Mediators of Abnormal Reproductive Function in Obesity (MARO)
Condition: Infertility, Female; Obesity
MeSH terms: Infertility; Infertility, Female; Obesity
Study type: Interventional
Phase: Early Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Microdialysis; Vascepa - Fish Oil; Aspirin; Pioglitazone
Intervention type(s): Other; Dietary Supplement; Drug; Drug
Intervention description(s): Microdialysis probes will be inserted into the abdominal and femoral subcutaneous adipose tissue. Two "control" probes at each site will be perfused at 2.0 µL/min with Ringer's solution to measure basal interstitial testosterone and estradiol levels. One "experimental" probe at each site will be perfused with the 'compound' 20ug/dl at 2.0 µL/min to assess the interstitial conversion of androstenedione to estrone and estradiol. The 'compound' will be infused. Either one or the other hormone (androstenedione OR testosterone) will be used per experiment. The second "control" probe will be positioned at each site to ensure acquisition of data in the event that one of the other probes becomes dysfunctional. We will then collect microdialysis samples every 60 min over the next 120 min.; We will perform a control cycle of daily, first-morning voided urine, as previously reported by our group to assess the hormonal features of the menstrual cycle of each of the five participants in this arm. Upon completion of the control cycle, the participant will initiate therapy with aspirin 81mg per day, plus Vascepa 30mg daily. Participants will collect urine for a second menstrual cycle while on treatment, using methods that we have previously employed. At the completion of the second cycle of urine collection, the medications will be stopped and the study will be completed.; e will perform a control cycle of daily, first morning voided urine as previously reported by our group, to assess the hormonal features of the menstrual cycle of each of the five participants. Upon completion of the control cycle, the participant will initiate therapy with pioglitazone, 45 mg daily, a dose that has previously been shown to result in a 30% reduction in fasting insulin. She will take the pioglitazone without any monitoring for a second menstrual cycle and then collect urinary hormones for the third menstrual cycle, continuing the pioglitazone until the third menstrual cycle is completed.
Other intervention name(s): Actos
Intervention MeSH terms: Aspirin; Pioglitazone; Eicosapentaenoic acid ethyl ester
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science