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Reprometabolic Syndrome Mediates Subfertility in Obesity

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02653092
Recruitment Status : Recruiting
First Posted : January 12, 2016
Last Update Posted : May 10, 2019
Information provided by (Responsible Party):
University of Colorado, Denver

Brief Summary:
Obesity plays an adverse role at every stage of conception and pregnancy and mounting evidence implicates relative hypogonadotropic hypogonadism, and reduced menstrual cycle hormone secretion as likely contributors to the subfertility phenotype and possible contributors to complications of pregnancy and the developmental origin of adult diseases such as diabetes and cardiovascular disease. This study will be the first comprehensive investigation to tie together the patterns of hyperinsulinemia, hyperlipidemia and inflammation, characteristic of obesity and obesity-caused relative hypogonadotropic hypogonadotropism and its potential adverse reproductive outcomes. The investigators findings will be used to inform a subsequent clinical intervention to optimize reproductive outcomes for obese women and their offspring.

Condition or disease Intervention/treatment Phase
Obesity Infertility Hypogonadotropic Hypogonadotropism Hyperinsulinemia Drug: Insulin Drug: Intralipid Drug: Dextrose Drug: Heparin Drug: GnRH Procedure: Hyperinsulinemic Euglycemic Clamp Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Reprometabolic Syndrome Mediates Subfertility in Obesity
Study Start Date : June 2016
Estimated Primary Completion Date : July 2019
Estimated Study Completion Date : March 2020

Arm Intervention/treatment
Active Comparator: Aim 1

Reproduction of the reproductive phenotype of obesity in Normal Weight Women (NWW) by:

  1. infusing insulin and free fatty acids (FFAs) in short term experiments and measuring gonadotropin pulsatility and pituitary GnRH response; and
  2. inducing a chronic model of the reprometabolic syndrome by administering a eucaloric diet that is relatively high in pro-inflammatory omega-6 fatty acids and low in anti-inflammatory omega-3 fatty acids (high fat diet; HFD) for one month while monitoring gonadotropin pulsatility and daily urinary reproductive hormone excretion.
Drug: Insulin
Other Name: Humulin

Drug: Intralipid
Other Name: Free Fatty Acid

Drug: Dextrose
Other Name: d-glucose

Drug: Heparin
Other Name: anticoagulant

Drug: GnRH
Other Name: gonadorelin acetate

Experimental: Aim 2
Assessment of the gluco-regulatory and anti-lipolytic actions of insulin with a 2-stage, Hyperinsulinemic, Euglycemic Clamp (HEC) to evaluate both suppression of lipolysis and hepatic glucose production.
Drug: Insulin
Other Name: Humulin

Drug: Intralipid
Other Name: Free Fatty Acid

Drug: Dextrose
Other Name: d-glucose

Drug: Heparin
Other Name: anticoagulant

Drug: GnRH
Other Name: gonadorelin acetate

Procedure: Hyperinsulinemic Euglycemic Clamp
Other Name: HEC

Primary Outcome Measures :
  1. Change in LH pulse amplitude [ Time Frame: 4 hours ]
    LH-Luteinizing Pulse Amplitude

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 38 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Body Mass Index (BMI) at least 18 but less than 25 kg/m2
  • 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
  • Normal prolactin and thyroid stimulating hormone levels at screening
  • History of regular menstrual cycles every 25-35 days
  • Use of a reliable method of contraception (female or male partner sterilization; intra uterine device (IUD); abstinence; diaphragm)
  • Normal hemoglobin A1c
  • Screening hemoglobin >11gm/dl

Exclusion Criteria:

  • Women with a baseline dietary assessment indicative of >35% daily calorie consumption from fat (as calculated based upon initial screening survey) will be excluded, as the impact of increasing their dietary fat intake may be minimal.
  • Women with fasting triglycerides >300mg/dl at screening will be excluded, as they might be at risk for acute elevation of triglycerides and even pancreatitis if placed on a high fat diet
  • Inability to comply with the protocol. Individuals who travel frequently, or who eat most of their meals outside of their home will be excluded, as it will be difficult to impossible for them to comply with the diet, to pick up the food cartons, etc.
  • Because high proportions of dairy fat will be needed to attain 48% calories from fat in the diet, vegans and lactose intolerant individuals will be excluded.
  • Pregnant women or women planning to become pregnant will be excluded.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02653092

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Contact: Katherine Kuhn 303-724-5276
Contact: Kelsey Jones 303-724-5276

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United States, Colorado
University of Colorado Denver Recruiting
Aurora, Colorado, United States, 80045
Contact: Katherine Kuhn    303-724-5276   
Principal Investigator: Nanette Santoro, MD         
Sponsors and Collaborators
University of Colorado, Denver
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Principal Investigator: Nanette Santoro, MD University of Colorado, Denver

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Responsible Party: University of Colorado, Denver Identifier: NCT02653092     History of Changes
Other Study ID Numbers: 15-1052
UL1TR001082 ( U.S. NIH Grant/Contract )
First Posted: January 12, 2016    Key Record Dates
Last Update Posted: May 10, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
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Nutrition Disorders
Body Weight
Signs and Symptoms
Genital Diseases, Male
Genital Diseases, Female
Glucose Metabolism Disorders
Metabolic Diseases
Gonadal Disorders
Endocrine System Diseases
Insulin, Globin Zinc
Soybean oil, phospholipid emulsion
Hypoglycemic Agents
Physiological Effects of Drugs
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Fat Emulsions, Intravenous
Parenteral Nutrition Solutions
Pharmaceutical Solutions