Significant progress has been made in understanding the roles of FSH and LH on the growth and differentiation of the preovulatory follicle in primates. Information gained from these studies has rapidly been assimilated into new strategies for ovulation induction in clinical medicine. A major question that remains unsolved is the elucidation of the control mechanisms that govern the early stages of follicular development, as well as the mechanisms by which these early follicles become responsive to FSH. Because preovulatory follicles must come from the pool of early developing follicles, knowledge of the physiology of preantral and early antral follicles is essential to further the understanding and our ability to manipulate the ovarian cycle. Because of their important roles in early follicular development in rodents and the documented expression of these factors and their signal transduction pathways at comparable stages of folliculogenesis in primates, we have chosen to study the effects the oocyte product, GDF-9, and the granulosa cell product, activin, on early follicular development in macaque monkeys. We will use a novel drug delivery system to deliver GDF-9 and activin B directly to ovaries in vivo in combination with our previously developed """"""""gonadotropin clamp"""""""" model, which allows us to isolate local ovarian actions of autocrine/paracrine agents from systemic effects of these agents on gonadotropin secretion. This unique system will thus permit us to determine the local ovarian effects of these factors independently of systemic effects that have confused the results from previous studies.
The Specific Aims of this revised project are:
Specific Aim 1. To prepare and characterize recombinant GDF-9 and activin B for in vivo studies in monkeys.
Specific Aim 2. To determine the effects of recombinant activin B on preantral follicular growth and on the responsiveness of the ovary to FSH and LH.
Specific Aim 3. To determine the effects of recombinant GDF-9 on preantral follicular growth and on the responsiveness of the ovary to FSH and LH. An understanding of the regulation and development of early follicles in primates will lead to the possibility of therapies aimed at enhancing a cohort of follicles several cycles away from ovulation. In particular, in women who are """"""""poor responders"""""""" to our current ovulation induction therapies, a larger and healthier cohort of early antral follicles at the time of gonadotropin treatment would likely improve both the quantity and quality of mature preovulatory follicles. On the other hand, knowledge of the factors that govern early follicular growth would facilitate the development of novel methods of fertility control.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD008610-34
Application #
7843435
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
34
Fiscal Year
2009
Total Cost
$149,850
Indirect Cost
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Kawwass, Jennifer F; Sanders, Kristen M; Loucks, Tammy L et al. (2017) Increased cerebrospinal fluid levels of GABA, testosterone and estradiol in women with polycystic ovary syndrome. Hum Reprod 32:1450-1456
Vargas Trujillo, Marcela; Kalil, Bruna; Ramaswamy, Suresh et al. (2017) Estradiol Upregulates Kisspeptin Expression in the Preoptic Area of both the Male and Female Rhesus Monkey (Macaca mulatta): Implications for the Hypothalamic Control of Ovulation in Highly Evolved Primates. Neuroendocrinology 105:77-89
Kalil, Bruna; Ramaswamy, Suresh; Plant, Tony M (2016) The Distribution of Substance P and Kisspeptin in the Mediobasal Hypothalamus of the Male Rhesus Monkey and a Comparison of Intravenous Administration of These Peptides to Release GnRH as Reflected by LH Secretion. Neuroendocrinology 103:711-23
Walker, William H; Easton, Evan; Moreci, Rebecca S et al. (2015) Restoration of spermatogenesis and male fertility using an androgen receptor transgene. PLoS One 10:e0120783
Lomniczi, Alejandro; Wright, Hollis; Castellano, Juan Manuel et al. (2015) Epigenetic regulation of puberty via Zinc finger protein-mediated transcriptional repression. Nat Commun 6:10195
Shahab, M; Trujillo, M Vargas; Plant, T M (2015) A Reevaluation of the Question: Is the Pubertal Resurgence in Pulsatile GnRH Release in the Male Rhesus Monkey (Macaca mulatta) Associated With a Gonad-Independent Augmentation of GH Secretion? Endocrinology 156:3717-24
Verhagen, I; Ramaswamy, S; Teerds, K J et al. (2014) Time course and role of luteinizing hormone and follicle-stimulating hormone in the expansion of the Leydig cell population at the time of puberty in the rhesus monkey (Macaca mulatta). Andrology 2:924-30
Ramaswamy, Suresh; Dwarki, Karthik; Ali, Barkat et al. (2013) The decline in pulsatile GnRH release, as reflected by circulating LH concentrations, during the infant-juvenile transition in the agonadal male rhesus monkey (Macaca mulatta) is associated with a reduction in kisspeptin content of KNDy neurons of the arc Endocrinology 154:1845-53
Terasawa, Ei; Guerriero, Kathryn A; Plant, Tony M (2013) Kisspeptin and puberty in mammals. Adv Exp Med Biol 784:253-73
Stephens, Sahar M; Pau, Francis K Y; Yalcinkaya, Tamer M et al. (2013) Assessing the pulsatility of luteinizing hormone in female vervet monkeys (Chlorocebus aethiops sabaeus). Comp Med 63:432-8

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