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Reprometabolic Syndrome Mediates Subfertility in Obesity

Reprometabolic Syndrome Mediates Subfertility in Obesity

Status
Active, not recruiting
Phases
Unknown
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT02653092
Enrollment
84
Registered
2016-01-12
Start date
2016-06-01
Completion date
2026-12-11
Last updated
2026-03-02

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Obesity, Infertility, Hypogonadotropic Hypogonadotropism, Hyperinsulinemia

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.

Detailed description

Before any of the well-known adverse effects in pregnancy2,3, obesity causes a relatively hypogonadotropic hypogonadal phenotype. Reduced LH, FSH, estradiol (E2) and progesterone secretion are well documented during the menstrual cycles of obese women compared to normal weight women (NWW).4,5. Decreased gonadotropin secretion associated with obesity is related to reduced pituitary sensitivity to GnRH6. This reduction in pituitary sensitivity suggests mediation by circulating factors such as cytokines, insulin, or other pro-inflammatory signals known to be elevated in obesity. We have recently discovered that the combination of hyperinsulinemia and circulating free fatty acids (FFAs), but neither agent alone, can acutely decrease gonadotropin secretion in NWW as well as men, establishing a direct causal linkage for the central hypothesis of this proposal: that chronic pituitary suppression partially mediates obesity related subfertility. Our working model is that the combination of excess, possibly pro-inflammatory (omega-6) circulating FFAs and insulin resistance associated with obesity, cause decreased pituitary sensitivity to GnRH, with a resulting relative sex steroid deficit that further exacerbates the obese phenotype. We have named this phenotype the reprometabolic syndrome. We propose to examine the interrelationships among obesity, reproductive dysfunction and metabolic dysfunction in a mechanistic fashion. We will induce the hypogonadotropic hypogonadal phenotype of obesity in NWW, who will be primed with a high-fat diet (HFD) designed to increase circulating FFAs and produce short-term insulin resistance and higher insulin levels.1,7-11 Before and after priming, we will test the additive effects of lipid excess, insulin, and inflammation on the reproductive and metabolic axes.

Interventions

DRUGInsulin
DRUGIntralipid
DRUGDextrose
DRUGHeparin
DRUGGnRH

Sponsors

University of Colorado, Denver
Lead SponsorOTHER
National Center for Advancing Translational Sciences (NCATS)
CollaboratorNIH

Study design

Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE

Eligibility

Sex/Gender
FEMALE
Age
18 Years to 38 Years
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.

Design outcomes

Primary

MeasureTime frameDescription
Change in LH Pulse Amplitude Before and After Acute or Chronic FFA AdministrationFirst 4 hours of the frequent blood sampling study before and after FFA administrationLH-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.
Change in Steady State Amount of Glucose Metabolized at the Set Insulin Infusion Rate Under Euglycemic Conditions30 minutesPrimary 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).

Secondary

MeasureTime frameDescription
Change in GnRH Response Before and After Acute or Chronic FFA AdministrationAfter the administration of GnRH at each FSS before and after acute and chronic FFA administration was assessed for up to 4 hours.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.
Change in Mean FSH Parameter Before and After Acute or Chronic FFA AdministrationBefore and after FFA adminstrationFSH 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.
Changes in Gonadotropin Pulse Frequency4 hoursThe 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
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)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.
Glucose Measurements Before and After FFA Administration.60 Minutes during HECGlucose will be measured by the CTRC laboratories before and after FFA administration..
Comparison of RBC Lipids Before and After the FFA Administration30 Minutes during the HECRBC 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
DEXA Body Composition Comparison5 months-before and after the interventation.DEXA body composition will be measured before and after the intervention.

Countries

United States

Contacts

PRINCIPAL_INVESTIGATORNanette Santoro, MD

University of Colorado, Denver

Participant flow

Participants by arm

ArmCount
Aim 1
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
26
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 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
58
Total84

Baseline characteristics

CharacteristicAim 2Aim 1Total
Age, Categorical
<=18 years
0 Participants0 Participants0 Participants
Age, Categorical
>=65 years
0 Participants0 Participants0 Participants
Age, Categorical
Between 18 and 65 years
58 Participants26 Participants84 Participants
Age, Continuous29.53 years
STANDARD_DEVIATION 6.17
30.63 years
STANDARD_DEVIATION 5.46
30.01 years
STANDARD_DEVIATION 5.85
BMI21.57 kg/m^2
STANDARD_DEVIATION 1.97
21.60 kg/m^2
STANDARD_DEVIATION 1.32
21.58 kg/m^2
STANDARD_DEVIATION 1.65
Ethnicity (NIH/OMB)
Hispanic or Latino
5 Participants3 Participants8 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
50 Participants23 Participants73 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
3 Participants0 Participants3 Participants
Hormones58 Participants26 Participants84 Participants
Race (NIH/OMB)
American Indian or Alaska Native
0 Participants0 Participants0 Participants
Race (NIH/OMB)
Asian
6 Participants3 Participants9 Participants
Race (NIH/OMB)
Black or African American
2 Participants0 Participants2 Participants
Race (NIH/OMB)
More than one race
0 Participants1 Participants1 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
3 Participants0 Participants3 Participants
Race (NIH/OMB)
Unknown or Not Reported
3 Participants1 Participants4 Participants
Race (NIH/OMB)
White
44 Participants21 Participants65 Participants
Region of Enrollment
United States
58 participants26 participants84 participants
Sex: Female, Male
Female
58 Participants26 Participants84 Participants
Sex: Female, Male
Male
0 Participants0 Participants0 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
deaths
Total, all-cause mortality
0 / 130 / 18
other
Total, other adverse events
1 / 130 / 18
serious
Total, serious adverse events
0 / 130 / 18

Outcome results

Primary

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.

Time frame: 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.

ArmMeasureValue (MEAN)Dispersion
Aim 1-Supplementation of FFAs in an Acute or Chronic Model.Change in LH Pulse Amplitude Before and After Acute or Chronic FFA Administration2.33 IU/LStandard Error 1.21
Aim 2-Hyperinsulinemic Euglycemic Clamp.Change in LH Pulse Amplitude Before and After Acute or Chronic FFA Administration2.4 IU/LStandard Error 1.1
Primary

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).

Time frame: 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.

ArmMeasureValue (MEAN)Dispersion
Aim 1-Supplementation of FFAs in an Acute or Chronic Model.Change in Steady State Amount of Glucose Metabolized at the Set Insulin Infusion Rate Under Euglycemic Conditions1.98 mg/dLStandard Error 0.14
Aim 2-Hyperinsulinemic Euglycemic Clamp.Change in Steady State Amount of Glucose Metabolized at the Set Insulin Infusion Rate Under Euglycemic Conditions0.0485 mg/dLStandard Error 0.0641
Secondary

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

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.

Time frame: 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.

ArmMeasureValue (MEAN)Dispersion
Aim 1-Supplementation of FFAs in an Acute or Chronic Model.Change in GnRH Response Before and After Acute or Chronic FFA Administration567.63 IU/L*minStandard Error 1.22
Aim 2-Hyperinsulinemic Euglycemic Clamp.Change in GnRH Response Before and After Acute or Chronic FFA Administration355.12 IU/L*minStandard Error 1.23
Secondary

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

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.

Time frame: Before and after FFA adminstration

Population: normal weight women

ArmMeasureValue (MEAN)Dispersion
Aim 1-Supplementation of FFAs in an Acute or Chronic Model.Change in Mean FSH Parameter Before and After Acute or Chronic FFA Administration242.46 IU/L*minStandard Error 1.23
Aim 2-Hyperinsulinemic Euglycemic Clamp.Change in Mean FSH Parameter Before and After Acute or Chronic FFA Administration158.99 IU/L*minStandard Error 1.25
Secondary

Changes in Gonadotropin Pulse Frequency

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

Time frame: 4 hours

Population: Normal Weight women

ArmMeasureValue (MEAN)Dispersion
Aim 1-Supplementation of FFAs in an Acute or Chronic Model.Changes in Gonadotropin Pulse Frequency2.33 IU/LStandard Error 1.21
Aim 2-Hyperinsulinemic Euglycemic Clamp.Changes in Gonadotropin Pulse Frequency1.49 IU/LStandard Error 1.23
Secondary

Comparison of RBC Lipids Before and After the FFA Administration

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

Time frame: 30 Minutes during the HEC

Secondary

DEXA Body Composition Comparison

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

Time frame: 5 months-before and after the interventation.

Secondary

Glucose Measurements Before and After FFA Administration.

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

Time frame: 60 Minutes during HEC

Secondary

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

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.

Time frame: 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.

ArmMeasureValue (MEAN)Dispersion
Aim 1-Supplementation of FFAs in an Acute or Chronic Model.Urinary Hormone Profiles Before, During and After High Fat Diet Administration.-10.71 mIU/mg CreatinineStandard Error 2.2

Source: ClinicalTrials.gov · Data processed: Mar 3, 2026