Reproductive Hormonal Alterations in Obesity

Not Applicable

Completed

Conditions: Obesity

Interventions: Drug: Cetrorelix
Drug: Gonadorelin-GnRH
Drug: Recombinant LH
Drug: Letrozole

Registration Number: NCT01457703

Lead Sponsor: University of Colorado, Denver

Brief Summary: 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:

1. 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)

2. 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: 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

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 62

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
BMI ≥30 kg/m2	Gonadorelin-GnRH	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.
BMI 18-25 kg/m2	Recombinant LH	* 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.
BMI ≥30 kg/m2	Cetrorelix	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.
BMI ≥30 kg/m2	Letrozole	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.
BMI 18-25 kg/m2	Gonadorelin-GnRH	* 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.
BMI ≥30 kg/m2	Recombinant LH	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.
BMI 18-25 kg/m2	Cetrorelix	* 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.
BMI 18-25 kg/m2	Letrozole	* 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.

Primary Outcome Measures

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

Secondary Outcome Measures

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