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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

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Andreas Poplinski, Peter Wieacker, Sabine Kliesch, and Jörg Gromoll


46,XX-maleness affects 1 in 20 000 live male newborns resulting in infertility and hypergonadotrophic hypogonadism. Although the phenotypes of XX-males have been well described, the molecular nature of the X chromosomes remains elusive. We assessed the X inactivation status by DNA methylation analysis of four informative loci and compared those to Klinefelter syndrome (KS) and Turner syndrome.

Design and methods

Patient cohort consisted of ten sex-determining region of the Y (SRY+) XX-males, two (SRY−) XX-males, ten 47,XXY Klinefelter men, six 45,X Turner females and ten male and female control individuals each. Methylation analysis was carried out by bisulphite sequencing of DNA from peripheral blood lymphocytes analysing X-inactive-specific transcript (XIST), phosphoglycerate kinase 1 (PGK1), ferritin, heavy peptide-like 17 (FTHL17) and short stature homeobox (SHOX).


XIST methylation was 18% in (SRY+) XX-males, and thus they were severely hypomethylated compared to (SRY−) XX-males (48%; P<0.01), Klinefelter men (44%; P<0.01) and female controls (47%; P<0.01). Turner females and male controls displayed a high degree of XIST methylation of 98 and 94% respectively. Methylation of PGK1, undergoing X inactivation, was not significantly reduced in (SRY+) XX-males compared to female controls in spite of severe XIST hypomethylation (51 vs 69%; P>0.05). FTHL17, escaping X inactivation, but undergoing cell-type-specific inactivation was similarly methylated in XX-males (89%), KS patients (87%) and female controls (90%). SHOX, an X inactivation escapee located in the pseudoautosomal region, displays similarly low degrees of methylation for XX-males (7%), KS patients (7%) and female controls (9%).


XIST hypomethylation clearly distinguishes (SRY+) XX-males from Klinefelter men. It does not, however, impair appropriate epigenetic regulation of representative X-linked loci.

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Manuela Simoni, Jörg Peters, Hermann M Behre, Sabine Kliesch, Eckhard Leifke, and Eberhard Nieschlag

Simoni M, Peters J, Behre HM, Kliesch S, Leifke E, Nieschlag E. Effects of gonadotropin-releasing hormone on bioactivity of follicle-stimulating hormone (FSH) and microstructure of FSH. luteinizing hormone and sex hormone-binding globulin in a testosterone-based contraceptive trial: evaluation of responders and non-responders. Eur J Endocrinol 1996;135:433–9. ISSN 0804–4643

Only a proportion of normal men participating in testosterone-based contraceptive trials develop azoospermia (responders). This study analyzed whether serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and sex hormone-binding globulin (SHBG) are qualitatively different between responders and non-responders. Determination of in vitro bioactive FSH after stimulation with gonadotropin-releasing hormone (GnRH) and analysis of molecular heterogeneity of serum FSH. LH and SHBG was carried out by chromatofocusing and concanavalin-A affinity chromatography in eight men who had participated in a previous contraceptive study with testosterone buciclate. Blood was withdrawn at 15-min intervals on two basal occasions and 30, 45 and 60 min after iv administration of GnRH (100 μg). Pools of sera were separated by chromatofocusing in the pH range 3–6 and by lectin chromatography on concanavalin A. Immunoreactive FSH, LH and SHBG were assayed in the eluates. Bioactive FSH was analyzed by the rat Sertoli cell bioassay. Serum bioactive FSH increased after GnRH stimulation, without significant differences between responders and non-responders. The chromatofocusing profiles of serum FSH showed a significant shift towards the less acidic region after GnRH. The isoform distribution was similar in responders and non-responders. No significant differences were found in the relative proportion of FSH, LH and SHBG retained by concanavalin A. It is concluded that the extent of suppression of sperm production by androgen administration cannot be foreseen either on the basis of the response of bioactive FSH to GnRH administration or from the glycosylation pattern of serum FSH, LH and SHBG.

E Nieschlag, Institute of Reproductive Medicine of the University, Domagkstr. 11, D-48129 Münster, Germany

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Julia Rohayem, Frank Tüttelmann, Con Mallidis, Eberhard Nieschlag, Sabine Kliesch, and Michael Zitzmann


Classical congenital adrenal hyperplasia (CAH), a genetic disorder characterized by 21-hydroxylase deficiency, impairs male fertility, if insufficiently treated.


A 30-year-old male was referred to our clinic for endocrine and fertility assessment after undergoing unilateral orchiectomy for a suspected testicular tumor. Histopathological evaluation of the removed testis revealed atrophy and testicular adrenal rest tumors (TARTs) and raised the suspicion of underlying CAH. The remaining testis was also atrophic (5 ml) with minor TARTs. Serum 17-hydroxyprogesterone levels were elevated, cortisol levels were at the lower limit of normal range, and gonadotropins at prepubertal levels, but serum testosterone levels were within the normal adult range. Semen analysis revealed azoospermia. CAH was confirmed by a homozygous mutation g.655A/C>G (IVS2-13A/C>G) in CYP21A2. Hydrocortisone (24 mg/m2) administered to suppress ACTH and adrenal androgen overproduction unmasked deficient testicular testosterone production. As azoospermia persisted due to sustained hypogonadotropic hypogonadism, a combined s.c. gonadotropin replacement with human chorionic gonadotropin (hCG) (1500 IU twice weekly) and FSH (human menopausal gondadotropin (hMG) 150 IU three times weekly) was initiated.


Normalization of testosterone levels and a stable low sperm concentration (0.5 mill/ml) with good sperm motility (85% A+B progressive) were achieved within 21 months of treatment. Despite persisting TARTs, while receiving treatment, the patient successfully impregnated his wife twice, the latter impregnation leading to the birth of a healthy girl.


TARTs in unrecognized (simple virilizing) CAH may lead to unnecessary orchiectomy. In hypogonadotropic, azoospermic CAH, a combined treatment with oral corticosteroids and subcutaneously administered hCG and FSH can successfully restore testicular testosterone production and fertility, even if only one hypoplastic and atrophic testis with adrenal rest tumors is present.

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Julia Rohayem, Lena Maria Bäumer, Michael Zitzmann, Susanne Fricke-Otto, Klaus Mohnike, Bettina Gohlke, Felix Reschke, Claus Jourdan, Hermann L Müller, Désirée Dunstheimer, Johannes Weigel, Norbert Jorch, Elke Müller-Roßberg, Erwin Lankes, Imke Gätjen, Annette Richter-Unruh, Berthold P Hauffa, Sabine Kliesch, Aniko Krumbholz, and Jurgen Bramswig

Objective: To study the impact of the quality of therapeutic control on fertility and on the prevalence of testicular adrenal rest tumors (TARTs) in young males with congenital adrenal hyperplasia (CAH).

Design: Combined cross-sectional and retrospective clinical study.

Methods: Twenty-nine patients and age-matched controls underwent clinical investigation, including semen analysis, testicular and adrenal ultrasound imaging, and serum and hair steroid analysis. The quality of therapeutic control was categorized as “poor”, “moderate” or “medium”. Evaluation of current control was based on concentrations of 17-hydroxy-progesterone and androstenedione in serum and 3 cm hair; previous control was categorized based on serum 17-hydroxy-progesterone concentrations during childhood and puberty, anthropometric and puberty data, bone age data and adrenal sizes.

Results: Semen quality was similar in males with CAH and controls (p = 0.066), however patients with “poor” past control and large TARTs, or with “poor” current CAH control, had low sperm counts. Follicle-stimulating hormone was decreased, if current CAH control was “poor” (1.8 ± 0.9 U/L; “good”: 3.9 ± 2.2 U/L); p = 0.015); luteinizing hormone was decreased if it was “poor” (1.8 ± 0.9 U/L; p = 0.041) or “moderate” (1.9 ± 0.6 U/L; “good”: 3.0 ± 1.3 U/L; p = 0.025). None of the males with “good” past CAH control, 50% of those with “moderate” past control and 80% with “poor” past control had bilateral TARTs. The prevalence of TARTs in males with severe (class null or A) CYP21A2 mutations was 53%, and 25% and 0% in those with milder class B and C mutations, respectively.

Conclusions: TART development is favoured by inadequate long-term hormonal control in CAH. Reduced semen quality may be associated with large TARTs. Gonadotropin suppression by adrenal androgen excess during the latest spermatogenic cycle may contribute to impairment of spermatogenesis.