Impact of endocrine disruptors on neurons expressing GnRH or kisspeptin and pituitary gonadotropin

Reproduction is a complex process that is controlled centrally via a network of hypothalamic neurons to modulate the pulsatile release of gonadotropin-releasing hormone (GnRH) and subsequently pituitary gonadotropins. The gonadotropins, luteinizing hormone and follicle stimulating hormone, drive gametogenesis and hormone production from the gonads. The hypothalamic-pituitary exchange is controlled by gonadal steroids through negative and positive feedback mechanisms via steroid receptors. Due to the expression of these receptors, GnRH neurons, the hypothalamic neurons that control them, and pituitary gonadotropes are sensitive to exogenous compounds that interact with steroid and nuclear receptors or alter hormone production and metabolism. The compounds, called endocrine disrupting compounds (EDCs), are ubiquitous and persistent in human environments and could bioaccumulate in the body. EDCs include plasticizers (like bisphenol A), dioxin, polychlorinated biphenyls (PCBs), organochlorine pesticides, flame retardants, and perfluorinated akyl substances (PFAS). Numerous studies have reported that perinatal, juvenile, or adult exposure to these EDCs, primarily in rats, disrupt the hypothalamic control of pituitary gonadotropin production leading to disruption of gonadal steroid production and estrous cyclicity. The purpose of this review is to evaluate these studies primarily focusing on GnRH and kisspeptin neurons and anterior pituitary gonadotropins and to discuss the need for deeper investigations into the hypothalamic-pituitary-gonadal axis.

The Role of Gonadotropin-Releasing Hormone (GnRH) in Endometrial Cancer

Endometrial cancer (EC) is one of the most common gynecological malignancies. Gonadotropin releasing hormone (GnRH) is a decapeptide first described to be secreted by the hypothalamus to regulate pituitary gonadotropin secretion. In this systematic review, we analyze and summarize the data indicating that most EC express GnRH and its receptor (GnRH-R) as part of an autocrine system regulating proliferation, the cell cycle, and apoptosis. We analyze the available data on the expression and function of GnRH-II, its putative receptor, and its signal transduction. GnRH-I and GnRH-II agonists, and antagonists as well as cytotoxic GnRH-I analogs, have been shown to inhibit proliferation and to induce apoptosis in human EC cell lines in pre-clinical models. Treatment with conventional doses of GnRH-agonists that suppress pituitary gonadotropin secretion and ovarian estrogen production has become part of fertility preserving therapy of early EC or its pre-cancer (atypical endometrial hyperplasia). Conventional doses of GnRH-agonists had marginal activity in advanced or recurrent EC. Higher doses or more potent analogs including GnRH-II antagonists have not yet been used clinically. The cytotoxic GnRH-analog Zoptarelin Doxorubicin has shown encouraging activity in a phase II trial in patients with advanced or recurrent EC, which expressed GnRH-R. In a phase III trial in patients with EC of unknown GnRH-R expression, the cytotoxic GnRH doxorubicin conjugate was not superior to free doxorubicin. Further well-designed clinical trials exploiting the GnRH-system in EC might be useful.