Obesity
Conditions
Keywords
LH pulsatility, Obesity, Reproduction
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
Interventions
DRUGCetrorelix
Abolishes pituitary sensitivity to GnRH.
DRUGGonadorelin-GnRH
GnRH is used to stimulate the pituitary gland to produce LH and FSH.
DRUGRecombinant LH
Used to stimulate ovarian function in women.
DRUGLetrozole
An aromatase inhibitor.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of Colorado, Denver
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BMI ≥30 kg/m2 * BMI ≥30 kg/m2
* History of regular menstrual cycles every 25-40 days
Letrozole, Gonadorelin-GnRH, Luveris-lutropin, cetrorelix: Reproductive Hormonal Alterations in Obesity, Aims #1 and 2 Description: comparative study of pathophysiology | 29 |
| BMI 18-25 kg/m2 * BMI 18-25 kg/m2
* History of regular menstrual cycles every 25-35 days
Letrozole, Gonadorelin-GnRH, Luveris-lutropin, cetrorelix: Reproductive Hormonal Alterations in Obesity, Aims #1 and 2 Description: comparative study of pathophysiology | 33 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Screen Failure | 5 | 7 |
| Overall Study | Withdrawal by Subject | 1 | 4 |
Baseline characteristics
| Characteristic | BMI ≥30 kg/m2 | BMI 18-25 kg/m2 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants | 33 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 5 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants | 28 Participants | 52 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants |
| Gender Female | 29 Participants | 33 Participants | 62 Participants |
| Gender Male | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 6 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 6 Participants | 8 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) White | 15 Participants | 19 Participants | 34 Participants |
| Region of Enrollment United States | 29 participants | 33 participants | 62 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 29 | 0 / 33 |
| serious Total, serious adverse events | 0 / 29 | 0 / 33 |
Outcome results
Primary
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.
Time frame: Measured hourly and averaged over the 12 hour study visit
Population: This study was divided into two aims, and 10 obese and 10 normal weight women completed the study procedures and contributed data for analyses related to Aim 1.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| BMI ≥30 kg/m2 | Changes in Luteinizing Hormone (LH) Pulse Amplitude (Aim 1) | 4.1 IU/L |
| BMI 18-25 kg/m2 | Changes in Luteinizing Hormone (LH) Pulse Amplitude (Aim 1) | 3.6 IU/L |
Primary
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.
Time frame: Measured hourly and averaged over the 12 hour study visit
Population: This study was divided into two aims, and only 12 obese and 11 normal weight women completed the study procedures for Aim 2 that allowed measure of LH pulse amplitude.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BMI ≥30 kg/m2 | Changes in Luteinizing Hormone (LH) Pulse Amplitude (Aim 2) | 2.21 IU/L | Standard Deviation 0.32 |
| BMI 18-25 kg/m2 | Changes in Luteinizing Hormone (LH) Pulse Amplitude (Aim 2) | 4.44 IU/L | Standard Deviation 1.03 |
Primary
Changes in Pregnanediol Glucuronide (PdG) (Aim 2)
Pregnanediol glucuronide (PdG) was collected daily over the course of one menstrual cycle and averaged.
Time frame: Averaged over the length of menstrual cycle
Population: This study was divided into two aims, and only 12 obese and 10 normal weight women completed the urine collection study procedures for Aim 2 that allowed measure of PdG.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BMI ≥30 kg/m2 | Changes in Pregnanediol Glucuronide (PdG) (Aim 2) | 54.1 ug/cycle | Standard Deviation 33 |
| BMI 18-25 kg/m2 | Changes in Pregnanediol Glucuronide (PdG) (Aim 2) | 88.7 ug/cycle | Standard Deviation 64.6 |
Secondary
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.
Time frame: Measured hourly and averaged over the 12 hour study visit
Population: This study was divided into two aims, and only 10 obese and 10 normal weight women completed the study procedures for Aim 1 that allowed measure of FSH.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| BMI ≥30 kg/m2 | Changes in Follicle Stimulating Hormone (FSH) (Aim 1) | 3.8 IU/L |
| BMI 18-25 kg/m2 | Changes in Follicle Stimulating Hormone (FSH) (Aim 1) | 3.3 IU/L |
Secondary
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.
Time frame: Measured hourly and averaged over the 12 hour study visit
Population: This study was divided into two aims, and only 12 obese and 11 normal weight women completed the study procedures for Aim 2 that allowed measure of FSH.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BMI ≥30 kg/m2 | Changes in Follicle Stimulating Hormone (FSH) (Aim 2) | 5.31 IU/L | Standard Deviation 0.38 |
| BMI 18-25 kg/m2 | Changes in Follicle Stimulating Hormone (FSH) (Aim 2) | 6.18 IU/L | Standard Deviation 0.94 |