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The Role of Somatostatin in the Regulation of Gonadotropin Secretion in Sheep

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The Role of Somatostatin in the Regulation of Gonadotropin Secretion in Sheep Graduate Theses, Dissertations, and Problem Reports 2017 The Role of Somatostatin in the Regulation of Gonadotropin Secretion in Sheep Richard B. McCosh Follow this and additional works at: https://researchrepository.wvu.edu/etd Recommended Citation McCosh, Richard B., "The Role of Somatostatin in the Regulation of Gonadotropin Secretion in Sheep" (2017). Graduate Theses, Dissertations, and Problem Reports. 6194. https://researchrepository.wvu.edu/etd/6194 This Dissertation is protected by copyright and/or related rights. It has been brought to you by the The Research Repository @ WVU with permission from the rights-holder(s). You are free to use this Dissertation in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you must obtain permission from the rights-holder(s) directly, unless additional rights are indicated by a Creative Commons license in the record and/ or on the work itself. This Dissertation has been accepted for inclusion in WVU Graduate Theses, Dissertations, and Problem Reports collection by an authorized administrator of The Research Repository @ WVU. For more information, please contact [email protected]. The Role of Somatostatin in the Regulation of Gonadotropin Secretion in Sheep Richard B. McCosh Dissertation submitted to the School of Medicine at West Virginia University in partial fulfillment of the requirements for the degree of Doctor of Philosophy In Biomedical Science Cellular and Integrative Physiology Robert L. Goodman, PhD; Mentor Stanley M. Hileman, PhD; Chair Michael W. Vernon, PhD Steven L. Hardy, PhD Donal C. Skinner, PhD Department of Physiology and Pharmacology Morgantown, West Virginia 2017 Key Words: gonadotropin releasing hormone, luteinizing hormone, somatostatin, kisspeptin, sheep Copyright 2017 Richard B. McCosh ABSTRACT The Role of Somatostatin in the Regulation of Gonadotropin Secretion in Sheep Two modes of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion are necessary for female fertility: surge and episodic secretion. However, the neural systems that regulate these GnRH secretion patterns are still under investigation. The neuropeptide somatostatin (SST) inhibits episodic luteinizing hormone (LH) secretion in humans and sheep, and several lines of evidence suggest SST may regulate secretion during the LH surge. Neither a SST receptor 2 (SSTR2) agonist (octreotide) or antagonist (CYN154806; CYN) altered the amplitude or timing of the LH surge. Administration of CYN to intact ewes during either the breeding season or anestrus increased LH secretion and increased c-Fos in a subset of GnRH and kisspeptin cells during anestrus. To determine if these stimulatory effects are steroid- dependent or -independent, we administered CYN to ovariectomized ewes. This SSTR2 antagonist increased LH pulse frequency in ovariectomized ewes during anestrus, but not during the breeding season. The results demonstrate that SST, acting through SSTR2, inhibits episodic LH secretion, likely acting in the mediobasal hypothalamus, but action at this receptor does not alter LH surge secretion. Additionally, these data provide evidence that SST contributes to the steroid-independent suppression of LH pulse frequency during anestrus. Potential sites for SST action in the ovine hypothalamus were investigated using immunohistochemistry to determine whether cells that produce kisspeptin (KNDy cells in the arcuate nucleus) or GnRH receive direct synaptic contact from SST fibers, and whether the amount of these inputs changes throughout the estrous cycle or by season. The majority of KNDy cells receive synaptic input (evident by presynaptic synaptophysin immunostaining) from SST cells, but the amount of these inputs did not differ among groups. A subset of GnRH cells in both the preoptic area (POA) and mediobasal hypothalamus also receive synaptic input from SST cells. A greater percentage of POA GnRH cells had SST synapses during the surge than in anestrus, the luteal or early follicular phase of the estrus cycle. The total number of synaptic inputs onto GnRH and KNDy cells was altered by phase of the estrous cycle and season, extending the hypothesis that changes in the GnRH and KNDy cell synaptic connectivity may contribute to altered gonadotropin secretion throughout the estrous cycle and between seasons. Several lines of evidence support the hypothesis that somatostatin (SST) cells in the ventral medial nucleus (VMN) may be involved in the generation of the LH surge in sheep. In this study, we confirmed that SST cells in the VMN are activated during the LH surge using c- Fos as a marker for cellular activation. One explanation for the discrepancy between the observations of SST cell activation during the LH surge, but no effect of pharmacological manipulation of SSTR2, is that the cells that contain SST in the VMN also produce additional signaling molecules, such as nitric oxide. We used immunohistochemistry to determine that a high percentage (70-80%) of these SST cells also contain neuronal nitric oxide synthase (nNOS). Triple-label immunohistochemistry was used to determine that a greater percentage of the dual labeled SST and nNOS cells contain c-Fos during the LH surge compared to the early follicular phase. In contrast, the percentage of single labeled nNOS or SST cells that contained c-Fos did not differ between the LH surge and early follicular phase. Thus we propose that this population of SST cells in the VMN also release nitric oxide and that this transmitter contributes to the generation of the LH surge in sheep. ACKNOWLEDGEMENTS I have many people to thank for my success West Virginia University. First I would like to thank my family, particularly my parents and sister, for the support and encouragement in moving across the country to pursue a career in research. I am also lucky to have strong and smart grandmothers (Iris and Bonnie) as role models. I would like to thank my research mentor Bob Goodman for continuous support and guidance in all areas. I would also like to thank Stan Hileman who has been a co-mentor. Their combined input and experience has provided a unique and rich experience. Many other faculty members have been instrumental, including Steve Hardy, John Connors, Mike Vernon and Bill Stauber. Each has generously shared their experiences and knowledge. Mike Lehman and Lique Coolen have been very helpful in teaching me neuroanatomical techniques. I would also like to thank Miro Valent for all of his help in the laboratory, and friendship. Fellow and past graduate students (Kati porter, Justin/Dustin/Jason Lopez, Michelle Bedenbaugh, and Ashley Lindo) have also helped me tremendously and have made the experiences more fun. Members of the Reproductive Physiology program, particularly (Keith Inskeep and Lizzie Bowdridge) have also enrichened my experiences here. A number summer intern students (Brett Szeligo, Bina Malapur, Audrey Haines, and Catherine Rainey) have also been very helpful and a lot of fun. Gail Nesselrod, Margaret Minch, and Jennifer Fridley and the OLAR staff have been extremely helpful with the animal work. It was only with the generous help of this large team that this work was completed. iv ABBREVIATIONS GnRH Gonadotropin- Releasing Hormone LH Lutienizing Hormone FSH Follicle Stimulating hormone hCG human Chronic Gonadotropin PMSG Pregnant Mare Serum Gonadotropin SST Somatostatin SSTR2 Somatostatin receptor 2 CYN CYN154806, SSTR2 antagonist NKB Neurokinin B Dyn Dynorphin KNDy Kisspeptin, Neurokinin B, Dynorphin E2 Estradiol P4 Progesterone ERα Estrogen Receptor-alpha OVX Ovariectomized PGF2α Prostaglandin F2α CIDR Controlled internal release device CL Corpus luteum MBH Mediobasal hypothalamus ARC Arcuate Nucleus VMN Ventral Medial Nucleus AHA Anterior hypothalamic Area RCh Retrochiasmatic area v POA Preoptic area DBB Diagonal Band of Broca OCh Optic chiasm ME Median eminence icv intracerebroventricular IHC Immunohistochemistry DAB 3,3’-diaminobenzidine tetrahydrochloride PB Phosphate Buffer PBS Phosphate Buffered Saline PBST Phosphate Buffered Saline with Trition X-100 IgG Immunoglobulin G IPI Interpulse interval AMPL Pulse amplitude vi TABLE OF CONTENTS THE ROLE OF SOMATOSTATIN IN THE REGULATION OF GONADOTROPIN SECRETION IN SHEEP ................................................................................................................. i ABSTRACT ................................................................................................................................. ii ACKNOWLEDGEMENTS ........................................................................................................ iv ABBREVIATIONS ......................................................................................................................v CHAPTER 1: LITERATURE REVIEW ................................................................................... 1 REPRODUCTIVE CYCLES ........................................................................................................2 OVARIAN FUNCTION THROUGHOUT THE ESTROUS CYCLE ................................... 4 HYPOTHALAMIC REGULATION OF THE ESTROUS CYCLE ....................................... 7 BRIEF COMPARISONS TO THE HUMAN MENSTRAUL CYCLE ................................ 16 BRIEF COMPARISONS TO THE RODENT ESTROUS CYCLE ..................................... 16 SEASONAL BREEDING IN SHEEP ........................................................................................18 STEROID-DEPENDENT SUPPRESSION OF
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