The Effects of an Intensive Lifestyle Intervention on Reproductive Outcomes
Condition: Subfertility; Anovulatory; Obese
MeSH terms: Infertility; Anovulation
Study type: Interventional

Summary: 
      This is a study to determine whether a low calorie diet using meal replacement shakes
      compared to current counseling about diet, followed by 3 cycles of clomiphene citrate (if
      needed) will result in: 1) improvements in ability to ovulate and achieve pregnancy either
      spontaneously or during 3 clomiphene citrate cycles 2) greater weight loss with reductions in
      waist and hip circumferences and improvements in hormones that are involved in allowing
      pregnancy to occur and hormones that are involved in metabolism, such as insulin and glucose
      (sugar) 3) improvements in other health conditions such as blood pressure, and emotional and
      physical well-being.

      Women eligible to participate will be between the ages of 18-35 with a BMI (ratio of weight
      in kg divided by height in m2) of ≥ 35≤45 kg/m2 who are seeking help for anovulatory
      infertility including women with a diagnosis of polycystic ovarian syndrome (PCOS).
    

Detailed description: 
      More than 33% of U.S. adults over the age of 20 are obese (BMI ≥30 kg/m2), and 6% are
      severely obese (BMI ≥40 kg/m2). As the prevalence and severity of obesity has increased, so
      has the number of women who have obesity-related abnormalities in reproductive function,
      including anovulation and infertility. Specifically, obesity contributes to ovulatory
      problems and compromises ovarian response to ovulation induction agents such as clomiphene.

      Women seeking assistance from specialists for reproductive concerns are both anxious to
      achieve pregnancy and highly motivated. We propose to assess the relative efficacy of very
      low energy diet (VLED) using liquid meal replacement vs. standard of care dietary counseling
      and education (DCE) on the metabolic effects of weight reduction in the obese, subfertile
      population and assess ovulation and time to conception in these women. We hypothesize that
      use of a very low energy diet with resultant rapid and profound weight loss and marked
      improvement in metabolic state, will increase the rate of spontaneous cycling, improve
      unassisted and clomiphene-assisted ovulation and significantly improve conception and
      pregnancy rates. Because of the direct relationship between obesity and anovulation, we will
      test whether evaluation of both habitual dietary intake and plasma metabolomic profiles can
      be used to identify specific dietary components and metabolites that predict successful or
      unsuccessful induction of ovulation and pregnancy in response to weight loss with or without
      clomiphene citrate.

      32 reproductive age women with a BMI ≥35≤45 kg/m2 will be randomized to 12 weeks of VLED or
      DCE and ovulation rates and time to conception between groups will be assessed over a 6 month
      period. We will also evaluate between group differences in rate of weight loss, absolute
      weight lost, BMI, waist and hip circumferences as well as reproductive and metabolic hormone
      levels. Luteinizing hormone (LH), follicle stimulating hormone (FSH), androgens, leptin,
      glucose and insulin (HOMA), and β-cell function (Matsuda Index).

      We will assess if clinical, hormonal, dietary or metabolomic profiles, can predict response
      to weight loss or clomiphene citrate in improving ovulation. Women will be assessed for
      clinical and molecular phenotypes, including plasma metabolomic profiles. Metabolomic
      profiles will be adjusted for chronic dietary intake. An initial assessment of the levels of
      dietary components, metabolites or metabolic pathways that predict response will be
      investigated.

      We will determine program acceptability and differences in the change in co-morbid health
      conditions, quality-of-life, and psychological well-being in standard of care and VLED-based
      weight loss participants. Important physiological benefits arise from weight loss and the
      magnitude of these changes will be assessed in the group of patients seeking reproductive
      assistance.

      This pilot study will provide the first information on the relative success of aggressive,
      short-term weight loss in the treatment of infertility as defined by improvement in ovulation
      and conception and provide data for larger, definitive trials of this approach. The study
      will allow assessment of the feasibility and acceptability of translating VLED
      treatment-based clinical care and research developed by the University of Michigan
      Investigational Weight Management Clinic to a specialized population seeking reproductive
      assistance. Finally, this study will provide important preliminary data for a larger trial to
      assess the health effects on the mother and the offspring as a result of aggressive
      intervention to alter the pre-pregnancy metabolic environment in reproductive age women.
    

Intervention name(s): Intensive Dietary Intervention; Placebo
Intervention type(s): Behavioral; Behavioral
Intervention description(s): Intensive dietary intervention of 800 kcal/day using liquid meal replacement for a total of 12 weeks to reduce weight to 15% from baseline weight.; Lifestyle counseling: standard dietary education and counseling with a goal of reducing to 1500-1800 kcal/day
Other intervention name(s): Very low energy diet; Lifestyle counseling
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Subfertility; Anovulatory; Obese; Women