Fat Mediated Modulation of Reproductive and Endocrine Function in Young Athletes

NCT00946192 | Completed Phase 3 Results DMC

• 2 other identifiers: 2009P000353R01HD060827-01A1
• Study Type: interventional
• Target: 121
• Locations: 1 country
• Sites: 1

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.

Conditions

Exercise-related Amenorrhea

Keywords

Amenorrhea; Adolescent; Endurance; Athletes; Females; Osteopenia; Osteoporosis; Estrogen

Outcome Measures

Primary Outcomes (1)

• Change in Lumbar Bone Mineral Density

  Change in bone density with transdermal estrogen versus oral estrogen or no estrogen in amenorrheic athletes

  12 months

Secondary Outcomes (1)

• Change in Total Volumetric Bone Mineral Density (Tibia)

  12 months

Study Arms (3)

Estrogen Patch

EXPERIMENTAL

17Beta-estradiol transdermal patch twice weekly application for 12 months

Drug: Transdermal 17Beta-estradiol, progesterone

Estrogen Pill

ACTIVE COMPARATOR

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

Control

SHAM COMPARATOR

Elemental calcium 1200 mg and Vit D 400 IU taken orally daily

Dietary Supplement: Sham Comparator

Interventions

Transdermal 17Beta-estradiol, progesterone DRUG

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

Also known as: Vivelle Dot transdermal patch, Prometrium

Estrogen Patch

Ethinyl Estradiol + Desogestrel DRUG

Oral ethinyl estradiol (0.03 mg) + desogestrel (0.15 mg) + Elemental calcium 1200 mg and Vit D 400 IU taken once daily

Also known as: Apri

Estrogen Pill

Sham Comparator DIETARY_SUPPLEMENT

Elemental calcium 1200 mg and Vit D 400 IU taken orally daily

Control

Eligibility Criteria

• Age: 14 Years - 21 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• Other conditions that may affect bone metabolism

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Related Publications (7)

• 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.

  PMID: 31603998 DERIVED

• 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.

  PMID: 30639922 DERIVED

• 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.

  PMID: 30476179 DERIVED

• 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.

  PMID: 30301734 DERIVED

• 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.

  PMID: 28297591 DERIVED

• 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.

  PMID: 22252944 DERIVED

• 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.

  PMID: 21816790 DERIVED

MeSH Terms

Conditions

Amenorrhea; Bone Diseases, Metabolic; Osteoporosis

Interventions

Progesterone; Desogestrel

Condition Hierarchy (Ancestors)

Menstruation Disturbances; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Corpus Luteum Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progesterone Congeners; Gonadal Steroid Hormones; Norpregnenes; Norpregnanes; Norsteroids

Results Point of Contact

• Title: Madhu Misra, MD; Chief, Pediatric Endocrine
• Organization: Massachusetts General Hospital and Harvard Medical School

mmisra@mgh.harvard.edu

6177245602

Study Officials

• Madhusmita Misra, MD, MPH

  Massachusetts General Hospital Pediatric Neuroendocrine Unit and Harvard Medical School

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Pediatrics

Study Record Dates

• First Submitted: July 22, 2009
• First Posted: July 24, 2009
• Study Start: May 1, 2009
• Primary Completion: February 1, 2020
• Study Completion: April 1, 2021
• Last Updated: June 11, 2021
• Results First Posted: March 18, 2020

Record last verified: 2021-06

Locations

US (1)