Background Injectable luteinizing hormone–releasing hormone agonists (e.g., leuprolide) are the standard agents for achieving androgen deprivation for prostate cancer despite the initial t...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa2004325?articleTools=true

Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer

Evolution of GnRH: diving deeper.

Wildlife, free-ranging and captive, poses and causes serious population problems not unlike those encountered with human overpopulation. Traditional lethal control programs, however, are not always legal, wise, safe, or publicly acceptable; thus, alternative approaches are necessary. Immunocontraception of free-ranging wildlife has reached the management level, with success across a large variety of species. Thus far, the immunocontraceptive research and management applications emphasis have been centered on porcine zona pellucida and gonadotropin-releasing hormone vaccines. Contraceptive success has been achieved in more than 85 different wildlife species, at the level of both the individual animal and the population. At the population management level with free-ranging species, the primary focus has been on wild horses, urban deer, bison, and African elephants. The challenges in the development and application of vaccine-based wildlife contraceptives are diverse and include differences in efficacy across species, safety of vaccines during pregnancy, the development of novel delivery systems for wild and wary free-ranging animals, and the constraints of certain non-contraceptive effects, such as effects on behavior. Beyond the constraints imposed by the public and a host of regulatory concerns, there exists a real limitation for funding of well-designed programs that apply this type of fertility control.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-0897.2011.01003.x

Contraceptive vaccines for wildlife: a review.

GnRH signaling regulates reproductive physiology in vertebrates via the hypothalamic-pituitary-gonadal axis. In addition, GnRH signaling has been postulated to act on the brain. However, elucidating its functional role in the central nervous system has been hampered because of the difficulty in identifying direct GnRH signaling targets in live brain tissue. Here we used a binary genetic strategy to visualize GnRH receptor (GnRHR) neurons in the mouse brain and started to characterize these cells. First, we expressed different fluorescent proteins in GnRHR neurons and mapped their precise distribution throughout the brain. Remarkably, neuronal GnRHR expression was only initiated after postnatal day 16, suggesting peri- and postpubertal functions of GnRH signaling in this organ. GnRHR neurons were found in different brain areas. Many GnRHR neurons were identified in areas influencing sexual behaviors. Furthermore, GnRHR neurons were detected in brain areas that process olfactory and pheromonal cues, revealing one efferent pathway by which the neuroendocrine hypothalamus may influence the sensitivity towards chemosensory cues. Using confocal Ca(2+) imaging in brain slices, we show that GnRHR neurons respond reproducibly to extracellular application of GnRH or its analog [D-TRP(6)]-LH-RH, indicating that these neurons express functional GnRHR. Interestingly, the duration and shape of the Ca(2+) responses were similar within and different between brain areas, suggesting that GnRH signaling may differentially influence brain functions to affect reproductive success. Our new mouse model sets the stage to analyze the next level of GnRH signaling in reproductive physiology and behavior.

/pdf/genetic-identification-of-gnrh-receptor-neurons-a-new-model-24bl4k9ked.pdf

Genetic identification of GnRH receptor neurons: a new model for studying neural circuits underlying reproductive physiology in the mouse brain.

Gonadotrophin-releasing hormone (GnRH) is a hypothalamic decapeptide with an undisputed role as a primary regulator of gonadal function. It exerts this regulation by controlling the release of gonadotrophins. However, it is becoming apparent that GnRH may have a variety of other vital roles in normal physiology. A reconsideration of the potential widespread action that this traditional reproductive hormone exerts may lead to the generation of novel therapies and provide insight into seemingly incongruent outcomes from current treatments using GnRH analogues to combat diseases such as prostate cancer.

Effects of gonadotrophin-releasing hormone outside the hypothalamic-pituitary-reproductive axis.

Immunoreactive GnRH type I receptors in the mouse and sheep brain.

Increasing evidence suggests that multihormonal cells in the pituitary gland may be more commonplace than previously thought This has forced us to reconsider our classical view of cell populations in the pituitary gland Studies so far have focused almost exclusively on the rat, and there is a dearth of information on other species Our first objective was to determine whether a subpopulation of gonadotropes also express somatotropin in the ewe, as reported in the rat In addition, we sought to determine whether gonadotropes express any of the other known pituitary hormones Finally, we investigated whether the stage of the estrous cycle influenced the occurrence of these pluripotential gonadotropes We found that a small population of βLH-immunoreactive cells also expresses immunoreactive GH, prolactin and TSH No gonadotropes colocalized with ACTH Significantly (P<0001) more gonadotropes expressed GH during the luteal (107±04%) than the late follicular (54±03%) phase but there was no difference between the luteal and follicular phases in the proportion of gonadotropes expressing prolactin (follicular: 57±07%; luteal: 55±06%) or TSH (follicular: 31±07%; luteal: 42±05%) Similarly, there was a significant (P<005) difference in the proportion of GH-immunoreactive cells expressing βLH immunoreactivity in the luteal (59±03%) and follicular (34±05%) phases but no difference in the proportion of prolactin- (follicular: 22±07%; luteal: 20±08%) or TSH-immunoreactive cells (follicular: 96±37%; luteal: 108±29%) expressing βLH The specific function of these multihormonal gonadotropes in sheep remains to be determined

Mallory Mignot

Papers

Effects of gonadotrophin-releasing hormone outside the hypothalamic-pituitary-reproductive axis.

Immunoreactive GnRH type I receptors in the mouse and sheep brain.

Colocalization of GH, TSH and prolactin, but not ACTH, with βLH-immunoreactivity: evidence for pluripotential cells in the ovine pituitary