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.
Eberhard Nieschlag and Susan Nieschlag
Klaus Hoffmann and Eberhard Nieschlag
A marked circadian rhythm of plasma testosterone was found in male Djungarian hamsters. Maximal values in the evening just prior to activity onset were about 12 times higher than minimum values in the early morning. The peak of serum testosterone concentration coincides with onset of oestrus in females.
Eberhard Nieschlag and Elena Vorona
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.
Manuela Simoni, Friedrich Jockenhövel and Eberhard Nieschlag
The new international standard for FSH, IS 83/575, has been analyzed, after isoelectric focusing separation, by Sertoli cell in vitro bioassay, radioligand receptor assay and two highly specific immunometric assays. Its molecular composition was then compared with the isoelectric focusing profiles obtained from the fractionation of the reference preparation 2nd IRP 78/549 and from pools of human male and female pituitary extracts and male and female sera. The results showed that >80% of immunoreactive and bioactive FSH in the IS 83/575 has a pI value <4, while such very acidic material was represented much less in the other FSH preparations tested. All the immunoreactive material contained in the IS 83/575 was shown to be capable of receptor binding and bioactivity in vitro. A generally good correspondence between IEF profiles obtained by bioassay and by immunofluorimetric assay was evident in the case of IS 83/575, 2nd IRP 78/549 and pituitary extracts, although the profiles recorded by immunofluorimetric assay were rather smooth and more isoforms were detected by bioassay. A striking discrepancy between immunoreactive FSH and bioactive FSH was observed after isoelectric focusing fractionation of the serum pools, in which some bioactive material was not detected by immunofluorimetric assay and some of the immunoreactive FSH peaks were devoid of bioactivity, indicating that serum contains inhibitors of FSH action and that immunometric assays based on monoclonal antibodies may miss some bioactive FSH isoforms. Taken together, these results suggest that the IS 83/575 is not fully representative of pituitary and serum FSH, and its use for calibration of modern immunometric methods based on monoclonal antibodies is unlikely to resolve current problems of inaccuracy in measurements of serum FSH.
Friedrich Jockenhövel, Shafiq A. Khan and Eberhard Nieschlag
Bioactive FSH and immunoreactive FSH were determined in 193 infertile men and in 23 men with proven fertility using the Sertoli cell aromatase bioassay for bioactive FSH measurement and a two-site fluoroimmunoassay for immunoreactive FSH measurement. Overall bioactive and immunoreactive FSH levels correlated well (r = 0.74, p < 0.001) but were significantly different from fertile men (bioactive FSH: 6.2 ± 0.3 U/l; immunoreactive FSH: 4.1 ± 0.4 U/l) in patients with Klinefelter's syndrome (24.1 ± 6.1; 26.9 ± 3.0), non-obstructive azoospermia (25.1 ± 4.3; 22.2 ± 4.0), maldescended testes (12.5 ± 4.6; 14.6 ± 1.6), and patients with severe oligozoospermia (11.9 ± 1.2; 11.2 ± 1.0). Infertile men with moderate oligozoospermia (8.9 ± 1.5; 8.0 ± 1.1) and normal sperm counts (9.6 ± 1.1; 7.6 ± 1.0) had insignificantly elevated bioactive FSH and immunoreactive FSH levels. Bioactive to immunoreactive FSH ratios were significantly reduced in all patient groups except for patients with normal sperm counts when compared with fertile men. A considerable number of patients exhibited elevated immunoreactive FSH concomitant with normal bioactive FSH levels. We conclude that 1. determination of immunoreactive FSH suffices for classification of patients; 2. bioactive to immunoreactive FSH ratios are reduced in infertile men; 3. some men might secrete immunoreactive FSH with reduced bioactivity.
Sabine Kliesch, Hermann M Behre and Eberhard Nieschlag
Kliesch S, Behre HM, Nieschlag E. High efficacy of gonadotropin or pulsatile gonadotropin-releasing hormone treatment in hypogonadotropic hypogonadal men. Eur J Endocrinol 1994;131:347–54. ISSN 0804–4643
In order to determine the efficacy of gonadotropin and gonadotropin-releasing hormone (GnRH) therapy in hypogonadotropic hypogonadal men, we performed a retrospective clinical analysis in the outpatient clinic of a University Center for Reproductive Medicine. Twenty-six men with either hypothalamic (idiopathic hypogonadotropic hypogonadism, N = 6; Kallmann syndrome, N = 8) or pituitary disorders (N = 12) were treated with gonadotropins or GnRH for induction of spermatogenesis in 33 treatment cycles and, additionally, for induction of pregnancy in the female partner in 18 out of 33 cases (12 of 26 patients). Patients were treated with a combination of 1000–2500 IE of human chorionic gonadotropin twice per week and 75–150 IE human menopausal gonadotropin three times per week intramuscularly or subcutaneously. Alternatively, GnRH was administered at doses of 5–20 μg every 120 min subcutaneously to men with hypothalamic disorders. Treatment lasted until sperm appeared in the ejaculate or pregnancy was induced. During therapy, testosterone levels increased into the normal range. Total testicular volumes increased significantly during therapy despite low initial testicular volumes and histories of maldescended testes. Sperm appeared in the ejaculate in 30 of 33 treated patients. Pregnancies occurred in 15 out of 18 cases even with sperm counts far below the normal range. We could not detect differences in the efficacy of gonadotropin or GnRH treatment in hypogonadotropic hypogonadism. Thus, we conclude that both gonadotropin and pulsatile GnRH therapy are most effective in the induction of spermatogenesis and pregnancies in hypogonadotropic hypogonadal men, despite maldescended testes, low initial testicular volumes or sperm concentrations below the normal limit.
E Nieschlag, Institute of Reproductive Medicine of the University, Steinfurter Strasse 107, D-48149 Münster, Germany
Georg Brabant, E. Jean Wickings and Eberhard Nieschlag
Histidyl-proline-diketopiperazine (DKP) - a stable degradation product of TRH - has been shown to selectively inhibit prolactin secretion in vitro in rat pituitary tissue. In this study the effects of DKP on serum prolactin in intact and anaesthetized male rhesus monkeys and on TRH-stimulated prolactin levels have been investigated.
In conscious monkeys 400 μg DKP significantly suppressed prolactin levels by 27%, and under ketamine anaesthesia, serum prolactin was suppressed in a dose-dependent manner by 150 and 400 μg DKP. The maximum prolactin response and the cumulative response to TRH (20 μg) was significantly and specifically inhibited by 400 μg DKP, while the lower dose was without effect. TSH levels were not affected by DKP in any instance.
Hence DKP can specifically inhibit prolactin release in the rhesus monkey, and may be discussed as a possible regulatory factor in prolactin secretion.
Monika Bals-Pratsch, Klaus Langer, Virgil A. Place and Eberhard Nieschlag
Abstract. Current testosterone substitution therapy either by injectable or oral testosterone esters suffers from markedly fluctuating serum testosterone levels often far above or below the physiological range. Recently, a transdermal therapeutic system (TTS) for the delivery of testosterone was developed which, when applied to the scrotum, provides smooth serum testosterone levels. Here we report results from seven hypogonadal men treated with the TTS for 14 months by applying a new patch every day. In all patients serum testosterone and dihydrotestosterone (DHT) determined 3–5 h after applying a new patch increased significantly and remained within the physiological range during the entire treatment period. The DHT/testosterone ratio remained constant. In 4 of these patients and 2 others under TTS treatment serum testosterone and DHT were also determined over a 24-h period at regular intervals. In these patients serum testosterone levels in the physiological range were seen during the entire observation period, whereas an increase in the DHT/testosterone ratio occurred towards the end of the one-day treatment phase. All patients in the 14-month treatment study were clinically well substituted and responded with good compliance. Clinical chemistry showed no abnormalities during treatment. Thus, the TTS appears to be an effective and safe new modality for the treatment of male hypogonadism.
Ulrich Fingscheidt, Gerhard F. Weinbauer, Shafiq A. Khan and Eberhard Nieschlag
Three adult rhesus monkeys were injected intramuscularly with human FSH at doses of 2, 10 or 25 IU/kg in a cross-over design with 3-week intervals between injections. On each occasion a fourth animal received saline only as control. Serum levels of exogenous FSH were monitored by a fluoroimmunoassay specific for human FSH. Serum inhibin was measured by a heterologous radioimmunoassay. Each FSH injection was followed by a rise in serum inhibin in a dose-dependent manner. The half-life of human FSH in rhesus monkeys ranged from 25.1 to 32.9 h with no significant differences between doses. The rise of inhibin occurred with a lag time of 53.3 to 61.9 h after injection of FSH, independent of the dose administered. These findings support the concept that inhibin secretion in male primates is stimulated by FSH.
Monika Bals-Pratsch, Hans-Udo Schweikert and Eberhard Nieschlag
Three brothers with congenital transposition of the penis, scrotal hypospadias, bifid scrotum, and bilateral undescended testes are described. Further signs of incomplete virilization, but no gynecomastia were seen. LH and FSH were elevated, whereas testosterone levels were reduced or in the normal range. Serum concentrations of 17-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, 5α-dihydrotestosterone and estradiol measured in two affected brothers were in the normal range. Fibroblasts from scrotal skin biopsies performed in two patients showed normal 5α-reductase activity (419 and 214 pmol · (mg protein)−1 · h−1; normal >1), whereas androgen receptors had reduced maximal binding capacity (Bmax 4 and 14 fmol · (mg protein)−1; normal ≥ 18) and an increased equilibrium dissociation constant (0.7 and 1.26 nmol/l; normal 0.2±0.08) indicating a quantitative and qualitative androgen receptor defect. These patients represent a further variant of androgen insensitivity.