Search

Summary 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.

Use of the integrated semen analysis system (ISAS ® ) for morphometric analysis and its role in assisted reproduction technologies

Der Begriff Altershypogonadismus als Mischform aus primarem und sekundarem Hypogonadismus wird der Tatsache gerecht, dass im Alter sowohl die endokrine Kapazitat der Testes als auch des hypothalamisch-hypophysaren Systems eingeschrankt ist und es vermehrt zu Hypogonadismus kommen kann. Bisher kann nicht endgultig beantwortet werden, in welchem Ausmas der Alterungsprozess mit dieser Erkrankung verknupft ist und deren Symptome modifiziert. Die Testosterongabe fur Manner mit Altershypogonadismus stellt ein Therapieprinzip dar, das nicht durch langfristige Studien abgesichert ist und sollte unter strengen Kontrollen in dafur spezialisierten Einrichtungen erfolgen. Derzeit werden Serumtestosteronspiegel

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.

Treatment of retrograde ejaculation and anejaculation The various options for the treatment of retrograde ejaculation (RE) and anejaculation (AE) are discussed systematically in this review. A total of 88 studies dealing with patients with RE emphasize medical treatment for reversal of RE and retrieval of spermatozoa from urine. In 136 studies concerning patients with AE, the main emphasis is on medical treatment, electroejaculation (EE) and electrovibration stimulation (EVS) for the reversal of AE. Sperm quality in patients with RE and AE is often impaired. However, with the help of assisted reproduction techniques (ART) available today, both ejaculation disorders can be considered as treatable diseases. The major problem when analysing the studies was the uneven methodological quality of the original articles and the difficulties presented by different drugs and dosages, equipment and techniques, along with different criteria for success. In conclusion, controlled clinical trials comparing different treatment options appear urgently warranted.

CD52 is a glycosylphosphatidylinositol-anchored glycoprotein secreted by the epididymis where it is incorporated into sperm membranes. The antigen is common to spermatozoa and lymphocytes, and its role is not known. Quantitative analysis using immunostaining with the monoclonal antibody CAMPATH-1G and flow cytometry indicated positive signals from approximately 80% of viable, washed ejaculated spermatozoa. Staining intensity increased after capacitation overnight, and decreased after short incubation with high density lipoprotein. After incubation of Percoll-washed spermatozoa with CAMPATH-1G, motility was reduced from 83 to 74% after 5 min and from 73 to 52% after 3.5 h. Swimming velocities were reduced by approximately 30% and linearity by 15% in 5 min, but no further decreases were observed over 3.5 h. After 20 min incubation with the antibody, cell viability was decreased by 10 and 20% in freshly washed and capacitated spermatozoa respectively. Comparison of fertile and infertile patients revealed no difference in the percentages of immunostained spermatozoa or in staining intensity and there were no differences in sperm labelling between normozoospermia and teratozoospermia. Compared with normozoospermia, percentages of stained spermatozoa were lower by 20 and 27% in asthenozoospermia and oligozoospermia respectively, whereas staining intensity in asthenozoospermia was less than half that in oligozoospermia. The correlation of percentages of stained spermatozoa with percentages of motile cells suggests the involvement of epididymal CD52 in the maturation of sperm function.

En prenant en consideration les desavantages des methodes de contraception masculine traditionnelles, a savoir l’abstinence periodique, le retrait, le preservatif et la vasectomie, le prerequis pour une contraception masculine pharmacologique ideale devrait [1] : itre utilisable independamment de l’acte sexuel ; itre acceptable pour les deux partenaires ; ne pas interferer avec la libido, l’erection, ou l’activite sexuelle ; n’avoir aucun effet indesirable a court ou long terme ; n’avoir aucun impact sur une descendance eventuelle ; itre rapidement efficace et completement reversible ; itre aussi efficace que les methodes comparables feminines.

Die andrologische Untersuchung des fertilitatsgestorten Patienten umfast neben der korperlichen Untersuchung auch die Ejakulatuntersuchung und die Hormondiagnostik. Ziel der andrologischen Basisdiagnostik ist es, die Ursache der Fertilitatsstorung herauszufinden. Obwohl bei 1/3 der Patienten eine sog. idiopathische Sterilitat besteht, konnten gerade in der letzten Zeit durch die rasche Entwicklung der Molekularbiologie zunehmend Patienten mit genetischen Ursachen identifiziert werden. Derzeit sind keine nachgewiesen wirksamen medikamentosen Therapien zur Verbesserung der Ejakulatparameter bei der mannlichen Sterilitat bekannt. Eine Ausnahme stellen die Patienten mit einem hypogonadotropen Hypogonadismus dar. Hier kann, analog zur Therapie der hypophysaren oder hypothalamischen Ovarialinsuffizienz, die Gonadotropinstimulation oder die pulsatile GnRH-Therapie mit sehr gutem Erfolg durchgefuhrt werden. Bisher konnte Patienten mit hochgradig eingeschrankten Ejakulatparametern, insbesondere bei Spermienkonzentrationen unter 5 Mio./ml, keine erfolgversprechende Therapie angeboten werden. Auch die vorhandenen reproduktionsmedizinischen Techniken wie die homologe Insemination oder In-vitro-Fertilisation bzw. Embryotransfer stellten keine uberzeugende Behandlungsmethoden dar. Mit der Entwicklung der intrazytoplasmatischen Spermieninjektion (ICSI) [38] steht jetzt erstmalig eine effektive Therapie zur Verfugung. Wenige Spermien im Ejakulat oder einzelne operativ aus dem Nebenhoden oder dem Hoden gewonnene Spermien reichen fur die erfolgreiche Mikroinjektion aus. Diese neuen Moglichkeiten unterstreichen die Notwendigkeit zur interdisziplinaren Zusammenarbeit zwischen Gynakologen und Andrologen.

Bradykinin (BK) has been suggested to be an active substance in the disputed therapeutic use of kallikrein to improve semen quality. The effects of exogenous BK and its antagonist Hoe 140, which acts on one of the bradykinin receptors (BK2), were examined in two groups of patients attending the fertility clinic: those with asthenozoospermia (group I) and normozoospermia (group II). Bradykinin (10nM-1 microM) added to washed human spermatozoa had no effect on most kinematic parameters and caused only a marginal increase (7%) in curvilinear velocity at 50 nM in group I patients; however, this increase was not suppressed by concomitant addition of the BK antagonist. The bradykinin antagonist itself had no effect on the percentage motility or kinematic motility parameters of washed human spermatozoa in either group of patients. The motility of spermatozoa in semen was also unaffected by the presence of the bradykinin antagonist. It is concluded that bradykinin does not act exogenously on washed spermatozoa nor endogenously on spermatozoa in semen to stimulate motility via BK2 receptors, regardless of the initial quality of the sperm motility.

Hormonal male contraception based on testosterone alone or on a combination of testosterone with a gestagen has been shown to suppress spermatogenesis effectively and to be fully reversible. However, clinical studies to date have only included volunteers with so-called 'normal' semen values by WHO standards. As a male contraceptive should be available to all interested men regardless of their semen parameters, we investigated how volunteers with subnormal semen parameters would respond to hormonal male contraception. During a 34-week treatment phase, the volunteers received injections of 1000 mg testosterone undecanoate in weeks 0, 6, 14 and 24. This was followed by a 24-week recovery and follow-up period. As it was not known whether men with subnormal semen parameters would recover to starting levels, cryopreservation of semen was offered to all subnormal volunteers. Twenty-three men with normal semen parameters and 18 with sperm counts below 20 million completed the trial. The normal volunteers showed the expected response with 17 suppressing sperm counts below 1 million/ejaculate (13 showing azoospermia) and six not-suppressing below 1 million sperm/ejaculate. By the end of the recovery period, all sperm counts had returned to the range of starting values. The subnormal group showed a similar pattern with 13 of 18 (= 72%) men suppressing below 1 million/ejaculate (8/18 = 44% showing azoospermia) and the remaining 5 of 18 (= 28%) not-suppressing sperm counts below 1 million/ejaculate. All sperm counts returned to the starting range. The study shows that in Caucasian men with normal sperm counts as well as in men with subnormal sperm counts, testosterone alone can produce azoospermia in about half and suppression below one million in about two-thirds of the volunteers. The same proportion of men in both groups appears to require an additional gestagen for full contraceptive protection. Most importantly, regarding suppressibility and reversibility, volunteers with normal and subnormal sperm counts display the same pattern.

The principle of hormonal male contraception based on suppression of gonadotropins and spermatogenesis has been established over the last three decades. All hormonal male contraceptives use testosterone, but only in East Asian men can testosterone alone suppress spermatogenesis to a level compatible with contraceptive protection. In Caucasians, additional agents are required of which progestins are favored. Current clinical trials concentrate on testosterone combined with norethisterone, desogestrel, etonogestrel, DMPA, or nestorone. The first randomized, placebo-controlled clinical trial performed by the pharmaceutical industry demonstrated the effectiveness of a combination of testosterone undecanoate and etonogestrel in suppressing spermatogenesis in volunteers.

The clinical workup of the infertile male with azoospermia aims at determining the aetiology and estimating the chances of finding spermatozoa by testicular sperm extraction (TESE). To establish prognostic criteria, 1583 consecutive patients with azoospermia consulting the Centre of Reproductive Medicine and Andrology, Münster, a tertiary referral centre, between 1976 and 2009 comprising 9.8% of all patients providing a semen sample were included in this retrospective analysis. The frequencies of diagnoses were as follows: 21% genetic causes (14% Klinefelter syndrome, 1% other chromosomal aberrations, 2% Y-chromosomal microdeletions, 1% hypogonadotropic hypogonadism, 3% congenital bilateral absence of the vas deferens), 31% current or former maldescended testes, varicocele, urogenital infections, 15% malignancies, 11% obstructions, 7% endocrine or other chronic diseases and 12% idiopathic azoospermia. Receiver-operating characteristic curves for chances of finding spermatozoa by testicular biopsy were calculated for testicular volume, serum follicle-stimulating hormone (FSH) and the seminal markers α-glucosidase, fructose and zinc where these data were available (N=283). Histograms of the seminal markers comparing data from men with obstructive azoospermia and normozoospermia visualize their discriminating power. Evidence-based threshold values for high chances of positive testicular biopsy serving as surrogate marker for TESE were derived from the subgroup of men with obstructive azoospermia for testicular volume (≥21mL), FSH (≤10U/L) and seminal α-glucosidase (≤18mU/ejaculate). Fructose and zinc could not predict the chances of finding spermatozoa upon biopsy. Based on these three parameters, positive biopsy and presumably TESE success can be quickly and reliably estimated in everyday practice with the colour-coded figures constructed from these data. As a seminal α-glucosidase reference limit of 18mU/ejaculate can also be used to diagnose congenital bilateral absence of the vas deferens, α-glucosidase (rather than seminal fructose) should be determined as part of the clinical routine when counselling patients before testicular biopsy.

Sperm chromatin compaction in the sperm head is achieved when histones are replaced by protamines during spermatogenesis. Haploinsufficiency of the protamine 1 (PRM1) or PRM2 gene causes infertility in mice. However, the published data remain inconclusive about a role of PRM1/2 variants in male infertility and their association with semen parameters. By full sequence analysis, we assessed the frequency of sequence variations in PRM1 and PRM2 in three groups of Caucasian patients with idiopathic teratozoospermia and normal (n = 88) or reduced sperm concentration (n = 83) and in men with a high percentage of normal sperm morphology and normal concentrations (n = 77). Two rare (c.54GA and c.102GT) and one common SNP (c.230AC) were identified in PRM1. In PRM2, some rare heterozygous mutations and the two common intronic SNPs 298GC and 373CA were detected. None of the PRM1/2 variants was associated with teratozoospermia or individually with other semen parameters. However, significant linkage disequilibrium was detected between the common SNPs of PRM1 and PRM2 which formed haplotypes. Analysis of the pooled group (n = 248) revealed that homozygous carriers of the common haplotype ACC had a twofold higher sperm concentration and count than men lacking this haplotype, with sperm counts of heterozygotes for ACC being midway between the homozygotes. This markedly decreased sperm output might either be caused by spermatozoa lacking the ACC haplotype not being viable, or subject to negative selection. In addition, a significant deviation from Hardy-Weinberg-Equilibrium of these SNPs might indicate natural selection in favour of the ACC allele which leads to higher sperm output and therefore better fertility. In conclusion, for the first time we describe an association of a common haplotype formed by PRM1 and PRM2 with sperm output in a large group of men.

We reported previously that after a single injection of a gonadotrophin-releasing hormone (GnRH) antagonist to male monkeys, exogenous GnRH stimulated LH secretion in a time- and dose-dependent manner, indicating that GnRH antagonist-induced blockade of LH secretion resulted from pituitary GnRH receptor occupancy. The present study was performed to investigate whether GnRH can also restore a blockade of LH and testosterone secretion during chronic GnRH antagonist administration. Four adult male cynomolgus monkeys (Macacafascicularis) received daily s.c. injections of the GnRH antagonist [N-Ac-d-pCl-Phe1,2,d-TRP3,d-Arg6,d-Ala10]-GnRH (ORG 30276) at a dose of 1400–1600 μg/kg for 8 weeks. Before the GnRH antagonist was given and during weeks 3 and 8 of treatment, pituitary stimulation tests were performed with 0·5, 5, 50 and 500 μg synthetic GnRH, administered in increasing order at intervals of 24 h. At 8 weeks, a dose of 1000 μg GnRH was also given. All doses of GnRH significantly (P < 0·05) stimulated serum concentrations of bioactive LH (3- to 8-fold) and testosterone (2·6- to 3·8-fold) before the initiation of GnRH antagonist treatment. After 3 weeks of GnRH antagonist treatment, only 50 and 500 μg GnRH doses were able to increase LH and testosterone secretion. Release of LH was significantly (P < 0·05) more elevated with 500 μg compared with 50 μg GnRH. After 8 weeks, only the highest dose of 1000 μg elicited a significant (P < 0·05) rise in LH secretion. Basal hormone levels just before the bolus injection of GnRH were similar (P > 0·10–0·80). This finding eliminated the possibility that the increasing doses of GnRH had primed the pituitary thereby resulting in higher stimulatory effects of the larger doses of GnRH. In conclusion, the present data indicate that, even after prolonged exposure to a GnRH antagonist, the pituitary retains some degree of responsiveness to GnRH. This observation supports the view that the inhibitory effects of chronic GnRH antagonist treatment are also mediated, at least in part, by occupancy of the pituitary GnRH receptor rather than by receptor down-regulation. Journal of Endocrinology (1992) 133, 439–445

Animal experiments and clinical studies on the interactions between growth hormone (GH) and the male hypothalamic-pituitary-gonadal axis have predominantly concentrated on GH and sex steroid interactions in the regulation of growth and development, or on the metabolic effects of GH. In contrast, little attention has been paid to the possible effects of GH on spermatogenesis, although the first report dealing with this topic was published almost 30 years ago. The interactions of GH and its main mediator, insulin-like growth factor I (IGF-I), with the hypothalamic-pituitary-gonadal axis, and their role in spermatogenesis have recently been investigated using in vitro systems and different animal models (mice and rats). Using Leydig and Sertoli cell cultures, complex interactions between GH/IGF-I and the gonadotropins affecting differentiated cell functions, e.g. steroidogenesis and cell division, have been demonstrated at the cellular level. In vivo studies using immature and mature hypophysectomized rats and GH-deficient mutant male mice and rats indicate that IGF-I can play an important role in the regulation of steroidogenesis and spermatogenesis. Furthermore, although follicle-stimulating hormone and luteinizing hormone are the major regulators of testicular IGF-I production, GH may play an indirect role by potentiating the actions of the gonadotropins in regulating testicular IGF-I content. A large proportion of men presenting at male-infertility clinics are diagnosed as having idiopathic infertility. Further studies are necessary to investigate whether defects associated with GH and/or IGF-I effects in the testis are the cause of male infertility in a small group of these patients.

Auch in diesem Kapitel gehen wir bei der Einteilung der Krankheitsbilder nach dem Gesichtspunkt vor, in welchem Organ oder physiologischen System die Krankheitsursache liegt (▸ Kap. 4). Allen hier beschriebenen Entitaten liegt eine in unterschiedlichem Auspragungsgrad gestorte Wirkung der Androgene oder Ostrogene an ihren Zielorganen zugrunde. Bei der Gynakomastie stellt dies eher die Ausnahme dar, die Darstellung dieses vieldeutigen Befundes erfolgt hier mehr unter klinisch-praktischen Gesichtspunkten als unter streng nosologischen Kriterien.

Epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) have been shown to regulate Leydig cell steroidogenesis in several species. We have investigated the effects, if any, of EGF and IGF-I on in vitro testosterone production of human Leydig cells. Interstitial cells or Percoll purified Leydig cells were isolated from the testes obtained from patients (n = 9) undergoing orchidectomies for treatment of prostate cancer and were cultured for different time periods with hCG, dibutyryl cAMP, EGF and IGF-I. Testosterone in the culture media was measured by radioimmunoassay. While EGF had a stimulatory effect on basal testosterone production of isolated interstitial cells or purified Leydig cells, IGF-I was ineffective. When the interstitial cells were cultured in the presence of hCG or EGF for 3, 6 or 24 h, the stimulatory effects of EGF on testosterone production were only evident after 24 h. On the other hand, hCG stimulated testosterone production at all time points (i.e after 3, 6, 24 h of incubation). When added in the presence of maximal concentrations of hCG and dibutyryl cAMP, EGF did not further enhance steroidogenesis. On the other hand, IGF-I potentiated the effects of hCG on testosterone production. These studies suggest that EGF and IGF-I may play a regulatory role in steroidogenic function of the human testes.

Morphometric study revealed that, at 40 days after the start of vitamin A replacement, A1 spermatogonia and preleptotene spermatocytes appeared in more than 70% of the whole mounts of seminiferous tubules of vitamin A-deficient rats. By 42 days, the appearance of these cell types was reduced by 50%, and A2 and A3 spermatogonia were predominant. By 46 days, A1-A3 spermatogonia appeared in less than 30% of the tubular length while A4, intermediate and B spermatogonia became the major cell types in the basement compartment of seminiferous tubules. The predominance of spermatogonia noted at given times was corroborated by higher frequencies of tubular cross-sections of stages in which that particular type of spermatogonium resides. These results indicate that seminiferous tubules of vitamin A-replaced-vitamin A-deficient rats are 'enriched' for particular stages. Tracing the development of [3H]thymidine-labelled preleptotene spermatocytes revealed normal kinetics of germ cell differentiation in these animals. Furthermore, the spermatogonial proliferations in the vitamin A-replaced-vitamin A-deficient rats were quantitatively normal. We suggest that vitamin A replacement may result in temporal suppression of the differentiation of A2-B spermatogonia, leading to a stimulation or synchronization of certain groups of undifferentiating spermatogonia which undergo active proliferation simultaneously. These synchronized populations of spermatogonia continue to proliferate and differentiate, thus resulting in the stage-enrichments noted at later times.

Objective: Testosterone-containing gels have improved testosterone substitution therapy, but they are associated with the risk of interpersonal transfer. Therefore, we tested a new hydroalcoholic 2.5% testosterone gel (TGW), which was removed by washing 10 min after administration. Design: The gel was applied to scrotal or non-scrotal skin in comparison to two 2.5 mg Androderm® patches in a randomised, three-arm, parallel-group, controlled multicentre trial over a period of 24 weeks. We included symptomatic hypogonadal men whose morning testosterone levels were n = 54) or 5 g to non-scrotal skin (n = 56) once daily; the patch group (n = 52) applied two patches/day. Dose titration was allowed. Results: Whereas serum testosterone levels and the pre-post changes of the areas under the curve of testosterone and free testosterone between weeks 0 and 24 indicated equivalent treatment success for the patch and scrotal groups, the dermal gel group was significantly superior to the other two groups. Questionnaires on sexual function, mood and quality of life did not differ significantly between study groups, nor were prostate volume, prostate-specific antigen (PSA) levels and prostate symptoms different. However, tolerability was much better in the gel groups than the patch group. Conclusion: Efficacy, safety and tolerability suggest TGW as a favourable treatment for hypogonadal patients.

Im Alter sinken die Testosteronspiegel des Mannes schleichend. Bei einem nicht unerheblichen Anteil der alteren Manner fallen die Testosteronwerte in einen hypogonadalen Bereich. Dieser altersassoziierte Hypogonadismus ist von anderen Formen des Hypogonadismus abzugrenzen.

The definition of late-onset-hypogonadism as a hybrid form of primary and secondary hypogonadism corresponds to pathophysiological facts of the age-related decline in gonadal as well as hypothalamic-pituitary functions, eventually manifesting in clinically relevant hypogonadism. To what extent advancing age modulates incidence and nature of hypogonadal symptoms has not been completely investigated. The benefits of testosterone substitution therapy in older men await demonstration in long-term studies and to date, it should be restricted to specialized centers. Currently, serum testosterone levels12 nmol/l, accompanied by symptoms of androgen deficiency, are regarded as an indication for substitution, provided a prostate carcinoma has been excluded. While late-onset hypogonadism decreases libido, it does not play a direct role in the increasing incidence of erectile dysfunction with advancing age; this symptom is rather associated with vessel-endothelial impairment and may serve as a sentinel symptom for cardiovascular disease. Treatment with phosphodiesterase-5-inhibitors can be regarded as standard; in case of concomitant late-onset hypogonadism, testosterone will have a positive synergistic effect on erectile function.

During recent years several studies have suggested that a slight increase in the number of CAG repeat sequences in exon 1 of the androgen receptor gene causes idiopathic oligozoospermia. We tested whether CAG repeats are more numerous in men with idiopathic infertility compared to those with known causes of oligozoospermia. CAG repeats were analysed in a consecutive sample of 217 infertile men covering a wide range of diagnoses and sperm counts. Data were compared with those of a control group of 131 normozoospermic men including 62 fathers. CAG repeats (x +/- SD) did not differ between idiopathically (21.4 +/- 2.9) and non-idiopathically infertile men (21.6 +/- 2.8) or normozoospermic men of unproven fertility (20.6 +/- 3.0). Only fathers had significantly fewer repeats (19.4 +/- 3.1; p0.001). Different from controls, no correlation between CAG repeats and any semen parameter existed in patients. Comparison of our and published studies showed that odds ratios for infertility in men with CAG repeat length in the upper quartile of the normal range increased when the controls were selected by proven fertility. We conclude that more numerous CAG repeats do not directly cause oligozoospermia and propose that men with longer CAG repeats might be more prone to develop infertility in response to any pathogen/epigenetic factors.

Auch wenn die Lebenserwartung des Mannes standig zunimmt, bleibt sie doch hinter der der Frau zuruck. Da dieser Unterschied erst seit Ende des 19. Jahrhunderts verzeichnet wird, bleibt fraglich, ob dafur ausschlieslich exogene Einflusse verantwortlich sind. Neben genetischen Faktoren werden vor allem endokrine Ursachen angenommen. Wahrend bei der Frau endogene Ostrogene eher lebensverlangernd und Androgene lebensverkurzend wirken, konnte ein vergleichbarer Effekt bei Mannern bisher nicht nachgewiesen werden. Kastraten haben eine ahnliche Lebenserwartung wie intakte Manner [6]. Allerdings wird ein Testosteronmangel von einer erheblichen Symptomatik und verminderter Lebensqualitat begleitet. Daher stellt sich die Frage, ob das Alter des Mannes mit einem substitutionsbedurftigen Testosteronmangel einhergeht.

Among the treatment modalities for ejaculatory disorders pharmacological treatment is the least invasive option. In this review, medical treatments for retrograde ejaculation (RE) and anejaculation (AE) are discussed systematically. Thirty-six studies dealing with patients with RE and 40 with AE evaluated the use of medical treatment and were included in this review. In addition four articles dealing with prostatic massage in anejaculatory patients were considered. Sperm quality in patients with retrograde and AE is often impaired. In patients with RE no differences in response to medical treatment could be detected between the different underlying diagnoses. Compared with ephedrine, imipramine and chlorpheniramine + phenylpropanalamine showed significantly higher reversal rates, while differences between the other treatments were not significant. Regarding the reversal of AE, the alpha agonistic drugs were significantly inferior to treatment with parasympathetic drugs. Of the different alpha agonistic medical treatments for the reversal of AE, milodrin showed significantly better rates than imipramine (p = 0.008), pseudoephidrine (p = 0.02) and ephedrine (p = 0.044), while all other treatments were not significantly different (p = 0.4). In conclusion, medical treatment for reversal of RE offers a realistic chance of conceiving offspring naturally and should be the treatment modality of first choice. In contrast, in AE, medical treatment cannot be recommended generally as treatment of first choice as it shows low overall success rates compared with electrovibration stimulation and electroejaculation. Under consideration of the mostly uncontrolled design of the majority of studies published, controlled clinical trials comparing different treatment options appear urgently warranted.

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.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).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.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.

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.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.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 P0.01).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.

Sonographic detection of multiple, small hyperechogenic lesions in the testis (testicular microlithiasis; TM) can indicate germ cell tumors. However, it has not been well established whether this finding signifies a risk factor for development of testicular neoplasm in all cases or whether it indicates premalignant changes only in those men with additional risk factors for germ cell cancer, such as infertility, a history of testicular maldescent, or the presence of an atrophic testis. In a retrospective analysis of 1701 consecutively performed scrotal sonographies of patients with (n = 1399) and without (n = 219) infertility or with contralateral testicular tumors (n = 83), the prevalence of TM was compared with that in 198 healthy men who volunteered for different clinical trials. TM was equally frequent in all groups (2.3% [32/1399] of infertile patients, 2.3% [5/219] of other patients without infertility, and 1.5% [3/198] of healthy men). Results of testicular biopsies were available for a subgroup of infertile men. Carcinoma in situ (CIS) was present only in cases with TM (2/11). In addition, sonographic follow-up examinations were performed in another 14 men with TM. Testicular tumors had developed in 2 patients, one whom was infertile and one in the control group. None of these patients had a history of testicular maldescent but all testes affected either by CIS or tumors were reduced in volume. We conclude that diagnosis of TM, especially if it is present in an atrophic testis, demands a diagnostic biopsy or at least sonographic follow-up examinations.

Spermatogonia are the diploid cells in the testis, representing a small self-sustaining pool of male germ line stem cells as well as a larger pool of differentiating germ cells which enter the process of spermatogenesis. After going through prophase of meiosis as spermatocytes these cells finally leave the testis as sperm. Spermatogonia share many characteristics with other stem cells but also carry some specific physiological features. Many details about the kinetics of spermatogonial divisions, about the hormonal regulation of their expansion and differentiation and about their clinically relevant involvement as a cause for male infertility are poorly understood. However, the loss of spermatogonia following chemo- or radiotherapy leading to temporary or permanent infertility of the patient is a well known and unwanted site effect of many oncological therapies. Isolation and extracorporal storage of spermatogonia prior to the treatment and transplantation into the testis after recovery from the disease presents a promising future tool for fertility preservation in male patients undergoing oncological therapy.

The changes of reproductive functions, fertility and genetic risks of ageing females have been investigated relatively intensively. The state of knowledge about endocrine and reproductive changes in ageing men as well as possible age-related paternal genetic risks lags far behind. In general serum testosterone levels decrease with increasing age. In ageing men testis morphology and semen production can be absolutely normal. However, in some testes degenerative forms of germ cells can be observed. Fertility may be maintained up to a very high age. The genetic quality of sperm produced by older men may be reduced for several reasons, among which age-related increases in germ cell mutations, impairment of DNA-repair mechanisms and apoptotic processes are the most likely. The incidence of several autosomal dominant diseases, such as achondroplasia, polyposis coli, Marfan syndrome, Apert syndrome or basal cell naevi is associated with advanced paternal age, whereas there is no clear evidence for a paternal effect on structural or numeric chromosome anomalies. Hence even if offspring of older men have a slightly increased incidence of certain genetic diseases, the individual risk of such a new disease must be considered as extremely small, as the incidence of these diseases is very low.

Nonhormonal contraceptives that act by blocking energy metabolism within sperm have the advantage over spermatogenic inhibitors by their fast onset of infertility and their almost immediate restoration of fertility after withdrawal of the contraceptive agent. This study was done to test new chlorinated compounds for their contraceptive potency on rodent and human sperm in vitro. Cells were incubated in a medium containing glucose as the sole energy source with 1-chloro-3-hydroxypropanone (CHOP) and 1,6-dichloro-1,6-dideoxy-D-fructose (DCDF), chlorinated analogues of glycolytic substrates, as well as racemic (R,S)-alpha-chlorohydrin (ACH). After incubation, enzymatic activity and kinematic parameters were estimated. A dose-dependent inhibition of the glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), of rat and mouse distal cauda epididymidal and human ejaculated sperm by ACH, CHOP, and DCDF was demonstrated. Triosephosphate isomerase (TPI) was inhibited by ACH, but not by CHOP and DCDF, irrespective of species. All compounds inhibited sperm motility and kinematic parameters with increasing concentration. The results confirm that inhibition of glycolytic enzymes of sperm, including those of human, can be effectively brought about by a variety of chloro-compounds that can be converted to (S)-3-chlorolactaldehyde, the stereospecific chloro-derivative of the enzyme's natural substrate, (R)-glyceraldehyde 3-phosphate, and could be developed into contraceptive agents for men.

Recent trials for hormonal male contraception are based on gestagens or GnRH antagonists combined with oral or injectable testosterone substitution. However, the efficacy of most trials remained disappointing. Norethisterone enanthate (NETE) has been used as a long-acting injectable female contraceptive and has shown sustained suppression of spermatogenesis in male monkeys and prolonged suppression of gonadotropins in men. This study was designed to prove the efficacy of the long-acting testosterone undecanoate ester (TU) alone or in combination with NETE in a phase II clinical trial. Fourteen healthy men received injections of 1000 mg TU in combination with injections of 200 mg NETE every 6 weeks over a period of 24 weeks, followed by a control period of 28 weeks. Another 14 volunteers received TU alone. During the study semen variables, reproductive hormones, clinical chemistry and lipid parameters, well-being, and sexual function were monitored. Scrotal content and prostates were checked sonographically. During the entire treatment period mean testosterone serum concentrations remained within the normal limits. Marked suppression of gonadotropins in both treatment groups resulted in azoospermia in 7 of 14 and 13 of 14 volunteers and in oligozoospermia in 7 of 14 and 1 of 14 in the groups given TU only or TU/NETE, respectively. However, the highest azoospermia rate in the TU/NETE group was achieved 8 weeks after the end of the treatment period, and 1 volunteer with very high initial sperm counts (mean, 190 million/mL at baseline) remained oligozoospermic (10.2 million/mL). From week 20 to week 24 there was a significant, fully reversible maximum weight gain of 3.7 kg, on the average, in the NETE group. In the NETE and TU alone groups there were significant 26.6% and 11.5% maximum decreases in high density lipoprotein cholesterol compared with baseline values during the treatment period. A significant elevation of low density lipoprotein and a decrease in lipoprotein(a) were detected in the TU/NETE group. In conclusion, combination treatment with NETE showed suppression of spermatogenesis comparable with results using testosterone esters in combination with GnRH antagonists or cyproterone acetate, but had more favorable injection intervals and better efficacy. Because of its long-lasting, profound suppression of spermatogenesis and the absence of serious side-effects, the combination of TU and NETE can be considered a first choice for further studies of hormonal male contraception.

Demographic studies show an increasing proportion of older people in developed countries. For example, during the last 100 years in Germany the mean life expectancy has approximately doubled (Fig. 21.1). This development is largely due to improved hygiene, reduction of newborn mortality and more effective therapy and prevention of acute diseases in age. With larger numbers of people reaching advanced age, health problems as well as social and psychological problems of older men play an increasingly important role in clinical medicine and in research.