The broad goal of this project is to investigate the critical autocrine/paracrine role of the inhibin/activin/follistatin system in normal human follicular development and in women with Polycystic Ovary Syndrome (PCOS). To address the underlying defects leading to the classic PCOS ovarian appearance of numerous peripherally arranged, small follicles, we hypothesize that an excess of bioavailable activin contributes to both increased follicular development as well as developmental arrest of maturing follicles. Our approach is to obtain transvaginal follicular aspirates from well-characterized normal or PCOS volunteers, which can then be used to document the progression from an activin-B dominant to an inhibin-A dominant microenvironment suggested by previous immunohistochemical approaches. Specifically, we propose:
Specific Aim 1 : To delineate the role of the intrafollicular inhibin/activin/follistatin axis in the autocrine/paracrine regulation of normal folliculogenesis and ovulation in the human.
Specific Aim 2. To characterize defects in inhibin/activin subunit biosynthesis, processing or dimerization in the abnormal follicular maturation observed in PCOS.
Specific Aim 3. To determine the role of intrafollicular follistatin in regulating activin activity, and thereby follicular growth, in women with PCOS.
Specific Aim 4. To determine the mechanism whereby FS regulates activin action at the cell surface in human granulosa cells and related cell line models. Thus, this Project strives to provide key information to facilitate the transition from bench (Specific Aim 4) to bedside (Specific Aims 2 and 3) while also providing a valuable normative database (Specific Aim 1) for analysis of PCOS and other studies of ovarian pathophysiology.
|Glister, Claire; Sunderland, Simon J; Boland, Maurice P et al. (2015) Comparison of bioactivities, binding properties and intrafollicular levels of bovine follistatins. Reproduction 150:85-96|
|Evans, William S; Taylor, Ann E; Boyd, David G et al. (2007) Lack of effect of short-term diazoxide administration on luteinizing hormone secretion in women with polycystic ovary syndrome. Fertil Steril 88:118-24|
|Hansen, Karl R; Thyer, Angela C; Sluss, Patrick M et al. (2005) Reproductive ageing and ovarian function: is the early follicular phase FSH rise necessary to maintain adequate secretory function in older ovulatory women? Hum Reprod 20:89-95|
|Welt, Corrine K; Taylor, Ann E; Fox, Janis et al. (2005) Follicular arrest in polycystic ovary syndrome is associated with deficient inhibin A and B biosynthesis. J Clin Endocrinol Metab 90:5582-7|
|Hall, Janet E; Sullivan, Jason P; Richardson, Gary S (2005) Brief wake episodes modulate sleep-inhibited luteinizing hormone secretion in the early follicular phase. J Clin Endocrinol Metab 90:2050-5|
|Welt, Corrine K; Falorni, Alberto; Taylor, Ann E et al. (2005) Selective theca cell dysfunction in autoimmune oophoritis results in multifollicular development, decreased estradiol, and elevated inhibin B levels. J Clin Endocrinol Metab 90:3069-76|
|Klein, Nancy A; Houmard, Brenda S; Hansen, Karl R et al. (2004) Age-related analysis of inhibin A, inhibin B, and activin a relative to the intercycle monotropic follicle-stimulating hormone rise in normal ovulatory women. J Clin Endocrinol Metab 89:2977-81|
|Welt, Corrine K (2004) Regulation and function of inhibins in the normal menstrual cycle. Semin Reprod Med 22:187-93|
|Adams, Judith M; Taylor, Ann E; Crowley Jr, William F et al. (2004) Polycystic ovarian morphology with regular ovulatory cycles: insights into the pathophysiology of polycystic ovarian syndrome. J Clin Endocrinol Metab 89:4343-50|
|Barbieri, Robert L (2003) Metformin for the treatment of polycystic ovary syndrome. Obstet Gynecol 101:785-93|
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