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The objective of this study was to examine the changes in basal plasma gonadotropin, α-subunit, sex steroid, and prolactin levels and the prolactin and luteinizing hormone (LH) secretion pattern before, during and 161 days after treatment with a depot preparation of D-Trp-6-GnRH in young men. Gonadotropins, α-subunit, sex steroids, and prolactin were measured in pooled plasma samples. Additionally, before treatment, several times during its course and on day 161 after treatment, blood samples were drawn for 8h every 15 min for prolactin and LH measurements. After initial stimulation of the pituitary, administration of a depot preparation of D-Trp-6-GnRH resulted in a constant decrease in gonadotropin and sex steroid concentrations with LH and testosterone concentrations remaining within the limits of prepubertal levels from days 16 to 48. α-Subunit concentrations (0.4 ± 0.09 IU/l; mean ± SE) increased after application of D-Trp-6-GnRH, and remained elevated until day 48. Basal prolactin levels (3.5 ± 0.25 μg/l) did not change significantly during treatment but afterwards increased consistently with maximal levels at day 141 (15.3 ± 3.8 μg/l); they had decreased at day 161 to 10.3 ± 1.8 μg/l which is significantly higher than before treatment (p D-Trp-6-GnRH to 6 young men, there was a rise in basal prolactin levels and prolactin pulse amplitude as a long-term side effect of treatment, with maximal levels at 141 days after application.

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

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

For several years, it has been possible to determine renin by a direct RIA. In the present study, plasma active renin concentration (PRC) was related to plasma renin activity (PRA) and aldosterone as a function of a standardized posture test. Using PRC, our target was to define the shortest necessary test duration. The three parameters were examined in 10 healthy male subjects (22-34 years old). Salt balance was determined in 24-hour urine, and plasma potassium and sodium were measured. Volunteers were hospitalized for 1 night, and at 8 a.m. the next morning they were subjected to the following postural changes: 3 h active orthostasis and 3 h recumbency. Frequent blood samples were taken. Orthostasis induced a significant rise in PRC, PRA and aldosterone already after 15 min. PRC and PRA reached a maximum level after 90 min of orthostasis and remained relatively stable, while aldosterone reached its highest level already after 30 min and then gradually decreased. Significant correlations were found between PRA and PRC (p0.001), between PRC and aldosterone (p0.001), and between PRA and aldosterone (p0.001). The PRC/PRA ratio changed during the course of the test, especially in supine subjects. When subjects returned to the supine position, all the parameters measured began a continual decrease. There were no significant changes in serum potassium and sodium levels throughout the duration of the test.(ABSTRACT TRUNCATED AT 250 WORDS)