Mediators of Abnormal Reproductive Function in Obesity (MARO)

NCT01817400 | Completed Early Phase 1 DMC

• 2 other identifiers: 12-1414U54HD058155
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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.

Conditions

Infertility, Female; Obesity

Outcome Measures

Primary Outcomes (1)

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

  Two menstrual cycles

Secondary Outcomes (3)

• Estradiol

  3 hours

• Luteinizing hormone (LH)

  two menstrual cycles

• Estrone conjugates (E1c)

  two menstrual cycles

Other Outcomes (1)

• Follicle stimulating hormone (FSH)

  two menstrual cycles

Study Arms (3)

Microdialysis

EXPERIMENTAL

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

Anti-inflammatory treatment

EXPERIMENTAL

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; Drug: Aspirin

Insulin-lowering therapy

EXPERIMENTAL

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

Interventions

Microdialysis OTHER

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.

Microdialysis

Vascepa - Fish Oil DIETARY_SUPPLEMENT

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.

Anti-inflammatory treatment

Aspirin DRUG

Anti-inflammatory treatment

Pioglitazone DRUG

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.

Also known as: Actos

Insulin-lowering therapy

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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%

You may not qualify if:

• 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%

Sponsors & Collaborators

• University of Colorado, Denver: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

University of Colorado Denver Anschutz Medical Campus

Aurora, Colorado, 80045, United States

Location

MeSH Terms

Conditions

Infertility, Female; Obesity

Interventions

Microdialysis; Aspirin; Pioglitazone

Condition Hierarchy (Ancestors)

Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Infertility; Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Dialysis; Chemistry Techniques, Analytical; Investigative Techniques; Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Thiazolidinediones; Thiazoles; Sulfur Compounds; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Nanette Santoro, MD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 15, 2013
• First Posted: March 25, 2013
• Study Start: March 1, 2013
• Primary Completion: December 1, 2014
• Study Completion: December 1, 2014
• Last Updated: March 17, 2015

Record last verified: 2015-03

Locations

US (1)