Reprometabolic Syndrome Mediates Subfertility in Obesity

NCT02653092 | Active Not Recruiting Results

• 2 other identifiers: 15-1052UL1TR001082
• Study Type: interventional
• Target: 84
• Locations: 1 country
• Sites: 1

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.

Conditions

Obesity; Infertility; Hypogonadotropic Hypogonadotropism; Hyperinsulinemia

Outcome Measures

Primary Outcomes (2)

• Change in LH Pulse Amplitude Before and After Acute or Chronic FFA Administration

  LH-Luteinizing Hormone Pulse Amplitude before and after administration of FFAs. This is a measure of the post supplementation frequent blood sampling session and the baseline session.

  First 4 hours of the frequent blood sampling study before and after FFA administration

• Change in Steady State Amount of Glucose Metabolized at the Set Insulin Infusion Rate Under Euglycemic Conditions

  Primary outcome will be M, which represents the steady state amount of glucose metabolized at the set insulin infusion rate under euglycemic conditions, which is equal to the glucose infused when the participant is euglycemic during the second stage of the HEC49. The final 30 minutes of the clamp period will be considered steady state. Glucose concentrations will be determined with the glucose oxidase method (Beckman Glucose Analyzer 2; Beckman Instruments, Fullerton, CA), while ELISA methods will be used for insulin measurements (Alpco, Salem, NH).

  30 minutes

Secondary Outcomes (7)

• Change in GnRH Response Before and After Acute or Chronic FFA Administration

  After the administration of GnRH at each FSS before and after acute and chronic FFA administration was assessed for up to 4 hours.

• Change in Mean FSH Parameter Before and After Acute or Chronic FFA Administration

  Before and after FFA adminstration

• Changes in Gonadotropin Pulse Frequency

  4 hours

• Urinary Hormone Profiles Before, During and After High Fat Diet Administration.

  Urinary assays will be measured for 4 menstrual cycles (approximately 4 months or 115 days)

• Glucose Measurements Before and After FFA Administration.

  60 Minutes during HEC

Study Arms (2)

Aim 1-Administration of FFA in an acute model

ACTIVE COMPARATOR

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 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; Drug: Intralipid; Drug: Dextrose; Drug: Heparin; Drug: GnRH

Aim 2-Hyperinsulinemic Euglycemic Clamp after a chronic administration of a diet

EXPERIMENTAL

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. 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; Drug: Dextrose; Drug: Heparin; Drug: GnRH; Procedure: Hyperinsulinemic Euglycemic Clamp

Interventions

Insulin DRUG

Also known as: Humulin

Aim 1-Administration of FFA in an acute model; Aim 2-Hyperinsulinemic Euglycemic Clamp after a chronic administration of a diet

Intralipid DRUG

Also known as: Free Fatty Acid

Aim 1-Administration of FFA in an acute model

Dextrose DRUG

Also known as: d-glucose

Aim 1-Administration of FFA in an acute model; Aim 2-Hyperinsulinemic Euglycemic Clamp after a chronic administration of a diet

Heparin DRUG

Also known as: anticoagulant

Aim 1-Administration of FFA in an acute model; Aim 2-Hyperinsulinemic Euglycemic Clamp after a chronic administration of a diet

GnRH DRUG

Also known as: gonadorelin acetate

Aim 1-Administration of FFA in an acute model; Aim 2-Hyperinsulinemic Euglycemic Clamp after a chronic administration of a diet

Hyperinsulinemic Euglycemic Clamp PROCEDURE

Also known as: HEC

Aim 2-Hyperinsulinemic Euglycemic Clamp after a chronic administration of a diet

Eligibility Criteria

• Age: 18 Years - 38 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Colorado, Denver: lead
• National Center for Advancing Translational Sciences (NCATS): collaborator

Study Sites (1)

University of Colorado Denver

Aurora, Colorado, 80045, United States

Location

Related Publications (2)

• Nguyen T, Kuhn K, Bolt M, Duffy K, Bradford AP, Santoro N. Analysis of Inflammatory Markers in Response to Induction of Reprometabolic Syndrome by a Eucaloric High Fat Diet in Normal Weight Women. Reprod Sci. 2024 Sep;31(9):2820-2828. doi: 10.1007/s43032-024-01586-9. Epub 2024 May 6.

  PMID: 38710978 DERIVED

• Santoro N, Schauer IE, Kuhn K, Fought AJ, Babcock-Gilbert S, Bradford AP. Gonadotropin response to insulin and lipid infusion reproduces the reprometabolic syndrome of obesity in eumenorrheic lean women: a randomized crossover trial. Fertil Steril. 2021 Aug;116(2):566-574. doi: 10.1016/j.fertnstert.2021.03.005. Epub 2021 Apr 8.

  PMID: 33838870 DERIVED

MeSH Terms

Conditions

Obesity; Infertility; Hyperinsulinism

Interventions

Insulin; Insulin, Regular, Human; soybean oil, phospholipid emulsion; Fatty Acids, Nonesterified; Glucose; Heparin; Anticoagulants; Gonadotropin-Releasing Hormone

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Genital Diseases; Urogenital Diseases; Glucose Metabolism Disorders; Metabolic Diseases

Intervention Hierarchy (Ancestors)

Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Fatty Acids; Lipids; Hexoses; Monosaccharides; Sugars; Carbohydrates; Glycosaminoglycans; Polysaccharides; Hematologic Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Neuropeptides; Oligopeptides; Nerve Tissue Proteins; Proteins

Results Point of Contact

• Title: Dr. Nanette Santoro
• Organization: University of Colorado School of Medicine

Nanette.Santoro@uanschutz.edu

303-724-2041

Study Officials

• Nanette Santoro, MD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 5, 2016
• First Posted: January 12, 2016
• Study Start: June 1, 2016
• Primary Completion: December 11, 2023
• Study Completion (Estimated): December 11, 2026
• Last Updated: March 2, 2026
• Results First Posted: June 1, 2023

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)