Fat Mediated Modulation of Reproductive and Endocrine Function in Young Athletes

This study is currently recruiting participants.
Verified December 2013 by Massachusetts General Hospital
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Madhusmita Misra, Massachusetts General Hospital
ClinicalTrials.gov Identifier:
NCT00946192
First received: July 22, 2009
Last updated: December 10, 2013
Last verified: December 2013

July 22, 2009
December 10, 2013
May 2009
June 2015   (final data collection date for primary outcome measure)
Increase in bone density with transdermal estrogen versus oral estrogen or no estrogen in amenorrheic athletes [ Time Frame: 12 months ] [ Designated as safety issue: No ]
We will test the hypothesis that in adolescent athletes: (i) Suboptimal energy availability preferentially lowers fat mass with sparing of lean mass. [ Time Frame: 5 years ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00946192 on ClinicalTrials.gov Archive Site
Improvement in bone microarchitecture with transdermal estrogen versus oral estrogen or no estrogen in amenorrheic athletes [ Time Frame: 12 months ] [ Designated as safety issue: No ]
Not Provided
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Fat Mediated Modulation of Reproductive and Endocrine Function in Young Athletes
Fat Mediated Modulation of Reproductive and Endocrine Function in Young Athletes

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.

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.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Exercise-related Amenorrhea
  • 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:
    • Vivelle Dot transdermal patch
    • Prometrium
  • 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 Name: Apri
  • Dietary Supplement: Sham Comparator
    Elemental calcium 1200 mg and Vit D 400 IU taken orally daily
  • Experimental: Estrogen Patch
    17Beta-estradiol transdermal patch twice weekly application for 12 months
    Intervention: Drug: Transdermal 17Beta-estradiol, progesterone
  • 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.
    Intervention: Drug: Ethinyl Estradiol + Desogestrel
  • Sham Comparator: Control
    Elemental calcium 1200 mg and Vit D 400 IU taken orally daily
    Intervention: Dietary Supplement: Sham Comparator

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
230
December 2015
June 2015   (final data collection date for primary outcome measure)

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
Female
14 Years to 21 Years
Yes
Contact: Madhusmita Misra, MD, MPH 617-724-5602 mmisra@partners.org
United States
 
NCT00946192
2009P000353, R01HD060827-01A1
Yes
Madhusmita Misra, Massachusetts General Hospital
Massachusetts General Hospital
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Principal Investigator: Madhusmita Misra, MD, MPH Massachusetts General Hospital Pediatric Neuroendocrine Unit and Harvard Medical School
Massachusetts General Hospital
December 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP