Estrogen Sensitivity and Ovulatory Dysfunction in Obesity

Estrogen Sensitivity and Ovulatory Dysfunction in Obesity

The sole purpose of this study is to evaluate pathophysiology of disease. The disease state that is being evaluated is the obesity-related alterations in reproductive hormones

• The obesity epidemic in the United States is advancing at an accelerated pace. It is estimated that by 2015, 41% of U.S. adults will be obese as defined by a body mass index (BMI) of greater than 30 kg/m2. The U.S. government's 2010 Dietary Guidelines regard obesity as the single greatest health hazard in this century. Female adult obesity is associated with menstrual cycle irregularities, ovulatory dysfunction and a higher risk of obstetrical complications. This reproductive phenotype of obesity is worsened by further increases in BMI and is not solely due to anovulatory infertility. While the association of adiposity with subfertility is well documented in population studies, the underlying mechanisms remain poorly understood. The main objective of this proposal is to clarify the nature of the obesity-related reproductive endocrine abnormalities and identify potential etiologies amenable to therapy.
• Hypothesis: The hypothalamic-pituitary axis is abnormally sensitive to estradiol negative feedback in obesity.

• Design: paired assessments Pre and Post estrogen administration in obese and normal weight women
• AIM 1: To test the pituitary and hypothalamic responsiveness in obesity, we will examine the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) pulsatility during frequent blood sampling.
• AIM 2: To test the ovarian responsiveness in obesity, we will examine urinary reproductive hormones (E1c, estrone conjugates, and Pdg, pregnanediol glucuronide) over an entire menstrual cycle.
• AIM 3: To test the hypothesis that central adiposity is associated with reproductive hormone alterations in obesity, we will quantitatively assess body composition by dual energy x-ray absorptiometry (DXA).

Inclusion Criteria:

• Age 18-42 at study entry
• Regular menstrual cycles every 25-40 days
• BMI 18- 25 kg/m2 or ≥30kg/m2
• Good general health
• Prolactin and thyroid-stimulating hormone (TSH) within normal laboratory ranges at screening
• Baseline hemoglobin >11 gm/dl.

Exclusion Criteria:

• Positive screen for Activated Protein C resistance
• Any contraindications to exogenous estrogen, including previous thromboembolic events or stroke, history of an estrogen-dependent tumor, active liver disease, undiagnosed abnormal uterine bleeding, hypertriglyceridemia, smoking, hypertension
• History of chronic disease affecting hormone production, metabolism or clearance (including diabetes mellitus) or abnormal renal or liver function at screening, such as elevated aspartate or alanine aminotransferases or elevated blood urea nitrogen (BUN) or creatinine
• Current use of thiazolidinediones or metformin (known to interact with reproductive hormones)
• Use of hormones affecting hypothalamic-pituitary ovarian axis within three months of enrollment
• Strenuous exercise (>4 hours per week)
• Pregnancy, breast-feeding or current active attempts to conceive