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  • Author: Dietrich Klingmüller x
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Lieselotte Sommer, Kerstin Zanger, Thomas Dyong, Christoph Dorn, Johannes Luckhaus, Klaus Diedrich and Dietrich Klingmüller

Sommer L, Zanger K, Dyong T, Dorn C, Luckhaus J, Diedrich K, Klingmüller D. Seven-day administration of the gonadotropin-releasing hormone antagonist Cetrorelix in normal cycling women. Eur J Endocrinol 1994;131:280–5. ISSN 0804–4643

In contrast to gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists do not show any stimulatory effect on the pituitary but their clinical usage was precluded by severe side effects and high dose requirements. We report here on a 7-day treatment using the potent GnRH antagonist Cetrorelix ([Ac-d-Nal(2)1, d-Phe(4Cl)2, d-Pal(3)3, d-Cit6, d-Ala10]GnRH) on five women 23–33 years old. All women were ovulatory and were studied during three consecutive cycles: a control cycle, a treatment cycle and a post-treatment control cycle. Throughout the control cycles blood samples were obtained daily during cycle days 8–18 and on days 21 and 23 during the remainder of the control cycles. On the eighth day of the treatment cycle women were hospitalized at 07.00 h for 26 h. Repeated blood samples were drawn at 15-min intervals during the entire period. Subjects received 3 mg of Cetrorelix sc for the first time at 09.00 h on the eighth day of the cycle and daily at 08.00 h for the following 6 days. Blood samples were obtained daily over a period of 25 days and every third day throughout the remainder of the treatment cycle. Twenty-four hours after the first application of Cetrorelix, luteinizing hormone (LH) and estradiol were in the subnormal range and remained subnormal until the end of medication. The suppressive effect of Cetrorelix compared to pretreatment values lasted at least 6 days for LH and FSH and 11 days after the last Cetrorelix injection for estradiol. An LH surge followed by postovulatory progesterone values was found 22.6 ± 1.4 days after the last injection. During application of the GnRH antagonist, LH was reduced to 16.1 ± 0.7%, FSH to 58.7 ± 1.3% and estradiol to 17.9 ± 0.4% compared to the individual pretreatment values. The consecutive cycle after completion of treatment was comparable to the length of the pretreatment cycle. No serious side effects were observed. In summary, the results of this study give evidence of the effectiveness and safety of this new GnRH antagonist used in low dosages for possible therapeutic application in sex-hormone-dependent diseases in women.

Dietrich Klingmüller, Institut für Klinische Biochemie der Universität Bonn, Sigmund Freud Str. 25, D53105 Bonn, Germany

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Wolfgang Brennemann, Lieselotte Sommer, Birgit Stoffel-Wagner, Frank Bidlingmaier and Dietrich Klingmüller

Brennemann W, Sommer L, Stoffel-Wagner B, Bidlingmaier F, Klingmüller D. Secretion pattern of immunoreactive inhibin in men. Eur J Endocrinol 1994;131:273–9. ISSN 0804–4643

Chronological changes in serum concentrations of inhibin, a gonadal glycoprotein hormone, were studied in healthy male volunteers (age 24–27 years). Secretion profiles of immunoreactive inhibin (ir-inhibin) were compared with those of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone. Blood samples were collected every 15 min for 24 h. Serum inhibin concentrations were measured by a two-site immunoenzymatic assay with antibodies raised against distinct epitopes of the recombinant 1–32 amino acids of the α-subunit of human inhibin. The normal range for men was 0.79–3.1 U/l × 10−3, the sensitivity of the assay was 0.1 U/l × 10−3 (cv: within-assay, 6.8%; between-assay, 8.2%). Luteinizing hormone and FSH were measured by immunoradiometric assay and testosterone by radioimmunoassay. Secretion profiles of inhibin and testosterone were tested for diurnal variations by cosinor rhythmometry. Highest ir-inhibin concentrations were observed in the morning at 08.00 h, with peak values of 2.45–3.20 U/l × 10−3. During the evening and the night, ir-inhibin levels were relatively low; lowest concentrations were observed between 01.00 h and 02.00 h at night: 1.20–1.86 U/l × 10−3. Highest testosterone levels were observed in the morning (20.5–36.6 pmol/I), lowest concentrations were detected at night (7.35–12.6 pmol/l). Cosinor rhythmometry supported the suggestion that there is a clear circadian secretion of ir-inhibin and testosterone, respectively. The secretion pattern of ir-inhibin was analyzed by the Cluster pulse analysis computed algorithm, which identified four to seven inhibin pulses per day, depending on the person under observation. A significant correlation could be observed between median testosterone and ir-inhibin concentrations (r = 0.449, p < 0.001). In conclusion, ir-inhibin and testosterone in healthy male volunteers follow a clear diurnal rhythm. Moment to moment changes of ir-inhibin can be observed in all secretion profiles investigated. A probable physiological role for pulsatile inhibin secretion is not yet clarified.

Dietrich Klingmüller, Institut für Klinische Biochemie, Universität Bonn, Sigmund-Freud-Str. 25, D-53105 Bonn, Germany

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Annegret Quade, Michael Rahn, Hans-Udo Schweikert, Frank Bidlingmaier and Dietrich Klingmüller

Urinary GH excretion reflects average plasma levels. Using a highly sensitive sandwich enzyme immunoassay we determined GH concentrations in the 24 h accumulated urine samples of 54 healthy persons (aged 1.5–90 years), 8 acromegalic patients, 4 acromegalic patients after enucleation of a GH-producing adenoma, 8 patients with partial hypopituitarism and in first morning urine and 12 h accumulated daytime urine of 4 healthy children and 3 children with growth failure. GH secretion is age-dependent, with high rates between ages 1 and 20 (ages 0–20 years: 10.4 ng/g creatinine±6.3 vs age > 20–75 years: 3.1 ng/g creatinine±1.6). An age-dependent increase in urinary GH is found in the pubertal age group (10 ng/24 h±6.8 vs prepubertal group: 4.6 ng/24 h±2.95). GH excretion of patients with acromegaly differs significantly from healthy subjects (72 ng/24 h±49 vs 3.9 ng/24 h±2.3). After a successful operation, acromegalic patients do not differ from the collective norm. Six of 8 patients with partial hypopituitarism show lower GH concentrations in urine than healthy subjects (1.2 ng/l±0.2 vs 2.6 ng/l±1.2), but daily GH output does not differ, since significantly more urine is then excreted. At night, healthy children secrete significantly more GH than during the day (night: 0.16 ng·kg−1·(12 h)−1±0.02 vs day: 0.07 ng·kg−1·(12 h)−1±0.03), while output is the same for GH-deficient children. Both groups have similar GH daytime output, but GH-deficient children have significantly less nocturnal output. In conclusion, measuring urinary GH excretion seems to be a suitable means of diagnosing GH hypo- and hypersecretion.

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Sally Tantawy, Lin Lin, Ilker Akkurt, Guntram Borck, Dietrich Klingmüller, Berthold P Hauffa, Heiko Krude, Heike Biebermann, John C Achermann and Birgit Köhler


Steroidogenic factor 1 (SF-1, NR5A1) is a key transcriptional regulator of many genes involved in the hypothalamic–pituitary–gonadal axis and mutations in NR5A1 can result in 46,XY disorders of sex development (DSD). Patients with this condition typically present with ambiguous genitalia, partial gonadal dysgenesis, and absent/rudimentary Müllerian structures. In these cases, testosterone is usually low in early infancy, indicating significantly impaired androgen synthesis. Further, Sertoli cell dysfunction is seen (low inhibin B, anti-Müllerian hormone). However, gonadal function at puberty in patients with NR5A1 mutations is unknown.

Subjects and methods

Clinical assessment, endocrine evaluation, and genetic analysis were performed in one female and one male with 46,XY DSD who showed spontaneous virilization during puberty. The female patient presented at adolescence with clitoral hypertrophy, whereas the male patient presented at birth with severe hypospadias and entered puberty spontaneously. Molecular analysis of NR5A1 was performed followed by in vitro functional analysis of the two novel mutations detected.


Testosterone levels were normal during puberty in both patients. Analysis of NR5A1 revealed two novel heterozygous missense mutations in the ligand-binding domain of SF-1 (patient 1: p.L376F; patient 2: p.G328V). The mutant proteins showed reduced transactivation of the CYP11A promoter in vitro.


Patients with 46,XY DSD and NR5A1 mutations can produce sufficient testosterone for spontaneous virilization during puberty. Phenotypic females (46,XY) with NR5A1 mutations can present with clitoromegaly at puberty, a phenotype similar to other partial defects of androgen synthesis or action. Testosterone production in 46,XY males with NR5A1 mutations can be sufficient for virilization at puberty. As progressive gonadal dysgenesis is likely, gonadal function should be monitored in adolescence and adulthood, and early sperm cryopreservation considered in male patients if possible.