Evaluation of Ovarian Morphology and Function in Overweight Women During Weight Loss

Not Applicable

Completed

Conditions: Anovulation
Amenorrhea
Infertility
Weight Loss

Interventions: Behavioral: Commercial Weight Loss Program

Registration Number: NCT01785719

Lead Sponsor: Cornell University

Brief Summary: The objective of this study is to explore the effects of weight loss on body composition, metabolic status, reproductive hormones, and ovarian follicle development in obese women with regular menstrual cycles versus obese women with irregular menstrual cycles and/or polycystic ovary syndrome (PCOS).

Detailed Description: Polycystic ovary syndrome (PCOS) is a complex endocrine condition that impacts one in ten women of reproductive age worldwide. It is characterized by a collection of signs and symptoms, including: (1) oligo- or anovulation, (2) hyperandrogenism, and (3) polycystic ovarian morphology. Because obesity worsens the reproductive and metabolic features of the condition, lifestyle intervention aimed at weight loss is recommended as the first-line therapy in overweight / obese patients. Many studies have shown that modest weight loss (5-10%) can improve symptomology in women with PCOS. Yet, the mechanism whereby weight loss might stimulate ovulation or restore menstrual cyclicity remains unclear.

Hence, the goal of this study is to explore the effects of weight loss on body composition, metabolic status, reproductive hormones, and ovarian follicle development in obese women with regular menstrual cycles versus obese women with irregular menstrual cycles and/or PCOS. The researchers believe that a hypocaloric and low-glycemic index eating pattern, based on the nutrition recommendations of the USDA Dietary Guidelines for Americans and American Diabetes Association, will reduce endocrine and metabolic disturbances and consequently improve ovulatory and menstrual cyclicity in PCOS.

To accomplish this objective, the researchers plan to recruit up to 50 obese (i.e. body mass index \>30 kg/m\*m) women with regular menstrual cycles and up to 50 obese women with irregular menstrual cycles and/or PCOS. Exclusion criteria will include ages \<18 or \>35 y and the use of hormonal contraception, fertility therapy, or insulin-sensitizing medication in the three months prior to enrollment. This study entails one month of data collection during a baseline interval (Month 1) and six months of data collection during a commercial weight loss program (Nutrisystem® D; Month 2 thru Month 7).

Participants will be evaluated every other day (in Months 1 and 7) or twice per week (in Months 2 thru 6) by transvaginal ultrasonography and venipuncture. Ultrasound images of the ovaries will be assessed for the total number and diameter of individual follicles. Serum samples will be assessed for follicle-stimulating hormone, luteinizing hormone, estradiol, and progesterone. Participants will also be evaluated at up to four time points using multiple metabolic and behavioral tests. Time points of interest will include: (1) Month 1 (i.e. pre-intervention), (2) after 5% weight loss, (3) after 10% weight loss, and (4) Month 7 (i.e. post-intervention). Assessments and endpoints of interest will include: (1) fasting blood tests (to detect serum androgens and markers of metabolic syndrome); (2) an oral glucose tolerance test (to characterize glucose and insulin dynamics at 0, 30, 60, 90, and 120-minutes post-glucose ingestion); (3) a physical examination (to measure height, weight, waist and hips circumference, blood pressure, heart rate, and hirsutism score); (4) a dual x-ray absorptiometry scan (to quantify total and regional fat and lean mass); and (5) a quality of life questionnaire (to evaluate health-related quality of life).

To evaluate further changes in ovarian morphology, reproductive hormones, metabolic status, and body composition after the intervention, participants will be invited to return to the research unit six months after the study ends. The aforementioned procedures (transvaginal ultrasound scan; fasting blood tests; oral glucose tolerance test; physical examination; dual x-ray absorptiometry scan; and quality of life questionnaire) will be repeated.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 79

Inclusion Criteria

BMI ≥ 30.0 kg/m*m.
Self-reported history of regular menstrual cycles, irregular menstrual cycles, or PCOS.
Absence of hormonal contraception, fertility therapy, or insulin-sensitizing medication in the three months prior to enrollment.

Exclusion Criteria

Pregnant, breastfeeding, or lactating
Lack of one or both ovaries and/or uterus
Previous diagnosis of bleeding disorder(s) or current use of blood thinners/anticoagulants
Vegan or gluten free
Soy or peanut allergy

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Overweight Women	Commercial Weight Loss Program	Regardless of reproductive history, each participant will be provided with six months of the commercial weight loss program, Nutrisystem® D. Nutrisystem® D is a portion-controlled, low calorie, and low glycemic index meal delivery system that provides 1250-1500 kcal/day. It has been proven to help overweight adults achieve real and sustainable weight loss results. When meals and snacks are consumed as instructed, average weight loss is 1-2 lbs per week or 15-20% body weight by the end of six months. Nutrisystem® D offers a balanced meal plan that is consistent with the nutrition recommendations of the USDA for Americans and American Diabetes Association. Each participant will be encouraged to take a daily multivitamin to help meet her micronutrient needs on the program.

Primary Outcome Measures

Name	Time	Method
Change From Baseline Ovulatory/Menstrual Function	Up to 7 months	Participants with irregular menstrual cycles at baseline were categorized as "responders" or "non-responders" based on any changes they experienced in menstrual cyclicity over the course of the intervention. "Responders" were defined as participants who shifted towards a more favorable menstrual cycle status over the course of the intervention. "Non-responders" were defined as participants who experienced no change or a shift to a less favorable menstrual cycle status over the course of the intervention. Menstrual cycle status categories were defined as "Amenorrhea" (mean cycle length\>90 days; least favorable), "Oligomenorrhea" (mean cycle length 36-90 days; unfavorable), and "Regular" (mean cycle length 21-35 days; most favorable). All participants with regular menstrual cycles at baseline maintained regular cycles over the course of the intervention and were therefore not included in this analysis.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline Follicle Number Per Ovary	Up to 7 months	Change in follicle number per ovary (FNPO) from baseline to the end of a hypocaloric dietary intervention. Ovarian images were collected using 3D transvaginal ultrasonography and were assessed for morphological endpoints by trained raters using the 2D offline grid method. FNPO was calculated by summing all 2-9 mm follicles in each ovary. Left and right FNPO were averaged for each participant before baseline to post-intervention changes were calculated.
Change From Baseline Reproductive Hormones	Up to 7 months	Change in reproductive hormones from baseline to the end of a hypocaloric dietary intervention. Blood samples were collected in the morning after an overnight fast during the early follicular phase as confirmed by the absence of a dominant follicle or corpus luteum on ultrasound. Hormones reported include: * Total testosterone: Evaluated by the Brigham Research Assay Core (Harvard) using liquid chromatography tandem mass-spectrometry. Results are reported in ng/dL. * Anti-Müllerian hormone (AMH): Evaluated using the Motive Biosciences (formerly Ansh Labs) picoAMH ELISA. Results are reported in ng/mL
Change From Baseline Metabolic Status (HOMA-IR)	Up to 7 months	Change in metabolic status from baseline to the end of a hypocaloric dietary intervention. HOMA-IR (Homeostasis Model Assessment of Insulin Resistance) was used as an indicator of metabolic status. HOMA-IR uses fasting blood glucose and insulin values to approximate insulin resistance. Blood glucose and insulin were measured in the morning after an overnight fast during the early follicular phase as confirmed by the absence of a dominant follicle or corpus luteum on ultrasound. HOMA-IR was calculated by multiplying blood glucose (mg/dL) by insulin (mIU/mL) and dividing by 405. A higher HOMA-IR score is indicative of increased insulin resistance.
Change From Baseline Total Percent Body Fat	Up to 7 months	Change in total percent body fat from baseline to the end of a hypocaloric dietary intervention. Body fat was measured using the Hologic Discovery A Dual X-Ray Absorptiometry (DXA) Scanner.
Change From Baseline Ovarian Volume	Up to 7 months	Change ovarian volume (cm\^3) from baseline to the end of a hypocaloric dietary intervention. Ovarian images were collected using 3D transvaginal ultrasonography and were assessed for morphological endpoints by trained raters using the 2D offline grid method. Ovarian volume was calculated using a modified formula for a prolate ellipsoid. Left and right ovarian volumes were averaged for each participant before baseline to post-intervention changes were calculated.
Change From Baseline Free Androgen Index (FAI)	Up to 7 months	Change in FAI from baseline to the end of a hypocaloric dietary intervention. Blood samples were collected in the morning after an overnight fast during the early follicular phase as confirmed by the absence of a dominant follicle or corpus luteum on ultrasound. Free Androgen Index (FAI) is the ratio of total testosterone to sex hormone binding globulin (SHBG), indicating the amount of active testosterone in the blood. SHBG was evaluated by the Cornell Human Nutrition Chemistry Service Laboratory using Immulite 2000 immunoassay. FAI levels of 5 or higher are indicative of PCOS.
Change From Baseline BMI	Up to 7 months	Change in BMI from baseline to the end of a hypocaloric dietary intervention.