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HormonesNCT02858336

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

A study testing NEA and DEA in people with Hormones, run by National Institute of Environmental Health Sciences (NIEHS) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 28 years, women only
Conditions the study is for
Hormones
What is being tested?
NEA and DEA
Could I receive a placebo?
No, everyone receives an active treatment
How many people
38 participants
Where
1 siteUnited States
Study dates
12 Jan 2017to 29 Jun 2019
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 28 years
  • Women only
  • No healthy volunteers
  • Adult

Who may be able to join

  • Participants will be enrolled with distribution across race. Each potential participant must meet all of the following inclusion criteria in order to be eligible to enroll in the study:
  • Female
  • Between 18 and 28 years of age (inclusive)
  • Reported menarche between the ages of 11 and 14 years
  • Gynecological age of <= 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
Show all 14Show fewer
  • A BMI of 18.5 to 27 kg x m^2 and a weight >= 93 lbs.
  • Agrees to use barrier contraception method for the duration of the study and the follow up period
  • 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
  • Agrees to abstain from biotin supplements for the duration of 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

Who cannot join

  • A potential participant meeting any of the following exclusion criteria is not eligible to enroll in the study:
  • 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 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
Show all 23Show fewer
  • 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 regular overnight awake periods, for example overnight or rotating shift work, that will continue during the study, at the discretion of the investigator
  • 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.
  • 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 <= 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

Trial locations and contacts

1 site in 1 country.

United States1 site
  • NIEHS Clinical Research Unit (CRU)

    Research Triangle Park, North Carolina, 27709

Other trials in United States

About this study

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.

Read more

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.

Read the 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 300 participants with a target for study completion of 36 subjects. Eligible participants will be females >= 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.

Conditions
Hormones
Being tested
NEA, DEA
Keywords
Luteinizing Hormone (LH), Weight Loss, Functional Hypothalamic Amenorrhea (HA), Gonadotropin-Releasing Hormone (GnRH), Energy Deficiency
Medical subject headings
Weight Loss

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • NEABehavioural

    Neutral Energy Availability: 5-day outpatient intervention of prescribed diet and exercise to elicit an energy availability of 45 kcal/kg LBM day.

  • DEABehavioural

    Deficient Energy Availability: 5-day outpatient intervention of prescribed diet and exercise to elicit an energy availability of 20 kcal/kg LBM day.

Study groups in NCT02858336
Study groupRoleWhat they receive
ControlActive comparatorAll participants will receive the NEA availability to act as their own control to the experimental DEA intervention.
Receives: Behavioral: NEA
ExperimentalExperimentalAll participants will be in the experimental arm and receive the DEA intervention.
Receives: Behavioral: DEA

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. The primary outcome measure will be change in daytime LH pulse frequency following 5 days of neutral energy availability as compared to LH pulse frequency following 5 days deficient energy availability. LH pulse frequency.

    Change in LH pulse frequency collected by sampling every 10 minutes over 8 hours during a study visit.

    Measured: NEA Intervention Day 5 and DEA Intervention Day 5

Secondary outcomes (3)
  1. Change in hormone measures (LH, FSH, estradiol, and progesterone) from daily urine samples and blood spots, total cycle, follicular and luteal phase length during the cycle following NEA or DEA

    Change in Laboratory Values during each menstrual cycle.

    Measured: Menstrual cycle of the NEA Intervention and menstrual cycle of DEA Intervention

  2. Change in leptin, ghrelin, adiponectin, insulin, and glucose in response to standardized breakfast, lunch, and snack

    Change in Laboratory Values collected by sampling after standardized breakfast, lunch, and snack over 8 hours during a study visit.

    Measured: NEA Intervention Day 5 and DEA Intervention Day 5

  3. Change in cortisol, TSH, TT3, and fT4

    Change in Laboratory Values collected by sampling over 8 hours during a study visit.

    Measured: NEA Intervention Day 5 and DEA Intervention Day 5

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Aug 2016 (estimated)
  2. Study start12 Jan 2017
  3. Primary completion29 Jun 2019
  4. Study completion29 Jun 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Basic science
Allocation
Non-randomised
Intervention model
Crossover
Masking
None (open label)
Enrolment
38 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02858336
Sponsor's protocol ID
160157
Other IDs
16-E-0157
Status last verified
20 May 2026
First submitted
5 Aug 2016
Last updated
16 Oct 2026
Results posted
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: Aggregated and summarized data will be made available as part of associated publication.@@@Deidentified patient-level data, with appropriate IRB approvals, could be made available for sharing.@@@@@@This project generates data from a behavioral intervention study that includes the following data types:@@@-Demographic data@@@-Clinical evaluation@@@-Patient questionnaires@@@-Laboratory studies (including hormonal testing)@@@-Metabolic paramaters (e.g., VO2 max, REE)@@@-Imaging studies (e.g., Ultrasound, DEXA)@@@

Publications

  • Loucks AB. The response of luteinizing hormone pulsatility to 5 days of low energy availability disappears by 14 years of gynecological age. J Clin Endocrinol Metab. 2006 Aug;91(8):3158-64. doi: 10.1210/jc.2006-0570. Epub 2006 May 23.

    PubMed 16720651
  • Loucks AB, Thuma JR. Luteinizing hormone pulsatility is disrupted at a threshold of energy availability in regularly menstruating women. J Clin Endocrinol Metab. 2003 Jan;88(1):297-311. doi: 10.1210/jc.2002-020369.

    PubMed 12519869
  • Williams NI, Young JC, McArthur JW, Bullen B, Skrinar GS, Turnbull B. Strenuous exercise with caloric restriction: effect on luteinizing hormone secretion. Med Sci Sports Exerc. 1995 Oct;27(10):1390-8.

    PubMed 8531610
  • Shekhar S, Tessa Tonleu J, Okigbo CC, Leka H, Kim AE, Purse BP, Hirsch KR, Stolze BR, McGrath JA, Smith-Ryan AE, Soldin SJ, Hall JE. Thyroid axis adaptations to moderate short-term energy restriction in healthy, young women. Eur J Endocrinol. 2025 Apr 30;192(5):568-576. doi: 10.1093/ejendo/lvaf083.

    PubMed 40265345

Questions about this trial

What is this clinical trial studying?

A study testing NEA and DEA in people with Hormones, run by National Institute of Environmental Health Sciences (NIEHS) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 16 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

The primary outcome measure will be change in daytime LH pulse frequency following 5 days of neutral energy availability as compared to LH pulse frequency following 5 days deficient energy availability. LH pulse frequency. (time frame: NEA Intervention Day 5 and DEA Intervention Day 5). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02858336, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Oct 2026.

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