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

NCT02858336 | Completed

• 2 other identifiers: 16015716-E-0157
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Hormones

Keywords

Luteinizing Hormone (LH); Weight Loss; Functional Hypothalamic Amenorrhea (HA); Gonadotropin-Releasing Hormone (GnRH); Energy Deficiency

Outcome Measures

Primary Outcomes (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.

  NEA Intervention Day 5 and DEA Intervention Day 5

Secondary Outcomes (3)

• 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

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

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

  NEA Intervention Day 5 and DEA Intervention Day 5

• Change in cortisol, TSH, TT3, and fT4

  NEA Intervention Day 5 and DEA Intervention Day 5

Study Arms (2)

Control

ACTIVE COMPARATOR

All participants will receive the NEA availability to act as their own control to the experimental DEA intervention.

Behavioral: NEA

Experimental

EXPERIMENTAL

All participants will be in the experimental arm and receive the DEA intervention.

Behavioral: DEA

Interventions

NEA BEHAVIORAL

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

Control

DEA BEHAVIORAL

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

Experimental

Eligibility Criteria

• Age: 18 Years - 28 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• National Institute of Environmental Health Sciences (NIEHS): lead

Study Sites (1)

NIEHS Clinical Research Unit (CRU)

Research Triangle Park, North Carolina, 27709, United States

Location

Related Publications (4)

• 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.

  PMID: 16720651 BACKGROUND

• 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.

  PMID: 12519869 BACKGROUND

• 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.

  PMID: 8531610 BACKGROUND

• 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.

  PMID: 40265345 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Weight Loss

Condition Hierarchy (Ancestors)

Body Weight Changes; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Natalie D Shaw, M.D.

  National Institute of Environmental Health Sciences (NIEHS)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 5, 2016
• First Posted: August 8, 2016
• Study Start: January 12, 2017
• Primary Completion: June 29, 2019
• Study Completion: June 29, 2019
• Last Updated: July 17, 2026

Record last verified: 2026-05-20

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: Data will be made available as part of published manuscripts to individual researchers upon reasonable request related to the original study protocol research questions, after the study team has finished its analysis.
• Access Criteria: Aggregated summary and statistical analysis will be publicly available. All the patient-level data will require controlled access.@@@@@@@@@@@@Outside investigators may apply for research collaborations related to the original research questions, that will be IRB approved for use and a data transfer agreement will be signed, and coded, deidentified data will be provided with a data dictionary. For studies unrelated to the original research, only deidentified data can be provided and only when subjects consented to future research.

Locations

US (1)