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David J Handelsman

Publications and source records attributed to David J Handelsman.

At least 19 recordsLinked to original sources
PubMed2007

Osteoblast deletion of exon 3 of the androgen receptor gene results in trabecular bone loss in adult male mice.

UNLABELLED: The mechanism of androgen action on bone was studied in male mice with the AR deleted in mature osteoblasts. These mice had decreased trabecular bone volume associated with a decrease in trabecular number, suggesting that androgens may act directly on osteoblasts to maintain trabecular bone. INTRODUCTION: Androgens modulate bone cell activity and are important for the maintenance of bone mass. However, the mechanisms by which they exert these actions on bone remain poorly defined. The aim of this study was to investigate the role of androgens acting through the classical androgen receptor (AR) signaling pathways (i.e., DNA-binding dependent pathways) in osteoblasts using male mice in which exon 3 of the AR gene was deleted specifically in mature osteoblasts. MATERIALS AND METHODS: Mice with a floxed exon 3 of the AR gene were bred with Col 2.3-cre transgenic mice, in which Cre recombinase is expressed in mineralizing osteoblasts. The skeletal phenotype of mutant mice was assessed by histomorphometry and quantitative microCT at 6, 12, and 32 weeks of age (n=8 per group). Wildtype, hemizygous exon 3 floxed and hemizygous Col 2.3-cre male littermates were used as controls. Data were analyzed by one-way ANOVA and Tukey's posthoc test. RESULTS: microCT analysis of the fifth lumbar vertebral body showed that these mice had reduced trabecular bone volume (p<0.05) at 32 weeks of age compared with controls. This was associated with a decrease in trabecular number (p<0.01) at 12 and 32 weeks of age, suggesting increased bone resorption. These effects were accompanied by a reduction in connectivity density (p<0.01) and an increase in trabecular separation (p<0.01). A similar pattern of trabecular bone loss was observed in the distal femoral metaphysis at 32 weeks of age. CONCLUSIONS: These findings show that inactivation of the DNA binding-dependent functions of the AR, specifically in mature osteoblasts in male mice, results in increased bone resorption and decreased structural integrity of the bone, leading to a reduction in trabecular bone volume at 32 weeks of age. These data provide evidence of a role for androgens in the maintenance of trabecular bone volume directly through DNA binding-dependent actions of the AR in mature osteoblasts.

Aging↗
PubMed2006

Men in Australia Telephone Survey (MATeS): predictors of men's help-seeking behaviour for reproductive health disorders.

OBJECTIVE: To identify sociodemographic factors associated with help-seeking behaviour for reproductive health disorders in middle-aged and older Australian men. DESIGN: A cross-sectional, population-based, computer-assisted telephone interview exploring sociodemographic factors and general and reproductive health. PARTICIPANTS AND SETTING: Analysis of data from the Men in Australia Telephone Survey (MATeS) of 5990 Australian men aged 40 years and older interviewed between September and December 2003. MAIN OUTCOME MEASURES: Self-reported diagnosis of prostate disease and erectile dysfunction (ED), help-seeking behaviour (including visiting a doctor, prostate-specific antigen testing, treatment of prostate disease, speaking to a health professional about ED and treatment of ED). RESULTS: Age was a significant predictor of all help-seeking behaviour studied, other than treatment for ED. Controlling for all predictor variables, never-married status predicted a lower likelihood of visiting a doctor (odds ratio [OR], 0.68 [95% CI, 0.48-0.97]) or speaking to a health professional about ED (OR, 0.44 [95% CI, 0.21-0.93]), while divorced/separated status predicted lower likelihood of having a prostate-specific antigen test (OR, 0.63 [95% CI, 0.50-0.79]). Living in a regional or remote area or being from a non-English-speaking background predicted lower likelihood of receiving treatment for ED (ORs, 0.62 [95% CI, 0.42-0.92] and 0.41 [95% CI, 0.24-0.72], respectively), but did not influence screening for prostate disease. CONCLUSION: Seeking advice or treatment for male reproductive health disorders is predicted by sociodemographic factors specific to different reproductive health problems. As middle-aged and older men do attend doctors, opportunities exist for health professionals to optimise their consultations by routinely discussing reproductive health with all men, to identify under-reported male reproductive health disorders.

Adult↗
PubMed2006

Testosterone: use, misuse and abuse.

Testosterone is among the oldest drugs in medicine. It has a long efficacy and safety record for its prime role of androgen replacement therapy in men with androgen deficiency. Testosterone and synthetic analogue androgens have also been used in pharmacological androgen therapy (PAT) to produce androgenic effects on marrow, muscle or bone. Although PAT is increasingly being superseded by newer, more expensive drugs, androgens remain cost-effective in many older applications. Androgen misuse is the systematic over-prescribing for unproven medical indications. Misuse is increasingly evident for male ageing ("andropause") and some other clinical conditions. Further trials for new indications for androgens require reliable safety data, but rising costs may make it increasingly attractive to circumvent the need for evidence by promoting off-label mass marketing. Androgen abuse is the illicit self-administration of often massive doses of androgens for non-medical purposes - notably power sports and body building. In parallel with effective detection reducing androgen abuse in elite sports, more focus is needed on non-sporting cosmetic, recreational and occupational androgen abuse. Despite ongoing androgen misuse and abuse, testosterone remains under-prescribed for younger men with classical androgen deficiency that frequently remains undiagnosed.

Aging↗
PubMed2006

Rate, extent, and modifiers of spermatogenic recovery after hormonal male contraception: an integrated analysis.

BACKGROUND: Hormonal methods for safe, reliable, and reversible contraception based on the suppression of spermatogenesis could soon become available. We have investigated the rate, extent, and predictors of reversibility of hormonal male contraception. METHODS: We undertook an integrated multivariate time-to-event analysis of data from individual participants in 30 studies published in 1990-2005, in which sperm output was monitored every month until recovery. The primary outcome was the time for the sperm concentration to recover to a threshold of 20 million per mL, an indicator of fertility. We undertook univariate and multivariate analyses, using Kaplan-Meier and Cox's methods. FINDINGS: 1549 healthy eugonadal men who were white (n=965), Asian (almost all Chinese men; n=535), or of other origins (n=49) and aged 18-51 years underwent 1283.5 man-years of treatment and 705 man-years of post-treatment recovery. These data represented about 90% of all published data from individuals using androgen or androgen-progestagen regimens. The median times for sperm to recover to thresholds of 20, 10, and 3 million per mL were 3.4 months (95% CI 3.2-3.5), 3.0 months (2.9-3.1), and 2.5 months (2.4-2.7), respectively. Multivariate Cox's analysis showed higher rates of recovery with older age, Asian origin, shorter treatment duration, shorter-acting testosterone preparations, higher sperm concentrations at baseline, faster suppression of spermatogenesis, and lower blood concentrations of luteinising hormone at baseline. The typical probability of recovery to 20 million per mL was 67% (61-72) within 6 months, 90% (85-93) within 12 months, 96% (92-98) within 16 months, and 100% within 24 months. INTERPRETATION: Hormonal male contraceptive regimens show full reversibility within a predictable time course. Various covariables affect the rate but not the extent of recovery, although their effect sizes are minor. These data are crucial for the further safe and practical development of such regimens.

Adult↗
PubMed2006

Continuous testosterone administration prevents skeletal muscle atrophy and enhances resistance to fatigue in orchidectomized male mice.

Androgens promote anabolism in skeletal muscle; however, effects on subsequent muscle function are less well defined because of a lack of reliable experimental models. We established a rigorous model of androgen withdrawal and administration in male mice and assessed androgen regulation of muscle mass, structure, and function. Adult C57Bl/6J male mice were orchidectomized (Orx) or sham-operated (Sham) and received 10 wk of continuous testosterone (T) or control treatment (C) via intraperitoneal implants. Mass, fiber cross-sectional area (CSA), and in vitro contractile function were assessed for fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus (SOL) muscles. After 10 wk, Orx+C mice had reduced body weight gain (P < 0.05), seminal vesicle mass (P < 0.01), and levator ani muscle mass (P < 0.001) compared with Sham+C mice, and these effects were prevented with testosterone treatment. Orx+T mice had greater EDL (P < 0.01) and SOL (P < 0.01) muscle mass compared with Orx+C mice; however, median fiber CSA was not significantly altered in these muscles. EDL and SOL muscle force was greater in Sham+T compared with Orx+C mice (P < 0.05) in proportion to muscle mass. Unexpectedly, Orx+T mice had increased fatigue resistance of SOL muscle compared with Orx+C mice (P < 0.001). We used a rigorous model of androgen withdrawal and administration in male mice to demonstrate an essential role of androgens in the maintenance of muscle mass and force. In addition, we showed that testosterone treatment increases resistance to fatigue of slow- but not fast-twitch muscle.

Animals↗
PubMed2006

Zoledronic acid prevents bone loss after liver transplantation: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Clinically important rapid bone loss occurs within 3 to 6 months after liver transplantation and may be associated with osteoporotic fractures. OBJECTIVE: To determine whether bisphosphonate treatment with zoledronic acid reduces transplant-related bone loss more than placebo in adults having liver transplantation for chronic liver disease. DESIGN: 12-month randomized, double-blind, placebo-controlled trial. SETTING: 2 large liver transplantation centers in Australia. PATIENTS: 62 adults having liver transplantation for chronic liver disease. INTERVENTIONS: Infusions of zoledronic acid, 4 mg (n = 32), or saline (n = 30) were given within 7 days of transplantation and again at months 1, 3, 6, and 9 after transplantation. All patients received supplementation with calcium carbonate, 600 mg/d, and ergocalciferol, 1000 U/d. MEASUREMENTS: The primary outcome was bone mineral density (BMD) measured by dual x-ray absorptiometry before transplantation and 3, 6, and 12 months later. Secondary outcomes included bone turnover markers that were measured before transplantation and 1, 3, 6, 9, and 12 months later. RESULTS: There were statistically significant interactions between treatment effects and time for BMD measurements at the lumbar spine (P = 0.002), femoral neck (P = 0.001), and total hip (P < 0.001). Differences in acute bone loss 3 months after transplantation favored zoledronic acid over placebo. Differences between groups in percentage change from baseline adjusted for baseline weight and serum parathyroid hormone (PTH) level were 4.0% (95% CI, 1.1% to 7.0%) for the lumbar spine, 4.7% (CI, 1.9% to 7.6%) for the femoral neck, and 3.8% (CI, 1.7% to 6.0%) for the total hip. At 12 months after transplantation, the difference in percentage change from baseline between the 2 groups adjusted for baseline weight and serum PTH level was 1.1% (CI, -2.1% to 4.4%) for the lumbar spine, 2.7% (CI, 0.0% to 5.4%) for the femoral neck, and 2.4% (CI, 0.1% to 4.7%) for the total hip. Treatment with zoledronic acid induced temporary secondary hyperparathyroidism and postinfusion hypocalcemia statistically significantly more often than did placebo. LIMITATIONS: The trial was not powered to assess fractures, and 10 of 62 (16%) patients were not included in adjusted analyses because of missing weight or serum PTH measurements. CONCLUSION: Treatment with zoledronic acid can prevent bone loss within the first year after liver transplantation.

Bone Density↗
PubMed2006

Clinical review: The rationale for banning human chorionic gonadotropin and estrogen blockers in sport.

CONTEXT: The objective of the study was to review the rationale underlying the banning of human chorionic gonadotropin (hCG) and estrogen blockers (antiestrogens, specific estrogen receptor modulators, aromatase inhibitors) in sports for male and female athletes in the light of gender differences in regulation of reproductive physiology. EVIDENCE ACQUISITION: We reviewed well-controlled clinical studies of exogenous testosterone effects on human muscle size and strength in men and all available evidence relevant to the effects of hCG and estrogen blockers on blood testosterone in men and women. EVIDENCE SYNTHESIS: Well-designed placebo-controlled clinical studies in men with suppressed pituitary-testicular axis establish a strong case that, across a wide range from sub- to supraphysiological doses, muscle growth and strength is proportional to exogenous testosterone dose and resulting blood testosterone concentrations. In men, there is unequivocal evidence that hCG and estrogen blockers cause consistent and sustained rise in blood testosterone concentrations. In women, although there has been no direct testing of ergogenic or myotrophic properties of exogenous testosterone in healthy women, either hCG or estrogen blockers do not produce any consistent or biologically significant increase blood testosterone concentrations. CONCLUSIONS: In men undergoing potential stimulation of endogenous blood testosterone concentrations, blood testosterone concentration is a reasonable surrogate measure for muscle growth and increased strength in men. Because hCG and estrogen blockers produce marked increase in blood testosterone concentration in men, this provides strong evidence to support the banning of hCG and estrogen blockers in men. In women, however, the negligible effect on blood testosterone suggests that drug-induced performance enhancement by hCG or estrogen blockers is highly unlikely. Furthermore, routine urinary hCG testing in young women risks invasion of privacy by detecting unrecognized pregnancy. These considerations suggest that prohibition of hCG and estrogen blockers should be restricted to men in which they are well justified.

Chorionic Gonadotropin↗
PubMed2006

Maintenance of spermatogenesis by the activated human (Asp567Gly) FSH receptor during testicular regression due to hormonal withdrawal.

The first activating mutation of the FSH receptor (FSHR*D567G) was identified in a gonadotropin-deficient hypophysectomized man who exhibited persistent spermatogenesis and fertility with only androgen replacement. We have determined the ability of FSHR* activity to maintain spermatogenesis and/or steroidogenesis during gonadotropin and androgen deprivation in mature transgenic FSHR* mice (Tg(Abpa-FSHR*D567G)1Cmal), hereafter referred to as Tg-FSHR* mice. Testes of untreated adult Tg-FSHR* males were equivalent in weight to nontransgenic controls but exhibited increased total Sertoli cell (24%) and spermatogonia (34%) numbers and nonsignificantly elevated spermatocyte-spermatid numbers (13%-17%). During sustained GNRH1 agonist treatment that markedly reduced (96%-98%) serum LH and testosterone (T) and decreased serum FSH (68%-72%), the testes of GNRH1 agonist-treated Tg-FSHR* mice remained significantly larger than treated nontransgenic controls. After 4 wk of gonadotropin suppression, Sertoli cell numbers were reduced in Tg-FSHR* testes to levels comparable with nontransgenic testes, whereas spermatogonia numbers were maintained at higher levels relative to nontransgenic testes. However, after 8 wk of GNRH1 agonist treatment, the total spermatogonia, spermatocyte, or postmeiotic spermatid numbers were reduced to equivalent levels in Tg-FSHR* and nontransgenic mice. FSHR* effects were further examined in gonadotropin-deficient hypogonadal Gnrh1hpg/Gnrh1hpg (Gnrh1(-/-)) mice during testicular regression following withdrawal of T after maximal T-stimulated spermatogenesis. After 6 wk of T withdrawal, spermatogonia, spermatocyte, and postmeiotic spermatid numbers in Tg-FSHR* Gnrh1(-/-) testes decreased to levels found in untreated Tg-FSHR* Gnrh1(-/-) testes. Basal serum T levels in untreated Tg-FSHR* Gnrh1(-/-) males were 2-fold higher than Gnrh1(-/-) controls, but following T treatment/withdrawal, serum T and epididymal weights declined to basal levels found in nontransgenic Gnrh1(-/-) mice. Therefore, FSHR* was unable to sustain circulating T or androgen-dependent epididymal size or postmeiotic spermatogenic development. We conclude that FSHR* activity enhances Sertoli and spermatogenic development in normal testes but has limited ability to maintain spermatogenesis during gonadotropin deficiency, in which the testicular response provided by the FSHR*D567G mutation resembled typical FSH-mediated but not steroidogenic activity.

Amino Acid Substitution↗
PubMed2005

Perinatal testosterone surge is required for normal adult bone size but not for normal bone remodeling.

Although testosterone (T) has striking effects on mature skeletal size and structure, it is not clear whether this depends exclusively on adult circulating levels of T or whether additional early-life factors also play a role. We have compared the androgen-deficient hypogonadal (hpg) mutant mouse with intact, orchidectomized, and T-treated non-hpg mice to determine relative contributions of adult and perinatal T to bone growth and development. At 3 wk of age, although trabecular and cortical bone structure was normal, bone turnover was significantly altered in hpg male mice; osteoid volume (OV/BV) and osteoblast surface (ObS/BS) were significantly lower and osteoclast surface (OcS/BS) significantly higher in hpg mice compared with age-matched non-hpg mice, pointing to a role for the perinatal T surge in determining bone turnover levels before sexual maturity. At 9 wk of age, the hpg bone phenotype mimicked closely that of age-matched non-hpg mice that had been orchidectomized at 3 wk of age, including low trabecular bone mass and high bone turnover. These bone phenotypes of hpg and orchidectomized non-hpg mice were all prevented by replacement doses of T or dihydrotestosterone (DHT), suggesting that these are determined by adult sex steroid hormones. In contrast, a short bone phenotype that could not be prevented by T or DHT treatment was observed in 9-wk-old hpg mice yet not in intact or castrated non-hpg mice. These data suggest a role for the perinatal T surge in determining adult bone length and confirms that adult circulating T determines adult bone density.

Androgens↗
PubMed2005

Valproate is an anti-androgen and anti-progestin.

Anti-convulsant treatment is associated with a high prevalence of reproductive dysfunction compared with age-matched non-epileptics. We examined the widely used anti-convulsants valproate (VPA) and carbamazepine (CBZ) for steroidal bioactivity using a yeast-based steroid receptor-beta-galactosidase reporter assay for the androgen receptor (AR), progesterone receptor (PR) or estrogen receptor (ER). Bioassays were performed (a) to detect agonist activity by exposing yeast to 100 microM CBZ or VPA or (b) to detect antagonist activity by exposing yeast stimulated with testosterone (5 x 10(-9) M, AR), progesterone (1.6 x 10(-9) M, PR) or estradiol (2.6 x 10(-11) M, ER) together with either VPA or CBZ for 4 (PR) or 16 (AR, ER) hours. VPA showed dose-dependent (1-800 microM) inhibition of progesterone-induced PR- and testosterone-induced AR activity but had no ER antagonist bioactivity and no significant PR, AR or ER agonist bioactivity. VPA also showed a dose-dependent (1-200 microM) blockade of DHT's suppression of AR-mediated NF-kappaB activation in human mammalian cells. By contrast, CBZ had no significant PR, AR or ER agonist or AR and ER antagonist bioactivity but at the highest concentration tested (800 microM) it did antagonize PR activity. We conclude that VPA is a non-steroidal antagonist for human AR and PR but not ER. VPA's androgen and progesterone antagonism at concentrations within therapeutic blood levels (350-700 microM) seems likely to contribute to the frequency of reproductive endocrine disturbances among patients treated with VPA.

Androgen Antagonists↗
PubMed2005

Growth and development during early manhood as determinants of prostate size in later life.

BACKGROUND: Age and androgens are key determinants of benign prostate hyperplasia, but the mechanisms remain unclear. We examine the relationship between androgens and total, central, and peripheral prostate volume with a focus on early life factors. METHODS: We conducted a cross-sectional observational study of 406 community-dwelling Australian men aged 20-82 yr old without known prostate disease. Prostate zonal (total, central, and peripheral) volumes were measured by planimetric transrectal ultrasound. Participants completed questionnaires, underwent physical examination, and provided blood samples to measure total, free, and bioavailable testosterone, dihydrotestosterone, estradiol, SHBG, LH, FSH, and prostate-specific antigen. RESULTS: Prostate zonal volumes were positively associated with age, prostate-specific antigen, early onset of puberty, current height, body surface area, lean body mass, hip and waist circumference as well as recalled height and weight during puberty and adolescence but not current weight, fat mass, or body mass index. Stepwise multivariate regression modeling indicated that age and height were the only independent predictors of prostate zonal volumes. When adjusted for age and sampling time of day, the negative correlations of age-adjusted prostate zonal volumes with current blood total, free, and bioavailable testosterone and the positive correlation with blood SHBG were no longer significant. CONCLUSIONS: This study suggests that early and long-term androgen exposure may have long-acting effects on mature prostate zonal volumes, whereas relationships with current blood androgens and related hormones levels were mostly a result of confounding by age. Additional studies on the mechanism of androgen effects on late-life prostate diseases should consider lasting effects of early-life androgen exposure.

Adult↗
PubMed2005

Reproductive hormone reference intervals for healthy fertile young men: evaluation of automated platform assays.

CONTEXT: Management of male infertility and/or androgen deficiency requires accurate hormonal measurements with valid reference intervals. OBJECTIVE: The objective of this study was to develop a valid reference panel of blood samples from healthy eugonadal young men with verified normal reproductive function and to use this panel to evaluate the performance of seven fully automated, commercial multiplex immunoassay platforms used to measure serum total testosterone (T), LH, and FSH. DESIGN: This was an observational study of consistency among seven different automated immunoassays for each of total T, LH, and FSH. Each method was implemented in two laboratories, with each repeating the analysis of the full reference panel samples twice. Serum T concentrations were also measured by gas chromatography/mass spectrometry (GC/MS), and serum inhibin B levels were determined by an ELISA. SETTING: The study was performed at commercial, high-volume, clinical pathology laboratories. PARTICIPANTS: From 147 men screened, sera from 124 healthy, reproductively normal men (age, 21-35 yr) with normal sperm output were used as a reference panel. All laboratories selected for elite performance in the national immunoassay quality assurance program agreed to participate. MAIN OUTCOME MEASURE(S): For each of the 868 assays, descriptive statistics were calculated in the natural and log-transformed scales and were analyzed by nested, repeated measures ANOVA after log transformation. Reference intervals, defined as 95% confidence limits, were calculated using arithmetic (natural scale), geometric (log scale) and nonparametric methods. RESULTS: Descriptive statistics and reference intervals for serum T, LH, and FSH differed widely and significantly between methods, but variation between laboratories for the same assay was negligible. All T methods showed significant differences in regression slope and intercept in deviance plots as well as in estimated reference ranges compared with the independent GC/MS reference method. Although similar between-method differences existed for gonadotropin assays, the smaller quantitative discrepancies allowed assignment of consensus reference intervals for serum FSH (1.3-8.4 IU/liter) and LH (1.6-8.0 IU/liter), although these differed from manufacturers' currently quoted expected values. CONCLUSIONS: Using a reference panel of sera from healthy eugonadal young men with verified normal reproductive function, major differences exist between commercial T immunoassays as well as divergence from the GC/MS standard. This impairs their clinical diagnostic utility and requires substantial improvements in automated T immunoassay technologies or a switch to GC/MS methods. Gonadotropin assays showed less variability, but current high-throughput immunoassays remain suboptimal to confirm accurate diagnosis of azoospermia or androgen deficiency.

Adult↗
PubMed2005

Gonadotropin control of inhibin secretion and the relationship to follicle type and number in the hpg mouse.

Inhibin is secreted in two distinct heterodimeric forms, A and B, but the mechanism for the differential control of these two forms is unclear. To evaluate the relationship between secretion of inhibin forms and folliculogenesis, the effects of gonadotropins on inhibin concentrations were studied in parallel with stereological enumeration of ovarian follicle types in gonadotropin-deficient hypogonadal (hpg) female mice treated with recombinant human FSH (10 IU/day), hCG (1 IU/day), or both for 20 days. Treatment with FSH alone significantly increased blood concentrations of both inhibin A and inhibin B, whereas hCG alone had no effect on either inhibin. The combination of FSH and hCG further increased the concentration of inhibin A but had no effect on the concentration of inhibin B beyond that of FSH. The number of primordial follicles per ovary was significantly reduced in FSH-treated hpg mice, but was not affected by hCG treatment. Antral follicles were absent in the untreated hpg mice, present following treatment with FSH, and were present in only limited numbers following hCG treatment alone. Preovulatory follicles were observed only in the wild-type and combined FSH and hCG treatment groups. These results demonstrate that secretion of both inhibins is associated with the presence of antral follicles. Inhibin A secretion is increased by the presence of preovulatory follicles, whereas the concentration of inhibin B is not affected. The observed effects of gonadotropins on inhibin A and B secretion may be explained by corresponding gonadotropin effects on follicle development.

Animals↗
PubMed2005

Rates of suppression and recovery of human sperm output in testosterone-based hormonal contraceptive regimens.

BACKGROUND: Practical hormonal male contraceptive regimens are likely to have delayed onset and offset of reliable contraception dictated by the length of the spermatogenic cycle and clearance rate of pre-formed sperm from the ductular system. While delayed onset of contraceptive efficacy is an accepted feature of vasectomy, reliable time estimates for a hormonal male contraceptive of time to onset and offset of reliable contraception and of resumption of normal male fertility are required. METHODS AND RESULTS: We utilized the sperm output data from three male contraceptive efficacy studies to define quantitative estimates of suppression and recovery rates from an androgen alone (testosterone enanthate) and an androgen/progestin (testosterone/depot medroxyprogesterone acetate) study. Using nearly 14,000 semen samples from World Health Organization (WHO) studies #85921 and #89903 with identical protocols, the rate of suppression of sperm output was best modelled as a two-parameter, single exponential decay function with effective half-time to suppression of 5.5 weeks and times of 6.8 weeks to 10 x 10(6)/ml, 8.7 weeks to 5 x 10(6)/ml, 10.0 weeks to 3 x 10(6)/ml and 13.0 weeks to 1 x 10(6)/ml. The rate of recovery using absolute sperm concentration was best modelled as a three-parameter, sigmoidal curve with effective time to reach half of the recovery plateau of 10.5 weeks and times of 9.0 weeks to 3 x 10(6)/ml, 9.9 weeks to 5 x 10(6)/ml, 11.5 weeks to 10 x 10(6)/ml, and 13.6 weeks to 20 x 10(6)/ml. Using relative sperm output, defined as a percentage of the participants' own baseline, recovery approached an asymptotic plateau of approximately 85% of geometric mean pre-treatment sperm concentration. In the combination androgen/progestin study, suppression rate was significantly faster (effective time to reach half maximal suppression of 3.0 weeks) and recovery significantly slower (effective time to reach half of recovery plateau of 14.7 weeks) and less complete (asymptotic recovery plateau of 43% of baseline) than in the androgen-alone WHO studies. CONCLUSION: These findings therefore provide large sample estimates of the suppression and recovery rates from an androgen-alone hormonal male contraceptive regimen as a basis for comparison with other second-generation combination androgen/progestin regimens that are the most promising approach to developing practical male hormonal regimens.

Contraception↗