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| ID | Type | Description | Link |
|---|---|---|---|
| UL1TR001082 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Center for Advancing Translational Sciences (NCATS) | NIH |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Insulin | Drug |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | After the administration of GnRH at each FSS before and after acute and chronic FFA administration was assessed for up to 4 hours. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Nanette Santoro, MD | University of Colorado, Denver | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Colorado Denver | Aurora | Colorado | 80045 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38710978 | Derived | 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. | |
| 33838870 | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Aim 1-Acute Infusion of FFA and Chronic Model | Reproduction of the reproductive phenotype of obesity in Normal Weight Women (NWW) by:
Insulin Intralipid Dextrose Heparin GnRH |
| FG001 | 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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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. | Posted | Mean | Standard Error | IU/L | First 4 hours of the frequent blood sampling study before and after FFA administration |
|
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Aim 1 | Reproduction of the reproductive phenotype of obesity in Normal Weight Women (NWW) by:
Insulin Intralipid Dextrose Heparin GnRH |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache and Nausea | Investigations | CTCAE (4.0) | Non-systematic Assessment | One participant had a headache and experienced nausea towards the end of the infusion/frequent blood sampling session. She was removed from the infusion and give medication for the nausea and headache. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Nanette Santoro | University of Colorado School of Medicine | 303-724-2041 | Nanette.Santoro@uanschutz.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 5, 2020 | Feb 23, 2023 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Oct 7, 2020 | Feb 23, 2023 | ICF_001.pdf |
Not provided
| ID | Term |
|---|---|
| D009765 | Obesity |
| D007246 | Infertility |
| D006946 | Hyperinsulinism |
| ID | Term |
|---|---|
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
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Not provided
| ID | Term |
|---|---|
| D007328 | Insulin |
| D061386 | Insulin, Regular, Human |
| C545823 | soybean oil, phospholipid emulsion |
| D005230 | Fatty Acids, Nonesterified |
| D005947 | Glucose |
| D006493 | Heparin |
| D000925 | Anticoagulants |
| D007987 | Gonadotropin-Releasing Hormone |
| ID | Term |
|---|---|
| D011384 | Proinsulin |
| D061385 | Insulins |
| D010187 | Pancreatic Hormones |
| D036361 | Peptide Hormones |
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Not provided
Not provided
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Not provided
| Intralipid | Drug |
|
|
| Dextrose | Drug |
|
|
| Heparin | Drug |
|
|
| GnRH | Drug |
|
|
| Hyperinsulinemic Euglycemic Clamp | Procedure |
|
|
| 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. | 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 | 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. | 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.. | 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 | 30 Minutes during the HEC |
| DEXA Body Composition Comparison | DEXA body composition will be measured before and after the intervention. | 5 months-before and after the interventation. |
| 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 |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| BMI | Mean | Standard Deviation | kg/m^2 |
|
| Hormones | Count of Participants | Participants |
|
| OG001 | 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 |
|
|
| 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). | 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. | Posted | Mean | Standard Error | mg/dL | 30 minutes |
|
|
|
| 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. | All participants completed both Aim 1 and Aim 2 in the study. | Posted | Mean | Standard Error | IU/L*min | After the administration of GnRH at each FSS before and after acute and chronic FFA administration was assessed for up to 4 hours. |
|
|
|
| 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. | normal weight women | Posted | Mean | Standard Error | IU/L*min | Before and after FFA adminstration |
|
|
|
| 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 | Normal Weight women | Posted | Mean | Standard Error | IU/L | 4 hours |
|
|
|
| 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. | 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. | Posted | Mean | Standard Error | mIU/mg Creatinine | Urinary assays will be measured for 4 menstrual cycles (approximately 4 months or 115 days) |
|
|
|
| Secondary | Glucose Measurements Before and After FFA Administration. | Glucose will be measured by the CTRC laboratories before and after FFA administration.. | Not Posted | 60 Minutes during HEC | Participants |
| 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 | Not Posted | 30 Minutes during the HEC | Participants |
| Secondary | DEXA Body Composition Comparison | DEXA body composition will be measured before and after the intervention. | Not Posted | 5 months-before and after the interventation. | Participants |
| 0 |
| 13 |
| 0 |
| 13 |
| 1 |
| 13 |
| EG001 | 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. Insulin Intralipid Dextrose Heparin GnRH Hyperinsulinemic Euglycemic Clamp | 0 | 18 | 0 | 18 | 0 | 18 |
|
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| D001835 |
| Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D006728 |
| Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D005227 | Fatty Acids |
| D008055 | Lipids |
| D006601 | Hexoses |
| D009005 | Monosaccharides |
| D000073893 | Sugars |
| D002241 | Carbohydrates |
| D006025 | Glycosaminoglycans |
| D011134 | Polysaccharides |
| D006401 | Hematologic Agents |
| D045506 | Therapeutic Uses |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
| D010906 | Pituitary Hormone-Releasing Hormones |
| D007028 | Hypothalamic Hormones |
| D009479 | Neuropeptides |
| D009842 | Oligopeptides |
| D009419 | Nerve Tissue Proteins |
| D011506 | Proteins |