase length associated with an early acute rise in follicular phase E, reflecting accelerated development of a dominant follicle. We conclude that older reproductive age women have accelerated development of a dominant follicle in the presence of the monotropic FSH rise. This is manifested as a shortened follicular phase and elevated follicular phase E. The fact that ovarian steroid and inhibin secretion were similar to those in the younger women suggests that elevated FSH in women of advanced reproductive age may represent a primary neuroendocrine change associated with reproductive aging.
Adult↗
Inhibin-B: a likely candidate for the physiologically important form of inhibin in men.
Inhibin is a glycoprotein hormone that is defined on the basis of inhibition of pituitary FSH production, However, previous data have not shown any correlation between RIA measurements of inhibin and FSH in men. New enzyme-linked immunosorbent assays, specific for inhibin A, inhibin B, and inhibin pro-alphaC-related immunoreactivity, were applied to the measurement of inhibin in 32 healthy men. Further measurements of inhibin B and pro-alphaC-RI were carried out on groups of men exhibiting a wide range of FSH concentrations, including semen donors, infertile men, and men with elevated FSH concentrations. Inhibin A was undetectable (<2 pg/mL) in all men studied. The healthy men studied all had measurable concentrations of inhibin B (135.6 pg/mL; confidence interval, 108.4-169.4) and pro-alphaC-RI (426.3 pg/mL; confidence interval, 378.4-480.2). A close negative correlation was found between the inhibin B and FSH concentrations in the semen donors (r = -0.69; P < 0.001), the infertile men (r = -0.81; P < 0.001), and the men with elevated FSH concentrations (r = -0.54; P < 0.01), but not in a group of healthy volunteers (r = -0.08; P = NS). No correlation was observed between concentrations of pro-alphaC-RI and FSH in any of the groups studied. These results strongly suggest that the physiologically important form of inhibin in men is inhibin B, which has a critical effect on FSH release. Inhibin B may offer a clinically useful serum marker of testicular function.
Adult↗
A combined regimen of cyproterone acetate and testosterone enanthate as a potentially highly effective male contraceptive.
In this study we tested the effectiveness of the combined administration of cyproterone acetate (CPA) and testosterone enanthate (TE) in suppressing spermatogenesis. After a control phase of 3 months, 15 normal men were randomized to receive TE (100 mg/week) plus CPA at a dose of 100 mg/day (CPA-100; n = 5) or 50 mg/day (CPA-50; n = 5) or TE (100 mg/week) alone (n = 5) for 16 weeks. Semen analysis was performed every 2 weeks. Every 4 weeks, fasting blood samples were drawn for the measurement of LH, FSH, testosterone, estradiol, and biochemical and hematological parameters; subjects underwent a physical examination; and they and their partners filled in a sexual and behavioral questionnaire. Regardless of the dose, each of the 10 subjects receiving CPA plus TE became azoospermic, whereas only 3 of 5 subjects treated with TE alone achieved azoospermia. Times to azoospermia were 6.8 +/- 0.5, 8.4 +/- 1.0, and 14.0 +/- 1.2 weeks in groups CPA-100, CPA-50, and TE alone, respectively (P = NS). Throughout treatment, both gonadotropins tended to be higher in the TE alone group than in the other groups. This difference was mostly due to the higher gonadotropin levels present in the 2 men treated with TE alone that remained oligospermic. No difference in testosterone or estradiol levels was found among the groups. No significant change in lipoprotein levels or liver function tests could be detected. In the CPA-100 and CPA-50 groups, hemoglobin, hematocrit, and red blood cells were lower at the end of the treatment phase, whereas no change was detected in TE alone group. A tendency for a decrease in body weight was detected in subjects treated with CPA, whereas there was no change in subjects receiving TE alone. At the end of the treatment phase, a decrease in testis size was present in all groups. There was no significant change in sexual function, aggressive behavior, mood states, or satisfaction with relationship in any group. These results suggest that the combined administration of CPA and TE is very effective in suppressing spermatogenesis and may represent a promising regimen for reversible contraception in males.
Adult↗
Serum inhibin B levels reflect Sertoli cell function in normal men and men with testicular dysfunction.
We used a recently developed ELISA format to test the hypothesis that inhibin B is the physiologically active form of inhibin in men. We measured and compared inhibin A, inhibin B, and pro-alpha-C-related immunoreactive peptides (pro-alpha-C-RI) in normal men before and after perturbations of their gonadotropin levels and baseline values in normal men and men with various disturbances of the hypothalamic-pituitary-testicular axis including men with idiopathic hypogonadotropic hypogonadism, infertile men with elevated FSH, men with Klinefelter's syndrome, and orchidectomized men. Mean serum inhibin concentrations were significantly higher in normal men than untreated men with idiopathic hypogonadotropic hypogonadism, infertile men with elevated FSH, untreated men with Klinefelter's syndrome, and orchidectomized men (187 +/- 28 vs 45 +/- 11, 37 +/- 6, 11 +/- 3, and < or = 10 pg/mL, respectively; P < 0.05). Inhibin B levels were below the limit of detection in all of the orchidectomized men. Pro-alpha-C-RI levels were detectable in all men studied including the orchidectomized men, and no significant differences in the pro-alpha-C-RI levels were noted between the normal men and men with various testicular diseases were noted except that orchidectomized men had significantly lower pro-alpha-C-RI levels than all other groups (P < 0.05). Inhibin A was undetectable in all men tested in this study. Six normal men who were administered exogenous levonorgestrel and testosterone had significantly lower serum gonadotropin, inhibin B, and pro-alpha-C-RI levels during the treatment period than the control and recovery periods (P < 0.05). Ten normal men who were administered human recombinant FSH had significantly higher peak serum FSH (21.85 +/- 3.23 IU/L vs. 3.01 +/- 0.51 IU/L), inhibin B (311 +/- 88 pg/mL vs. 151 +/- 23 pg/mL) and pro-alpha-C-RI (646 +/- 69 vs. 402 +/- 38 pg/mL) levels during the treatment period than the baseline values (P < 0.05). We conclude that inhibin B is a unique testicular product that is not detectable in the sera of orchidectomized men, is responsive to FSH stimulation, and has a reciprocal relationship with serum FSH levels in men with various forms of testicular disease. Therefore, inhibin B is likely to be the physiologically important form of inhibin in men.
Adult↗
The anterior pituitary response to a gonadotropin-releasing hormone challenge test in normal older reproductive-age women.
OBJECTIVE: To assess the pituitary responsiveness to GnRH stimulation of premenopausal women relative to age. DESIGN: Older and younger reproductive-age women underwent the GnRH stimulation test in the early follicular phase of the menstrual cycle. SETTING: Female subjects in an academic research environment. PATIENTS: Women aged 21 to 44 years consisting of normal volunteers and infertility patients. INTERVENTIONS: Gonadotropin-releasing hormone was administered intravenously between days 2 and 4 of the menstrual cycle. Blood samples were collected from -20 minutes before to 120 minutes after administration. MAIN OUTCOME MEASURE: Luteinizing hormone, FSH, inhibin, and E2 levels. RESULTS: No significant difference in baseline values existed between older and younger women with regard to LH, inhibin, and E2, but basal FSH levels were higher in older women. A significantly diminished percent of LH and percent FSH change above baseline occurred 30 minutes after GnRH administration in the older women compared with younger women. No change in inhibin or E2 levels could be detected during the sampling period. CONCLUSIONS: The present study demonstrates marked attenuation of the acute pituitary LH response (sensitivity) to GnRH stimulation in older women when compared with a younger cohort.
Adult↗
Hypothyroidism-induced macroorchidism: use of a gonadotropin-releasing hormone agonist to understand its mechanism and augment adult stature.
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Adolescent↗
Developmental regulation of androgen receptor in rat ovary.
Androgen receptor (AR) distribution and developmental regulation in the rat ovary were examined by semiquantitative immunohistochemistry. Ovarian AR mRNA levels were also determined by Northern analysis of total RNA and compared with the levels of cytochrome P450aromatase (P450arom), an established marker of preovulatory follicular maturity. Hypophysectomized immature female rats were treated with recombinant human (rh)-FSH and/or rh-LH, or human menopausal gonadotrophin (HMG). AR was predominantly located in granulosa cells. There was no indication of specific AR immunoreactivity in thecal cells, but scattered stromal cells did stain positively. In control and LH-treated ovaries, only small preantral/early antral follicles were present. Granulosa cells in these follicles showed intense AR immunostaining. Treatment with FSH, FSH and LH or HMG stimulated varying degrees of preovulatory follicular development. In these follicles, the intensity of AR immunostaining progressively declined as follicular development progressed. In intact immature rats treated with FSH, the abundance of ovarian AR mRNA was significantly decreased to 35% of the control value while combined treatment of FSH and LH resulted in further down-regulation of AR mRNA expression to 17% of the control value. A decrease in the abundance of AR mRNA was accompanied by a simultaneous increase in the abundance of P450arom mRNA. Similar results were obtained in hypophysectomized immature rats treated with FSH and LH, suggesting an inverse relationship between AR mRNA expression and granulosa cell maturity. These results suggest that (1) the AR is most abundant in the granulosa cells of rat ovaries and (2) the expression of AR and its mRNA are developmentally regulated, being down-regulated during FSH-stimulated preovulatory follicular development.
Animals↗
Effects of aging on menstrual cycle hormones and endometrial maturation.
OBJECTIVE: To investigate changes in menstrual cycle hormones and endometrial maturation that may contribute to the decline in fertility with aging. DESIGN: Prospective controlled clinical study. SETTING: Normal human volunteers in an academic research institution. SUBJECTS: Women with regular menstrual cycles. INTERVENTIONS: Thirty-two women, aged 20 to 30 or 40 to 50 years, had daily blood drawing starting on cycle day 6 to 10 and continuing until 2 days after the onset of next menses. In addition, 60 women, aged 20 to 30 or 40 to 50 years, had a total of 93 endometrial biopsies performed on day 7 to 9 after the LH surge. MAIN OUTCOME MEASURES: Serum LH, FSH, E2, inhibin, P, and placental protein 14 (PP14) levels and histologic maturation of the endometrium. RESULTS: Serum FSH levels were increased whereas inhibin concentrations were reduced in the luteal-follicular transition of women > 40 years. No other hormonal changes were seen in this population, including P and PP14 secretion. Disruption of endometrial maturation occurred at a similar frequency in both age groups. CONCLUSIONS: Follicular recruitment, but not luteal function or endometrial maturation, is disturbed in cycling women > 40 years and may contribute to the decline in fertility with aging.
Adult↗