Pharmacokinetics of testosterone and estradiol gel preparations in healthy young men.

The paucity of pharmacokinetic data on testosterone gel formulations and absence of such data on estradiol administration in healthy young men constitutes a fundamental gap of knowledge in behavioral endocrinological research. We addressed this issue in a double-blind and placebo controlled study in which we applied a topical gel containing either 150mg of testosterone (N=10), 2mg of estradiol (N=8) or a respective placebo (N=10) to 28 healthy young men. We then assessed serum concentrations of estradiol and testosterone in one hour intervals up to seven hours after drug application, measured LH, SHBG and cortisol levels once at baseline and three, four as well as six hours after gel administration. Treatment with testosterone gel resulted in maximum total serum testosterone concentration three hours after administration and did not suppress LH, cortisol and SHBG levels at any time point. Administration of estradiol gel led to maximum estradiol serum concentration two hours after administration. There was no suppression of cortisol, SHBG and absolute LH levels. We report here, for the first time, pharmacokinetic data on both high dose testosterone and estradiol gel application in healthy young males. The proposed model will assist in the design of future studies that seek to establish causality between testosterone and estradiol gel administration and behavioral as well as neurophysiological effects.

World Health Organization reference values for human semen characteristics.

BACKGROUND: Semen quality is taken as a surrogate measure of male fecundity in clinical andrology, male fertility, reproductive toxicology, epidemiology and pregnancy risk assessments. Reference intervals for values of semen parameters from a fertile population could provide data from which prognosis of fertility or diagnosis of infertility can be extrapolated. METHODS: Semen samples from over 4500 men in 14 countries on four continents were obtained from retrospective and prospective analyses on fertile men, men of unknown fertility status and men selected as normozoospermic. Men whose partners had a time-to-pregnancy (TTP) of < or =12 months were chosen as individuals to provide reference distributions for semen parameters. Distributions were also generated for a population assumed to represent the general population. RESULTS: The following one-sided lower reference limits, the fifth centiles (with 95th percent confidence intervals), were generated from men whose partners had TTP < or = 12 months: semen volume, 1.5 ml (1.4-1.7); total sperm number, 39 million per ejaculate (33-46); sperm concentration, 15 million per ml (12-16); vitality, 58% live (55-63); progressive motility, 32% (31-34); total (progressive + non-progressive) motility, 40% (38-42); morphologically normal forms, 4.0% (3.0-4.0). Semen quality of the reference population was superior to that of the men from the general population and normozoospermic men. CONCLUSIONS: The data represent sound reference distributions of semen characteristics of fertile men in a number of countries. They provide an appropriate tool in conjunction with clinical data to evaluate a patient's semen quality and prospects for fertility.

Body fat content and testosterone pharmacokinetics determine gonadotropin suppression after intramuscular injections of testosterone preparations in normal men.

Interindividual differences in gonadotropin suppression achieved by short- and long-acting intramuscular testosterone (T) preparations were studied to detect factors hindering complete suppression of gonadotropins as the prerequisites for effective male contraception. Forty healthy men received a single injection of T propionate; 4 weeks later they received 2 injections of 1000 mg of T undecanoate (TU) given 6 weeks apart. Following TU, declines of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were consistent in 17.5% and almost absent in 25% of men. Men showing the most rapid and consistent declines in LH and FSH levels received a slightly higher dose per body weight of TU (13.1 +/- 0.6 vs 11.3 +/- 0.6 mg/kg; P = NS) and reached higher maximal concentrations of total T (40 +/- 4.8 vs 18.4 +/- 2.4 nmol/L; P < .001) and free T as well as estradiol. Men with high fat mass (mean +/- SEM, 10.3 +/- 1.5 vs 23.2 +/- 6.4 kg) had a delayed increase in T levels and an impaired relative decline in LH (12 +/- 2% vs 53 +/- 10%) and FSH (17 +/- 6%. vs 70 +/- 25%) levels within the first 2 weeks after the first TU injection. We conclude that overweight reduces the chance of rapid and profound gonadotropin suppression during treatment with TU. Body weight needs to be considered to avoid failure of hormonal male contraception.

Role of sequence variations of the GnRH receptor and G protein-coupled receptor 54 gene in male idiopathic hypogonadotropic hypogonadism.

OBJECTIVE: To determine the frequency of mutations of the gonadotropin-releasing hormone receptor (GnRHR) and of the G protein-coupled receptor 54 (GPR54) genes in normosmic idiopathic hypogonadotropic hypogonadism (IHH). METHODS: In a retrospective study we analyzed the GnRHR and the GPR54 genes of 45 IHH patients and 50 controls. Genomic DNA was amplified by PCR to obtain partially overlapping amplicons encompassing the exon-intron boundaries of the GnRHR and GPR54 genes and analyzed by single-stranded conformation polymorphism gel electrophoresis and/or DNA sequencing. RESULTS: One heterozygous R262Q mutation of the GnRHR gene was identified in one patient with familial IHH. The silent single-nucleotide polymorphism (SNP) 453C > T occurred at the same frequency in patients and controls. One patient with sporadic IHH and consanguineous parents showed a novel homozygous sequence variation of the GPR54 gene (1001_1002insC) resulting in an open reading frame shift and elongation of 43 amino acids with an increased number of proline residues in the intracellular receptor domain. This patient had delayed puberty, low testosterone (3.4 nmol/l), and low-normal LH and FSH levels responsive to GnRH. Pulsatile GnRH administration normalized testosterone levels and induced spermatogenesis sufficiently to induce a pregnancy with assisted reproduction. Two common SNPs in exon 1 and exon 5 of the GPR54 gene showed similar frequency distribution and hormonal profiles in IHH and controls. CONCLUSIONS: Mutations of the GnRHR and of the GPR54 gene are rare in IHH and should be investigated especially in cases with autosomal recessive transmission. Common SNPs of the GnRHR and GPR54 genes do not play any role in IHH.

A clinical trial of 7 alpha-methyl-19-nortestosterone implants for possible use as a long-acting contraceptive for men.

Several preparations of testosterone and its esters are being investigated alone or in combination with other gonadotropin-suppressing agents as possible antifertility agents for men. We studied the effectiveness of 7 alpha-methyl-19-nortestosterone (MENT) as an antispermatogenic agent in men. MENT has been shown to be more potent than testosterone and to be resistant to 5 alpha-reduction. For sustained delivery of MENT, we used a system consisting of ethylene vinyl acetate implants containing MENT acetate (Ac), administered subdermally. Thirty-five normal volunteers were recruited in 3 clinics and were randomly assigned to 1 of 3 doses: 1 (12 men), 2 (11 men), or 4 (12 men) MENT Ac implants. The initial average in vitro release rate of MENT Ac from each implant was approximately 400 micro g/day. Implants were inserted subdermally in the medial aspect of the upper arm under local anesthesia. The duration of treatment was initially designed to be 6 months. However, in 2 clinics the duration of treatment was extended to 9 months for the 2-implant group and to 12 months for the 4-implant group. Dose-related increases in serum MENT levels and decreases in testosterone, LH, and FSH levels were observed. Effects on sperm counts were also dose related. None of the subjects in the 1-implant group exhibited oligozoospermia (sperm count, <3 million/ml). Four subjects in the 2-implant group became oligozoospermic, 2 of whom reached azoospermia. Eight subjects in the 4-implant group reached azoospermia, with 1 exhibiting oligozoospermia, whereas 2 were nonresponders. Side effects generally seen with androgen administration, such as increases in erythrocyte count, hematocrit, and hemoglobin and a decrease in SHBG, were also seen in this study and were reversible. Changes in lipid parameters were moderate and transient. Liver enzymes showed small changes. This study demonstrates that MENT Ac, when administered in a sustained release fashion via subdermal implants, can inhibit spermatogenesis over a prolonged period after a single administration and has the potential to be used as a male contraceptive.

Maintenance of spermatogenesis in hypogonadotropic hypogonadal men with human chorionic gonadotropin alone.

OBJECTIVE: It is generally accepted that both gonadotropins LH and FSH are necessary for initiation and maintenance of spermatogenesis. We investigated the relative importance of FSH for the maintenance of spermatogenesis in hypogonadotropic men. SUBJECTS AND METHODS: 13 patients with gonadotropin deficiency due to idiopathic hypogonadotropic hypogonadism (IHH), Kallmann syndrome or pituitary insufficiency were analyzed retrospectively. They had been treated with gonadotropin-releasing hormone (GnRH) (n=1) or human chorionic gonadotropin/human menopausal gonadotropin (hCG/hMG) (n=12) for induction of spermatogenesis. After successful induction of spermatogenesis they were treated with hCG alone for maintenance of secondary sex characteristics and in order to check whether sperm production could be maintained by hCG alone. Serum LH, FSH and testosterone levels, semen parameters and testicular Volume were determined every three to six Months. RESULTS: After spermatogenesis had been successfully induced by treatment with GnRH or hCG/hMG, hCG treatment alone continued for 3-24 Months. After 12 Months under hCG alone, sperm counts decreased gradually but remained present in all patients except one who became azoospermic. Testicular Volume decreased only slightly and reached 87% of the Volume achieved with hCG/hMG. During treatment with hCG alone, FSH and LH levels were suppressed to below the detection limit of the assay. CONCLUSION: Once spermatogenesis is induced in patients with secondary hypogonadism by GnRH or hCG/hMG treatment, it can be maintained in most of the patients qualitatively by hCG alone, in the absence of FSH, for extended periods. However, the decreasing sperm counts indicate that FSH is essential for maintenance of quantitatively normal spermatogenesis.

Treatment of male hypogonadism with testosterone undecanoate injected at extended intervals of 12 weeks: a phase II study.

This paper reports the result of an open-label, non-randomized clinical trial investigating the efficacy and safety of an injectable preparation of testosterone undecanoate (TU) dissolved in castor oil and given over a 3.2-year period. In a previous study we demonstrated that injections of TU every 6 weeks resulted in satisfactory substitution but a tendency toward testosterone accumulation. Here we investigate prolonged TU treatment at extended injection intervals in 7 hypogonadal men. Injections were given at gradually increasing intervals between the fifth and 10th injection, and from then on every 12 weeks. Steady state kinetics were obtained after the 13th injection. Well-being, sexual activity, clinical chemistry, prostate volume, and prostate-specific antigen (PSA) and serum hormone levels were monitored. Patients were clinically well-adjusted throughout the study. Before the next injection, testosterone, dihydrotestosterone, and estradiol levels were mostly within the normal range and showed a tendency to decrease with increasing injection intervals. Body weight, hemoglobin, serum lipids, PSA, and prostate volume did not change significantly during the 3.2 years of treatment. PSA levels were always within the normal limit. Maximal testosterone levels during steady state kinetics were measured after 1 week with 32.0 +/- 11.7 nmol/L (mean +/- SD). Before the last injection, mean testosterone concentrations were 12.6 +/- 3.7 nmol/L. Compared with conventional testosterone enanthate or cypionate treatment requiring injection intervals of 2-3 weeks and resulting in supraphysiological serum testosterone levels, injections of TU at intervals of up to 3 months offer an excellent alternative for substitution therapy of male hypogonadism.

An effective hormonal male contraceptive using testosterone undecanoate with oral or injectable norethisterone preparations.

Suppression of spermatogenesis to azoospermia is the goal of hormonal male contraception based on T combined with gestagens. The combination of the long-acting T, ester testosterone undecanoate (TU), with norethisterone (NET) enanthate (E) showed high efficacy. In the present study, we tested the validity of this approach by varying the NET dose and mode of application. The aim of the study was to achieve high rates of suppression of spermatogenesis as reflected by sperm counts, monitor gonadotropins as well as other hormones, and evaluate any possible side effects. In a phase II clinical trial, groups of normal volunteers received: 1000 mg TU im at wk 2, 6, 12, and 18 combined with 200 mg NETE im at wk 0, 6, 12, and 18 (group I); 1000 mg TU im and 400 mg NETE im at wk 0, 6, 12, and 18 (group II); and 1000 mg TU im at wk 0, 6, 12, and 18 with daily oral NET acetate (NETA) from wk 0 to 24 (group III). In all groups marked suppression of gonadotropins resulted in a significant decrease of spermatogenesis and azoospermia in 13/14, 11/12, and 12/14 men in groups I to III, respectively. The remaining men all had less than 1 million sperm/ml. Reversible side effects included increase in body weight, erythrocytes, hemoglobin, and hematocrit and decrease in high-density lipoprotein cholesterol and alkaline phosphatase in all groups and increase in liver enzymes in the oral NETA group. This study documents the high efficacy of TU in combination with NET and confirms that this dose and mode of application (1000 mg TU im every 6 wk plus 400 mg NETE im every 6 wk or plus 10 mg daily oral NETA) is as effective as the previously reported regimen containing 1000 mg TU + 200 mg NETE im every 6 wk. The contraceptive efficacy of this combination of TU and NETE should be evaluated in further clinical trials.