Fat Mediated Modulation of Reproductive and Endocrine Function in Young Athletes
Primary Purpose
Exercise-related Amenorrhea
Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Transdermal 17Beta-estradiol, progesterone
Ethinyl Estradiol + Desogestrel
Sham Comparator
Sponsored by
About this trial
This is an interventional treatment trial for Exercise-related Amenorrhea focused on measuring Amenorrhea, Adolescent, Endurance, Athletes, Females, Osteopenia, Osteoporosis, Estrogen
Eligibility 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
Sites / Locations
- Massachusetts General Hospital
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Active Comparator
Sham Comparator
Arm Label
Estrogen Patch
Estrogen Pill
Control
Arm Description
17Beta-estradiol transdermal patch twice weekly application for 12 months
One pill containing estrogen and progesterone taken daily for 21 days followed by placebo pills only for 7 days; regimen repeated for 12 months.
Elemental calcium 1200 mg and Vit D 400 IU taken orally daily
Outcomes
Primary Outcome Measures
Change in Lumbar Bone Mineral Density
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)
Change in total volumetric bone density at the tibia with transdermal estrogen versus oral estrogen or no estrogen in amenorrheic athletes
Full Information
NCT ID
NCT00946192
First Posted
July 22, 2009
Last Updated
June 4, 2021
Sponsor
Massachusetts General Hospital
Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
1. Study Identification
Unique Protocol Identification Number
NCT00946192
Brief Title
Fat Mediated Modulation of Reproductive and Endocrine Function in Young Athletes
Official Title
Fat Mediated Modulation of Reproductive and Endocrine Function in Young Athletes
Study Type
Interventional
2. Study Status
Record Verification Date
June 2021
Overall Recruitment Status
Completed
Study Start Date
May 2009 (Actual)
Primary Completion Date
February 2020 (Actual)
Study Completion Date
April 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Massachusetts General Hospital
Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
4. Oversight
Data Monitoring Committee
Yes
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Exercise-related Amenorrhea
Keywords
Amenorrhea, Adolescent, Endurance, Athletes, Females, Osteopenia, Osteoporosis, Estrogen
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
121 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Estrogen Patch
Arm Type
Experimental
Arm Description
17Beta-estradiol transdermal patch twice weekly application for 12 months
Arm Title
Estrogen Pill
Arm Type
Active Comparator
Arm Description
One pill containing estrogen and progesterone taken daily for 21 days followed by placebo pills only for 7 days; regimen repeated for 12 months.
Arm Title
Control
Arm Type
Sham Comparator
Arm Description
Elemental calcium 1200 mg and Vit D 400 IU taken orally daily
Intervention Type
Drug
Intervention Name(s)
Transdermal 17Beta-estradiol, progesterone
Other Intervention Name(s)
Vivelle Dot transdermal patch, Prometrium
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Ethinyl Estradiol + Desogestrel
Other Intervention Name(s)
Apri
Intervention Description
Oral ethinyl estradiol (0.03 mg) + desogestrel (0.15 mg) + Elemental calcium 1200 mg and Vit D 400 IU taken once daily
Intervention Type
Dietary Supplement
Intervention Name(s)
Sham Comparator
Intervention Description
Elemental calcium 1200 mg and Vit D 400 IU taken orally daily
Primary Outcome Measure Information:
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
Secondary Outcome Measure Information:
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
10. Eligibility
Sex
Female
Minimum Age & Unit of Time
14 Years
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Madhusmita Misra, MD, MPH
Organizational Affiliation
Massachusetts General Hospital Pediatric Neuroendocrine Unit and Harvard Medical School
Official's Role
Principal Investigator
Facility Information:
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
31603998
Citation
Ackerman KE, Singhal V, Slattery M, Eddy KT, Bouxsein ML, Lee H, Klibanski A, Misra M. Effects of Estrogen Replacement on Bone Geometry and Microarchitecture in Adolescent and Young Adult Oligoamenorrheic Athletes: A Randomized Trial. J Bone Miner Res. 2020 Feb;35(2):248-260. doi: 10.1002/jbmr.3887. Epub 2019 Nov 7.
Results Reference
derived
PubMed Identifier
30639922
Citation
Plessow F, Singhal V, Toth AT, Micali N, Eddy KT, Misra M. Estrogen administration improves the trajectory of eating disorder pathology in oligo-amenorrheic athletes: A randomized controlled trial. Psychoneuroendocrinology. 2019 Apr;102:273-280. doi: 10.1016/j.psyneuen.2018.11.013. Epub 2018 Nov 16.
Results Reference
derived
PubMed Identifier
30476179
Citation
Singhal V, Ackerman KE, Bose A, Flores LPT, Lee H, Misra M. Impact of Route of Estrogen Administration on Bone Turnover Markers in Oligoamenorrheic Athletes and Its Mediators. J Clin Endocrinol Metab. 2019 May 1;104(5):1449-1458. doi: 10.1210/jc.2018-02143.
Results Reference
derived
PubMed Identifier
30301734
Citation
Ackerman KE, Singhal V, Baskaran C, Slattery M, Campoverde Reyes KJ, Toth A, Eddy KT, Bouxsein ML, Lee H, Klibanski A, Misra M. Oestrogen replacement improves bone mineral density in oligo-amenorrhoeic athletes: a randomised clinical trial. Br J Sports Med. 2019 Feb;53(4):229-236. doi: 10.1136/bjsports-2018-099723. Epub 2018 Oct 9.
Results Reference
derived
PubMed Identifier
28297591
Citation
Baskaran C, Cunningham B, Plessow F, Singhal V, Woolley R, Ackerman KE, Slattery M, Lee H, Lawson EA, Eddy K, Misra M. Estrogen Replacement Improves Verbal Memory and Executive Control in Oligomenorrheic/Amenorrheic Athletes in a Randomized Controlled Trial. J Clin Psychiatry. 2017 May;78(5):e490-e497. doi: 10.4088/JCP.15m10544.
Results Reference
derived
PubMed Identifier
22252944
Citation
Ackerman KE, Slusarz K, Guereca G, Pierce L, Slattery M, Mendes N, Herzog DB, Misra M. Higher ghrelin and lower leptin secretion are associated with lower LH secretion in young amenorrheic athletes compared with eumenorrheic athletes and controls. Am J Physiol Endocrinol Metab. 2012 Apr 1;302(7):E800-6. doi: 10.1152/ajpendo.00598.2011. Epub 2012 Jan 17.
Results Reference
derived
PubMed Identifier
21816790
Citation
Ackerman KE, Nazem T, Chapko D, Russell M, Mendes N, Taylor AP, Bouxsein ML, Misra M. Bone microarchitecture is impaired in adolescent amenorrheic athletes compared with eumenorrheic athletes and nonathletic controls. J Clin Endocrinol Metab. 2011 Oct;96(10):3123-33. doi: 10.1210/jc.2011-1614. Epub 2011 Aug 3.
Results Reference
derived
Links:
URL
http://pituitary.mgh.harvard.edu/
Description
Click here for up-to-date information about the Neuroendocrine Unit at Massachusetts General Hospital including ongoing research studies, staff listing, and educational resources.
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Fat Mediated Modulation of Reproductive and Endocrine Function in Young Athletes
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