CaREFREE Study (Calorie Restriction, Environment and Fitness: Reproductive Effects Evaluation Study)
Condition: Hormones
Study type: Interventional

Summary: 
      Background:

      Functional hypothalamic amenorrhea (functional HA) is a condition where a woman s period
      stops for a temporary time. This is due to improper function of the hypothalamus. This is the
      part of the brain that directs the whole reproductive system. Researchers want to learn more
      about functional HA. They also want to learn how diet, exercise, and other factors may change
      women s menstrual cycles.

      Objective:

      To better understand functional HA.

      Eligibility:

      Healthy women ages 18-28 years old who:

        -  Have regular periods

        -  Exercise no more than 4 hours a week

        -  Had their first period at age 11-14

      Design:

      Participants will be prescreened over the phone.

      Participants will be screened with:

        -  Blood and urine tests

        -  Medical history

        -  Physical exam.

      Participants will have 9 or 10 visits over about 3 menstrual cycles. These include:

        -  Repeat of screening tests

        -  Questionnaires

        -  Exercise test

        -  Resting energy expenditure test: Participants fast overnight before the test. They lie
           on their back under a canopy for a half hour.

        -  Body composition test: This is done with a dual energy x-ray absorptiometry (DXA) scan.

        -  Pelvic ultrasound

        -  For two full-day visits, an IV is inserted into an arm vein. The IV takes a blood sample
           every 10 minutes for 8 hours.

      Participants will keep logs:

        -  Menstrual cycle log

        -  Diet log for three 4-day cycles

      Participants will receive test kits to complete at home:

        -  Daily blood and urine sample

        -  Ovulation

      Participants will take a daily iron supplement. They will wear a wristband that monitors
      activity 24 hours a day.

      Participants will stick to a special diet for two 5-day periods of time. They will complete
      two 4-day exercise programs....
    

Detailed description: 
      Functional hypothalamic amenorrhea (HA) is a reversible form of hypogonadotropic hypogonadism
      (HH) that can be triggered by stressors such as exercise, nutritional deficits, and
      psychological stress. Dysfunction of the hypothalamic component of the reproductive axis
      plays a key role in functional HA and is manifest by an altered pattern of luteinizing
      hormone (LH) pulses detectable in peripheral blood. There is ample evidence supporting the
      use of LH as a surrogate marker of hypothalamic gonadotropin-releasing hormone (GnRH)
      secretion from the hypothalamus. There is also significant evidence that women vary in their
      susceptibility to such stress-induced amenorrhea, pointing to a role for both environmental
      and genetic factors in the etiology of functional HA. However, the variation in changes in
      GnRH pulse frequency in response to stressors in healthy women has not been defined. Data
      from previous work in our lab has suggested that rare variants in genes associated with other
      forms of HH may also contribute to the variability seen in susceptibility to functional HA.
      The long-term goal of our research is to examine the interaction of environment and genes in
      HA. In this pilot study we propose to examine the inter-individual variability in pulsatile
      LH secretion in response to standardized neutral and deficient energy availability (NEA and
      DEA, respectively) in normal women. We will then relate this primary end-point to proposed
      predictive factors including past reproductive and family history and markers of current
      metabolic status and their response to energy availability. Our initial analyses will help to
      determine simplified biomarkers that can be translated to larger studies examining the
      potential combined effect of energy availability and genotype.

      The proposed pilot study is a single-site, 2-period study in healthy female volunteers. The
      study will enroll approximately 150 participants over 2 years with a target for study
      completion of 25 subjects. Eligible participants will be females greater than or equal to 18
      years of age. Eligible participants will have had menarche at or before 14 years of age and
      no earlier than age 11. Eligible participants will have a gynecological age (years after
      menarche) of 14 years or less. The upper age limit will vary based on each subject s age of
      menarche and fall between 25 and 28 among participants. Eligible participants will confirm at
      the pre-screening call having normal menstrual cycles (self-reported) for at least the
      previous 2 months and ovulation will be confirmed during the menstrual cycle before the start
      of intervention.

      The primary outcome will be changes in daytime LH pulse frequency, when comparing NEA vs DEA.
      Secondary measures will evaluate past reproductive history, family history, and current
      metabolic status using medical history interviews, lifestyle questionnaires and maximum
      oxygen uptake (as a measure of fitness). Resting energy expenditure, body composition as well
      as metabolic and stress hormones will be measured at baseline and in association with the
      interventions. Blood samples will be collected for eventual genotyping.
    

Intervention name(s): NEA; DEA
Intervention type(s): Behavioral; Behavioral
Intervention description(s): Neutral Energy Availability: 5-day outpatient intervention of prescribed diet and exercise to elicit an energy availability of 45 kcal/kg LBM day.; Deficient Energy Availability: 5-day outpatient intervention of prescribed diet and exercise to elicit an energy availability of 20 kcal/kg LBM day.
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Luteinizing Hormone (LH); Weight Loss; Functional Hypothalamic Amenorrhea (HA); Gonadotropin-Releasing Hormone (GnRH); Energy Deficiency