Polycystic ovarian syndrome (PCOS) is the most common endocrinopathy and it affects 10 percent of reproductive-aged women. The etiology of chronic hyperandrogenic anovulations, such as PCOS, may have genetic underpinnings. Although the underlying mechanisms are unknown, PCOS is now recognized as hyperandrogenism accompanied by anovulation. Polycystic ovarian morphology is highly correlated with conditions in which the fetus has been exposed to high amounts of sex steroids before birth. For example, women with classical 21-hydroxylase deficiency mimic PCOS, exhibit anovulation, ovarian hyperandrogenism, and LH hypersecretion. Perhaps excess sex steroids early in life may provide a hormonal """"""""insult"""""""" that results in manifestation of PCOS later in adulthood. This proposal aims to use a new model, the prenatally-androgenized sheep (long gestation, mono-ovular species), to investigate causal mechanisms for the developmental origins of PCOS. Our preliminary studies indicate that these sheep develop ovulatory defects during adulthood similar to those of women with PCOS: anovulation, elevated LH levels, hyperandrogenemia, hyperinsulinemia, and multifollicular ovaries. In this proposal, we will test the following hypothesis: prenatal exposure to androgens disrupts adult reproductive function culminating in hyperandrogenic anovulation and that this disruption is mediated via reduced sensitivity to the positive feedback actions of estradiol, abnormal gonadotropic drive and/or altered ovarian sensitivity to FSH.
The specific Aims of the proposed research are to determine 1) the extent to which fetal exposure to androgens disrupts reproductive cyclicity, ovarian function, ovulatory capacity and fertility in adulthood, (2) if reduced sensitivity to estradiol stimulatory feedback of gonadotropin secretion contributes to the disruptive effects of prenatal- androgenization on postnatal reproductive cyclicity, and (3) if abnormal gonadotropic drive and/or reduced ovarian sensitivity to FSH contributes to the disruptive effects of prenatal- androgenization on postnatal reproductive cyclicity. If our hyposthesis proves to be correct, this would form the basis for a distinct developmental origin of an important reproductive disease in adulthood. Specifically it will establish that discrete, experimentally induced androgen excess of fetal sheep provides the first clear etiology for hyperandrogenic anovulation in adulthood.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD041098-04
Application #
6761831
Study Section
Special Emphasis Panel (ZHD1-MCHG-B (21))
Program Officer
Grave, Gilman D
Project Start
2001-08-08
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
4
Fiscal Year
2004
Total Cost
$377,500
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Sheppard, K M; Padmanabhan, V; Coolen, L M et al. (2011) Prenatal programming by testosterone of hypothalamic metabolic control neurones in the ewe. J Neuroendocrinol 23:401-11
Cheng, Guanliang; Coolen, Lique M; Padmanabhan, Vasantha et al. (2010) The kisspeptin/neurokinin B/dynorphin (KNDy) cell population of the arcuate nucleus: sex differences and effects of prenatal testosterone in sheep. Endocrinology 151:301-11
Roberts, Eila K; Flak, Jonathan N; Ye, Wen et al. (2009) Juvenile rank can predict male-typical adult mating behavior in female sheep treated prenatally with testosterone. Biol Reprod 80:737-42
Steckler, Teresa L; Lee, James S; Ye, Wen et al. (2008) Developmental programming: exogenous gonadotropin treatment rescues ovulatory function but does not completely normalize ovarian function in sheep treated prenatally with testosterone. Biol Reprod 79:686-95
Manikkam, Mohan; Thompson, Robert C; Herkimer, Carol et al. (2008) Developmental programming: impact of prenatal testosterone excess on pre- and postnatal gonadotropin regulation in sheep. Biol Reprod 78:648-60
Roberts, Eila K; Padmanabhan, Vasantha; Lee, Theresa M (2008) Differential effects of prenatal testosterone timing and duration on phenotypic and behavioral masculinization and defeminization of female sheep. Biol Reprod 79:43-50
Veiga-Lopez, A; Ye, W; Phillips, D J et al. (2008) Developmental programming: deficits in reproductive hormone dynamics and ovulatory outcomes in prenatal, testosterone-treated sheep. Biol Reprod 78:636-47
Dumesic, Daniel A; Abbott, David H; Padmanabhan, Vasantha (2007) Polycystic ovary syndrome and its developmental origins. Rev Endocr Metab Disord 8:127-41
Steckler, T L; Roberts, E K; Doop, D D et al. (2007) Developmental programming in sheep: administration of testosterone during 60-90 days of pregnancy reduces breeding success and pregnancy outcome. Theriogenology 67:459-67

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