The broad goal of this project is to continue to investigate the neuroendocrine and gonadal regulation of reproduction in women, focusing on the complex interrelationships between FSH, estradiol and the inhibins. There is now evidence that both estradiol and the inhibins contribute to the negative feedback control of FSH in women. However, their relative roles in the precise control of FSH during the follicular and luteal phases of the normal menstrual cycle have not been delineated. There are two unique circumstances in which we have shown that the coordinated secretion of estradiol and the inhibins is altered: in reproductive aging, estradiol levels are increased in the presence of low levels of inhibin while in African-American women, normal reproductive cycles are characterized by increased estradiol relative to Caucasian women in the face of identical levels of inhibin. Determining the mechanisms responsible for these changes will provide us with important insights into the interactions of inhibin, estradiol and gonadotropins in normal reproductive physiology.
Aim 1 will determine the relative contributions of estradiol and the inhibins to the negative feedback regulation of FSH secretion during the follicular and luteal phases of the normal menstrual cycle using normal and GnRH-deficient women in whom estrogen secretion is altered by aromatase blockade.
Aim 2 will seek to elucidate the mechanisms underlying the dichotomy between estradiol and inhibin secretion in reproductive aging by investigating inhibin and estradiol secretion in response to fixed FSH stimulation and by determining the number of granulosa cells and inhibin subunit expression and aromatase function and expression in antral and preovulatory follicles as a function of reproductive aging.
Aim 3 will determine the feedback and feed-forward interactions between FSH, estradiol and the inhibins that result in an increase in estradiol levels across normal reproductive cycles in African- American women. Feedback will be examined using an estrogen infusion protocol while feed-forward will examine the control of estradiol and inhibin secretion in preovulatory follicles. Understanding the feedback and feed-forward dynamics of the hypothalamic-pituitary and ovarian components of the reproductive system is critical to an appreciation of the pathophysiology of reproductive disorders. This information is ultimately required for the design of therapeutic options for patients with reproductive disorders including infertility.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Parrott, Estella C
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Massachusetts General Hospital
United States
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Shaw, N D; Srouji, S S; Welt, C K et al. (2015) Compensatory Increase in Ovarian Aromatase in Older Regularly Cycling Women. J Clin Endocrinol Metab 100:3539-47
Shaw, N D; Srouji, S S; Welt, C K et al. (2014) Evidence that increased ovarian aromatase activity and expression account for higher estradiol levels in African American compared with Caucasian women. J Clin Endocrinol Metab 99:1384-92
Abel, Brent S; Shaw, Natalie D; Brown, Jenifer M et al. (2013) Responsiveness to a physiological regimen of GnRH therapy and relation to genotype in women with isolated hypogonadotropic hypogonadism. J Clin Endocrinol Metab 98:E206-16
Costa-Barbosa, Flavia Amanda; Balasubramanian, Ravikumar; Keefe, Kimberly W et al. (2013) Prioritizing genetic testing in patients with Kallmann syndrome using clinical phenotypes. J Clin Endocrinol Metab 98:E943-53
Gianetti, Elena; Hall, Janet E; Au, Margaret G et al. (2012) When genetic load does not correlate with phenotypic spectrum: lessons from the GnRH receptor (GNRHR). J Clin Endocrinol Metab 97:E1798-807
Shaw, N D; Klingman, K M; Srouji, S S et al. (2012) Gonadotropin responses to estrogen-positive and -negative feedback are identical in African-American and Caucasian women. J Clin Endocrinol Metab 97:E106-9
Marsh, E E; Shaw, N D; Klingman, K M et al. (2011) Estrogen levels are higher across the menstrual cycle in African-American women compared with Caucasian women. J Clin Endocrinol Metab 96:3199-206
Shaw, Natalie D; Seminara, Stephanie B; Welt, Corrine K et al. (2011) Expanding the phenotype and genotype of female GnRH deficiency. J Clin Endocrinol Metab 96:E566-76
Caronia, Lisa M; Martin, Cecilia; Welt, Corrine K et al. (2011) A genetic basis for functional hypothalamic amenorrhea. N Engl J Med 364:215-25
Gianetti, Elena; Tusset, Cintia; Noel, Sekoni D et al. (2010) TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood. J Clin Endocrinol Metab 95:2857-67

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