Dysregulation of FSH in Obesity: Functional and Statistical Analysis

Study Overview
=================
Brief Summary
-----------------
Excess maternal weight, especially obesity, influences almost every aspect of fertility, from conception to problems during pregnancy. The investigators will use novel statistical methods to clarify the hormonal changes behind reproductive health conditions. A better understanding of reproductive hormonal changes in obese women may offer a way to identify new treatments.

Detailed Description
-----------------
Hypothesis. Insufficient FSH (Follicle-stimulating hormone) pulsatility, as seen in obesity, results in inadequate folliculogenesis and reduced ovarian steroid and protein production. AIM: To test the hypothesis that insufficient FSH pulsatility, as seen in obesity, results in inadequate folliculogenesis and reduced ovarian steroid and protein production. The investigators will determine if exogenous FSH administered in a pulsatile fashion results in a significant increase of ovarian hormones in obese women. Serial inhibin B and E2 levels will be measured in obese and normal weight women undergoing frequent blood sampling studies before and after GnRH (Gonadotropin-releasing hormone) antagonist blockade.

Official Title
-----------------
Dysregulation of Follicle Stimulating Hormone (FSH) in Obesity: Functional and Statistical Analysis

Conditions
-----------------
Obesity, Fertility

Intervention / Treatment
-----------------
* Drug: Degarelix (GnRH antagonist)
* Drug: recombinant FSH
* Drug: Cetrorelix


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age between 21 to 39 years old with regular menstrual cycles every 25-40 days Body mass of 18.5 kg/m2-24.9kg/m2 (normal weight controls) or greater than 30.0 kg/m2 (obese group) Prolactin and thyroid-stimulating hormone (TSH) within normal laboratory ranges at screening Baseline hemoglobin >11 gm/dl. Exclusion Criteria: Diagnosis of polycystic ovary syndrome (PCOS), defined by the 2003 Rotterdam criteria as suggested by 2012 NIH Workshop History of chronic disease affecting hormone production, metabolism or clearance or use of thiazolidinediones or metformin (known to interact with reproductive hormones) Use of hormones affecting hypothalamic-pituitary-gonadal (HPO) axis (such as hormonal contraceptives) within 3 months of entry Strenuous exercise (>4 hours of intense physical activity per week) Pregnancy Breast-feeding Current attempts to conceive Significant recent weight loss or gain

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 39 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Frequent Blood Sampling, Degarelix<br>Investigators will assess the change in inhibin B levels following repeated bolus dosing of recombinant FSH (rFHS) following Degarelix (GnRH antagonist) blockade over a 2-day period. This arm was terminated due to Adverse Events and the study was continued with the Cetrorelix product. | Drug: Degarelix (GnRH antagonist)<br>* Day-1: Blood samples will be obtained every 10 minutes for 10 hours. After 10 hours of blood samples have been collected, the GnRH antagonist degarelix will be given subcutaneously.<br>* Other names: Firmagon;Drug: recombinant FSH<br>* Day-2: Blood samples will again be obtained every 10 minutes for 10 hours. Repeated boluses of exogenous recombinant FSH (rFSH) will be given by IV during this 10 hour visit.<br>* Other names: rFHS;|
| Experimental: Frequent Blood Sampling, Cetrorelix<br>Investigators will assess the change in inhibin B levels following repeated bolus dosing of recombinant FSH (rFHS) following Cetrorelix blockade over a 2-day period. | Drug: recombinant FSH<br>* Day-2: Blood samples will again be obtained every 10 minutes for 10 hours. Repeated boluses of exogenous recombinant FSH (rFSH) will be given by IV during this 10 hour visit.<br>* Other names: rFHS;Drug: Cetrorelix<br>* Day-1: Blood samples will be obtained every 10 minutes for 10 hours. After 10 hours of blood samples have been collected, the GnRH antagonist Cetrorelix will be given subcutaneously.<br>* Other names: Cetrotide;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference Between Peak Inhibin B | This is defined as the maximum hormone value during Day 1 of the study subtracted from the maximum hormone value during Day 2. | Every 10 minutes over 2 10-hour frequent blood sampling sessions. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Inhibin B Per Subject | Peak inhibin B will be measured every 10 minutes during day 1 and day 2 of the study. The highest inhibin B value will be defined as the peak. | Every 10 minutes over 10 hours on Day 1 and Day 2 of the study. | 
| Peak E2 Per Subject | E2 will be measured every 10 minutes on Day 1 and Day 2 of the study. The highest E2 value will be designated as the peak E2 value. | Every 10 minutes over 10 hours of Day 1 and Day 2 of the study. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
obesity, fertility, infertility, reproductive hormones