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

Hormones Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02858336
• Other study ID #: 160157
• Secondary ID: 16-E-0157
• Status: Completed
• Phase: N/A
• Start date: January 12, 2017
• Est. completion date: June 29, 2019

Study information

• Verified date: July 28, 2023
• Source: National Institutes of Health Clinical Center (CC)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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 300 participants with a target for study completion of 36 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 38
• Est. completion date: June 29, 2019
• Est. primary completion date: June 29, 2019
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 28 Years

Eligibility

• INCLUSION CRITERIA:

Participants will be enrolled without regard to race or ethnicity. Each potential participant must meet all of the following inclusion criteria in order to be eligible to enroll in the study:

1. Female

2. Between 18 and 28 years of age (inclusive)

3. Reported menarche between the ages of 11 and 14 years

4. Gynecological age of less than or equal to 14 years

5. 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

6. A BMI of 18.5 to 27 kg (Summation)m(2) and a weight >= 93 lbs.

7. Agrees to use barrier contraception method for the duration of the study and the follow up period

8. Agrees to abstain from alcohol consumption during both 5-day diet/exercise study interventions

9. Agrees to abstain from donating blood during the study and within 30 days of completing the study

10. Agrees to abstain from biotin supplements for the duration of the study

11. Is willing and able to fulfill the requirements of the protocol and to provide informed consent

12. Able to speak and read English

13. Lives within 50 miles of the Clinical Research Unit

EXCLUSION CRITERIA:

A potential participant meeting any of the following exclusion criteria is not eligible to enroll in the study:

1. Currently lactating or pregnant or planning on becoming pregnant for the duration of the study

2. Has ever given birth

3. History in the past 3 months of dieting or weight loss amounting to greater than 2 kg

4. > 4 hours per week of aerobic exercise for the past 3 months

5. 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

6. Currently using hormone-based contraception, including those administered orally, vaginally, via injection, sub-dermally, or transdermally

7. 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

8. Current use of recreational drugs (alcohol intake will be monitored and excluded during the two intervention periods)

9. Unable to consume food containing dairy or nuts

10. 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 LBM*day

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

Related Conditions & MeSH terms

• Hormones

Intervention

Behavioral:
• NEA
Neutral Energy Availability: 5-day outpatient intervention of prescribed diet and exercise to elicit an energy availability of 45 kcal/kg LBM day.
• DEA
Deficient Energy Availability: 5-day outpatient intervention of prescribed diet and exercise to elicit an energy availability of 20 kcal/kg LBM day.

Locations

Country	Name	City	State
United States	NIEHS Clinical Research Unit (CRU)	Research Triangle Park	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Environmental Health Sciences (NIEHS)

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.	Menstrual cycle of the NEA Intervention and menstrual cycle of DEA Intervention
Secondary	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.	NEA Intervention Day 5 and DEA Intervention Day 5
Secondary	Change in cortisol, TSH, TT3, and fT4	Change in Laboratory Values collected by sampling over 8 hours during a study visit.	NEA Intervention Day 5 and DEA Intervention Day 5

External Links

•   NIH Clinical Center Detailed Web Page