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Objective: To delineate the role of gonadotropins in male androgen biosynthesis pathways., Design: Case-control study., Patients and Measurements: Twenty five males with congenital hypogonadotropic hypogonadism (CHH) underwent hCG/rFSH and testosterone treatment sequentially. Serum steroid hormone profiles (testosterone precursors and metabolites) on both replacement regimens were analysed, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and compared to those of healthy controls, matched by age, BMI and serum testosterone., Results: On testosterone replacement, serum concentrations of the classic Δ4 pathway hormones progesterone and 17-hydroxy-progesterone (17-OHP), and the marker steroid of an alternative pathway of testosterone synthesis (androstenediol) were decreased, compared to controls. Androstanediol, a marker of the backdoor pathway of dihydrotestosterone (DHT) synthesis, was increased. 17-OH-pregnenolone, androstenedione and DHEAS (Δ5 pathway), three 11-oxygenated C19 androgens (11-keto-A4, 11-keto-T and 11-keto-DHT) and the testosterone (T) metabolites DHT and 17ß-oestradiol (E2) were similar to controls. On gonadotropin replacement, 17-OHP, 17-OH-pregnenolone, DHEAS and androstenedione, as well as DHT, androstenediol, and all 11-oxygenated C19 androgens were normal. Progesterone (Δ4 pathway) was slightly decreased, and androstanediol (backdoor DHT pathway) and E2 (T metabolite) were increased., Conclusions: In males with CHH, serum steroid hormone profiles resemble those of healthy men, if hCG/rFSH is used for substitution. Gonadotropins contribute to steroid hormone production along the classic Δ4 pathway and co-activate an alternative pathway of testosterone biosynthesis via androstenediol. Backdoor DHT biosynthesis, Δ5 17-OH-pregnenolone, DHEA(S) and androstenedione synthesis and 11-oxygenated C19 androgen production are activated independently of gonadotropins. The androgen replacement modality used for treatment of hypogonadal males with absent or reduced endogenous LH/FSH secretion may impact on long-term health and quality of life., (© 2020 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Objective: To understand the clinical significance of immature germ cells commonly found in ejaculates with low sperm counts by a novel and stringent flow cytometric quantitative method. PATIENTS/MEASUREMENTS: A total of 65 azoospermic, 38 cryptozoospermic and 42 severe oligozoospermic patients underwent routine hormone and semen analysis. Cells from each ejaculate were stained for DNA and mitochondria and analysed as spermatozoa (HC), round spermatids (1N), primary spermatocytes (4N) or diploid cells (2N)., Results: About 90% of HC particles were eliminated as contaminants of the spermatozoa population by the analysis of their laser light scatter pattern and mitochondria staining intensity. Ploidy identification accuracy was improved by selection of singlets and elimination of cell aggregates for analysis. Distribution peaks for HC, 1N and 4N cells were displayed in 53%, 56% and 25% ejaculates, respectively, with prevalence in severe oligozoospermia > cryptozoospermia > azoospermia. 1N cell numbers were correlated with 4N and HC cells. For HC and 1N cells, the number/ejaculate and the incidence of distribution peaks were correlated with serum testosterone levels, and inversely with FSH for HC, 1N and 4N cells, suggesting that the abnormal shedding of 1N and 4N germ cells is the consequence rather than the cause of spermatogenic failure in these patients. Ploidy data bear no association with clinical diagnosis except for Klinefelter patients., Conclusion: Whereas incidence of HC cells in azoospermic ejaculates may suggest minimal spermatogenic activity which evades detection by routine semen analysis, the presence of 1N and 4N cells in semen of patients provides noninvasive information about their spermatogenic status.

Male hypogonadism is one of the most frequent, but also most underdiagnosed, endocrinopathies. However, the required testosterone treatment is simple and very effective if properly administered. Although testosterone has been available for clinical use for seven decades, until quite recently the treatment modalities were far from ideal. Subdermal testosterone pellets require minor surgery for insertion and often cause local problems. The injectable testosterone enanthate, for a long period the most frequently used mode of administration, lasts for two to four weeks, but produces supraphysiological levels initially and low levels before the next injection. The oral testosterone undecanoate has to be taken three times daily, has an uncertain absorption pattern and results in peaks and valleys of serum testosterone levels throughout the day. With the advent of transdermal testosterone preparations, the desired physiological serum levels could be achieved for the first time. Scrotal testosterone patches were the first to fulfil this requirement. These were followed by nonscrotal skin patches, which, however, cause considerable skin reactions including erythema and blisters. Recently introduced, invisible transdermal testosterone gels increased the intervals of application and are now slowly replacing other modalities. A mucoadhesive buccal testosterone tablet with sustained release is also a recent competing modality. Finally, injectable testosterone undecanoate in castor oil was made into a real depot preparation requiring only four injections per year for replacement therapy. These new preparations with a desired pharmacokinetic testosterone profile give the patient a real choice and make treatment easier. Based on pharmacogenetic considerations taking the androgen receptor polymorphism into account, treatment may be individualized for each patient in the future.

Objective: Adiponectin is an adipocyte-specific secretory protein which exhibits antiatherogenic, anti-inflammatory and antidiabetic properties. We hypothesized that testosterone plays an important role in the regulation of its secretion in humans, as adiponectin concentrations are higher in women than in men and as testosterone administration is accompanied by a reduction in serum adiponectin in animals and by reduced protein secretion in cultured adipocytes. This study aimed to evaluate adiponectin levels in hypogonadal men prior to and during testosterone replacement therapy., Subjects and Methods: In a retrospective study, adiponectin, total and free testosterone, oestradiol, SHBG, total cholesterol and triglyceride levels were evaluated in 31 hypogonadal men [HM; age, mean +/- SEM: 36.5 +/- 2.4 years; body mass index (BMI) 24.6 +/- 0.8 kg/m2] and 29 weight-matched eugonadal men (EM; age 30.8 +/- 1.5 years; BMI 23.4 +/- 0.6 kg/m2). In 13 HM (age 33.9 +/- 3.2 years; BMI 24.2 +/- 0.9 kg/m2) the same parameters were also evaluated after 6 months of testosterone replacement therapy. Correlation analysis between adiponectin and hormonal, biochemical and anthropometric parameters was performed in all subjects., Results: Testosterone, free testosterone and oestradiol concentrations were significantly lower in HM than in EM (4.4 +/- 0.4 nmol/l, 78.4 +/- 10.9 pmol/l and 36.1 +/- 3.0 pmol/l, respectively, in HM vs. 21.9 +/- 0.7 nmol/l, 507.9 +/- 13.8 pmol/l and 65.2 +/- 1.8 pmol/l, respectively, in EM, P < 0.0001), while SHBG levels in HM were higher than in EM (54.4 +/- 7.5 vs. 30.9 +/- 2.2 nmol/l, P < 0.005). Serum adiponectin levels in HM were significantly higher than in EM (9.53 +/- 0.73 vs. 6.80 +/- 0.55 microg/ml, P < 0.01). Calculation of the Pearson coefficient showed that adiponectin levels in HM were not correlated with any of the anthropometric and hormonal parameters examined, but showed a significant negative correlation with serum triglycerides (r = -0.38, P < 0.05). Serum adiponectin levels were negatively correlated with body weight (r = -0.41, P < 0.05) in EM but not with other anthropometric, hormonal or biochemical parameters. Six months after initiation of testosterone replacement therapy, which increased testosterone and free testosterone levels to the normal range, adiponectin levels were significantly reduced in HM (6.37 +/- 0.93 vs. 9.26 +/- 1.01 microg/ml, P < 0.01) and similar to those recorded in EM., Conclusions: Compared to eugonadal subjects, hypogonadal men show higher adiponectin levels which are reduced by testosterone replacement therapy. This study indicates that testosterone exerts a regulatory role on adiponectin secretion in humans.

Objective: Nonuniformity in suppression of spermatogenesis induced by various hormones or hormone combinations has impeded the development of an effective hormonal male contraceptive. The basis for this heterogeneity in response remained unresolved to date; however, the presence of ethnic differences points to an involvement of genetic factors., Patients and Measurements: In a retrospective analysis we investigated the impact of a CAG repeat polymorphism in the androgen receptor and polymorphic sites in the oestrogen and FSH receptor genes on spermatogenic suppression in 85 Caucasian men treated with different regimens of hormonal contraception., Results: Failure to reduce sperm concentrations below 3 million/ml was significantly associated with insufficient suppression of gonadotrophins. The extent of gonadotrophin suppression was not explained by any polymorphism but was primarily pharmacological, resulting from addition of gestagens to testosterone. When LH and FSH suppression was rapid and persistent none of the polymorphisms studied explained why some men failed to achieve azoospermia. In cases with incomplete gonadotrophin suppression the chances of becoming azoospermic were 2.5 times higher in men having more than 22 CAG repeats., Conclusions: In summary, our analysis shows that in a subset of men, effective hormonal male contraception can be achieved even in the absence of complete gonadotrophin suppression.

Objective: Transdermal testosterone gel treatment is an effective androgen substitution therapy with several advantages over conventional substitution therapies. Whereas side-effects due to overdosing of hypogonadal patients are unlikely, testosterone gel application without protection may cause severe side-effects in other subjects (partners, family members) by contamination. Therefore, the risk of testosterone transfer of a newly developed 2.5% testosterone gel preparation was evaluated., Design: In two clinical randomized open single-centre studies on healthy male volunteers the percentage of testosterone remaining on the skin after gel application over time (n = 12) and the possibility of a transfer of testosterone to another person (n = 28) was evaluated. In the second study the endogenous testosterone production in the receiving subjects was suppressed by injecting 400 mg norethisterone enanthate (NETE)., Results: After 8 h approximately 60% of testosterone applied to the skin could be recovered. When the skin had been previously washed with water, only about 14% of applied testosterone could be recovered. After intense skin contact with a volunteer who had applied testosterone before on his forearm, no increase in testosterone serum levels could be found in NETE-suppressed men., Conclusion: Although considerable amounts of testosterone remain on the intact skin for several hours after evaporation of the alcohol vehicle, contamination of a second, especially female or prepubertal, subject causing side-effects seems very unlikely.

Objective: Bone metabolism and bone density (BD) are influenced by sex hormones. Testosterone (T) action is exerted through the androgen receptor (AR). We investigated the potential impact of the CAG repeat (CAGR) polymorphism within the AR gene on BD and bone metabolism in healthy younger males., Patients and Measurements: The number of CAGRs in 110 healthy men aged 20-50 years was determined by sequence analysis. We assessed BD by the radiation-free method of quantitative ultrasound (QUS) of the phalanges. Serum levels of bone-specific alkaline phosphatase (BAP) and urine secretion of free deoxypyridinoline (DPD, corrected for creatinine), serum levels of sex hormones, body fat content and lifestyle factors were determined., Results: In stepwise multiple regression models controlling for age, body fat content and lifestyle factors, the number of CAGRs was an independent negative predictor of BD (partial r = - 0.286, P = 0.001), whereas it was positively associated with markers of bone turnover (for BAP: partial r = 0.32, P= 0.001; for DPD: partial r = 0-241, P = 0.013). Levels of free T and oestradiol showed an independent and positive association with BD; age contributed significantly to lower BD. Age and free T were negatively associated with markers of bone turnover, whereas oestradiol showed a positive correlation with BAP and DPD. ANOVA in groups according to age and the CAGR length suggested an increased age-dependent bone loss in subjects with a CAGR length of 22-31 compared with 14-21 CAGRs (overall P < 0.01)., Conclusions: A high number of CAG repeats within the androgen receptor gene attenuates testosterone effects on bone density and bone metabolism. This seems to be associated with accelerated age-dependent bone loss.

Objective: Gestagens are known to suppress gonadotrophins in women and are currently also under investigation for the development of hormonal male contraceptives. The aim of the study was to assess the potential of norethisterone enanthate (NETE) for male contraception., Design and Measurements: The suppressive effect of a single injection of 200 mg NETE on serum gonadotrophins, serum testosterone, lipids, spermatogenesis, well-being and sexual function was evaluated in seven healthy men., Results: In this single dose study treatment was well tolerated by all volunteers. NETE led to a rapid, profound and significant suppression of serum LH (day 6 - day 10), FSH (day 2 - day 29), testosterone (day 1 - day 29 and day 35) and SHBG (day 6 - day 35). At study end sperm counts were significantly suppressed. Numbers of spontaneous erections (day 17, 23 and 26), number of sexual fantasies (day 20 and 23) as well as libido (day 20 and 26) were significantly decreased compared to baseline. All other parameters including lipids, augmented glucose, testicular volume and well-being showed no significant alterations., Conclusion: Because of its strong, rapid and sustained suppression of serum FSH and testosterone norethisterone enanthate offers great potential for hormonal male contraception if combined with testosterone esters.

Objective: Approaches to hormonal male contraception are based on injectable testosterone esters alone or in combination with gestagens or GnRH analogs but the short half-life of clinically used testosterone esters have long hindered further development. This study was designed to prove the efficacy of the long-acting testosterone undecanoate ester (TU) alone or in combination with oral levonorgestrel (LNG) in a phase II clinical trial., Design and Subjects: Twenty-eight healthy men were randomized to receive injections of 1000 mg TU every 6 weeks in combination with daily oral LNG (250 microg) or daily oral placebo treatment over a period of 24 weeks, followed by a control period of 28 weeks., Measurements: During the course of the study semen analysis, reproductive hormone analysis, analysis of clinical chemistry and lipid parameters, well-being and sexual function, sonography of scrotal contents and prostate were performed., Results: Marked suppression of gonadotrophins in both treatment groups resulted in azoospermia in 8/14 and 7/14 volunteers and severe oligozoospermia (< 3 x 1012/l) in 4/14 and 7/14 in the placebo and gestagen treated groups, respectively. Time to induction of azoospermia (mean +/- SEM) was not significantly different between the placebo (week 19.5 +/- 2.2) and LNG groups (week 15.4 +/- 2.2). During the whole treatment period mean testosterone serum concentrations remained within normal limits. Although not significant, it was evident that volunteers who became azoospermic had a better suppression of gonadotrophins and lower SHBG levels during treatment compared to non-azoospermic volunteers. Despite better gonadotrophin suppression in the LNG group no significant differences compared to placebo could be observed in the extent and kinetics of suppression of spermatogenesis, thus not demonstrating a major beneficial effect of LNG in the combination with injectable TU. Treatment led in both groups to a decrease of HDL and Lp(a) which was more pronounced in the LNG group (P > 0.05)., Conclusion: Treatment with 1000 mg testosterone undecanoate injected at 6 weekly intervals or in combination with levonorgestrel showed suppression of spermatogenesis comparable to weekly injections of 200 mg testosterone enanthate. Because of its long half-life and in the absence of severe side-effects, testosterone undecanoate can be considered as first choice testosterone ester in further studies of hormonal male contraception.

Objective: To investigate the suitability of intramuscular testosterone undecanoate (TU) injections for substitution therapy in hypogonadal men., Study Design: Clinical, open-label, non-randomized trial of 13 hypogonadal men receiving 4 intramuscular injections of 1000 mg TU in 4-ml castor oil at 6-week intervals. General wellbeing, sexual parameters, clinical chemistry, hormone levels, prostate size and prostate-specific antigen (PSA) were evaluated over 24 weeks and compared with baseline values., Results: Testosterone serum levels were never found below the lower limit of normal and only briefly after the 3rd and 4th injection above the upper limit of normal, while peak and trough values increased over the 24-week observation period. Oestradiol and dihydrotestosterone followed this pattern, not exceeding the normal limits. No serious side-effects were noted. Slight increases in body weight, haemoglobin, haematocrit, prostate volume and PSA, suppression of gonadotrophins as well as increased ejaculation frequency occurred as signs of adequate testosterone substitution., Conclusion: Testosterone undecanoate is well tolerated by the patients. The injection intervals can be extended even beyond the 6-week periods chosen in the present study. Altogether, intramuscular testosterone undecanoate appears to be well suited for long-term substitution therapy in hypogonadism and hormonal male contraception.

Objective: Testosterone (T) substitution of hypogonadal men by conventional intramuscular injection of T esters is not considered optimal because it induces unphysiologically fluctuating serum T levels. In contrast, scrotal T patches produce normal serum (T) levels mimicking diurnal variations. In order to assess the quality of this new form of T substitution we followed hypogonadal men treated by transdermal T up to 10 years., Patients: Eleven men aged 35.9 +/- 9.8 years (mean +/- SD) at the beginning of the study were treated with transscrotal T patches (Testoderm) because of primary (n = 4) or secondary (n = 7) hypogonadism. Clinical examinations were performed every 3 months during the first 5 years and every 6 months thereafter. All 11 patients were seen for 7 years and some for longer periods: eight for 8 years, six for 9 years and four for 10 years., Measurements and Results: With daily application of one patch T levels rose from 5.3 +/- 1.3 nmol/l (mean +/- SE) to 16.7 +/- 2.6 nmol/l at month 3 and remained in the normal range throughout treatment. Serum 5 alpha-dihydrotestosterone (DHT) rose from 1.3 +/- 0.4 nmol/l to 3.9 +/- 1.4 nmol/l and oestradiol from 52.3 +/- 9.3 to 71.3 +/- 9.6 pmol/l and remained stable without significant variations throughout the observation period. Patients reported absence of local side-effects except for occasional itching. No relevant changes occurred in clinical chemistry, including total cholesterol levels and triglycerides. Haemoglobin and erythrocyte counts remained normal. Bone density measured by QCT increased slightly from 113.6 +/- 5.4 to 129.7 +/- 9.3 mg/cm3 during the observation period (P = 0.028). In the nine patients aged < 50 years prostate volumes showed a small but insignificant increase from 16.8 +/- 1.5 to 18.8 +/- 2.1 ml during transscrotal T therapy. In the two older patients prostate volume remained constant or decreased slightly during T therapy after an initial increase in the previously untreated patient. Prostate specific antigen levels were constantly low in all patients., Conclusion: Transscrotal testosterone patches are well-accepted and safe in long-term testosterone substitution therapy for male hypogonadism.

Objective: Leptin serves as a hormonal signal linking food intake and energy expenditure to fat mass. As significant effects of testosterone administration on body composition and adipose tissue have been described recently, we examined a possible association between serum levels of leptin and testosterone which has not been reported so far., Subjects: Three groups comprising a total of 58 adult age-matched males were included in this cross-sectional analysis by computer-assisted clinical database selection. Group 1 (n = 22) consisted of untreated hypogonadal patients with testosterone serum levels lower than 7 nmol/l. The inclusion criterion for Groups II (n = 20) and III (n = 16) was a serum testosterone level higher than 30 nmol/l. Group II involved hypogonadal patients under effective androgen substitution therapy; Group III comprised males without any endocrine disorder attending our clinic., Measurements: Morning blood samples were taken for determination of serum levels of leptin, testosterone, oestradiol and sex-hormone binding globulin (SHBG). Serum levels of leptin were measured by homologous radioimmunoassay, the other hormones by standard immunoassays., Results: No significant differences in serum leptin, serum testosterone, and body mass index (BMI) were detected between Group II (3.7 +/- 1.5 micrograms/l, 40.3 +/- 7.6 nmol/ l, 24.4 +/- 4.9 kg/m2, respectively (mean +/- SD)), and Group III (4.0 +/- 2.0 micrograms/l, 35.9 +/- 6.5 nmol/l, 24.8 +/- 2.6 kg/m2, respectively). However, hypogonadal patients of Group I who were selected for low testosterone serum levels (4.3 +/- 1.7 nmol/l) had significantly higher leptin serum levels of 18.8 +/- 9.7 micrograms/l (P < 0.001) and significantly higher BMI of 30.0 +/- 6.6 kg/m2 (P < 0.001). Multiple linear regression analysis revealed a significant independent association of leptin with testosterone serum levels (partial correlation coefficient = -0.84; P < 0.001) and with BMI (partial correlation coefficient = 0.44; P = 0.001), whereas serum levels of oestradiol and SHBG had no additional influence., Conclusions: This study demonstrates a close association between serum levels of testosterone and leptin in males which has not been described previously. Serum testosterone levels could be an important contributor to the known gender difference in serum leptin levels which can be found even after correction for body composition. These findings might be of clinical relevance for testosterone substitution therapy of hypogonadal as well as ageing men.

Objective: The potential use of testosterone preparations for substitution therapy for ageing men and for male contraception, in addition to the well established substitution therapy of male hypogonadism, make increased testosterone use likely. However, little clinical information is available on the effect of testosterone therapy on the prostate in hypogonadal men., Design and Measurements: In a controlled cross-sectional study, prostate volume measured by transrectal ultrasonography, serum levels of prostate-specific antigen (PSA) and sex hormones, and uroflow parameters were determined., Patients: Three groups of age-matched men were enrolled in the study: 47 newly diagnosed hypogonadal men before testosterone treatment, 78 hypogonadal men with at least 6 months of effective testosterone therapy and 75 normal men., Results: Regression analysis revealed a significant positive correlation of prostate volume with age in normal men and testosterone-treated hypogonadal men, whereas no significant correlation was detected in untreated hypogonadal men. Prostate volume was significantly lower in untreated hypogonadal men (12.2 (11.0-13.5) ml) (mean (95% confidence limits)) compared to both other groups. However, no significant difference in prostate volume was detected between testosterone-treated hypogonadal men (21.3 (19.9-22.8) ml) and normal men (22.9 (21.4-24.4) ml). Similar results were obtained for PSA with comparable values in the testosterone-treated hypogonadal men (0.98 (0.88-1.10) micrograms/l) and normal men (1.02(0.91-1.14) micrograms/l), and significantly lower concentrations in the untreated hypogonadal men (0.64 (0.55-0.73) micrograms/l). No differences in uroflow parameters were detected between the three study groups., Conclusions: Effective testosterone treatment of hypogonadal men results in prostate volume and prostate-specific antigen levels comparable to age-matched normal men. Therefore, testosterone-induced prostate growth should not preclude hypogonadal men from testosterone substitution therapy.

Objective: Recently we have shown that single dose injections of the new GnRH antagonist cetrorelix ([Ac-D-Na(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala]GnRH; SB-75) decrease serum LH and testosterone in a dose-dependent manner in normal men. These results prompted us to investigate the effectiveness and safety of multiple daily injections of cetrorelix in normal male volunteers., Design and Volunteers: Following two control examinations 16 young men were randomly assigned to four study groups (n = 4/group). Daily doses of 0 (placebo), 2, 5, and 10 mg cetrorelix were injected subcutaneously at 0800 h for 8 days and morning and evening blood samples were obtained for 3 weeks., Results: One day after the first cetrorelix injection, serum LH and testosterone concentrations were significantly suppressed in all treatment groups. Whereas in the 2 and 5-mg dose groups LH and testosterone showed some fluctuations, daily injections of 10 mg cetrorelix consistently suppressed LH and testosterone in all men. In addition, in this group serum FSH concentrations were significantly suppressed to subnormal values 1 day after the first injection and remained in this range up to 5 days after the last injection. A time and dose-dependent increase of high-density lipoprotein cholesterol was observed during cetrorelix-induced testosterone deprivation with a maximal increase of 0.38 +/- 0.13 mmol/l (14.8 +/- 5.1 mg/dl; mean +/- SEM) in the 10-mg dose group. In addition, parallel to suppressed testosterone the volunteers' libido was significantly reduced under the GnRH antagonist. Apart from those symptoms caused by androgen deficiency, the only adverse side-effect observed was a mild painless local erythema at the injection site that disappeared within an hour., Conclusions: Daily injections of 10 mg cetrorelix effectively and consistently suppress serum LH, FSH and testosterone concentrations, and therefore it has potential for treatment of sex hormone-dependent diseases and for male contraception.

Objective: In patients with azoospermia serum FSH helps to differentiate between obstruction or spermatogenetic dysfunction as the possible cause of this condition. The role of FSH in the diagnosis of infertile men with oligoasthenoteratozoospermia is less clearly defined. In order to evaluate the diagnostic significance of serum FSH in the management of male infertility, serum FSH levels were related to testicular morphology from bilateral biopsies of infertile men., Design and Patients: Testicular biopsies were obtained from 213 infertile men and evaluated in semi-thin sections. Biopsies were performed either in order to distinguish between obstructive and non-obstructive azoospermia or because of subnormal semen variables when history, clinical investigation and hormone levels failed to explain infertility. Serum FSH was measured by fluoroimmunoassay., Results: Patients were divided into five groups on the basis of morphological criteria. The mean serum FSH value of patients with obstructive azoospermia and normal histology (group 1, n = 14) was normal (3.0 (2.2-4.1) IU/l) (mean (95% confidence limits)). Serum levels of FSH in non-obstructive oligo or azoospermia were as follows: group 2: mixed atrophy of tubular tissue without focal Sertoli cell only syndrome (SCO) (n = 104) (4.5 (4.0-5.1) IU/l), group 3: mixed atrophy with unilateral focal Sertoli cell only (n = 39) (7.4 (6.1-9.0) IU/l), group 4: mixed atrophy with bilateral focal SCO (n = 36) (10.7 (8.7-13.0) IU/l). Group 5: bilateral or unilateral total Sertoli cell only (n = 20) (16.0 (12.1-20.9) IU/l). Mean serum FSH levels were significantly different between all groups (P < 0.05)., Conclusions: Elevation of serum FSH correlates with the appearance of Sertoli cell only tubules. Elevated FSH serum levels make testicular biopsies superfluous for diagnostic purposes, but normal FSH does not exclude severe derangement of spermatogenesis in individual cases.

Objective: The present study was performed to characterize the molecular heterogeneity of serum FSH in normal males and to investigate the possible influence of testosterone on serum FSH in androgen-deficient men before and during testosterone administration., Design and Patients: Serum samples were taken at 10-minute intervals between 0730 and 0830 h from nine healthy, eugonadal men and from eight men with primary hypogonadism (Klinefelter's syndrome). In the hypogonadal patients, sampling was performed before treatment (n = 8), 4-5 days after the first and the third injection of 250 mg testosterone enanthate given intramuscularly at three-weekly intervals (n = 6), as well as 3 months after the onset of therapy (n = 3). Sampling was repeated 7 days apart in two of the nine healthy volunteers., Measurements: Aliquots from the individual serum samples were pooled and fractionated by chromatofocusing in the pH range 6-3. Immunoreactive FSH was measured by immunofluorometric assay (IFMA) in each fraction and the individual serum samples. In each serum pool, bioactive FSH was determined by in-vitro bioassay (rat Sertoli cell aromatase bioassay), testosterone by RIA and LH by IFMA., Results: After grouping the percentage of immunoreactive FSH recovered in the individual fractions into intervals of 0.5 pH units, significant differences between controls and patients were observed in the pH regions 4-4.5, 5.5-6 and 6-6.5. No statistically significant changes in the isoform distribution of FSH were detected during therapy in the Klinefelter patients. A high degree of variability, which did not follow a common pattern, was observed in the isoform distribution of FSH within the same individuals, both in the hypogonadal patients during treatment and in the two normal men whose blood samples were taken on two different occasions., Conclusions: Serum FSH is highly heterogeneous in normal and hypogonadal men. There is a spontaneous intra-individual variability in the relative abundance of the different FSH isoforms in serum that may most probably be related to metabolic deglycosylation of FSH. Minor but significant differences in the molecular heterogeneity of serum FSH could be demonstrated in Klinefelter patients compared to normal men. These differences are not modified by administration of testosterone enanthate at doses achieving normal androgenization, suggesting that factors different from testosterone may modulate FSH pleomorphism.

The pharmacokinetics of a human FSH preparation widely used in clinical practice was evaluated in healthy male volunteers whose endogenous FSH was suppressed by 19-nortestosterone injections. 9.7 h following intramuscular injection of 150 IU FSH the mean immunoreactive peak concentration over baseline was 3.8 IU/1. Injection of 450 IU FSH led to a mean immunoreactive peak level of 10.4 IU/1 at 9.8 h. Mean half-life was 24.6 h (150 IU FSH) and 32.6 h (450 IU FSH). Serum bioFSH concentrations were suppressed below the detection limit after injection of the 19-nortestosterone and rose to preinjection levels after administration of FSH. Mean bioactive peak level for the 450 IU FSH was 7.3 IU/1 FSH at 7.4 h. The half-life of bioFSH was calculated to be 13.4 h and is considerably shorter than the half-life of immunoFSH. Serum inhibin levels were suppressed by 19-nortestosterone and did not change significantly after injection of the FSH preparation, suggesting that the FSH dose was insufficient to elicit this biological response. It is concluded that the currently used dose regimen for the treatment of male hypogonadism is inadequate for maintenance of serum bioFSH levels in the normal range.

The antigenicity of HCG was tested in twenty-three young healthy men receiving two different HCG preparations (A and B). Each subject received 5000 i.u. HCG intramuscularly daily for three consecutive days, followed by another course, 3 weeks later, of 5000 i.u. HCG injections daily for 3 days. Two of the fifteen subjects treated with preparation A developed HCG antibodies in response to the HCG injections. The results show that although HCG is of human origin and also occurs normally in men, it may induce antibody formation even after brief treatment.

In order to investigate whether isolated elevated FSH levels in men with idiopathic oligospermia can be lowered by pulsatile LHRH therapy, six patients were treated for 6 weeks with 5 micrograms LHRH pulses every 2 h. The pulses were delivered from a portable minipump (Zyklomat) through a subcutaneously inserted needle. At the end of treatment prepulse serum LH levels were no different from the levels before treatment while serum FSH was significantly reduced in all patients (16.9 +/- 2.5 U/l vs 11.3 +/- 1.9 U/l, mean +/- SEM; P less than 0.01). The normal FSH range was reached in one of the six patients. The areas under the LH curves following the first and the last (i.e. 504th) pulse were no different, while the areas under the FSH curves were significantly smaller (2870 +/- 434 vs 1776 +/- 237 U/l X min; P less than 0.01). Serum testosterone and oestradiol were significantly higher at the end of treatment (11.0 +/- 1.2 vs 15.2 +/- 1.9 nmol/l 146 +/- 18 vs 214 +/- 25 pmol, respectively). Thus increased FSH levels in men with idiopathic oligospermia can be selectively reduced by pulsatile LHRH treatment. If the increased FSH levels are not the result but rather a factor contributing to the pathogenesis of certain types of oligospermia these findings may have implications for the treatment of this condition.

In order to evaluate GnRH administration for the treatment of infertile men with elevated serum FSH levels we administered GnRH in pulses via portable electronic infusion pumps initially to seven patients with low sperm counts and high FSH values over 12 weeks and later to nine further patients over 24 weeks who also underwent testicular biopsies. Fifty microlitres containing 5 micrograms GnRH were infused subcutaneously for 1 min every 120 min in the short-term study and every 90 min in the long-term study. Although FSH levels could be lowered in both groups of patients, none showed any improvement in sperm count or other seminal parameters. Therefore, pulsatile GnRH treatment cannot be recommended for therapy of severe oligozoospermia with elevated FSH levels.

Previously we have demonstrated that sperm counts of normal young men decreased during constant subcutaneous infusion of the LHRH agonist buserelin (118 or 230 micrograms/d). In order to test whether azoospermia can be achieved with higher doses, seven young men received 450 micrograms buserelin subcutaneously daily for 12 weeks via extracorporeal osmotic minipumps. To avoid symptoms of androgen deficiency, oral supplementation with 80 mg/d testosterone undecanoate (TU) was initiated in week 5 and was increased to 120 mg/d by week 8. Follow-up after treatment lasted for another 12 weeks. In order to evaluate possible psychotropic effects of treatment-related endocrine changes, continuous psychometric testing was performed focusing on personality, emotions and sexuality. After an initial rise, both serum LH and FSH returned to normal. FSH was below normal during the 3rd-5th week following treatment. LHRH stimulation tests performed at the end of treatment showed pituitary desensitization. Serum T (always measured between 0800 and 1300 h at least 12 h after last TU) tended to decrease by week 7 and remained slightly depressed until the end of treatment while libido, potency and emotional well-being remained unchanged. While testicular volumes showed a reduction from week 7 of treatment to week 10 post-treatment, sperm counts decreased only insignificantly from 65 +/- 10 to 44 +/- 14 million per ml in week 12 post-treatment. Severe oligo- or azoospermia was not observed in any of the seven men. It is concluded that full androgen substitution by TU can drastically delay if not abolish the antifertility effect of LHRH-induced pituitary desensitization.