Gonadotrophin-releasing hormone (GnRH) stimulates the production of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The concentration of these hormones over time in females regulates the menstrual cycle. GnRH expressing neurons (GEN) are scattered throughout the forebrain and hypothalamus and secrete into ducts leading to the pituitary gland, causing the
secretion of FSH and LH into the bloodstream. Ca+2 concentrations oscillate in time, changing the electric membrane potential of the GnRH neurons, GEN. The period of the oscillation is only a few seconds in duration. The mechanism controlling the oscillating membrane potential is unknown, but during maturation the frequency of the oscillations of the Ca+2 concentration in the GEN
increases.
A. Explain how the absence of direct contact among the GnRH neurons and the coordinated release of FSH and LH suggest another timing mechanism. An association of high concentrations of anti-Mullerian hormone (AMH) and elevated LH levels among women with a common reproductive disorder called polycystic ovary syndrome (PCOS) caused investigators to study the effects of AMH on membrane potentials of GnRH expressing neurons. The researchers (Cimino et al., Nature Communications, 7, 2016) found that very small concentrations of AMH initiated oscillations.
B. The graph illustrates the time dependence of LH and estrogen in the blood of a female. A goal of research in human reproductive physiology is to construct a model that accounts for the spike in luteinizing hormone at approximately 14 days. Predict how a positive feedback loop involving the release of a hormone such as AMH could be used to account for this response. Explain why estrogen is probably not a good candidate for use in this model. Figure 28.21 FSH and LH inhibit production of GnRH. Exposure of ovarian follicles to high levels of FSH and LH causes the follicle to rupture, releasing an oocyte to the oviduct. Birth control drugs suppress the LH surge by maintaining a constant blood concentration of progesterone (PG). After 40 years of use, the mechanism of suppression is still unknown. However, we do know that during pregnancy progesterone levels remain elevated and that cells in both the pituitary gland and GnRH expressing neurons (GEN) have progesterone nuclear receptors (PGR) that act as transcription factors to either i) inhibit production of GnRH possibly by blocking transcription of GNRH1, the gene coding for GnRH, or ii) inhibit production of LH by blocking transcription in the GnRH neurons of the gene, LH1, coding for LH.
C. Construct two alternative explanations of the role of progesterone as a birth control drug. Your explanation can be in the form of descriptions or in terms of diagrams involving the key molecular components PG, PGR, LH, LH1, GEN, GnRH, and GnRH1. An endocrine disruptor is a molecule with a structure that mimics a hormone and can interfere with regulation. The chemical bis-phenol A (BPA) has been used for many years in the production of plastics and is now widespread. BPA mimics estrogen. BPA is present in most humans at the concentration of 5 micrograms per kilogram of body weight. Whether or not that concentration is harmful is uncertain. In a study of Ca+2 oscillations in GnRH expressing neurons, Klenke and co-workers (Endocrinology, 157, 2016) presented evidence that BPA switches off oscillations even at these very low concentrations. This suggests a mechanism for the results from an earlier investigation in which female rats were fed low and high levels of estrogen (EE) and BPA during pregnancy. Measurements were made of the levels of expression of an estrogen nuclear receptor in the hypothalamus of the pups just after birth (Cao et al., Toxicological Sciences, 133, 2013). Their data are shown in the graph below. Figure 28.22 Using the data, the graph at the top compares expression in a do-nothing control (NaĂŻve) and a control (Vehicle) in which a feeding tube is used to deliver nutrients during pregnancy. The graph at the bottom shows expression levels in pups born to female rats with four different treatments of estrogen (EE) and bis-phenol A (BPA). Chapter 28 | The Endocrine System 1255
D. Compared to the naĂŻve control where homeostasis is not disrupted, qualitatively analyze these data for the disruption of the endocrine system in offspring of a female rat exposed to both physical and chemical stresses.
E. In female sheep, the estrus cycle is coordinated by the length of the day and does not begin until day length shortens. The gestation period of sheep is roughly 150
days.
• Predict the effect on fitness of this control of gene expression by an external stimulus.
• The ram effect is a livestock management practice in Australia to induce ovulation by exposing an anestrus (when the estrus cycle is inactive) ewe to a ram. Compare this phenomenon with the results of delivering nutrients and hormones using a feeding tube to construct a possible explanation for the ram effect.