Fat Mediated Modulation of Reproductive and Endocrine Function in Young Athletes
Condition: Exercise-related Amenorrhea
MeSH terms: Amenorrhea
Study type: Interventional
Phase: Phase 3

Summary: 
      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.
    

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.
    

Intervention name(s): Transdermal 17Beta-estradiol, progesterone; Ethinyl Estradiol + Desogestrel; Sham Comparator
Intervention type(s): Drug; Drug; Dietary Supplement
Intervention description(s): 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; Oral ethinyl estradiol (0.03 mg) + desogestrel (0.15 mg) + Elemental calcium 1200 mg and Vit D 400 IU taken once daily; Elemental calcium 1200 mg and Vit D 400 IU taken orally daily
Other intervention name(s): Vivelle Dot transdermal patch; Prometrium; Apri
Intervention MeSH terms: Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Ethinyl Estradiol; Desogestrel; Estradiol; Polyestradiol phosphate; Progesterone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Amenorrhea; Adolescent; Endurance; Athletes; Females; Osteopenia; Osteoporosis; Estrogen