Abstract

The overall goal of this proposal is to examine the molecular basis for the development of hyperandrogenic states and consequent impairment of follicular function. Ovarian hyperandrogenism leads to ovulatory dysfunction including anovulation and infertility. In some cases such as polycystic ovarian syndrome, hyperandrogenism usually accompanies increased insulin resistance resulting in elevated insulin levels, and increased IGF-1 system. The altered endocrine and paracrine milieu results in increased androgen production by theca-interstitial cells, ovarian hyperplasia and loss of ovulatory capacity of the follicles. The objective of this proposal is to examine the cellular mechanisms responsible for hyperandrogenism and the resultant effects of excess androgen exposure on follicular function. To accomplish this, three specific aims are proposed.
Aim 1 will examine the role of increased cholesterol transport into theca-interstitial cells in response to insulin, IGF-1 and LH. This will be tested by examining the induction of HDL and LDL receptor expression in rat theca-interstitial cells by in situ hypbridization and by Northern blot analysis, and by determining the uptake and utilization of cholesterol for androgen synthesis.
Aim 2 will examine the cellular mechanism involved in the deleterious effects of androgen exposure on the ovarian follicular function in response to insulin/IGF-1 and FSH. This will be examined by analyzing changes in cell cycle constituents involved in the progression of restriction points in cell cycle, namely cyclins and cyclin-dependent kinases in response to insul/IGF-1 and FSH in androgen exposed follicles.
Aim 3 will examine the effect of androgen exposure on the follicular function. This will be determined by examining the signaling of insulin/IGF-1 and FSH in androgen-exposed follicles. The above studies will be carried out in rat and human tissues. The proposed studies address novel questions central to reproductive endocrinology and are directly relevant to the disorders affecting fertility.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD038424-04
Application #
6637050
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Yoshinaga, Koji
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
4
Fiscal Year
2003
Total Cost
$237,735
Indirect Cost

  Institution

Name
University of Michigan Ann Arbor
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109

  Publications

Palaniappan, Murugesan; Menon, Bindu; Menon, K M J (2013) Stimulatory effect of insulin on theca-interstitial cell proliferation and cell cycle regulatory proteins through MTORC1 dependent pathway. Mol Cell Endocrinol 366:81-9
Palaniappan, Murugesan; Menon, K M J (2012) Luteinizing hormone/human chorionic gonadotropin-mediated activation of mTORC1 signaling is required for androgen synthesis by theca-interstitial cells. Mol Endocrinol 26:1732-42
Kayampilly, Pradeep P; Menon, K M J (2012) AMPK activation by dihydrotestosterone reduces FSH-stimulated cell proliferation in rat granulosa cells by inhibiting ERK signaling pathway. Endocrinology 153:2831-8
Will, Matthew A; Palaniappan, Murugesan; Peegel, Helle et al. (2012) Metformin: direct inhibition of rat ovarian theca-interstitial cell proliferation. Fertil Steril 98:207-14
Palaniappan, Murugesan; Menon, K M J (2010) Human chorionic gonadotropin stimulates theca-interstitial cell proliferation and cell cycle regulatory proteins by a cAMP-dependent activation of AKT/mTORC1 signaling pathway. Mol Endocrinol 24:1782-93
Kayampilly, Pradeep P; Wanamaker, Brett L; Stewart, James A et al. (2010) Stimulatory effect of insulin on 5alpha-reductase type 1 (SRD5A1) expression through an Akt-dependent pathway in ovarian granulosa cells. Endocrinology 151:5030-7
Fisseha, Senait; Towns, Roberto; Harada, Miyuki et al. (2010) Inhibitory effect of valproic acid on ovarian androgen biosynthesis in rat theca-interstitial cells. Endocrine 37:187-93
Kayampilly, Pradeep P; Menon, K M J (2009) Follicle-stimulating hormone inhibits adenosine 5'-monophosphate-activated protein kinase activation and promotes cell proliferation of primary granulosa cells in culture through an Akt-dependent pathway. Endocrinology 150:929-35
Palaniappan, Murugesan; Menon, K M J (2009) Regulation of sterol regulatory element-binding transcription factor 1a by human chorionic gonadotropin and insulin in cultured rat theca-interstitial cells. Biol Reprod 81:284-92
Kayampilly, Pradeep P; Menon, K M J (2007) Follicle-stimulating hormone increases tuberin phosphorylation and mammalian target of rapamycin signaling through an extracellular signal-regulated kinase-dependent pathway in rat granulosa cells. Endocrinology 148:3950-7

Showing the most recent 10 out of 17 publications