Gonadotropin-releasing hormone and its receptor in normal and malignant cells

Abstract

Gonadotropin-releasing hormone (GnRH) is the hypothalamic factor that mediates reproductive competence. Intermittent GnRH secretion from the hypothalamus acts upon its receptor in the anterior pituitary to regulate the production and release of the gonadotropins, LH and FSH. LH and FSH then stimulate sex steroid hormone synthesis and gametogenesis in the gonads to ensure reproductive competence. The pituitary requires pulsatile stimulation by GnRH to synthesize and release the gonadotropins LH and FSH. Clinically, native GnRH is used in a pump delivery system to create an episodic delivery pattern to restore hormonal defects in patients with hypogonadotropic hypogonadism. Agonists of GnRH are delivered in a continuous mode to turn off reproductive function by inhibiting gonadotropin production, thus lowering sex steroid production, resulting in medical castration. They have been used in endocrine disorders such as precocious puberty, endometriosis and leiomyomata, but are also studied extensively in hormone-dependent malignancies. The detection of GnRH and its receptor in other tissues, including the breast, ovary, endometrium, placenta and prostate suggested that GnRH agonists and antagonists may also have direct actions at peripheral targets. This paper reviews the current data concerning differential control of GnRH and GnRH receptor expression and signaling in the hypothalamic-pituitary axis and extrapituitary tissues. Using these data as a backdrop, we then review the literature about the action of GnRH in cancer cells, the utility of GnRH analogs in various malignancies and then update the research in novel therapies targeted to the GnRH receptor in cancer cells to promote anti-proliferative effects and control of tumor burden.

GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism

“…Indeed, GNRH1 expression has been described in a number of other tissues, including prostate, retina, and developing teeth (25,30,31), but the fact that patient 1 exhibits no obvious phenotypes aside from IHH argues against a critical function for GNRH1 in these tissues. GnRH is also expressed in the testes (32), and at face value patient 1's subnormal response to hCG stimulation might suggest a direct role for GnRH in the testes.…”

Diversity of actions of GnRHs mediated by ligand-induced selective signaling

“…The functions for GnRH in juvenile to adult reproductive maturation and in the maintenance of adult reproductive tissues via autocrine-paracrine mechanisms are both common themes [15,41,68]. The manner in which local GnRH action modulates the physiology and patho-physiology of reproductive tissues is a focus of investigation [23,48,139]. More specialized roles in blastocyst implantation, physiological changes occurring during pregnancy, including modulation of the cellular immune system, and influences on reproductive and parental behavior are also regarded as possibilities in certain mammalian species [15,19,22,40,59,61].…”

“…These include various regions of the central and peripheral nervous system, in most reproductive tissues, in many non-reproductive tissues, in immune cells and also in many cancer cells [21,48].…”

Inhibition of Ovarian Cancer Growth by a Tumor-Targeting Peptide That Binds Eukaryotic Translation Initiation Factor 4E

“…This hypothalamus-derived decapeptide stimulates the pituitary gland to produce gonadotropins that control gonadal steroidogenesis (12). GnRH-RI is also widely expressed in breast, endometrial, and prostate cancers (13). GnRH agonists are used to treat endometriosis, uterine fibroids, infertility, precocious puberty, and prostate cancer (12,13).…”