CaREFREE Study (Calorie Restriction Environment and Fitness: Reproductive Effects Evaluation Study)

  • STATUS
    Recruiting
  • days left to enroll
    57
  • participants needed
    150
  • sponsor
    National Institute of Environmental Health Sciences (NIEHS)
Updated on 5 May 2021

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.

...

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.

Details
Condition Hormone, healthy, Normal Physiology, hormone agent
Treatment NEA, DEA
Clinical Study IdentifierNCT02858336
SponsorNational Institute of Environmental Health Sciences (NIEHS)
Last Modified on5 May 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age between 18 yrs and 28 yrs?
Are you female?
Do you have any of these conditions: Normal Physiology or healthy or Hormone?
Do you have any of these conditions: Hormone or hormone agent or Normal Physiology or healthy?
Do you have any of these conditions: Normal Physiology or hormone agent or healthy or Hormone?
Do you have any of these conditions: healthy or Normal Physiology or hormone agent or Hormone?
Do you have any of these conditions: Normal Physiology or healthy or Hormone or hormone agent?
Female
Between 18 and 28 years of age (inclusive)
Reported menarche between the ages of 11 and 14 years
Gynecological age of less than or equal to 14 years
A history of self-reported regular menstrual cycles when not on contraceptive medication of between 25 and 35 days (inclusive) at prescreen and knowledge of date of onset of menses before the screening visit
A BMI of 18.5 to 27 kg (Summation)m(2) and a weight >= 93 lbs
Agrees to use barrier contraception method for the duration of the study
Agrees to abstain from alcohol consumption during both 5-day diet/exercise study interventions
Agrees to abstain from donating blood during the study and within 30 days of completing the study
Is willing and able to fulfill the requirements of the protocol and to provide informed consent
Able to speak and read English
Lives within 50 miles of the Clinical Research Unit

Exclusion Criteria

Currently lactating or pregnant or planning on becoming pregnant for the duration of the study
Has ever given birth
History in the past 3 months of dieting or weight loss amounting to greater than 2 kg (4.4 lbs)
> 4 hours per week of aerobic exercise for the past 3 months
Has initiated training for an athletic sport or event in the past 3 months that, in the opinion of the investigator, may interfere with the results of the study
Currently using hormone-based contraception, including those administered orally, vaginally, via injection, sub-dermally, or transdermally
Current use of medications or supplements that may interfere with the results of the study, including
i.Steroids
ii.Hormone-based contraception
iii.Sleeping pills
iv.Homeopathic substances (e.g. Chinese herbs, protein or other powders, and
other-the-counter extracts)
v.Stimulants (e.g. Ritalin)
vi.Antidepressants or anti-epileptic medications or centrally acting anti-
hypertensive medications
\. Current use of recreational drugs (alcohol intake will be monitored and
excluded during the two intervention periods)
\. Unable to consume food containing dairy or nuts
\. Has currently or has a history of any of the following: autoimmune
heart, liver, renal disease, diabetes, or another health condition deemed by
the PI to be a contraindication to study participation. History of thyroid
disorder is permissible if the patient is biochemically euthyroid on
replacement
Additional Eligibility Criteria to be Met Prior to Start of Intervention(s)
Criteria 1 Habitual energy intake between 35-55 kcal/kg LBMday
Criteria 2 VO2max less than or equal to 40 ml/kg/min with the option to
increase this at the discretion of the PI, depending on the current and past
exercise level of the participant
Criteria 3 Hemoglobin, prolactin and TSH within normal female range for
testing laboratory
Criteria 4 Ovulation confirmed in the cycle before each study intervention by
self-reported positive urine test, ultrasound and/or progesterone blood-levels
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