Reproductive Hormonal Alterations in Obesity

Study Overview
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Brief Summary
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The purpose of this study is to determine why obese women have lower hormone levels and less fertility than women of normal body weight. The proposal will examine the reproductive system at the level of the brain and the ovary to define the changes that happen leading to lowered hormone production. Women will be studied throughout a menstrual cycle and given medications that will test how well their pituitary gland can make hormones that stimulate the ovary (luteinizing hormone (LH) and follicle stimulating hormone (FSH)). They will also be given a medication to abolish estrogen production in the body and their response to this medication will be assessed. Finally, the ovary's ability to produce progesterone after ovulation will be examined. --Hypotheses: Obese women have reduced pituitary sensitivity to exogenous gonadotropin-releasing hormone (GnRH), but normal clearance of exogenous LH. (comparative study of obese compared to normal weight women) Obese women have abnormally increased sensitivity to estradiol negative feedback which will be reversed by an aromatase inhibitor. (comparative study of obese compared to normal weight women)

Detailed Description
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AIM 1: test the hypothesis that reduced pituitary sensitivity to GnRH-induced LH and FSH secretion causes the relative hypogonadotropic hypogonadism of obesity AIM 2: test the hypothesis that the hypothalamic-pituitary axis is abnormally sensitive to estradiol negative feedback in obesity

Official Title
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Reproductive Hormonal Alterations in Obesity, AIMS #1 & #2

Conditions
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Obesity

Intervention / Treatment
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* Drug: Cetrorelix
* Drug: Gonadorelin-GnRH
* Drug: Recombinant LH
* Drug: Letrozole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18-40 at study entry BMI either 18-25 kg/m2 or ≥30 kg/m2 prolactin (PRL) and thyroid-stimulating hormone (TSH) within normal laboratory ranges at screening Baseline hemoglobin >11 gm/dl History of regular menstrual cycles every 25-35 days if BMI 18-25 kg/m2 History of regular menstrual cycles every 25-40 days if BMI ≥30 kg/m2 Exclusion Criteria: History of chronic disease affecting hormone production, metabolism or clearance Use of medications that are known to alter or interact with reproductive hormones (e.g., thiazolidinediones, metformin) Use of hormones within three months of enrollment Excessive exercise (>4 hours per week) Pregnancy, breast-feeding or current active attempts to conceive

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: BMI ≥30 kg/m2<br>Group 2: BMI ≥30 kg/m2 History of regular menstrual cycles every 25-40 days Gonadorelin-GnRH (Lutrepulse), GnRH antagonists - Cetrorelix (Cetrotide), Recombinant LH (Luveris) were administered in Aim 1. GnRH or gonadorelin (Lutrepulse) and Letrozole were administered in Aim 2. | Drug: Cetrorelix<br>* Abolishes pituitary sensitivity to GnRH.<br>* Other names: Cetrotide;Drug: Gonadorelin-GnRH<br>* GnRH is used to stimulate the pituitary gland to produce LH and FSH.<br>* Other names: Lutrepulse;Drug: Recombinant LH<br>* Used to stimulate ovarian function in women.<br>* Other names: Luveris;Drug: Letrozole<br>* An aromatase inhibitor.<br>* Other names: Femara;|
| Experimental: BMI 18-25 kg/m2<br>BMI 18-25 kg/m2 History of regular menstrual cycles every 25-35 days Gonadorelin-GnRH (Lutrepulse), GnRH antagonists - Cetrorelix (Cetrotide), Recombinant LH (Luveris) were administered in Aim 1. GnRH or gonadorelin (Lutrepulse) and Letrozole were administered in Aim 2. | Drug: Cetrorelix<br>* Abolishes pituitary sensitivity to GnRH.<br>* Other names: Cetrotide;Drug: Gonadorelin-GnRH<br>* GnRH is used to stimulate the pituitary gland to produce LH and FSH.<br>* Other names: Lutrepulse;Drug: Recombinant LH<br>* Used to stimulate ovarian function in women.<br>* Other names: Luveris;Drug: Letrozole<br>* An aromatase inhibitor.<br>* Other names: Femara;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Luteinizing Hormone (LH) Pulse Amplitude (Aim 1) | Luteinizing Hormone (LH) Pulse Amplitude was measured hourly during the 12 hour study visit, and was compared between the obese and normal weight groups. | Measured hourly and averaged over the 12 hour study visit | 
| Changes in Luteinizing Hormone (LH) Pulse Amplitude (Aim 2) | Luteinizing Hormone (LH) Pulse Amplitude was measured hourly during the 12 hour study visit, and was compared between the obese and normal weight groups. | Measured hourly and averaged over the 12 hour study visit | 
| Changes in Pregnanediol Glucuronide (PdG) (Aim 2) | Pregnanediol glucuronide (PdG) was collected daily over the course of one menstrual cycle and averaged. | Averaged over the length of menstrual cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Follicle Stimulating Hormone (FSH) (Aim 1) | Follicle-stimulating hormone was measured hourly during the 12 hour study visit, and was compared between the obese and normal weight groups. | Measured hourly and averaged over the 12 hour study visit | 
| Changes in Follicle Stimulating Hormone (FSH) (Aim 2) | Follicle-stimulating hormone was measured hourly during the 12 hour study visit, and was compared between the obese and normal weight groups. | Measured hourly and averaged over the 12 hour study visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LH pulsatility, Obesity, Reproduction