This study will be one of the first attempts to link the increased levels of estradiol and androgens/decreased levels of progesterone with miscarriages seen in women with PCOS to a mechanism which focuses on aberrant glucose utilization. Understanding the hormonal regulation of glucose uptake and metabolism in the uterine stroma during decidualization will potentially progress into the development of novel pharmacologic interventions to increase the rate of successful pregnancies in this population of women. This proposal is organized into three specific aims.
In Aim 1, we will investigate the effects of high levels of estradiol/androgens and low levels of progesterone on expression of glucose transporters, glucose utilization and decidualization in murine endometrial stromal cells. We will also perform the same studies in human endometrial stromal cells. We hypothesize that high E2 and low P4 will downregulate GLUT1 and glucose uptake in mESCs and hESCs.
In Aim 2, we will analyze the effects of changing GLUT1 expression as well as altering glucose metabolism on the process of decidualization of these cells. We will use siRNA/shRNA lentivirus to knockdown GLUT1, glucose flux studies to assess glucose utilization in these cells and then inhibit these pathways and assess decidualization in ESCs. We hypothesize that glucose is primarily metabolized via the pentose phosphate pathway during decidualization;and that inhibition either upstream (GLUT1 expression) or downstream (PPP inhibition) adversely affects decidualization. We will test this hypothesis in mouse and human ESCs. Finally, in Aim 3 we will focus on analyzing the in vivo effects of excess estradiol/androgen on decidualization and glucose utilization in the endometrial stroma by using a mouse model of increased DHEA. We will attempt to correct these effects by exposure to PPP activators used both in vivo and in vitro. We will also use leftover samples from patients with PCOS or oocyte donor patients and examine human ESCs. We predict that 1) DHEA exposed mice will have abnormal glucose utilization and thus abnormal decidualization with decreased numbers of pups, 2) the agents used to increase glucose utilization via the PPP will reverse decidualization abnormalities, and 3) human ESCs from these populations of patients will have similar abnormalities in glucose utilization.

Public Health Relevance

Women with polycystic ovary syndrome (PCOS), as well as other endocrine disorders with elevated estradiol or androgens, all experience embryo implantation failure and endometrial dysfunction. The general belief is that this is due to the effects of excess estrogen/androgen or progesterone deficiency, both characteristic of this patient population. Our hope is that as a result of our studies examining the effects of high estrogen/androgen levels on glucose utilization in the uterus, new therapeutic interventions for implantation failure in patients with PCOS, and these endocrine disorders, may be discovered.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD065435-03
Application #
8231301
Study Section
Special Emphasis Panel (ZRG1-EMNR-B (03))
Program Officer
Yoshinaga, Koji
Project Start
2010-05-01
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$497,423
Indirect Cost
$170,171
Name
Washington University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Jimenez, Patricia T; Frolova, Antonina I; Chi, Maggie M et al. (2013) DHEA-mediated inhibition of the pentose phosphate pathway alters oocyte lipid metabolism in mice. Endocrinology 154:4835-44
Schoeller, Erica L; Albanna, Gabriella; Frolova, Antonina I et al. (2012) Insulin rescues impaired spermatogenesis via the hypothalamic-pituitary-gonadal axis in Akita diabetic mice and restores male fertility. Diabetes 61:1869-78
Purcell, Scott H; Chi, Maggie M; Moley, Kelle H (2012) Insulin-stimulated glucose uptake occurs in specialized cells within the cumulus oocyte complex. Endocrinology 153:2444-54

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