Obesity, Fertility
Conditions
Brief summary
The United States has the highest prevalence of obesity among all countries surveyed in 2012 by the Organization for Economic Cooperation and Development. Maternal obesity is linked with anovulation, menstrual cycle abnormalities, subfertility, fetal loss, obstetrical complications and congenital anomalies. Changes in reproductive hormones and diminished oocyte quality have also been demonstrated. A gap of knowledge exists as the mechanisms underlying these harmful effects are poorly understood and no specific treatments exist. This proposal will test the hypothesis that dietary omega-3 fatty acids (FA) will improve the output of hypothalamicpituitary- ovarian axis in obese women. The investigators will perform paired assessments before and after supplementation in 10 obese and 10 normal weight women. To test the pituitary and hypothalamic output, the investigators will examine the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) responsiveness during frequent blood sampling. To test the corpus luteum function, the investigators will examine urinary reproductive hormones (E1c, estrone conjugates, and pregnanediol glucuronide (Pdg)) over an entire menstrual cycle. The investigators ultimate goal is to collect preliminary data for an adequately powered randomized control trial.
Interventions
DIETARY_SUPPLEMENTLOVAZA
Subjects will be instructed to take 2 grams twice daily of oral omega-3-acid ethyl esters (Lovaza) starting with day 1 to 3 of their menstrual period. Each capsule contains 60mg of other omega-3 FA. On day 1 of their subsequent menstrual period, subjects will be instructed to discontinue.
DRUGGnRH
An intravenous bolus of exogenous GnRH (75 ng/kg dosing based on total body weight) will be administered at 6 hours.
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
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 42 Years
Healthy volunteers
Yes
Inclusion criteria
1. Age 18-42 at study entry 2. Regular menstrual cycles every 25-40 days 3. BMI at least 30 kg/m2 (obese) or between 18.5 and 25 kg/m2 (normal) 4. Good general health 5. Prolactin and thyroid-stimulating hormone (TSH) within normal laboratory ranges at screening, baseline hemoglobin \>11 gm/dl.
Exclusion criteria
1. Diagnosis of polycystic ovary syndrome (by ultrasound or hyperandrogenic symptoms) 2. Fish or seafood allergy or hypersensitivity (e.g., anaphylactic reaction) to omega-3-acid ethyl esters or any component of the formulation 3. Coagulopathy or receiving therapeutic anticoagulation (due to potential for interaction with omega-3 FA) 4. History of chronic disease affecting hormone production, metabolism or clearance (including diabetes mellitus) 5. Abnormal renal or liver function at screening 6. Current use of thiazolidinediones or metformin (known to interact with reproductive hormones) 7. Use of hormones affecting hypothalamic output (HPO) axis (such as hormonal contraceptives) within three months of entry 8. Strenuous exercise (\>4 hours of intense physical activity per week) 9. Pregnancy 10. Breast-feeding 11. Current active attempts to conceive 12. History of significant recent weight loss or gain
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Average LH Pulse Amplitude | 10 minute intervals during 8 hour blood sampling studies. Subjects will undergo two menstrual cycles of study, one prior to dietary supplementation and one after supplementation. | To test the pituitary and hypothalamic output, we examined LH secretion (unstimulated and in response to gonadotropin-releasing hormone (GnRH) stimulation) during 8-hour blood sampling studies at 10 min intervals. The primary outcome measure is the change in the average LH pulse amplitude for each patient from baseline to after supplementation. |
Countries
United States
Participant flow
Recruitment details
39 regularly menstruating obese and normal-weight women were recruited from the community through campus-wide advertisements.
Pre-assignment details
Potential participants were screened out if they had polycystic ovary syndrome, allergies to seafood, used medications known to affect reproductive hormones, used exogenous sex steroids within the last 3 months, exercised vigorously more than 4 hours weekly, or were attempting pregnancy. Eligible subjects then had a baseline physical examination.
Participants by arm
| Arm | Count |
|---|---|
| Obese BMI \>= 30 kg/m2 | 20 |
| Normal Weight BMI 18-25 kg/m2 | 19 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Screen Failure | 3 | 4 |
| Overall Study | Withdrawal by Subject | 2 | 3 |
Baseline characteristics
| Characteristic | Obese | Normal Weight | Total |
|---|---|---|---|
| Age, Continuous | 34.8 years STANDARD_DEVIATION 1.2 | 28.4 years STANDARD_DEVIATION 1.2 | 31.6 years STANDARD_DEVIATION 5.3 |
| BMI | 37.8 kg/m^2 STANDARD_DEVIATION 1.5 | 21.8 kg/m^2 STANDARD_DEVIATION 0.5 | 31.6 kg/m^2 STANDARD_DEVIATION 9.1 |
| Region of Enrollment United States | 15 participants | 12 participants | 27 participants |
| Sex/Gender, Customized Female | 15 participants | 12 participants | 27 participants |
| Sex/Gender, Customized 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 / 15 | 0 / 12 |
| serious Total, serious adverse events | 0 / 15 | 0 / 12 |
Outcome results
Primary
Change in the Average LH Pulse Amplitude
To test the pituitary and hypothalamic output, we examined LH secretion (unstimulated and in response to gonadotropin-releasing hormone (GnRH) stimulation) during 8-hour blood sampling studies at 10 min intervals. The primary outcome measure is the change in the average LH pulse amplitude for each patient from baseline to after supplementation.
Time frame: 10 minute intervals during 8 hour blood sampling studies. Subjects will undergo two menstrual cycles of study, one prior to dietary supplementation and one after supplementation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Obese | Change in the Average LH Pulse Amplitude | -.04 IU/L | Standard Deviation 0.2 |
| Normal Weight | Change in the Average LH Pulse Amplitude | .4 IU/L | Standard Deviation 0.4 |