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Objective: To study the potential role for using serum biomarkers, including insulin-like factor 3 (INSL3), 17α-hydroxyprogesterone, antimüllerian 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, antimüllerian 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., (Copyright © 2013 American Society for Reproductive Medicine. All rights reserved.)

Objective: To demonstrate the efficacy and safety of follitropin alfa administered with hCG on spermatogenesis in adult male hypogonadotropic hypogonadism (HH) patients., Design: Phase III, multicenter, open-label, noncomparative., Setting: Seven US medical centers., Patient(s): A total of 36 adult males with severe HH., Intervention(s): A total of 1,000 U hCG on alternate days for 3 to 6 months, with dose adjustments after 2 months, if necessary, to normalize T levels, followed by follitropin alfa 150 U and hCG on the same alternate days for 18 months, with dose adjustments as necessary., Main Outcome Measure(s): Proportion of patients with sperm density > or =1.5 x 10(6)/mL. Pubertal advancement and long-term safety and tolerability were also evaluated., Result(s): In total, 22 of 29 patients (75.9%) who received > or =1 dose of follitropin alfa and 20 of 25 patients (80%) who completed 18 months of hCG + follitropin alfa treatments achieved a sperm concentration > or =1.5 x 10(6)/mL. A sperm concentration >20 x 10(6)/mL was achieved by 8 of 29 men (27.5%). Median sperm concentration at 18 months was 5.2 x 10(6)/mL. Pubertal development continued during the study, and testis volumes increased. Five clinical pregnancies were achieved. Acne (52% of patients) was the most common side effect, and gynecomastia was reported in 10% of patients., Conclusion(s): Long-term treatment of azoospermic HH men using follitropin alfa and hCG is effective for stimulating spermatogenesis and is well-tolerated.

Objective: To determine if serum concentrations of testosterone precursors would correlate with intratesticular testosterone (ITT) concentration measured directly by testicular aspiration and allow for a less invasive means of inferring ITT., Design: Controlled clinical study., Setting: Healthy volunteers in an academic research environment., Patient(s): Twenty-nine normal men., Intervention(s): We determined ITT concentration by testicular aspiration before and after treatment in men receiving exogenous T to block endogenous gonadotropin production and randomly assigned to one of four doses of hCG (0, 125 IU, 250 IU, or 500 IU every other day) for 3 weeks., Main Outcome Measure(s): The association between serum 17-hydroxyprogesterone (17OH-P), androstenedione, and DHEA and ITT., Result(s): With T administration alone, serum 17OH-P decreased significantly and increased significantly when 500 IU hCG was administered. End-of-treatment ITT strongly correlated with serum 17OH-P. Moreover, serum 17OH-P, but not androstenedione or DHEA, was independently associated with end-of-treatment ITT by multivariate linear regression., Conclusion(s): Serum 17OH-P is highly correlated with ITT in gonadotropin-suppressed normal men receiving T and stimulated with hCG. Serum 17OH-P is a surrogate biomarker of ITT and may be useful in research and in men receiving gonadotropin therapy for infertility.

Objective: To test the hypothesis that oral desogestrel (DSG) plus testosterone would uniformly and rapidly suppress sperm concentrations in young men as effectively as levonorgestrel (LNG) plus testosterone and cause less high-density lipoprotein (HDL) suppression and weight gain., Design: Single-blind, randomized trial., Setting: VA Puget Sound and University of Washington, Seattle, Washington., Patient(s): Twenty-four healthy young men, aged 20-49., Intervention(s): Subjects were randomized to three groups of men who were administered 6 months of therapy with oral DSG plus im testosterone enanthate: 150 microg of DSG plus 50 mg of testosterone (DSG 150-T 50), 150 microg of DSG plus 100 mg of testosterone (DSG 150-T 100) or 300 microg of DSG plus 100 mg of testosterone (DSG 300-T 100). We compared these three groups to two groups of historical controls of 100 mg of im testosterone alone or 150 microg of oral LNG plus 100 mg of im testosterone (LNG 125-T 100 group) enrolled in similar studies., Main Outcome Measure(s): Suppression of sperm counts to severe oligoazoospermia (sperm counts <1 x 10(6)/mL) and azoospermia, weight gain, and serum high-density cholesterol (HDL) suppression., Result(s): Azoospermia was achieved in all eight men receiving DSG 150-T 100 and seven of the eight men in the DSG 300-T 100 group. DSG 150 or 300 plus T 100 suppressed spermatogenesis as effectively as LNG 125-T 100 and more effectively than DSG 50-T 100 or testosterone alone. All groups tended to gain weight compared with their baseline, but the weight gain was greatest (and statistically significant) in the DSG 150-T 100, DSG 300-T 100, and LNG 125-T 100 groups. Serum HDL levels were modestly suppressed in all groups, and this effect was greatest in the DSG 300-T 100 and LNG 125-T 100 groups., Conclusion(s): The combination of DSG plus testosterone is a very effective regimen for suppression of spermatogenesis and has acceptably low side effects.

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 microg daily, n = 5) or levonorgestrel (125-250 microg 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 oligo- or azoospermia. Detailed studies on the sites of spermatogenic interruption are required to understand the variability in responses seen after contraceptive therapies in men.

Three men who volunteered as normal subjects were found to have abnormally high levels of serum follicle-stimulating hormone (FSH) despite having normal seminal fluid analyses and fertility. Two of the men had a history of previous orchitis, and one had an atrophic testis. Serum luteinizing hormone and testosterone levels were normal. These cases appear to represent compensated primary testicular disease, with normal sperm counts and fertility maintained at the expense of chronically elevated FSH levels. These results imply that in certain situations, the measurement of serum FSH levels may be a more sensitive index of testicular disease than the performance of seminal fluid analyses.

Men with idiopathic azoo-oligospermia and selective elevations of follicle-stimulating hormone (FSH) levels have evidence for decreased luteinizing hormone-releasing hormone (LH-RH) pulse frequency. We assessed whether increasing the frequency of pulsatile LH-RH stimulation can lower FSH levels in such men. We administered 5.0 microgram of pulsatile LH-RH subcutaneously at intervals of 30, 60, and 120 minutes for 1 week to four men who had azoospermia, elevated FSH levels, and normal LH and testosterone (T) levels. The order of administration was varied among subjects. Frequent blood samples were obtained for 6 hours before LH-RH treatment and during the last 6 hours of each regimen. Before LH-RH treatment, the FSH levels (mean +/- standard error of the mean) were 359 +/- 18 ng/ml (normal range, 30 to 230 ng/ml). During LH-RH treatment, FSH levels progressively declined from 397 +/- 68 ng/ml to 237 +/- 70 ng/ml to 175 +/- 43 ng/ml as the frequency of administration increased from every 120 to 60 to 30 minutes, respectively (P less than 0.05). Unlike the FSH levels, which showed a progressive decline, LH, T, and estradiol levels showed no consistent relationship to LH-RH pulse frequency. We conclude that (1) in men with idiopathic azoospermia and elevated FSH levels, it is possible to decrease FSH levels by increasing the frequency of pulsatile LH-RH stimulation; (2) this decline does not appear to be a result of changes in steroid feedback or pituitary down-regulation; and (3) the frequency of pulsatile LH-RH stimulation can differentially modulate LH and FSH secretion by the pituitary gland.

In male contraceptive trials, approximately half of normal men become azoospermic on high dosages of testosterone enanthate (TE), whereas the other half of men become severely oligozoospermic. To determine whether sperm function is reduced in men with severe oligozoospermia induced by TE, we studied sperm function in six normal men whose sperm counts were reduced to less than or equal to 5 X 10(6)/ml but not to azoospermia by high-dosage TE administration for 5 to 6 months and five normal men who received placebo (sesame oil) injections for the same period of time. Seminal fluid analysis and sperm function (as assessed by zona pellucida-free hamster ova penetration test, HOPT) were performed during a pretreatment period and after at least 3 months of TE or placebo treatment. HOPT was severely reduced in all six men, whose sperm counts were suppressed to severe oligozoospermia during TE (0.8 +/- 0.8% compared to 37 +/- 14% during the pretreatment period, P less than 0.05). Five men failed to penetrate any hamster ova, while the remaining man penetrated only 5% of ova during TE treatment. There were no significant changes in other seminal fluid measurements during high-dosage TE. The five men who received placebo injections did not demonstrate any significant changes in HOPT or seminal fluid analysis during the treatment period. In summary, we found that the fertilizing capacity of sperm is markedly diminished when sperm production is severely reduced by high-dosage TE administration. These findings suggest that male contraception may be achievable by reduction of spermatogenesis to severe oligozoospermia.(ABSTRACT TRUNCATED AT 250 WORDS)