Mediators of Abnormal Reproductive Function in Obesity (MARO)

The study is seeking to understand how being overweight and obese makes women less fertile. The studies the investigators have done so far indicate that there is a hormone or other substance produced by fat that goes into the blood and reduces reproductive hormones in women who are overweight and obese. The present study will try to find the most promising substances by studying small numbers of women and trying to remove the substances that are causing the problem.

Hypothesis: A circulating factor or factors, either hormonal, inflammatory or metabolic, causes relative pituitary hypofunction and correction of this reproductive deficit will allow obese women with infertility who have failed to reduce their body weight to normal to conceive, and may also prevent the horizontal passage of an adverse metabolic phenotype to the offspring.

Specific Aim 1: To determine whether aromatase activity is measurable in adipose tissue using the 'compound' (see appendix) as a precursor and whether aromatase is decreased in the adipose tissue of obese women, and whether this varies by regional fat location. The investigators will accomplish this by examining precursor/product ratios of hormones infused through microdialysis using the 'compound' as a substrate.

Hypothesis for specific aim 1: Aromatase activity will be measurable in adipose tissue using testosterone as a precursor. Estradiol, but not estrone production from androgen precursors will be decreased in obese women relative to those of normal weight.

Specific Aim 2: To determine whether nonspecific, systemic suppression of inflammation will lead to improved reproductive hormonal profiles of luteinizing hormone (LH), follicle stimulating hormone(FSH), Estrone conjugates (E1c) and pregnandiol glucuronide (Pdg) in obese women who undergo two menstrual cycles of study: one off treatment and one on treatment. This aim shall be accomplished by performing daily urinary hormone monitoring of two menstrual cycles, one prior to and one during treatment with low-dose aspirin and polyunsaturated fatty acids (PUFAs).

Hypothesis for specific aim 2: A nonspecific, systemic inflammatory suppression therapy will result in improved urinary profiles of LH, FSH, E1c and Pdg.

Specific Aim 3: To determine whether 4 weeks of reduction of circulating insulin will result in improved reproductive hormonal profiles of LH, FSH, Estrone conjugates (E1c) and pregnandiol glucuronide (Pdg) in obese women who undergo two menstrual cycles of study: one off treatment and one on treatment. This aim shall be accomplished by performing daily urinary hormone monitoring of two menstrual cycles, one prior to and one during treatment with pioglitazone.

Hypothesis for specific aim 3: Chronic lowering of insulin with pioglitazone treatment of obese women will result in improved urinary profiles of LH, FSH, E1c and Pdg.

Eligibility Criteria:
Inclusion Criteria:

Women aged 18-39\* who meet the following criteria will be enrolled:

\*Women age 40-60 can be enrolled in Group A

* BMI at least 30 kg/m2 (Groups B and C only)
* No history of chronic disease affecting hormone production, metabolism or clearance
* No use of medications known to alter or interact with reproductive hormones or insulin metabolism (e.g. thiazolidinediones, metformin)
* No use of reproductive hormones within 3 months of enrollment
* No medical conditions that are known to affect urinary hormone excretion or that may interfere with urinary hormone measurement (Groups B and C only)
* No history of or active bladder cancer (Group C only, since pioglitazone is contraindicated in individuals with bladder cancer)
* Normal prolactin and thyroid stimulating hormone levels at screening
* History of regular menstrual cycles every 25-40 days
* Use of a reliable method of contraception (female or male partner sterilization; intrauterine device (IUD); abstinence; diaphragm)
* Hemoglobin A1c \<6%

Exclusion Criteria:

Women aged 18-39\* who meet the following criteria will be enrolled:

\*Women age 40-60 can be enrolled in Group A

* BMI at least 30 kg/m2 (Groups B and C only)
* No history of chronic disease affecting hormone production, metabolism or clearance
* No use of medications known to alter or interact with reproductive hormones or insulin metabolism (e.g. thiazolidinediones, metformin)
* No use of reproductive hormones within 3 months of enrollment
* No medical conditions that are known to affect urinary hormone excretion or that may interfere with urinary hormone measurement (Groups B and C only)
* No history of or active bladder cancer (Group C only, since pioglitazone is contraindicated in individuals with bladder cancer)
* Normal prolactin and thyroid stimulating hormone levels at screening
* History of regular menstrual cycles every 25-40 days
* Use of a reliable method of contraception (female or male partner sterilization; IUD; abstinence; diaphragm)
* Hemoglobin A1c \<6%