Fat Mediated Modulation of Reproductive and Endocrine Function in Young Athletes
Study Details
Study Description
Brief 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| 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:
|
| 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:
|
| 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
|
Outcome Measures
Primary Outcome Measures
- Change in Lumbar Bone Mineral Density [12 months]
Change in bone density with transdermal estrogen versus oral estrogen or no estrogen in amenorrheic athletes
Secondary Outcome Measures
- Change in Total Volumetric Bone Mineral Density (Tibia) [12 months]
Change in total volumetric bone density at the tibia with transdermal estrogen versus oral estrogen or no estrogen in amenorrheic athletes
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Massachusetts General Hospital | Boston | Massachusetts | United States | 02114 |
Sponsors and Collaborators
- Massachusetts General Hospital
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
- Principal Investigator: Madhusmita Misra, MD, MPH, Massachusetts General Hospital Pediatric Neuroendocrine Unit and Harvard Medical School
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.- 2009P000353
- R01HD060827-01A1
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Estrogen Patch | Estrogen Pill | Control |
|---|---|---|---|
| Arm/Group Description | 17Beta-estradiol transdermal patch twice weekly application for 12 months 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 | One pill containing estrogen and progesterone taken daily for 21 days followed by placebo pills only for 7 days; regimen repeated for 12 months. 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 | Elemental calcium 1200 mg and Vit D 400 IU taken orally daily Sham Comparator: Elemental calcium 1200 mg and Vit D 400 IU taken orally daily |
| Period Title: Overall Study | |||
| STARTED | 43 | 40 | 38 |
| COMPLETED | 25 | 22 | 26 |
| NOT COMPLETED | 18 | 18 | 12 |
Baseline Characteristics
| Arm/Group Title | Estrogen Patch | Estrogen Pill | Control | Total |
|---|---|---|---|---|
| Arm/Group Description | 17Beta-estradiol transdermal patch twice weekly application for 12 months 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 | One pill containing estrogen and progesterone taken daily for 21 days followed by placebo pills only for 7 days; regimen repeated for 12 months. 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 | Elemental calcium 1200 mg and Vit D 400 IU taken orally daily Sham Comparator: Elemental calcium 1200 mg and Vit D 400 IU taken orally daily | Total of all reporting groups |
| Overall Participants | 43 | 40 | 38 | 121 |
| Age (years) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [years] |
19.86
(0.40)
|
20.30
(0.44)
|
19.35
(0.38)
|
19.84
(0.41)
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
43
100%
|
40
100%
|
38
100%
|
121
100%
|
| Male |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Ethnicity (NIH/OMB) (Count of Participants) | ||||
| Hispanic or Latino |
0
0%
|
0
0%
|
2
5.3%
|
2
1.7%
|
| Not Hispanic or Latino |
43
100%
|
40
100%
|
36
94.7%
|
119
98.3%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | ||||
| American Indian or Alaska Native |
1
2.3%
|
0
0%
|
0
0%
|
1
0.8%
|
| Asian |
4
9.3%
|
0
0%
|
1
2.6%
|
5
4.1%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| White |
37
86%
|
38
95%
|
35
92.1%
|
110
90.9%
|
| More than one race |
1
2.3%
|
2
5%
|
2
5.3%
|
5
4.1%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (participants) [Number] | ||||
| United States |
43
100%
|
40
100%
|
38
100%
|
121
100%
|
| BMI (kg/m^2) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [kg/m^2] |
20.45
(0.35)
|
20.80
(0.39)
|
20.75
(0.34)
|
20.67
(0.36)
|
Outcome Measures
| Title | Change in Lumbar Bone Mineral Density |
|---|---|
| Description | Change in bone density with transdermal estrogen versus oral estrogen or no estrogen in amenorrheic athletes |
| Time Frame | 12 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Estrogen Patch | Estrogen Pill | Control |
|---|---|---|---|
| Arm/Group Description | 17Beta-estradiol transdermal patch twice weekly application for 12 months 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 | One pill containing estrogen and progesterone taken daily for 21 days followed by placebo pills only for 7 days; regimen repeated for 12 months. 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 | Elemental calcium 1200 mg and Vit D 400 IU taken orally daily Sham Comparator: Elemental calcium 1200 mg and Vit D 400 IU taken orally daily |
| Measure Participants | 25 | 22 | 26 |
| Mean (Standard Error) [g/cm^2] |
0.025
(0.011)
|
0.008
(0.011)
|
0.012
(0.012)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Estrogen Patch, Estrogen Pill, Control |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | Least square means | |
| Statistical Test of Hypothesis | p-Value | 0.039 |
| Comments | ||
| Method | Mixed Models Analysis | |
| Comments | ||
| Title | Change in Total Volumetric Bone Mineral Density (Tibia) |
|---|---|
| Description | Change in total volumetric bone density at the tibia with transdermal estrogen versus oral estrogen or no estrogen in amenorrheic athletes |
| Time Frame | 12 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Estrogen Patch | Estrogen Pill | Control |
|---|---|---|---|
| Arm/Group Description | 17Beta-estradiol transdermal patch twice weekly application for 12 months 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 | One pill containing estrogen and progesterone taken daily for 21 days followed by placebo pills only for 7 days; regimen repeated for 12 months. 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 | Elemental calcium 1200 mg and Vit D 400 IU taken orally daily Sham Comparator: Elemental calcium 1200 mg and Vit D 400 IU taken orally daily |
| Measure Participants | 24 | 24 | 27 |
| Mean (Standard Error) [mg HA/cm^3] |
7.01
(3.06)
|
1.17
(3.05)
|
3.71
(4.44)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Estrogen Patch, Estrogen Pill, Control |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.018 |
| Comments | ||
| Method | Mixed Models Analysis | |
| Comments | ||
Adverse Events
| Time Frame | 1 year | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||
| Arm/Group Title | Estrogen Patch | Estrogen Pill | Control | |||
| Arm/Group Description | 17Beta-estradiol transdermal patch twice weekly application for 12 months 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 | One pill containing estrogen and progesterone taken daily for 21 days followed by placebo pills only for 7 days; regimen repeated for 12 months. 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 | Elemental calcium 1200 mg and Vit D 400 IU taken orally daily Sham Comparator: Elemental calcium 1200 mg and Vit D 400 IU taken orally daily | |||
All Cause Mortality |
||||||
| Estrogen Patch | Estrogen Pill | Control | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/43 (0%) | 0/40 (0%) | 0/38 (0%) | |||
Serious Adverse Events |
||||||
| Estrogen Patch | Estrogen Pill | Control | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/43 (7%) | 0/40 (0%) | 1/38 (2.6%) | |||
| Endocrine disorders | ||||||
| Fractures or sprains | 3/43 (7%) | 3 | 0/40 (0%) | 0 | 0/38 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Sinus surgery | 0/43 (0%) | 0 | 0/40 (0%) | 0 | 1/38 (2.6%) | 1 |
Other (Not Including Serious) Adverse Events |
||||||
| Estrogen Patch | Estrogen Pill | Control | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 10/43 (23.3%) | 13/40 (32.5%) | 1/38 (2.6%) | |||
| Endocrine disorders | ||||||
| Breast tenderness | 1/43 (2.3%) | 1 | 1/40 (2.5%) | 1 | 0/38 (0%) | 0 |
| Early menses | 0/43 (0%) | 0 | 1/40 (2.5%) | 1 | 0/38 (0%) | 0 |
| Gastrointestinal disorders | ||||||
| Nausea | 0/43 (0%) | 0 | 2/40 (5%) | 2 | 0/38 (0%) | 0 |
| Gastritis | 1/43 (2.3%) | 1 | 0/40 (0%) | 0 | 0/38 (0%) | 0 |
| Diarrhea | 1/43 (2.3%) | 1 | 0/40 (0%) | 0 | 0/38 (0%) | 0 |
| General disorders | ||||||
| Fatigue | 0/43 (0%) | 0 | 1/40 (2.5%) | 1 | 0/38 (0%) | 0 |
| Bloating | 2/43 (4.7%) | 2 | 0/40 (0%) | 0 | 0/38 (0%) | 0 |
| Generalized discomfort | 1/43 (2.3%) | 1 | 0/40 (0%) | 0 | 0/38 (0%) | 0 |
| Infections and infestations | ||||||
| Yeast infection | 0/43 (0%) | 0 | 1/40 (2.5%) | 1 | 0/38 (0%) | 0 |
| Mononucleosis | 0/43 (0%) | 0 | 1/40 (2.5%) | 1 | 0/38 (0%) | 0 |
| Investigations | ||||||
| Electrolyte changes | 0/43 (0%) | 0 | 1/40 (2.5%) | 1 | 0/38 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||
| Fluid retention | 0/43 (0%) | 0 | 1/40 (2.5%) | 1 | 0/38 (0%) | 0 |
| Nervous system disorders | ||||||
| Headache | 2/43 (4.7%) | 2 | 1/40 (2.5%) | 1 | 0/38 (0%) | 0 |
| Product Issues | ||||||
| Mood swings | 0/43 (0%) | 0 | 1/40 (2.5%) | 1 | 0/38 (0%) | 0 |
| Psychiatric disorders | ||||||
| Worsening depression | 1/43 (2.3%) | 1 | 1/40 (2.5%) | 1 | 0/38 (0%) | 0 |
| Reproductive system and breast disorders | ||||||
| Decreased libido | 0/43 (0%) | 0 | 1/40 (2.5%) | 1 | 0/38 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Upper respiratory symptoms | 0/43 (0%) | 0 | 0/40 (0%) | 0 | 1/38 (2.6%) | 1 |
| Skin and subcutaneous tissue disorders | ||||||
| Skin rash | 1/43 (2.3%) | 1 | 0/40 (0%) | 0 | 0/38 (0%) | 0 |
| Skin tags | 0/43 (0%) | 0 | 1/40 (2.5%) | 1 | 0/38 (0%) | 0 |
| Vascular disorders | ||||||
| Dizziness | 1/43 (2.3%) | 1 | 0/40 (0%) | 0 | 0/38 (0%) | 0 |
| Vasovagal response | 0/43 (0%) | 0 | 2/40 (5%) | 2 | 0/38 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Madhu Misra, MD; Chief, Pediatric Endocrine |
|---|---|
| Organization | Massachusetts General Hospital and Harvard Medical School |
| Phone | 6177245602 |
| mmisra@mgh.harvard.edu |
- 2009P000353
- R01HD060827-01A1