Mediators of Abnormal Reproductive Function in Obesity (MARO)

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by University of Colorado, Denver
Sponsor:
Collaborator:
Information provided by (Responsible Party):
University of Colorado, Denver
ClinicalTrials.gov Identifier:
NCT01817400
First received: March 15, 2013
Last updated: January 24, 2014
Last verified: January 2014
  Purpose

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.


Condition Intervention Phase
Infertility, Female
Obesity
Other: Microdialysis
Dietary Supplement: Vascepa - Fish Oil
Drug: Aspirin
Drug: Pioglitazone
Phase 0

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Mediators of Abnormal Reproductive Function in Obesity

Resource links provided by NLM:


Further study details as provided by University of Colorado, Denver:

Primary Outcome Measures:
  • Area under curve (AUC)- urinary pregnandiol glucuronide (Pdg) [ Time Frame: Two menstrual cycles ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Estradiol [ Time Frame: 3 hours ] [ Designated as safety issue: No ]
  • Luteinizing hormone (LH) [ Time Frame: two menstrual cycles ] [ Designated as safety issue: No ]
  • Estrone conjugates (E1c) [ Time Frame: two menstrual cycles ] [ Designated as safety issue: No ]

Other Outcome Measures:
  • Follicle stimulating hormone (FSH) [ Time Frame: two menstrual cycles ] [ Designated as safety issue: No ]

Estimated Enrollment: 27
Study Start Date: March 2013
Estimated Study Completion Date: March 2017
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Microdialysis
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.
Other: Microdialysis
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.
Experimental: Anti-inflammatory treatment
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 - Fish Oil 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.
Dietary Supplement: Vascepa - Fish Oil
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.
Drug: Aspirin
Experimental: Insulin-lowering therapy
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. 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.
Drug: Pioglitazone
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 Name: Actos

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.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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%
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01817400

Contacts
Contact: Celeste Robledo 303-724-2046 celeste.robledo@ucdenver.edu

Locations
United States, Colorado
University of Colorado Denver Anschutz Medical Campus Recruiting
Aurora, Colorado, United States, 80045
Principal Investigator: Nanette Santoro, MD         
Sponsors and Collaborators
University of Colorado, Denver
Investigators
Principal Investigator: Nanette Santoro, MD University of Colorado, Denver
  More Information

No publications provided

Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT01817400     History of Changes
Other Study ID Numbers: 12-1414, U54HD058155
Study First Received: March 15, 2013
Last Updated: January 24, 2014
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Genital Diseases, Male
Infertility
Infertility, Female
Obesity
Genital Diseases, Female
Overnutrition
Nutrition Disorders
Overweight
Body Weight
Signs and Symptoms
Testosterone
Aspirin
Eicosapentaenoic acid ethyl ester
Pioglitazone
Androgens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anti-Inflammatory Agents
Therapeutic Uses
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 20, 2014