Fat Mediated Modulation of Reproductive and Endocrine Function in Young 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.

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