Central aspects of systemic oestradiol negative‐ and positive‐feedback on the reproductive neuroendocrine system

The central nervous system regulates fertility via the release of gonadotrophin‐releasing hormone (GnRH). This control revolves around the hypothalamic‐pituitary‐gonadal axis, which operates under traditional homeostatic feedback by sex steroids from the gonads in males and most of the time in females. An exception is the late follicular phase in females, when homeostatic feedback is suspended and a positive‐feedback response to oestradiol initiates the preovulatory surges of GnRH and luteinising hormone. Here, we briefly review the history of how mechanisms underlying central control of ovulation by circulating steroids have been studied, discuss the relative merit of different model systems and integrate some of the more recent findings in this area into an overall picture of how this phenomenon occurs.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153639/1/jne12724.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153639/2/jne12724_am.pd

Live view of gonadotropin-releasing hormone containing neuron migration

Neurons that synthesize GnRH control the reproductive axis and migrate over long distances and through different environments during development. Prior studies provided strong clues for the types of molecules encountered and movements expected along the migratory route. However, our studies provide the first real-time views of the behavior of GnRH neurons in the context of an in vitro preparation that maintains conditions comparable to those in vivo. The live views provide direct evidence of the changing behavior of GnRH neurons in their different environments, showing that GnRH neurons move with greater frequency and with more changes in direction after they enter the brain. Perturbations of guiding fibers distal to moving GnRH neurons in the nasal compartment influenced movement without detectable changes in the fibers in the immediate vicinity of moving GnRH neurons. This suggests that the use of fibers by GnRH neurons for guidance may entail selective signaling in addition to mechanical guidance. These studies establish a model to evaluate the influences of specific molecules that are important for their migration

Targeted expression of a dominant-negative fibroblast growth factor (FGF) receptor in gonadotropin-releasing hormone (GnRH) neurons reduces FGF responsiveness and the size of GnRH neuronal population

Increasing evidence suggests that fibroblast growth factors (FGFs) are neurotrophic in GnRH neurons. However, the extent to which FGFs are involved in establishing a functional GnRH system in the whole organism has not been investigated. In this study, transgenic mice with the expression of a dominant-negative FGF receptor mutant (FGFRm) targeted to GnRH neurons were generated to examine the consequence of disrupted FGF signaling on the formation of the GnRH system. To first test the effectiveness of this strategy, GT1 cells, a GnRH neuronal cell line, were stably transfected with FGFRm. The transfected cells showed attenuated neurite outgrowth, diminished FGF-2 responsiveness in a cell survival assay, and blunted activation of the signaling pathway in response to FGF-2. Transgenic mice expressing FGFRm in a GnRH neuron-specific manner exhibited a 30% reduction in GnRH neuron number, but the anatomical distribution of GnRH neurons was unaltered. Although these mice were initially fertile, they displayed several reproductive defects, including delayed puberty, reduced litter size, and early reproductive senescence. Overall, our results are the first to show, at the level of the organism, that FGFs are one of the important components involved in the formation and maintenance of the GnRH system

The neuroendocrine signal for ovulation: Definition and regulation.

Ovulation is caused by a surge of luteinizing hormone (LH) release from the pituitary. The nature and regulation of the neuroendocrine signal for ovulation were defined in sheep. First, the neuroendocrine factor regulating reproduction, gonadotropin-releasing hormone (GnRH), was measured in pituitary portal blood during the preovulatory period. Low frequency GnRH pulses occurred during the luteal phase. Pulse frequency increased and amplitude decreased during the follicular phase. A robust GnRH surge began coincident with the preovulatory LH surge; the GnRH surge outlasted that of LH by several hours. Whether estradiol elicits these changes in GnRH release was investigated using a physiologic model for the follicular phase, in which estradiol was manipulated (removed or increased to peak follicular phase level) 16 hours after progesterone removal. Following estradiol removal, GnRH and LH were secreted in coincident bursts. Estradiol had a biphasic effect on GnRH release: first, it suppressed pulsatile GnRH release, second, it induced a GnRH surge. These results support the hypothesis estradiol regulates GnRH release, and that this central action is part of the mechanism by which estradiol induces the LH surge. Two studies were performed to examine the mechanism by which estradiol evokes the GnRH surge. Very frequent samples of pituitary portal blood were obtained to determine the moment-to-moment GnRH-release pattern during the surge. Estradiol shifted to pattern of GnRH release, permitting continuous elevation in portal blood, possibly by desynchronizing GnRH neurons, accelerating pulses beyond resolution of the technique, or recruiting an asynchronous surge-specific population of GnRH neurons. The latter was investigated in the final study in which active cells were localized by immunocytochemical staining for cFos--a marker of neural activity. A striking induction of cFos expression occurred in GnRH neurons during the surge. These cells, however, were not located in an anatomically distinct region, precluding identification of a surge-specific population of GnRH neurons. A surge-specific population of non-GnRH-positive cells was identified, raising the possibility these cells convey the positive feedback signal to the GnRH neurons. We conclude estradiol activates several neural populations and thereby induces the GnRH surge, which is a prerequisite neuroendocrine signal for ovulation in sheep.Ph.D.PhysiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/105576/1/9135655.pdfDescription of 9135655.pdf : Restricted to UM users only

Gonadotropin‐releasing hormone (GnRH) measurements in pituitary portal blood: a history

Much about the neuroendocrine control of reproduction is inferred from changes in the episodic release of luteinizing hormone (LH), as measured in samples of peripheral blood. This, however, assumes that LH precisely mirrors gonadotropin-releasing hormone (GnRH) release from the hypothalamus. As GnRH is not measurable in peripheral blood, characterization of the relationship between these two hormones required the simultaneous measurement of GnRH and LH in pituitary portal and peripheral blood, respectively. Here, we review the history of why and how portal blood collection was developed, the aspects of the true output of the central component of the hypothalamo-pituitary-gonadal axis that this methodology helped clarify, and conditions under which the pituitary fails to serve as an adequate bioassay for the release pattern of GnRH

Androgen Receptor Antagonism and an Insulin Sensitizer Block the Advancement of Vaginal Opening by High-Fat Diet in Mice1

Reduced hypothalamic sensitivity to steroid negative feedback may contribute to the onset of puberty. In high fat-fed rodents, the timing of vaginal opening (VO) is advanced, suggesting that puberty begins earlier. Because obesity can increase androgens, which interfere with normal steroid feedback in adult females, we hypothesized that androgens reduce hypothalamic sensitivity to negative feedback during puberty and that blocking androgen action would prevent advanced VO in high fat-fed mice. Age at VO was examined in mice fed high-fat or low-fat diets from weaning and treated with the androgen receptor antagonist flutamide or vehicle (controls). VO was advanced in high-fat vs. low-fat controls, and flutamide blocked this advancement. VO was also delayed in low fat-fed flutamide-treated females, suggesting involvement of androgens in the timing of normal puberty. We next investigated if high-fat diet-induced insulin resistance contributes to early VO, as elevated insulin can stimulate androgen production. VO was examined in mice on either diet treated with the insulin sensitizer metformin. Metformin blocked high-fat advancement of VO but did not alter the timing of VO in low fat-fed mice. Insulin was elevated in high fat-fed females that had undergone VO compared with age-matched low fat-fed or metformin-treated animals on either diet that had not undergone VO. Together, these data suggest a model in which metabolic changes induced by high-fat diet, including transient increased circulating insulin, act in part by increasing androgen action to influence the timing of puberty in females