Infertility, Obesity
Conditions
Keywords
LH pulsatility, Obesity, Reproduction
Brief summary
The sole purpose of this study is to evaluate pathophysiology of disease. The disease state that is being evaluated is the obesity-related alterations in reproductive hormones * The obesity epidemic in the United States is advancing at an accelerated pace. It is estimated that by 2015, 41% of U.S. adults will be obese as defined by a body mass index (BMI) of greater than 30 kg/m2. The U.S. government's 2010 Dietary Guidelines regard obesity as the single greatest health hazard in this century. Female adult obesity is associated with menstrual cycle irregularities, ovulatory dysfunction and a higher risk of obstetrical complications. This reproductive phenotype of obesity is worsened by further increases in BMI and is not solely due to anovulatory infertility. While the association of adiposity with subfertility is well documented in population studies, the underlying mechanisms remain poorly understood. The main objective of this proposal is to clarify the nature of the obesity-related reproductive endocrine abnormalities and identify potential etiologies amenable to therapy. * Hypothesis: The hypothalamic-pituitary axis is abnormally sensitive to estradiol negative feedback in obesity.
Detailed description
* Design: paired assessments Pre and Post estrogen administration in obese and normal weight women * AIM 1: To test the pituitary and hypothalamic responsiveness in obesity, we will examine the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) pulsatility during frequent blood sampling. * AIM 2: To test the ovarian responsiveness in obesity, we will examine urinary reproductive hormones (E1c, estrone conjugates, and Pdg, pregnanediol glucuronide) over an entire menstrual cycle. * AIM 3: To test the hypothesis that central adiposity is associated with reproductive hormone alterations in obesity, we will quantitatively assess body composition by dual energy x-ray absorptiometry (DXA).
Interventions
DRUGEstradiol
Subjects were instructed to apply 0.1 mg/d transdermal estrogen for one month.
DRUGGonadotropin-releasing hormone (GnRH)
Pituitary response was assessed to determine how estradiol administration alters pituitary sensitivity to GnRH.
DRUGProgesterone
Subjects who failed to initiate a menstrual period following 40 days on the patch were instructed to take 200 mg daily of progesterone for 10 days or as long as deemed necessary.
Sponsors
University of Colorado, Denver
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 42 Years
Healthy volunteers
Yes
Inclusion criteria
* Age 18-42 at study entry * Regular menstrual cycles every 25-40 days * BMI 18- 25 kg/m2 or ≥30kg/m2 * Good general health * Prolactin and thyroid-stimulating hormone (TSH) within normal laboratory ranges at screening * Baseline hemoglobin \>11 gm/dl.
Exclusion criteria
* Positive screen for Activated Protein C resistance * Any contraindications to exogenous estrogen, including previous thromboembolic events or stroke, history of an estrogen-dependent tumor, active liver disease, undiagnosed abnormal uterine bleeding, hypertriglyceridemia, smoking, hypertension * History of chronic disease affecting hormone production, metabolism or clearance (including diabetes mellitus) or abnormal renal or liver function at screening, such as elevated aspartate or alanine aminotransferases or elevated blood urea nitrogen (BUN) or creatinine * Current use of thiazolidinediones or metformin (known to interact with reproductive hormones) * Use of hormones affecting hypothalamic-pituitary ovarian axis within three months of enrollment * Strenuous exercise (\>4 hours per week) * Pregnancy, breast-feeding or current active attempts to conceive
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Luteinizing Hormone Pulse Amplitude | Baseline | The study is powered on luteinizing hormone pulse amplitude because it is the clinical outcome for which the most data is available. The primary comparison is whether there is a significant reduction in the pulse amplitude in the obese between the pre- and post-treatment periods and whether there is no change in the pulse amplitude in the normal weight patients between the pre and post-treatment periods. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Control Group 1 Control: Normal weight (BMI 18-25 kg/m2)
Estradiol, Lutrelef or gonadorelin | 13 |
| Experimental Group 2 Experimental: Obese (BMI \>30 kg/m2)
Estradiol, Lutrelef or gonadorelin | 17 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Physician Decision | 0 | 2 |
| Overall Study | Screen Failure | 2 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Experimental | Control | 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 | 17 Participants | 13 Participants | 30 Participants |
| Age, Continuous | 31.76 years | 29 years | 30.57 years |
| Region of Enrollment United States | 17 participants | 13 participants | 30 participants |
| Sex: Female, Male Female | 17 Participants | 13 Participants | 30 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 11 | 0 / 15 |
| serious Total, serious adverse events | 0 / 11 | 1 / 15 |
Outcome results
Primary
Luteinizing Hormone Pulse Amplitude
The study is powered on luteinizing hormone pulse amplitude because it is the clinical outcome for which the most data is available. The primary comparison is whether there is a significant reduction in the pulse amplitude in the obese between the pre- and post-treatment periods and whether there is no change in the pulse amplitude in the normal weight patients between the pre and post-treatment periods.
Time frame: Baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 - Normal Weight | Luteinizing Hormone Pulse Amplitude | 2.73 IU/L | Standard Error 0.46 |
| Group 2 - Obese | Luteinizing Hormone Pulse Amplitude | 1.12 IU/L | Standard Error 0.19 |
Primary
Luteinizing Hormone Pulse Amplitude
Time frame: Post estradiol at one month
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 - Normal Weight | Luteinizing Hormone Pulse Amplitude | 2.18 IU/L | Standard Error 0.4 |
| Group 2 - Obese | Luteinizing Hormone Pulse Amplitude | 1.59 IU/L | Standard Error 0.29 |