Estrogen Sensitivity and Ovulatory Dysfunction in Obesity

Study Overview
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Brief Summary
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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
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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).

Official Title
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Estrogen Sensitivity and Ovulatory Dysfunction in Obesity

Conditions
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Obesity, Infertility

Intervention / Treatment
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* Drug: Estradiol
* Drug: Gonadotropin-releasing hormone (GnRH)
* Drug: Progesterone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 42 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Group 1 - Normal Weight<br>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. | Drug: Estradiol<br>* Subjects were instructed to apply 0.1 mg/d transdermal estrogen for one month.<br>* Other names: Climara, transdermal estrogen;Drug: Gonadotropin-releasing hormone (GnRH)<br>* Pituitary response was assessed to determine how estradiol administration alters pituitary sensitivity to GnRH.<br>* Other names: Lutrelef or gonadorelin acetate;Drug: Progesterone<br>* 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.<br>* Other names: Prometrium or medroxyproge sterone acetate;|
| Experimental: Group 2 - Obese<br>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. | Drug: Estradiol<br>* Subjects were instructed to apply 0.1 mg/d transdermal estrogen for one month.<br>* Other names: Climara, transdermal estrogen;Drug: Gonadotropin-releasing hormone (GnRH)<br>* Pituitary response was assessed to determine how estradiol administration alters pituitary sensitivity to GnRH.<br>* Other names: Lutrelef or gonadorelin acetate;Drug: Progesterone<br>* 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.<br>* Other names: Prometrium or medroxyproge sterone acetate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Luteinizing Hormone Pulse Amplitude | The study is powered on luteinizing hormone pulse amplitude because it is the clinical outcome for which the most data is available. The primary comparison is whether there is a significant reduction in the pulse amplitude in the obese between the pre- and post-treatment periods and whether there is no change in the pulse amplitude in the normal weight patients between the pre and post-treatment periods. | Baseline | 
| Luteinizing Hormone Pulse Amplitude |  | Post estradiol at one month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LH pulsatility, Obesity, Reproduction