Fat Mediated Modulation of Reproductive and Endocrine Function in Young Athletes

June 4, 2021 updated by: Madhusmita Misra, Massachusetts General Hospital
One aim of this study is to determine changes in body composition and hormones that differentiate athletes who stop getting their periods versus those who continue to get their periods and non-athletes. The second aim of this study is to determine whether transdermal or oral estrogen (versus no estrogen) is effective in increasing bone density and improving bone microarchitecture in adolescent athletes who are not getting their periods and are thus estrogen deficient. The investigators hypothesize that transdermal estrogen will be more effective than oral estrogen or no estrogen in improving bone health in amenorrheic adolescent athletes.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

As many as 25% of adolescent and young adult endurance athletes develop amenorrhea, and factors that cause amenorrhea to occur in some, but not all, athletes have not been well characterized. Recent data indicate the critical importance of a negative energy balance state and leptin in regulating the Hypothalamic-pituitary-gonadal (H-P-G) axis. However, these factors do not completely account for alterations in this axis, and other contributing factors are unclear. Our preliminary data indicate the importance of low fat mass and fat related hormones in mediating hypogonadism in young athletes. This study will confirm these data and determine whether low fat mass and altered levels of adipokines, such as leptin and adiponectin, and hormones regulated by fat mass, such as ghrelin and peptide YY (PYY), determine alterations in LH pulsatility. A very concerning impact of amenorrhea in athletes is low bone mineral density (BMD). Preliminary data indicate lower BMD in adolescent athletes with amenorrhea (AA) compared with eumenorrheic athletes (EA) and non-athletic controls. The high prevalence of AA in adolescents is particularly concerning, because this population is potentially at greater risk as it is actively accruing bone. Of importance, bone microarchitecture, a better predictor of bone strength than BMD, has not been studied in AA. Because pubertal increases in estrogen are integral to optimizing peak bone mass, and AA is characterized by hypoestrogenism, this randomized study of transdermal estrogen versus oral estrogen or no estrogen will also examine whether estrogen replacement increases BMD and improves bone microarchitecture in adolescent AA 14-21 years old. EA and sedentary controls will be followed without intervention for this period. Despite the prevalent practice of prescribing oral contraceptives in AA, there is a paucity of data regarding benefits of this intervention in teenagers. Because transdermal estrogen, unlike oral estrogen, does not suppress IGF-1, an important bone anabolic factor, we expect effects of transdermal estrogen to exceed those of oral estrogen or no therapy. In addition, preliminary data indicate that low fat mass and alterations in fat related hormones may contribute to decreased bone accrual rates in athletes, and will be confirmed in this study. To summarize, a better understanding of the pathophysiology of reproductive dysfunction is critical to develop therapeutic strategies that will normalize the reproductive axis and bone accrual, and these are the questions that this study aims to answer.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
121

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Massachusetts General Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years to 21 years (ADULT, CHILD)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Females 14-21 years old Note: Our pilot data are reassuring in that young women 18-25 years old with hypothalamic amenorrhea are not adversely affected with estrogen use. In fact, in our prospective study, beneficial effects were observed both in young women 18-25 years old using oral estrogen, and in 14-18 year old adolescent girls using transdermal estrogen. We therefore feel that including girls in the 14-21 year age range will not be hazardous to their bone health. In fact, given the lack of data in this age group, it is important to study younger women and teenagers rather than extrapolate data from studies in adults to this younger population. Hormone dynamics differ in teenagers compared with adults, and bone mass accrual is even more dependent on estrogen and IGF-1 in younger than older women who have already achieved peak bone mass.
  • Bone age (BA) >15 years Note: 99% of adult height is achieved at a BA of 15 years, thus estrogen replacement will not result in stunting of height potential after this age. Although we could have chosen to include girls with a BA >14 in this study, we are limiting this to girls with a BA of >15 years. This is because 2% of growth potential persists at a BA of 14 years, versus only 1% at a BA of 15 years (~0.6" of potential height (130)). Thus, to avoid potential stunting of growth potential with estrogen replacement, we have chosen to include girls with BA of > 15 years.
  • BMI between 10th-90th percentiles for age.
  • Amenorrhea (for AA): absence of menses for > three months (74) within a period of oligomenorrhea (cycle length > six weeks) for >six months, or absence of menarche at >16 years.
  • Eumenorrhea (EA and controls): > nine menses (cycle length 21-35 days) in preceding year.
  • Non-athlete healthy controls will be eligible if weight bearing exercise activity is less than two hours a week and if they are not participating in organized team sports.
  • Endurance athletes Note: severity of low BMD and menstrual dysfunction differ by kind of exercise and activity. For example, runners have a higher prevalence of menstrual irregularity than swimmers and cyclists (131). By limiting enrollment to endurance athletes, we will eliminate variability from the type of activity. Endurance training is defined as > 4 h of aerobic weight-bearing training of the legs or specific endurance training weekly, or > 20 miles of running weekly for a period of > 6 months in the last year.

Exclusion Criteria:

  • Other conditions that may affect bone metabolism

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
EXPERIMENTAL: Estrogen Patch
17Beta-estradiol transdermal patch twice weekly application for 12 months
Drug: Transdermal 17Beta-estradiol, progesterone
100 mcg/day 17Beta-estradiol; transdermal twice weekly application for 12 months (with cyclic micronized progesterone pills (Prometrium): 200 mg taken orally daily Day 1 to Day 12 each month) + Elemental calcium 1200 mg and Vit D 400 IU taken orally daily
Other Names:
  • Prometrium
  • Vivelle Dot transdermal patch
ACTIVE_COMPARATOR: Estrogen Pill
One pill containing estrogen and progesterone taken daily for 21 days followed by placebo pills only for 7 days; regimen repeated for 12 months.
Drug: Ethinyl Estradiol + Desogestrel
Oral ethinyl estradiol (0.03 mg) + desogestrel (0.15 mg) + Elemental calcium 1200 mg and Vit D 400 IU taken once daily
Other Names:
  • Apri
SHAM_COMPARATOR: Control
Elemental calcium 1200 mg and Vit D 400 IU taken orally daily
Dietary supplement: Sham Comparator
Elemental calcium 1200 mg and Vit D 400 IU taken orally daily

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Change in Lumbar Bone Mineral Density
Time Frame: 12 months
Change in bone density with transdermal estrogen versus oral estrogen or no estrogen in amenorrheic athletes
12 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Change in Total Volumetric Bone Mineral Density (Tibia)
Time Frame: 12 months
Change in total volumetric bone density at the tibia with transdermal estrogen versus oral estrogen or no estrogen in amenorrheic athletes
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Massachusetts General Hospital

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Madhusmita Misra, MD, MPH, Massachusetts General Hospital Pediatric Neuroendocrine Unit and Harvard Medical School

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
May 1, 2009

Primary Completion (ACTUAL)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
February 1, 2020

Study Completion (ACTUAL)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
April 1, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 22, 2009

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 23, 2009

First Posted (ESTIMATE)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 24, 2009

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
June 11, 2021

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 4, 2021

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
June 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 2009P000353
  • R01HD060827-01A1 (NIH)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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