Estrogen Sensitivity and Ovulatory Dysfunction in Obesity

Not Applicable

Completed

Conditions: Infertility
Obesity

Interventions: Drug: Estradiol
Drug: Gonadotropin-releasing hormone (GnRH)
Drug: Progesterone

Registration Number: NCT01381016

Lead Sponsor: University of Colorado, Denver

Brief Summary: 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.

Detailed Description: * 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).

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 30

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 2 - Obese	Estradiol	Group 2: Obese (BMI \>30 kg/m2) Subjects were instructed to apply 0.1 mg/d transdermal estrogen (Estradiol) for one month. Pituitary response was assessed to determine how estradiol administration altered pituitary sensitivity to Gonadotropin-releasing hormone - GnRH. Subjects who failed to initiate a menstrual period following 40 days on the patch were instructed to take 200 mg daily of progesterone for 10 days or as long as deemed necessary.
Group 2 - Obese	Gonadotropin-releasing hormone (GnRH)	Group 2: Obese (BMI \>30 kg/m2) Subjects were instructed to apply 0.1 mg/d transdermal estrogen (Estradiol) for one month. Pituitary response was assessed to determine how estradiol administration altered pituitary sensitivity to Gonadotropin-releasing hormone - GnRH. Subjects who failed to initiate a menstrual period following 40 days on the patch were instructed to take 200 mg daily of progesterone for 10 days or as long as deemed necessary.
Group 1 - Normal Weight	Gonadotropin-releasing hormone (GnRH)	Group 1: Normal weight (BMI 18-25 kg/m2) Subjects were instructed to apply 0.1 mg/d transdermal estrogen (Estradiol) for one month. Pituitary response was assessed to determine how estradiol administration altered pituitary sensitivity to Gonadotropin-releasing hormone - GnRH. Subjects who failed to initiate a menstrual period following 40 days on the patch were instructed to take 200 mg daily of progesterone for 10 days or as long as deemed necessary.
Group 1 - Normal Weight	Estradiol	Group 1: Normal weight (BMI 18-25 kg/m2) Subjects were instructed to apply 0.1 mg/d transdermal estrogen (Estradiol) for one month. Pituitary response was assessed to determine how estradiol administration altered pituitary sensitivity to Gonadotropin-releasing hormone - GnRH. Subjects who failed to initiate a menstrual period following 40 days on the patch were instructed to take 200 mg daily of progesterone for 10 days or as long as deemed necessary.
Group 1 - Normal Weight	Progesterone	Group 1: Normal weight (BMI 18-25 kg/m2) Subjects were instructed to apply 0.1 mg/d transdermal estrogen (Estradiol) for one month. Pituitary response was assessed to determine how estradiol administration altered pituitary sensitivity to Gonadotropin-releasing hormone - GnRH. Subjects who failed to initiate a menstrual period following 40 days on the patch were instructed to take 200 mg daily of progesterone for 10 days or as long as deemed necessary.
Group 2 - Obese	Progesterone	Group 2: Obese (BMI \>30 kg/m2) Subjects were instructed to apply 0.1 mg/d transdermal estrogen (Estradiol) for one month. Pituitary response was assessed to determine how estradiol administration altered pituitary sensitivity to Gonadotropin-releasing hormone - GnRH. Subjects who failed to initiate a menstrual period following 40 days on the patch were instructed to take 200 mg daily of progesterone for 10 days or as long as deemed necessary.