An interventional study of Insulin and Intralipid in Obesity, Infertility and Hypogonadotropic Hypogonadotropism, sponsored by University of Colorado, Denver. Active, not recruiting at 1 site in United States. Open to female participants aged 18 Years to 38 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-03-02.
Sponsored by University of Colorado, Denver · Not applicable, Interventional, and Basic science
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.
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.
11,522 studies on the registry are indexed under Obesity; 2,033 are open to participants now.
This study's enrollment of 84 is above the median of 67 across 9,006 interventional studies indexed under Obesity.
Browse Obesity studies →University of Colorado, Denver is the lead sponsor of 1,543 studies on the registry; 317 are open to participants now.
Of its 147 completed or terminated interventional studies of FDA-regulated products, 92 (63%) have results posted.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
A blood test of average blood sugar over the past two to three months, given as a percentage or in mmol/mol. 6.5% (48 mmol/mol) or more is the usual threshold for diabetes, normally confirmed by a second test.
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
BMI (body mass index)
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HbA1c
A blood test of average blood sugar over the past two to three months, given as a percentage or in mmol/mol. 6.5% (48 mmol/mol) or more is the usual threshold for diabetes, normally confirmed by a second test.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hemoglobin (Hb)
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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
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
Also known as: Humulin
Also known as: Free Fatty Acid
Also known as: d-glucose
Also known as: anticoagulant
Also known as: gonadorelin acetate
Also known as: HEC
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
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
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.
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
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
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)
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
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
DEXA Body Composition Comparison
DEXA body composition will be measured before and after the intervention.
Time frame: 5 months-before and after the interventation.
| Milestone | Aim 1-Acute Infusion of FFA and Chronic Model | Aim 2- Hyperinsulinemic Euglycemic Clamp |
|---|---|---|
| Started | 26 | 58 |
| Completed | 13 | 18 |
| Not completed | 13 | 40 |
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.
| IU/L | Aim 1-Supplementation of FFAs in an Acute or Chronic Model. | Aim 2-Hyperinsulinemic Euglycemic Clamp. |
|---|---|---|
| Change in LH Pulse Amplitude Before and After Acute or Chronic FFA Administration | 2.33 ± 1.21 | 2.4 ± 1.1 |
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).
| mg/dL | Aim 1-Acute and Chronic Administration of FFAs. | Aim 2-Hyperinsulinemic Euglycemic Clamp |
|---|---|---|
| Change in Steady State Amount of Glucose Metabolized at the Set Insulin Infusion Rate Under Euglycemic Conditions | 1.98 ± 0.14 | 0.0485 ± 0.0641 |
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.
| IU/L*min | Aim 1-Administration of FFA in an Acute Model | Aim 2-Hyperinsulinemic Euglycemic Clamp After a Chronic Administration of a Diet |
|---|---|---|
| Change in GnRH Response Before and After Acute or Chronic FFA Administration | 567.63 ± 1.22 | 355.12 ± 1.23 |
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.
| IU/L*min | Aim 1-Supplementation of FFAs in an Acute or Chronic Model. | Aim 2-Hyperinsulinemic Euglycemic Clamp. |
|---|---|---|
| Change in Mean FSH Parameter Before and After Acute or Chronic FFA Administration | 242.46 ± 1.23 | 158.99 ± 1.25 |
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
| IU/L | Aim 1-Supplementation of FFAs in an Acute or Chronic Model. | Aim 2-Hyperinsulinemic Euglycemic Clamp. |
|---|---|---|
| Changes in Gonadotropin Pulse Frequency | 2.33 ± 1.21 | 1.49 ± 1.23 |
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.
| mIU/mg Creatinine | Chronic Model |
|---|---|
| Urinary Hormone Profiles Before, During and After High Fat Diet Administration. | -10.71 ± 2.2 |
Glucose will be measured by the CTRC laboratories before and after FFA administration..
Results for this outcome have not been posted.
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
Results for this outcome have not been posted.
DEXA body composition will be measured before and after the intervention.
Results for this outcome have not been posted.
Collected over The adverse events were collected over 6 years. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Aim 1 | 0/13 (0%) | 0/13 (0%) | 1/13 (7.7%) |
| Aim 2 | 0/18 (0%) | 0/18 (0%) | 0/18 (0%) |
| Event | Aim 1 | Aim 2 |
|---|---|---|
| Headache and NauseaInvestigations | 1/13 | — |
| Age, Categorical(Participants) | Aim 1 | Aim 2 | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 26 | 58 | 84 |
| >=65 years | 0 | 0 | 0 |
| Age, Continuous(years) | Aim 1 | Aim 2 | Total |
|---|---|---|---|
| Mean | 30.63 ± 5.46 | 29.53 ± 6.17 | 30.01 ± 5.85 |
| Sex: Female, Male(Participants) | Aim 1 | Aim 2 | Total |
|---|---|---|---|
| Female | 26 | 58 | 84 |
| Male | 0 | 0 | 0 |
| Ethnicity (NIH/OMB)(Participants) | Aim 1 | Aim 2 | Total |
|---|---|---|---|
| Hispanic or Latino | 3 | 5 | 8 |
| Not Hispanic or Latino | 23 | 50 | 73 |
| Unknown or Not Reported | 0 | 3 | 3 |
| Race (NIH/OMB)(Participants) | Aim 1 | Aim 2 | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 3 | 6 | 9 |
| Native Hawaiian or Other Pacific Islander | 0 | 3 | 3 |
| Black or African American | 0 | 2 | 2 |
| White | 21 | 44 | 65 |
| More than one race | 1 | 0 | 1 |
| Unknown or Not Reported | 1 | 3 | 4 |
| Region of Enrollment(participants) | Aim 1 | Aim 2 | Total |
|---|---|---|---|
| United States | 26 | 58 | 84 |
| BMI(kg/m^2) | Aim 1 | Aim 2 | Total |
|---|---|---|---|
| Mean | 21.60 ± 1.32 | 21.57 ± 1.97 | 21.58 ± 1.65 |
| Hormones(Participants) | Aim 1 | Aim 2 | Total |
|---|---|---|---|
| Count of participants | 26 | 58 | 84 |
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