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Mediators of Abnormal Reproductive Function in Obesity (MARO) (MARO)

Primary Purpose

Infertility, Female, Obesity

Status
Completed
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Microdialysis
Vascepa - Fish Oil
Aspirin
Pioglitazone
Sponsored by
University of Colorado, Denver
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Infertility, Female

Eligibility Criteria

18 Years - 60 Years (Adult)FemaleDoes not accept healthy volunteers

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%

Sites / Locations

  • University of Colorado Denver Anschutz Medical Campus

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Microdialysis

Anti-inflammatory treatment

Insulin-lowering therapy

Arm Description

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 - 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.

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.

Outcomes

Primary Outcome Measures

Area under curve (AUC)- urinary pregnandiol glucuronide (Pdg)

Secondary Outcome Measures

Estradiol
Luteinizing hormone (LH)
Estrone conjugates (E1c)

Full Information

First Posted
March 15, 2013
Last Updated
March 12, 2015
Sponsor
University of Colorado, Denver
Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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1. Study Identification

Unique Protocol Identification Number
NCT01817400
Brief Title
Mediators of Abnormal Reproductive Function in Obesity (MARO)
Acronym
MARO
Official Title
Mediators of Abnormal Reproductive Function in Obesity
Study Type
Interventional

2. Study Status

Record Verification Date
March 2015
Overall Recruitment Status
Completed
Study Start Date
March 2013 (undefined)
Primary Completion Date
December 2014 (Actual)
Study Completion Date
December 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Colorado, Denver
Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Infertility, Female, Obesity

7. Study Design

Primary Purpose
Basic Science
Study Phase
Early Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
10 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Microdialysis
Arm Type
Experimental
Arm Description
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.
Arm Title
Anti-inflammatory treatment
Arm Type
Experimental
Arm Description
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.
Arm Title
Insulin-lowering therapy
Arm Type
Experimental
Arm Description
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.
Intervention Type
Other
Intervention Name(s)
Microdialysis
Intervention Description
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.
Intervention Type
Dietary Supplement
Intervention Name(s)
Vascepa - Fish Oil
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Aspirin
Intervention Type
Drug
Intervention Name(s)
Pioglitazone
Other Intervention Name(s)
Actos
Intervention Description
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.
Primary Outcome Measure Information:
Title
Area under curve (AUC)- urinary pregnandiol glucuronide (Pdg)
Time Frame
Two menstrual cycles
Secondary Outcome Measure Information:
Title
Estradiol
Time Frame
3 hours
Title
Luteinizing hormone (LH)
Time Frame
two menstrual cycles
Title
Estrone conjugates (E1c)
Time Frame
two menstrual cycles
Other Pre-specified Outcome Measures:
Title
Follicle stimulating hormone (FSH)
Time Frame
two menstrual cycles

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
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%
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nanette Santoro, MD
Organizational Affiliation
University of Colorado, Denver
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Colorado Denver Anschutz Medical Campus
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States

12. IPD Sharing Statement

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Mediators of Abnormal Reproductive Function in Obesity (MARO)

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