Joachim Happ

Subcutaneous gonadotropin therapy in male patients with hypogonadotropic hypogonadism

OBJECTIVE The response to subcutaneous (SC) gonadotropin replacement therapy, using human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG) or hCG alone, was evaluated in male hypothalamic hypogonadism. DESIGN Sixteen patients with hypothalamic hypogonadism were treated with gonadotropins for induction of puberty and normalization of spermatogenesis. The results were analyzed retrospectively. SETTING The study was carried out in a clinical endocrinology department providing tertiary care and in private practices of endocrinology. PATIENTS Eight patients with idiopathic hypogonadotropic hypogonadism and eight patients with Kallmanns syndrome in prepubertal or early pubertal stages. INTERVENTIONS Human chorionic gonadotropin and hMG were administered SC in individual dosages. MAIN OUTCOME MEASURES Increase of serum testosterone (T), testicular volume, semen volume, and sperm count were evaluated. RESULTS Normalization of serum T and complete sexual maturation was achieved in all patients. Spermatogenesis was induced in all but two patients. Seven patients showed normal findings in semen volume and sperm count, and two patients had semen quality close to normal. In five patients sperm count remained less than 10 x 10(6)/mL. CONCLUSIONS The results obtained by SC gonadotropin replacement prove this mode of administration to be effective in stimulating steroidogenesis and spermatogenesis in hypogonadotropic males.

Pharmacodynamics and pharmacokinetics after subcutaneous and intramuscular injection of human chorionic gonadotropin

OBJECTIVE The pharmacokinetics and efficiency of human chorionic gonadotropin (hCG) after subcutaneous (SC) injection was to clarify in comparison with the intramuscular (IM) mode of administration. DESIGN In a prospective study, the pharmacokinetics of hCG and the response of serum testosterone (T), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) after an IM and SC injection of 5,000 IU hCG were evaluated up to 144 hours in two randomized groups. SETTING The study was carried out in a clinical dermatology department providing tertiary care. PARTICIPANTS Twenty-four healthy male volunteers with a mean age of 22.7 +/- 4.3 years were divided into two groups. INTERVENTIONS Human chorionic gonadotropin (5,000 IU) was injected IM or SC. MAIN OUTCOME MEASURE Serum concentration of /b-hCG, T, LH, and FSH were evaluated after IM and SC administration of hCG. Differences between the two groups were determined by t-test. RESULTS Compared with IM administration of hCG, peak serum drug concentration was significantly delayed (P = 0.01) and serum half-life was prolonged (P = 0.01) after SC injection; however, T, LH, and FSH responses were identical. CONCLUSIONS Subcutaneous application of 5,000 IU hCG is as effective as IM administration in terms of steroidogenesis.

Gonadotropin secretion in eugonadotropic human males and postmenopausal females under long-term application of a potent analog of gonadotropin-releasing hormone.

Long-acting analogs are of special interest in long-term treatment with gonadotropin-releasing hormone (GnRH). However, inhibitory effects of agonist analogs on gonadotropin secretion or on reproductive processes have been observed in rats as well as in human males. Since these inhibitory effects seem to be dose-related, we checked the findings for d-Leu 6 -des-Gly 10 -GnRH-ethylamide within the dose range proposed by us for treatment. In six eugonadotropic human males, a significant decrease of luteinizing hormone and follicle-stimulating hormone responsiveness to a standard dose of GnRH and significant decrease of testosterone basal secretion were observed after 2 and 4weeks of subcutaneous administration of 5μg of d-Leu 6 -des-Gly 10 -GnRH-ethylamide twice daily. In two eugonadotropic males, these effects could not be observed under pernasal administration of 50μg of the substance for 4weeks. In two postmenopausal women, subcutaneous long-term administration of 5μg of the substance produced a marked decrease of basal serum levels and decreased responsiveness of both gonadotropins within 2weeks of application. In one of the women, reversibility of the changes was tested 3months after treatment and could be confirmed. The findings are of great importance for therapeutic trials with d-Leu 6 -des-Gly 10 -GnRH-ethylamide and other GnRH analogs. They show that investigations are still necessary to find the optimal therapeutic regimens for this substance.

Treatment of Cryptorchidism with a Potent Analog of Gonadotropin-Releasing Hormone *

Pernasal therapy of cryptorchidism with D-Leu6-des-Gly10-gonadotropin-releasing hormone ethylamide (D-Leu6-des-Gly10-GnRH-EA), a potent, long-acting GnRH analog, was attempted. Eleven prepubertal cryptorchid boys received between 25 microgram once daily and 25 to 50 microgram twice daily for 5 to 12 weeks. Complete testicular descent was achieved in 4 of the 11 boys. GnRH tests (1.5 microgram/kg intravenously), conducted in six boys before treatment, after 4 weeks of treatment, and in 2 boys 3 months after treatment, did not reveal changes in gonadotropin secretion indicative of precocious puberty or of decreased hypophyseal sensitivity to GnRH. Antibodies to the GnRH analog or to GnRH could not be detected.

Endokrinologische Vorhersage der Therapieansprechbarkeit depressiver Patienten auf Lofepramin

In a pilot study of 15 depressive patients of the neurotic and endogenous type we could show that some neuroendocrinological parameters are apt to predict the thymoleptic efficacy of lofepramine. These parameters, which were measured with a simple global stimulation test (insulin hypoglycaemia combined with injection of TRH and LHRH), were as follows: high basal blood glucose; high hypoglycaemic blood glucose; high decrease of blood glucose in comparison to the basal level; low basal TSH; low increase of HGH and low increase of cortisol after hypoglycemia. A synopsis of these parameters allowed a correct classification of 14 out of 15 patients according to therapy response and therapy resistance.SummaryIn a pilot study of 15 depressive patients of the neurotic and endogenous type we could show that some neuroendocrinological parameters are apt to predict the thymoleptic efficacy of lofepramine. These parameters, which were measured with a simple global stimulation test (insulin hypoglycaemia combined with injection of TRH and LHRH), were as follows: high basal blood glucose; high hypoglycaemic blood glucose; high decrease of blood glucose in comparison to the basal level; low basal TSH; low increase of HGH and low increase of cortisol after hypoglycaemia. A synopsis of these parameters allowed a correct classification of 14 out of 15 patients according to therapy response and therapy resistance.ZusammenfassungIn einer Pilotuntersuchung an 15 nosologisch heterogenen vitalisiert depressiven Patienten konnte nachgewiesen werden, daß einzelne neuroendokrinologische Funktionsgrößen in der Lage sind, das Therapieansprechen dieser Patienten auf Lofepramin vorherzusagen. In einem technisch einfach durchzuführenden globalen Stimulationstest (Insulinhypoglykämie in Kombination mit TRH- und LHRH-Injektion) wurden die Basalwerte und die Stimulationswerte von Prokalin, TSH, LH, Cortisol, HGH und Blutzucker erfaßt. Die Therapieansprecher unterschieden sich von den Therapieversagern durch höheren Nüchternblutzucker, höheren Hypoglykämiewert, größeren Blutzuckerabfall in Bezug auf den Ausgangswert, niedrigeres basales TSH, kleineren Stimulationsanstieg des HGH und kleineren Stimulationsanstieg des Cortisol. Die Zusammenfassung dieser Funktionsgrößen in einen einzigen Indikationswert erlaubte es, 14 der 15 über 3 Wochen mit 210mg Lofepramin pro Tag behandelten Patienten zutreffend der Gruppe der Therapieansprecher bzw. Therapieversager zuzuordnen.

Gonadotropin and Testosterone Secretion in Normal Human Males After Stimulation With Gonadotropin-Releasing Hormone (Gnrh) or Potent Gnrh Analogs Using Different Modes of Application**Supported in part by Grant BE 601/3 from the Deutsche Forschungsgemeinschaft.

Gonadotropin-releasing hormone (GnRH) and some potent long-acting GnRH analogs, applied by different routes of administration, were tested in six healthy human males. The effects on gonadotropin secretion were compared with the one after intravenous (i.v.) bolus injection of 25 microgram of GnRH. The net increase of luteinizing hormone (deltaLH) in serum produced by 25 microgram of GnRH i.v. was matched by subcutaneous (s.c.) injection of 100 microgram of GnRH, dissolved in 20% gelatin or without gelatin; 5 microgram of D-Ser (TBU)6-des-Gly10-GnRH-ethylamide i.v.; 5 microgram of D-Leu6-des-Gly10-GnRH-ethylamide i.v.; and 50 microgram of D-Trp6-des Gly10-GnRH-ethylamide given pernasally (p.n.). D-Leu6-des-Gly10-GnRH-ethylamide, 50 microgram p.n., produced one-half such increase as did also multiple p.n. administrations of 200 microgram of GnRH every 2 hours. With 100 microgram of GnRH and all analogs, elevation of serum LH lasted for about 7 to 9 hours. The longest elevation was observed with GnRH dissolved in gelatin and with D-Ser (TBU)6-des-Gly10-GnRH-ethylamide, as reflected by the greatest areas under the curves of net increase. The longer the duration of the action of LH secretion, the higher was the observed increase in follicle-stimulating hormone (FSH). Correlation between effect on LH secretion and testosterone secretion was not found. By infusion of 1 microgram/kg/hour od D-Leu6-des-Gly10-GnRH-Ethylamide in two men over a period of 15 hours, a plateau of gonadotropin levels was reached within 7 to 9 hours. These plateau levels, especially of FSH, were higher than after bolus injection or p.n. application.