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Predominant suppression of follicle-stimulating hormone ?-immunoreactivity after long-term treatment of intact and castrate adult male rats with the gonadotrophin-releasing hormone agonist deslorelin.

ABSTRACT: Gonadotrophin-releasing hormone (GnRH) agonists are used to treat gonadal steroid-dependent disorders in humans and to contracept animals. These agonists are considered to work by desensitising gonadotrophs to GnRH, thereby suppressing follicle-stimulating hormone (FSH) and luteinising hormone (LH) secretion. It is not known whether changes occur in the cellular composition of the pituitary gland after chronic GnRH agonist exposure. Adult male Sprague-Dawley rats were treated with a sham, deslorelin, or deslorelin plus testosterone implant for 41.0 ± 0.6 days. In a second experiment, rats were castrated and treated with deslorelin and/or testosterone. Pituitary sections were labelled immunocytochemically for FSH? and LH?, or gonadotrophin ? subunit (?GSU). Deslorelin suppressed testis weight by two-thirds and reduced plasma FSH and LH in intact rats. Deslorelin decreased the percentage of gonadotrophs, although the effect was specific to the FSH?-immunoreactive (-ir) cells. Testosterone did not reverse the deslorelin-induced reduction in the overall gonadotroph population. However, in the presence of testosterone, the proportion of gonadotrophs that was FSH?-ir increased in the remaining gonadotrophs. There was no effect of treatment on the total LH?-ir cell population, although the loss of FSH? in bi-hormonal cells increased the proportion of mono-hormonal LH?-ir gonadotrophs. The castration-induced plasma LH and FSH increases were suppressed by deslorelin, testosterone or both. Castration increased both LH-ir and FSH-ir without increasing the overall gonadotroph population, thus increasing the proportion of bi-hormonal cells. Deslorelin suppressed these increases. Testosterone increased FSH-ir in deslorelin-treated castrate rats. Deslorelin did not affect ?GSU immunoreactivity, suggesting that the gonadotroph population per se is not eliminated by deslorelin, although the ability of gonadotrophs to synthesise FSH? is compromised. We hypothesise that the FSH dominant suppression may be central to the long-term contraceptive efficacy of deslorelin in the male.

SUBMITTER: Smith AW

PROVIDER: S-EPMC5559102 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Predominant suppression of follicle-stimulating hormone β-immunoreactivity after long-term treatment of intact and castrate adult male rats with the gonadotrophin-releasing hormone agonist deslorelin.

Smith A W AW Asa C S CS Edwards B S BS Murdoch W J WJ Skinner D C DC

Journal of neuroendocrinology 20120501 5

Gonadotrophin-releasing hormone (GnRH) agonists are used to treat gonadal steroid-dependent disorders in humans and to contracept animals. These agonists are considered to work by desensitising gonadotrophs to GnRH, thereby suppressing follicle-stimulating hormone (FSH) and luteinising hormone (LH) secretion. It is not known whether changes occur in the cellular composition of the pituitary gland after chronic GnRH agonist exposure. Adult male Sprague-Dawley rats were treated with a sham, deslor ...[more]

PMID: 22172059

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Project description:BackgroundGonadotrophin releasing hormone (GnRH) agonists and antagonists reduce testosterone levels for the treatment of advanced and metastatic prostate cancer. Androgen deprivation therapy (ADT) is associated with increased risk of cardiovascular (CV) events and CV disease (CVD), especially in patients with preexisting CVD treated with GnRH agonists. Here, we investigated the potential relationship between serum levels of the cardiac biomarkers N-terminal pro-B-type natriuretic peptide (NTproBNP), D-dimer, C-reactive protein (CRP), and high-sensitivity troponin (hsTn) and the risk of new CV events in prostate cancer patients with a history of CVD receiving a GnRH agonist or antagonist.MethodsPost-hoc analyses were performed of a phase II randomized study that prospectively assessed CV events in patients with prostate cancer and preexisting CVD, receiving GnRH agonist or antagonist. Cox proportional hazards models were used to determine whether the selected biomarkers had any predictive effect on CV events at baseline and across a 12-month treatment period.ResultsBaseline and disease characteristics of the 80 patients who took part in the study were well balanced between treatment arms. Ischemic heart disease (66%) and myocardial infarction (37%) were the most common prior CVD and the majority (92%) of patients received CV medication. We found that high levels of NTproBNP (p = 0.008), and hsTn (p = 0.004) at baseline were associated with the development of new CV events in the GnRH agonist group but not in the antagonist. In addition, a nonsignificant trend was observed between higher levels of NTproBNP over time and the development of new CV events in the GnRH agonist group.ConclusionsThe use of cardiac biomarkers may be worthy of further study as tools in the prediction of CV risk in prostate cancer patients receiving ADT. Analysis was limited by the small sample size; larger studies are required to validate biomarker use to predict CV events among patients receiving ADT.

Dataset Information

Predominant suppression of follicle-stimulating hormone ?-immunoreactivity after long-term treatment of intact and castrate adult male rats with the gonadotrophin-releasing hormone agonist deslorelin.

Publications

Predominant suppression of follicle-stimulating hormone β-immunoreactivity after long-term treatment of intact and castrate adult male rats with the gonadotrophin-releasing hormone agonist deslorelin.

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