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The US Supreme Court decision against abortion has once again triggered the call for male contraception. However, in addition to existing methods, there are further reasons why pharmacological reversible easy-to-use male contraception should be available. Green activists and environmentalists have to recognize that overpopulation consume resources. Medical progress results in increasing life expectancy and must be combined with contraception. Sharing the risks of contraception among partners and "Reproductive Autonomy for All" are ethical issues. The resistance of the pharmacological industry to becoming partners in male contraception must be overcome by public financial subsidies and popular demand.

In order to detect the misuse of testosterone (T), urinary steroid concentrations and concentration ratios are quantified and monitored in a longitudinal manner to enable the identification of samples exhibiting atypical test results. These suspicious samples are then forwarded to isotope ratio mass spectrometry (IRMS)–based methods for confirmation. Especially concentration ratios like T over epitestosterone (E) or 5α-androstanediol over E proved to be valuable markers. Unfortunately, depending on the UGT2B17 genotype and/or the gender of the athlete, these markers may fail to provide evidence for T administrations when focusing exclusively on urine samples. In recent years, the potential of plasma steroids has been investigated and were found to be suitable to detect T administrations especially in female volunteers. A current drawback of this approach is the missing possibility to confirm that elevated steroid concentrations are solely derived from an administration of T and cannot be attributed to confounding factors. Therefore, an IRMS method for plasma steroids was developed and validated taking into account the comparably limited sample volume. As endogenous reference compounds, unconjugated cholesterol and dehydroepiandrosterone sulfate were found suitable, while androsterone and epiandrosterone (both sulfo-conjugated) were chosen as target analytes. The developed method is based on multi-dimensional gas chromatography coupled to IRMS in order to optimize the overall assay sensitivity. The approach was validated, and a reference population encompassing n = 65 males and females was investigated to calculate population-based thresholds. As proof-of-concept, samples from volunteers receiving T replacement therapies and excretion study samples were investigated. Graphical abstract

Context Adolescent males with hypogonadotropic hypogonadism (HH) have traditionally been treated with exogenous testosterone (T) or human chorionic gonadotropin (hCG) to produce virilization; however, those modalities do not result in growth of the testes and may promote premature maturation and terminal differentiation of Sertoli cells prior to their proliferation, which may impact future fertility. Another option is to use gonadotropins in those individuals to induce testicular growth, proliferation and maturation of Sertoli cells, and production of endogenous T with consequent virilization. Objective We examined the efficacy and safety of corifollitropin alfa (CFA) combined with hCG for the induction of testicular growth and pubertal development in adolescent boys with HH. Methods This was a 64-week, multicenter, open-label, single-group study of CFA in adolescent boys, aged 14 to younger than 18 years, with HH. Seventeen participants initiated a 12-week priming period with CFA (100 μg if weight ≤ 60 kg, or 150 μg if weight > 60 kg) given subcutaneously once every 2 weeks, after which they entered a 52-week combined treatment period with CFA, once every 2 weeks, and subcutaneous hCG, twice-weekly (hCG dose adjusted between 500 IU and 5000 IU to keep total T and estradiol levels within protocol-specified ranges). The primary efficacy end point was change from baseline in testicular volume (TV), measured as the sum of volumes of left and right testes by ultrasound. Results After 64 weeks of therapy with CFA/CFA combined with hCG, geometric mean fold increase from baseline in TV was 9.43 (95% CI, 7.44-11.97) (arithmetic mean of change from baseline at week 64, 13.0 mL). Hormonal, Tanner stage, and growth velocity changes were consistent with initiation and progression of puberty. Treatment was generally well tolerated. No participant developed anti-CFA antibodies. Conclusion Treatment of adolescent boys with HH with CFA alone for 12 weeks followed by CFA combined with hCG for 52 weeks induced testicular growth accompanied by pubertal progression, increased T, and a pubertal growth spurt (EudraCT: 2015-001878-18).

Die Hauptindikation fur Testosteron ist der Hypogonadismus des Mannes. Eine Ubersicht uber die weiteren Anwendungsmoglichkeiten liefert ◘ Tab. 21.1.. Einigen dieser Verwendungen sind in diesem Buch spezielle Kapitel gewidmet, so dem Einsatz von Testosteron bei konstitutionell verzogerter Pubertat (▸ Kap. 12), beim Altershypogonadismus (▸ Kap. 14), bei der mannlichen hormonellen Kontrazeption (▸ Kap. 29) und bei idiopathischer Infertilitat (▸ Kap. 22). Daruber hinaus geht das vorliegende Kapitel auf den Einsatz bei ubermasigem Langenwachstum (▸ Kap. 21.5) und auf den Missbrauch im Doping bzw. bei Bodybuildern (▸ Kap. 21.6) ein. Aufgrund des erythropoetischen Effektes ist Testosteron auch zur Behandlung der aplastischen und renalen Anamie zugelassen, wurde in diesem Bereich aber seit Einfuhrung des Erythropoetins deutlich zuruckgedrangt. Zur Abhandlung dieser Indikation wird der Leser auf Lehrbucher der Inneren Medizin verwiesen. Open image in new window ◘Tab. 21.1. Verwendung von Testosteron beim Mann

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 17s-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.

Klinefelter syndrome (KS) is the most frequent chromosome disorder in males (1:650 newborn males), defined by 47,XXY karyotype. The classical phenotype is that of a tall male with relatively long legs, small, firm testes and gynecomastia. Azoospermia and infertility are almost inevitably present, but may be overcome by TESE and ICSI. Nevertheless, a broad spectrum of phenotypes has been described and more than 70% of the actually existing KS men may remain undiagnosed throughout their lifespan. Accordingly, hypogonadism is usually not evident until early adulthood and progresses with ageing. KS patients present a series of comorbidities that increase morbidity and mortality by 40%. Such disturbances are the impaired metabolic profile (obesity, dyslipidemia, insulin resistance) and a tendency to thrombosis, which all favor cardiovascular disease. They also present susceptibility for specific neoplasias (breast cancer, extragonadal germ cell tumors), autoimmune diseases as well as osteoporosis and bone fractures. Moreover, KS has been associated with verbal processing and attention deficits as well as social skill impairments, leading KS individuals to academic and professional achievements inferior to those of their peers of comparable socio-economic status. Nevertheless, the majority fall within the average range regarding their intellectual abilities and adaptive functioning. Testosterone replacement therapy (TRT) is the mainstay of treatment in hypogonadal KS patients; however, randomized trials are needed to determine optimal therapeutic regimens and follow-up schedules.

Although several progestins have been tested for hormonal male contraception, the effects of dosage and nature of various progestins on gonadotropin suppression combined with and without additional testosterone has not been performed in a comparative trial. The aim of this study was to evaluate the differential impact of four oral or transdermal progestins on the suppression of gonadotropins in healthy men: oral: cyproterone acetate (CPA), levonorgestrel (LNG), norethisterone acetate (NETA), and transdermal: Nestorone (NES), all in combination with transdermal testosterone (T). Randomized clinical trial testing was performed with four progestins at two doses each. After a 2-week progestin-only treatment, transdermal T was added for further 4 weeks and was followed by a 3-week recovery period. Progestin-dose per day: CPA 10 mg/20 mg, NES 2 mg/3 mg/dose e.g. 200/300 lg/day absorbed, NETA 5 mg/10 mg, LNG 120 lg/240 lg. From an andrology outpatient clinic, 56 healthy men aged 18–50 years, with body mass index ≤33 kg 9 m 2 were included in the study. Serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were studied. Secondary outcome measure included were serum testosterone concentrations, sperm concentrations, and safety parameters. Intergroup comparisons demonstrated that CPA and LNG had the strongest effect on LH/FSH suppression. Nevertheless, every substance showed significant inhibitory effects on gonadotropin secretion, especially in combination with transdermal T. A decrease in hematocrit and insulin sensitivity as well as cholesterol subfractions and triglycerides was uniformly seen for every group. The combination of oral or transdermal progestins with a transdermal testosterone preparation is able to suppress gonadotropins. Further dose titration studies with sperm suppression as an end-point should be conducted to determine the lowest effective dose for hormonal male contraception.

The term Late-onset hypogonadism (LOH) was coined in 2002 and defined as a disease entity in the ISA, ISSAM, EAU, EAA and ASA endorsed Recommendations for Investigation, Treatment and Monitoring of LOH (2005 and 2008) as 'a clinical and biochemical syndrome associated with advancing age, characterized by symptoms and a deficiency in serum testosterone (T)'. LOH was classified as a combined primary and secondary hypogonadism since the endocrine capacity of the testes and the pituitary are impaired. Symptoms of LOH include loss of libido, erectile dysfunction, loss of muscle mass, increased body fat, anemia, osteoporosis, depressed mood, decreased vitality, sweating, and hot flushes. Since these symptoms may also have origins other than LOH, exclusion of other disease entities and subnormal serum T levels are considered prerequisites for the diagnosis and possible treatment of LOH. However, during following years these guidelines were often neglected and, especially in the USA, indiscriminate prescribing of T was widely practised so that the US FDA warned against such irresponsible behavior. In Europe, T prescribing remained largely restricted to LOH as defined above. Nevertheless, a discussion started whether LOH really exists or is only a consequence of age-related comorbidities. Numerous studies have helped to clarify the situation, in particular, the European Male Aging Study (EMAS) and the US-initiated 7 T trials. Consequently, the newest US Endocrine Society Practice Guideline on T treatment (2018) includes advanced age as a cause of organic hypogonadism and recommends that 'in men >65 years who have symptoms or conditions suggestive of T deficiency … and consistently and unequivocally low morning T concentrations we suggest that clinicians offer T therapy on an individualised basis after explicit discussion of the potential risks and benefits'. Thus, the concept of LOH as conceived two decades ago has weathered criticism and survived the times.

Introduction and Objective Longterm data of Testosterone (T) substitution in hypogonadal men are scarce and clinical value of this treatment is especially debated in men with functional (so called “late-onset”) hypogonadism. A long-term registry comprising various groups of patients provides an efficient tool to approach this issue. Methods Registry data of max. 9 years comprising 650 patients with hypogonadism including 266 men with primary forms (mean age 34.0±11.7 years), 196 with secondary origin (mean age 31.9±12.0 years) and 188 with functional hypogonadism (mean age 42.3±11.3 years) all receiving uniform treatment using intramuscular T undecanoate (1000 mg). Results The registry contained 8358 time points with a subset of metabolic and safety parameters each. Serum T concentrations increased from 5.7±2.3 nmol/L to 19.4±2.8 nmol/L in men with classical hypogonadism and from 7.8±2.4 nmol/L to 19.2±3.1 nmol/L in men with functional hypogonadism (difference in delta T: p30 kg/m2, p=0.0006). Changes over time using Kaplan-Meier models revealed fundamental differences in inter-individual effects: men with functional hypogonadism were more likely to lose 10% weight and 5% of waist circumference (WC) than men with classical hypogonadism (hazard ratio 1.3 [1.1-1.4], p=0.008 and hazard ratio 1.4 [1.3-1.5], p=0.001). There was no difference for increase in hematocrit. Changes in PSA levels were more likely to occur in functional hypogonadism (hazard ratio 1.3 [1.1-1.6], p=0.003). Significantly more pronounced effects of T substitution in functional hypogonadism could also be attributed to changes in parameters of lipid metabolism (levels of total cholesterol, triglycerides, LDL- and HDL-cholesterol and glucose metabolism). Stepwise multiple Cox regression models could attribute these differences to the initial higher values in BMI, WC, lipids, glucose and age found in functional hypogonadism. The condition as such rather attenuated the effects of testosterone treatment compared to those seen in classical forms of hypogonadism, due to the lower increase of testosterone concentrations during treatment. Conclusions Major new findings regarding effects and safety of T substitution in different groups of hypogonadal men are provided. Effects on factors influencing cardiovascular health are modulated by diagnosis and age. Patients with functional hypogonadism seem to benefit to a larger extent from T substitution, this being a function of their initially worse status in cardiovascular risk factors compared to men with classical forms of hypogonadism.

As the most important male hormone, testosterone has an impact on almost all organs and body functions. The biological effects of testosterone and the testes have been known since antiquity, long before testosterone was identified as the active agent. Practical applications of this knowledge were castration of males to produce obedient servants, for punishment, for preservation of the prepubertal soprano voice and even for treatment of diseases. Testes were used in organotherapy and transplanted as treatment for symptoms of hypogonadism on a large scale, although these practices had only placebo effects. In reaction to such malpractice in the first half of the 20th century science and the young pharmaceutical industry initiated the search for the male hormone. After several detours together with their teams in 1935, Ernst Laqueur (Amsterdam) isolated and Adolf Butenandt (Gdansk) as well as Leopold Ruzicka (Zürich) synthesized testosterone. Since then testosterone has been available for clinical use. However, when given orally, testosterone is inactivated in the liver, so that parenteral forms of administration or modifications of the molecule had to be found. Over 85 years the testosterone preparations have been slowly improved so that now physiological serum levels can be achieved.

In recent years, genetic studies have yielded great progress in elucidating causes of male infertility. This investigation aims to identify frequent genetic abnormalities, that is, sex chromosome aneuploidies and Y-chromosome microdeletions among infertile men in Western Saudi Arabia. From a population of infertile patients, 88 male patients with either azoospermia or severe oligozoospermia (sperm concentration

Summary Patients with Klinefelter's syndrome experience progressive testicular degeneration resulting in impaired endocrine function and azoospermia. What proportion of adolescents develop testosterone deficiency during puberty and how many have spermatozoa in their semen is unclear to date. We aimed to investigate testicular function during puberty and young adulthood in patients with Klinefelter's syndrome and to assess testosterone effects in target tissues. The clinical data of 281 patients with non-mosaic Klinefelter's syndrome aged 10–25 years without previous testosterone replacement were reviewed. In late pubertal adolescents, semen analyses were evaluated, and testicular volumes, hormone and haemoglobin (Hb) levels, the number of CAG repeats and final height data were compared to those of 233 age-matched controls with pubertal gynaecomastia. Spontaneous pubertal virilisation to Tanner stages IV–V occurred. Serum T levels ≥10 nmol/L were reached in 62% of patients with Klinefelter's syndrome and in 85% of controls at ages 15–25 (TKFS: 12.2 ± 5.4 vs. TC: 16.6 ± 7.2 nmol/L). LHKFS levels were elevated >10 U/L in 84%, and normal in all controls (LHKFS: 18.6 ± 12.2 vs. LHC: 3.5 ± 1.6 U/L). In nine of 130 (7%) adolescents with Klinefelter's syndrome, spermatozoa (oligozoospermia) were found in semen; all had T levels >7 nmol/L and eight of nine had LH levels ≤18 U/L, while their hormone levels, number of CAG repeats and testicular volumes were not different from those of adolescents with azoospermia. Controls had normal sperm concentrations in 73% (46/63). Semen volumesKFS were normal in 55% vs. 78% in controls; HbKFS was normal in 89% (HbC: 97%). Mean final heightKFS was 185 ± 8 cm vs. 181 ± 7 cm in controls. Hypergonadotropic hypogonadism develops during early puberty in adolescents with Klinefelter's syndrome and remains compensated in over 60% during ages 15–25, with sufficient testosterone secretion for spontaneous accomplishment of pubertal development. Spermatozoa in semen are rare and associated with T levels >7 nmol/L. Parameters reflecting androgen deficiency in target tissues may help to optimise timing of testosterone substitution, which should preferably not be initiated before fertility status has been clarified.

Background Single nucleotide polymorphism of the follicle-stimulating hormone (FSH) receptor (FSHR) is an important marker of ovarian function. However, its role in female fecundity remains debatable. The aim of the study to assess the relationship of FSHR polymorphism of Serine/Serine, Asparagine/Asparagine and Asparagine/Serine variants directly against the time-to-pregnancy (TTP) in women. Methods Data were collected from 291 consecutive selected post-partum Caucasians using this criterion: ethnicity, age between 21 and 34-year-old new mothers and, 0–3 days after delivery of newborns in the Klaipeda University Hospital, Lithuania. Questionnaires on factors associated with conception were given to patients, and blood samples were collected for genomic DNA extractions as well as for analysis of follicle-stimulating hormone receptor gene polymorphism. Odds ratios (OR) and 95% confidence intervals (CI) for time-to-pregnancy were estimated by multivariate logistic regression. Women with unplanned pregnancies and those who received assisted reproductive technologies were not included in the study. Results After adjustment for other possible factors, increased risk for time-to-pregnancy of 12 or more months was associated with: Serine/Serine polymorphism variant (OR = 1.38, 95% CI 1.56–2.71, p = 0.007), age of 30 or more years (OR = 1.95, 95% CI 1.25–2.71, p = 0.015), gynaecological diseases in the past (OR = 2.21, 95% CI 1.12–5.74, p = 0.027), prior contraception use (OR = 1.87, 95% CI 1.14–3.64, p = 0.016), and fertility problems in the past (OR = 1.57, 95% CI 1.16–4.76, p = 0.019). Conclusion The results suggest a possible relationship of FSH receptor gene Serine/Serine variant for the lower possibility of conception during the first 12 months of planned conception.

Despite the fact that sports organizations and legislators have introduced various mechanisms to discourage athletes from using performance and appearance enhancing substances a high percentage of athletes admits to their unabated application. In competitive athletics, bodybuilding and in recreational sports anabolic androgenic steroids (AAS) continue to be the substances most abused. This review summarizes the side effects of AAS abuse on organs and system functions in both sexes. High doses of AAS cause a significant increase of erythrocytes and hemoglobin concentration, which may lead to thromboembolism, intracardiac thrombosis and stroke. Long-term AAS abusers have a higher incidence of arrhythmias, atherosclerosis, concentric left-ventricular myocardial hypertrophy with impaired diastolic function and also sudden cardiac death. Changes of liver function and structure, up to hepatocellular carcinoma, have been described, mainly in cases of chronic misuse of 17α-alkylated AAS. Sleeplessness, increased irritability, depressive mood status are often observed in AAS abuse. In former AAS abusers depression, anxiety and melancholy may persist for many years. Due to negative feedback in the regulation of the hypothalamic-pituitary-gonadal axis AAS can cause reversible suppression of spermatogenesis up to azoospermia. In women the changes most often caused by AAS abuse are hirsutism, irreversible deepening of voice, dysmenorrhea, secondary amenorrhea with anovulation and infertility. AAS abuse notwithstanding, under clinical conditions testosterone remains the most important hormone for substitution therapy of male hypogonadism.

In pre-pubertal boys ≥ 14 years, the differentiation between constitutional delay of growth and puberty (CDGP) and hypogonadotropic hypogonadism (HH) is challenging, as current diagnostic tools have limitations in sensitivity and specificity. The aim of this study was to assess the usefulness of markers of gonadal activity, growth axis activation and adrenarche in differentiation between pre-pubertal CDGP and HH. This retrospective study was carried out between 2006 and 2015 in an academic out-patient referral centre. The clinical data of 94 boys, aged 13.9-23.2 years and referred for "pubertal delay" were reviewed. Definite diagnoses were established on initial work-up and clinical follow-up: 24 boys were diagnosed with HH, 22 boys with CDGP, pre-pubertal (PP CDGP) at referral and 28 boys with CDGP, early pubertal at referral (EP CDGP), the latter serving as control group. Twenty patients were excluded from evaluation because of previous sex steroid treatment or associated chronic disease. Inhibin B and AMH were measured in all (n = 74); INSL3, IGF1, IGFBP3 and DHEAS in a subset of patients (n = 45) in serum of first presentation. Inhibin B and AMH were higher in boys with PP CDGP than in boys with HH: inhibin B: 87.6 ± 42.5 vs. 19.8 ± 13.9 pg/mL; p

Anabolic androgenic steroids (AASs) are appearance and performance-enhancing drugs (APEDs) used in competitive athletics, in recreational sports, and by body-builders. The global lifetime prevalence of AASs abuse is 6.4% for males and 1.6% for women. Many AASs, often obtained from the internet and dubious sources, have not undergone proper testing and are consumed at extremely high doses and in irrational combinations, also along with other drugs. Controlled clinical trials investigating undesired side effects are lacking because ethical restrictions prevent exposing volunteers to potentially toxic regimens, obscuring a causal relationship between AASs abuse and possible sequelae. Because of the negative feedback in the regulation of the hypothalamic–pituitary–gonadal axis, in men AASs cause reversible suppression of spermatogenesis, testicular atrophy, infertility, and erectile dysfunction (anabolic steroid-induced hypogonadism). Should spermatogenesis not recover after AASs abuse, a pre-existing fertility disorder may have resurfaced. AASs frequently cause gynecomastia and acne. In women, AASs may disrupt ovarian function. Chronic strenuous physical activity leads to menstrual irregularities and, in severe cases, to the female athlete triad (low energy intake, menstrual disorders and low bone mass), making it difficult to disentangle the effects of sports and AASs. Acne, hirsutism and (irreversible) deepening of the voice are further consequences of AASs misuse. There is no evidence that AASs cause breast carcinoma. Detecting AASs misuse through the control network of the World Anti-Doping Agency (WADA) not only aims to guarantee fair conditions for athletes, but also to protect them from medical sequelae of AASs abuse.

Klinefelter syndrome (KS) and undescended testes (UDT) are known etiologies for non-obstructive azoospermia (NOA), and coexistence of both etiologies is not uncommon. Patients with both KS and a history of UDT are therefore considered to have extremely reduced chances for paternity. We aimed to analyze the impact of previous surgically corrected unilateral or bilateral UDT on sperm retrieval rates (SRRs) by microsurgical testicular sperm extraction (mTESE) in azoospermic men with KS. Age, testicular volumes, and hypothalamo-pituitary-gonadal axis function were investigated in relation to SRRs in 29 non-mosaic KS patients (47,XXY) with a history of UDT (group 1) who underwent mTESE between 2008 and 2016 in our center and compared to the data of age- and serum testosterone-matched non-mosaic KS controls with eutopic testes at birth (group 2), and to those of 51 men with NOA and a normal male karyotype (46,XY), but previous UDT (group 3). SRRs in KS patients with surgically corrected UDT during childhood were comparable to SRRs of KS patients with eutopic testes at birth: 31% (35% in unilateral and 22% in bilateral UDT) vs. 38% (p = 0.581). SRRs and Leydig cell function in group 1 were negatively correlated with age. Significantly higher SRRs (66%) were found in euploid azoospermic men with surgically corrected UDT (p < 0.001). A history of UDT does not preclude chances for future fatherhood in young azoospermic males with KS. In one of three men with previous unilateral UDT and in one of 4-5 in those with previous bilateral UDT, spermatozoa can be harvested by mTESE during late adolescence or young adulthood for immediate or future use in assisted reproduction.

Androgens comprise testosterone and anabolic steroids derived from testosterone. Testosterone preparations are predominantly prescribed for treatment of male hypogonadism, but also for other medical conditions in both men and women. Misuse of androgens, however, has become an extensive problem of increasing proportion. Therefore, it is important for students, scientists, and clinicians to be familiar with the risks and benefits of androgen use.

Extirpation and transplantation of endocrine glands are among the earliest tools in experimental endocrinology. The testes, with their exposed position, are vulnerable and easily accessible to external manipulation, including trauma and forceful removal. Thus, the effects of testosterone and its absence as a consequence of loss of the testes became known quite early in the history of mankind. Castration, leading to a loss of virility and fertility, has been used over centuries for punishment of criminal acts and high treason, for the creation of obedient slaves and servants and for preserving the prepubertal soprano voices for musical entertainment. Although the testes were correctly identified as the source of androgenicity, attempts to use them in organotherapy can only have led to placebo effects. Testosterone itself was isolated only in 1935 and, since then, has been available as a powerful medication for the treatment of hypogonadism. Only recently has it become possible to produce injectable or transdermal testosterone preparations generating serum levels in the physiological range.

The Klinefelter syndrome (KS), with an incidence of 1 to 2 per 1000 male neonates, is one of the most frequent congenital chromosome disorders. The 47,XXY karyotype causes infertility, testosterone deficiency and a spectrum of further symptoms and comorbidities. In recent years, significant progress has been made in the elucidation of the pathophysiology and the treatment of the KS. It became clear that, to a large extent, the clinical picture is determined by gene dosage effects of the supernumerary X-chromosome. The origin of the extra X-chromosome from either the father or the mother influences behavioural features of patients with KS. The CAGn polymorphism of the androgen receptor, located on the X-chromosome, has a distinct impact on the KS phenotype. KS predisposes to the metabolic syndrome and its cardiovascular sequelae, contributing to the increased mortality of patients with KS. Neuroimaging studies have correlated anomalies in brain structures with psychosocial problems. The unexpected possibility to produce pregnancies and live birth with either ejaculated sperm--about 8% of KS men have a few sperm in semen--or with sperm extracted from individual tubules obtained by testicular biopsy can be considered a breakthrough. Testosterone substitution requires further optimisation in terms of when to initiate therapy and which preparations and dosages to use. Recently developed animal models help to further elucidation the genetic and pathophysiological basis and may lead to new therapeutic approaches to KS.

Obwohl bei etwa der Halfte der Paare mit unerfulltem Kinderwunsch auch der Mann Storungen der Fortpflanzungsfahigkeit aufweist, werden die Untersuchung und Behandlung der mannlichen Fertilitatsstorungen immer noch vernachlassigt. Auch wenn es keine Beweise fur die oft in den Medien diskutierte „Spermienkrise“ gibt, ist die Offentlichkeit uber diese Berichte beunruhigt. Hingegen finden die mit dem Alter von uber 40 Jahren nachlassende Zeugungsfahigkeit des Mannes und auch die mit seinem Alter ansteigenden Risiken fur den Nachwuchs keine Beachtung. Zur Diagnostik bei einem infertilen Mann gehoren neben einer korperlichen Untersuchung, die durch eine Ultrasonographie der Skrotalorgane erganzt wird, die Ejakulatanalyse nach den Richtlinien der WHO, Hormonbestimmungen sowie zyto- und molekulargenetische Untersuchungen. Nur wenige Storungen der mannlichen Fertilitat sind einer rationalen Therapie zuganglich. Hierzu zahlen die Behandlung des sekundaren Hypogonadismus mit Gonadotropinen, die Bekampfung von sexuell ubertragbaren Infektionen mit Antibiotika und die mikrochirurgische Rekonstruktion blockierter ableitender Samenwege. Praventive Masnahmen wie die fruhzeitige Behandlung eines Hodenhochstands im Sauglingsalter oder Veranderungen des Lebensstils (z. B. Einstellung des Rauchens) konnen eine Infertilitat verhindern. Nach den Kriterien der evidenzbasierten Medizin erweisen sich bisher praktizierte empirische Therapien als ineffektiv: So wurde fur die interventionelle Therapie einer Varikozele eine Steigerung der Schwangerschaftsraten nicht nachgewiesen. Gegenwartig erweist sich die intrazytoplasmische Spermieninjektion (ICSI) eventuell mit einzelnen aus einer Hodenbiopsie gewonnenen Spermien (TESE) als erfolgreichste, wenn auch nur symptomatische Behandlung bei Azoospermie bzw. bei sehr niedrigen Spermienkonzentrationen.

Testosterone is an essential part of all regimens for hormonal male contraception tested to date. Initial efficacy trials revealed that the half-life of the testosterone preparations available at that time was too short to be used for male contraception. The ensuing search for long-acting preparations yielded testosterone buciclate and undecanoate as well as 7α-methyl-19-nortestosterone (MENT). Following description of the principle of male hormonal contraception and the efficacy trials performed to date, the systematic development of MENT for substitution of male hypogonadism and use in male contraception by the Population Council is reviewed here.