Trial Outcomes & Findings for Reprometabolic Syndrome Mediates Subfertility in Obesity (NCT NCT02653092)

Last Updated: 2025-05-14

Results Overview

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.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

Target enrollment

84 participants

Primary outcome timeframe

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

Results posted on

2025-05-14

Participant Flow

Participant milestones

Participant milestones
Measure	Aim 1-Acute Infusion of FFA and Chronic Model 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. Insulin Intralipid Dextrose Heparin GnRH	Aim 2- Hyperinsulinemic Euglycemic Clamp 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. Insulin Intralipid Dextrose Heparin GnRH Hyperinsulinemic Euglycemic Clamp
Overall Study STARTED	26	58
Overall Study COMPLETED	13	18
Overall Study NOT COMPLETED	13	40

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Reprometabolic Syndrome Mediates Subfertility in Obesity

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Aim 1 n=26 Participants Reproduction of the reproductive phenotype of obesity in Normal Weight Women (NWW) by infusing insulin and free fatty acids (FFAs) in short term experiments and measuring gonadotropin pulsatility and pituitary GnRH response; and Insulin Intralipid Dextrose Heparin GnRH	Aim 2 n=58 Participants 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 before and after a eucaloric high-fat diet. Reproduction of the reproductive phenotype of obesity in Normal Weight Women (NWW) by 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. Insulin Dextrose Heparin GnRH Hyperinsulinemic Euglycemic Clamp	Total n=84 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Age, Categorical Between 18 and 65 years	26 Participants n=93 Participants	58 Participants n=4 Participants	84 Participants n=27 Participants
Age, Categorical >=65 years	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Age, Continuous	30.63 years STANDARD_DEVIATION 5.46 • n=93 Participants	29.53 years STANDARD_DEVIATION 6.17 • n=4 Participants	30.01 years STANDARD_DEVIATION 5.85 • n=27 Participants
Sex: Female, Male Female	26 Participants n=93 Participants	58 Participants n=4 Participants	84 Participants n=27 Participants
Sex: Female, Male Male	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=93 Participants	5 Participants n=4 Participants	8 Participants n=27 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	23 Participants n=93 Participants	50 Participants n=4 Participants	73 Participants n=27 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	3 Participants n=4 Participants	3 Participants n=27 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Asian	3 Participants n=93 Participants	6 Participants n=4 Participants	9 Participants n=27 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	3 Participants n=4 Participants	3 Participants n=27 Participants
Race (NIH/OMB) Black or African American	0 Participants n=93 Participants	2 Participants n=4 Participants	2 Participants n=27 Participants
Race (NIH/OMB) White	21 Participants n=93 Participants	44 Participants n=4 Participants	65 Participants n=27 Participants
Race (NIH/OMB) More than one race	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=93 Participants	3 Participants n=4 Participants	4 Participants n=27 Participants
Region of Enrollment United States	26 participants n=93 Participants	58 participants n=4 Participants	84 participants n=27 Participants
BMI	21.60 kg/m^2 STANDARD_DEVIATION 1.32 • n=93 Participants	21.57 kg/m^2 STANDARD_DEVIATION 1.97 • n=4 Participants	21.58 kg/m^2 STANDARD_DEVIATION 1.65 • n=27 Participants
Hormones	26 Participants n=93 Participants	58 Participants n=4 Participants	84 Participants n=27 Participants

PRIMARY outcome

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

Population: There were only 15 women who completed Aim 1 of the study. There were 19 women who completed aim 2 of the study and one had to be excluded due to not meeting the inclusion criteria once in the study.

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.

Outcome measures

Outcome measures
Measure	Aim 1-Supplementation of FFAs in an Acute or Chronic Model. n=15 Participants 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. Insulin Intralipid Dextrose Heparin GnRH	Aim 2-Hyperinsulinemic Euglycemic Clamp. n=18 Participants 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. Insulin Intralipid Dextrose Heparin GnRH Hyperinsulinemic Euglycemic Clamp
Change in LH Pulse Amplitude Before and After Acute or Chronic FFA Administration	2.33 IU/L Standard Error 1.21	2.4 IU/L Standard Error 1.1

PRIMARY outcome

Timeframe: 30 minutes

Population: Aim 1 included 15 participants who completed the studies. In Aim 2 one participant was excluded due to the fact once the analysis was completed she did not meet the inclusion/exclusion criteria and the total number of participants who completed the clamp was 15 per study design.

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).

Outcome measures

Outcome measures
Measure	Aim 1-Supplementation of FFAs in an Acute or Chronic Model. n=15 Participants 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. Insulin Intralipid Dextrose Heparin GnRH	Aim 2-Hyperinsulinemic Euglycemic Clamp. n=15 Participants 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. Insulin Intralipid Dextrose Heparin GnRH Hyperinsulinemic Euglycemic Clamp
Change in Steady State Amount of Glucose Metabolized at the Set Insulin Infusion Rate Under Euglycemic Conditions	1.98 mg/dL Standard Error 0.14	0.0485 mg/dL Standard Error 0.0641

SECONDARY outcome

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

Population: All participants completed both Aim 1 and Aim 2 in the study.

GnRH response will be compared between the non-intervention and intervention study as described above for gonadotropin pulsatility. The Investigator have used area under the curve methods to determine the LH response to exogenous GnRH and will utilize the same methodology as the investigator have done in the past.

Outcome measures

Outcome measures
Measure	Aim 1-Supplementation of FFAs in an Acute or Chronic Model. n=15 Participants 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. Insulin Intralipid Dextrose Heparin GnRH	Aim 2-Hyperinsulinemic Euglycemic Clamp. n=15 Participants 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. Insulin Intralipid Dextrose Heparin GnRH Hyperinsulinemic Euglycemic Clamp
Change in GnRH Response Before and After Acute or Chronic FFA Administration	567.63 IU/L*min Standard Error 1.22	355.12 IU/L*min Standard Error 1.23

SECONDARY outcome

Timeframe: Before and after FFA adminstration

Population: normal weight women

FSH parameters will be compared between the non-intervention and intervention studies for both aims as described above for gonadotropin pulsatility. The investigator will compare mean FSH, as pulsatility of FSH is less obvious than LH.

Outcome measures

Outcome measures
Measure	Aim 1-Supplementation of FFAs in an Acute or Chronic Model. n=15 Participants 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. Insulin Intralipid Dextrose Heparin GnRH	Aim 2-Hyperinsulinemic Euglycemic Clamp. n=12 Participants 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. Insulin Intralipid Dextrose Heparin GnRH Hyperinsulinemic Euglycemic Clamp
Change in Mean FSH Parameter Before and After Acute or Chronic FFA Administration	242.46 IU/L*min Standard Error 1.23	158.99 IU/L*min Standard Error 1.25

SECONDARY outcome

Timeframe: 4 hours

Population: Normal Weight women

The investigator will compare changes in gonadotropin pulse frequency (for LH, and if we can detect distinct FSH pulses, we will compare FSH as well), mean LH and FSH and kinetics of LH, and if possible, FSH, before and after the intervention, as previously reported

Outcome measures

Outcome measures
Measure	Aim 1-Supplementation of FFAs in an Acute or Chronic Model. n=15 Participants 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. Insulin Intralipid Dextrose Heparin GnRH	Aim 2-Hyperinsulinemic Euglycemic Clamp. n=12 Participants 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. Insulin Intralipid Dextrose Heparin GnRH Hyperinsulinemic Euglycemic Clamp
Changes in Gonadotropin Pulse Frequency	2.33 IU/L Standard Error 1.21	1.49 IU/L Standard Error 1.23

SECONDARY outcome

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

Population: Eighteen Normal weight women urinary hormones were measured during 4 menstrual cycles which was before, during and after the high fat diet administration. We looked at the change in peak LH before and after the high fat diet.

Urinary hormone profiles will be assessed for the entire cycle before and two cycles after initiation of the HFD using previously described menstrual cycle parameters suitable for urinary hormone determinations. The LH peak will be determined for all cycles that demonstrate a Progesterone increment consistent with ovulation. Follicular and luteal phase lengths will be calculated, as will integrated follicular, luteal and whole cycle LH, FSH, E1c and Progesterone. The measurement is the change in value from baseline to 4 menstrual cycles (approximately 4 months) after baseline.

Outcome measures

Outcome measures
Measure	Aim 1-Supplementation of FFAs in an Acute or Chronic Model. n=18 Participants 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. Insulin Intralipid Dextrose Heparin GnRH	Aim 2-Hyperinsulinemic Euglycemic Clamp. 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. Insulin Intralipid Dextrose Heparin GnRH Hyperinsulinemic Euglycemic Clamp
Urinary Hormone Profiles Before, During and After High Fat Diet Administration.	-10.71 mIU/mg Creatinine Standard Error 2.2	—

SECONDARY outcome

Timeframe: 60 Minutes during HEC

Glucose will be measured by the CTRC laboratories before and after FFA administration..

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 30 Minutes during the HEC

RBC lipids will also be compared, as the investigator predict that the HFD will result in increased omega-6 rich FFAs and less omega-3 FFAs

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 5 months-before and after the interventation.

DEXA body composition will be measured before and after the intervention.

Outcome measures

Outcome data not reported

Adverse Events

Aim 1

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Aim 2

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Aim 1 n=13 participants at risk 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. Insulin Intralipid Dextrose Heparin GnRH	Aim 2 n=18 participants at risk 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. Insulin Intralipid Dextrose Heparin GnRH Hyperinsulinemic Euglycemic Clamp
Investigations Headache and Nausea	7.7% 1/13 • Number of events 1 • The adverse events were collected over 6 years participants were not at risk for mortality due the nature of intervention. The participants were monitored for AEs by the investigator.	0.00% 0/18 • The adverse events were collected over 6 years participants were not at risk for mortality due the nature of intervention. The participants were monitored for AEs by the investigator.

Additional Information

Dr. Nanette Santoro

University of Colorado School of Medicine

Phone: 303-724-2041

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place