Pituitary desensitization and the regulation of pituitary gonadotropin-releasing hormone (GnRH) receptors following chronic administration of a superactive GnRH analog and testosterone

doi:10.1016/0024-3205(82)90257-0

Life Sciences

Volume 30, Issue 26, 28 June 1982, Pages 2301-2308

https://doi.org/10.1016/0024-3205(82)90257-0 Get rights and content

Abstract

We recently demonstrated that chronic daily administration of a superactive GnRH analog to intact rats resulted in an initial stimulation of serum LH levels with a subsequent return of LH levels to baseline at a time when testosterone levels were marked decreased. These data demonstrated pituatary desensitization following chronic GnRH analog treatment. Administration of GnRH analog with a dose of testosterone which did not markedly lower serum LH levels when administered alone prevented the stimulation of LH secretion by analog. The present studies were undertaken to determine the effects of GnRH analog and testosterone administration on the regulation of pituitary GnRH receptors. Pituitary GnRH receptor binding was increased by analog treatment alone at 20 days and returned to control levels at 40 and 60 days of treatment in parallel to the observed changes in serum LH, demonstrating that one mechanism by which chronic GnRH analog treatment leads to pituitary desensitization is down-regulation of pituitary GnRH receptors. Testosterone administration alone decreased pituitary GnRH receptor binding. Combined GnRH analog and testosterone administration prevented the increase in pituitary GnRH receptors observed with analog administration alone. These studies demonstrate that changes in pituitary GnRH receptor binding correlate with changes in serum LH and that the stimulatory effects of analog administration on LH are sensitive to inhibition by small doses of testosterone.

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Citation Excerpt :
Indeed, some drug therapies have been developed based on this phenomenon. In the treatment of endometriosis, for example, gonadotropin-releasing hormone (GnRH) agonist suppresses downstream hormone production through downregulation of its receptor via continuous administration of large amounts of ligand [9,17,18]. Also, GLP-1R is a G-protein-coupled receptor (GPCR).
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Seven-week-old male db/db and db/m mice were given either Dula (0.6 mg/kg × 2/week) or a control vehicle (CTL) for 17 weeks. Various metabolic parameters, such as glucose-stimulated insulin secretion (GSIS), insulin and TG content in islets, were evaluated after the intervention. β-cell-related gene expression was also analyzed by real-time RT-PCR.
In db/m mice, GLP-1R expression in β-cells did not decrease, not even after long-term administration of Dula, compared with control mice, while GLP-1R expression in 24-week-old db/db mice treated with Dula was augmented, rather than downregulated, compared with 24-week-old CTL db/db mice. This was probably due to improved glycaemic control. In db/db mice treated with Dula, food intake and blood glucose levels were significantly decreased up to 24 weeks of age compared with CTL db/db mice, and their expression levels of various β-cell-related genes, insulin content and GSIS were also enhanced. In contrast, oxidative and endoplasmic reticulum stress, inflammation, fibrosis and apoptosis were suppressed with Dula treatment.
Dula exerts beneficial effects on glycaemic control and has long-lasting protective effects on pancreatic β-cells. GLP-1R expression levels were not reduced at all in non-diabetic as well as diabetic mice despite long-term dulaglutide exposure.
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The hypothalamic-pituitary-testis axis regulates androgen production and spermatogenesis. Neurons in the hypothalamus secrete gonadotropin-releasing hormone (GnRH), which stimulates gonadotropin secretion by the pituitary. Luteinizing hormone release leads to increased testosterone production in the Leydig cells. Follicle stimulating hormone leads to increased production of regulatory proteins by the Sertoli cells and stimulates spermatogenesis. GnRH release is mediated by a hypothalamic neuronal network involving kisspeptin. Steroidogenesis involves multiple enzymes that catalyze the conversion of cholesterol to testosterone. Testosterone has effects on multiple organ systems, and hypogonadism can have various effects, depending on the patient’s stage of development.
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Citation Excerpt :
The sequencing of the hypothalamic gonadotropin-releasing hormone (GnRH) was followed by the development of synthetic agonists with prolonged half-life and potency [3]. Chronic GnRH-agonist administration results in suppression of luteinising hormone (LH) from the anterior pituitary gland and, consequently, results in an inhibition of testosterone secretion through a down-regulation of the GnRH receptors in the pituitary [4–6]. However, the GnRH agonists initially activate the receptors, resulting in a surge in LH and testosterone as well as a delayed reduction in prostate-specific antigen (PSA) levels for 2–3 wk before androgen deprivation is achieved [7,8].
Degarelix is a gonadotropin-releasing hormone antagonist (GnRH receptor blocker) with immediate onset of action, suppressing gonadotropins, testosterone, and prostate-specific antigen (PSA) in prostate cancer.
To determine the efficacy and safety of initial doses of 200 mg or 240 mg of degarelix and thereafter monthly subcutaneous maintenance doses of 80 mg, 120 mg, or 160 mg of degarelix for the treatment of prostate cancer.
The 1-yr study was of open-label, randomised design and involved 187 patients (range: 52–93 yr, median: 72 yr) with histologically confirmed adenocarcinoma of the prostate and a baseline PSA >2 ng/ml.
At baseline, median serum testosterone was 4.13 ng/ml (range: P25–P75, 3.37–5.19 ng/ml) and PSA was 27.6 ng/ml (range: P25–P75, 11.9–55.0 ng/ml). On day 3, 88% and 92% of patients in the groups to whom 200-mg and 240-mg initial doses of degarelix were administered, respectively, had testosterone levels ≤0.5 ng/ml. For patients with testosterone levels ≤0.5 ng/ml at 1 mo, the testosterone levels remained ≤0.5 ng/ml until the end of the study in 100% of the patients treated with a monthly maintenance dosage of 160 mg of degarelix. No evidence of testosterone surge was detected. PSA decreased by 97–98% after 1 yr and the median time to 90% reduction in PSA was 8 wk in all but one patient (from the 80-mg dosage treatment group at the intial 200-mg dose of degarelix). Thirteen patients (6%) withdrew from the study due to adverse events, largely related to androgen deprivation.
Degarelix treatment for 1 yr resulted in a fast, profound, and sustained suppression of testosterone and PSA, with no evidence of testosterone surge. Degarelix was well tolerated.

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Pituitary desensitization and the regulation of pituitary gonadotropin-releasing hormone (GnRH) receptors following chronic administration of a superactive GnRH analog and testosterone

Abstract

J. Biol. Chem.

Biochem. Biophys. Res. Comm.

Mol. Cell Endocrinol.

Acta. Endocrinol. (Copenhagen)

Science

Endocrinology

Endocrinology

Clin. Chem.