Fat Mediated Modulation of Reproductive and Endocrine Function in Young Athletes

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ClinicalTrials.gov Identifier: NCT00946192

Recruitment Status : Active, not recruiting

First Posted : July 24, 2009

Results First Posted : March 18, 2020

Last Update Posted : June 11, 2020

Sponsor:

Collaborator:

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Information provided by (Responsible Party):

Madhusmita Misra, Massachusetts General Hospital

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition	Exercise-related Amenorrhea
Interventions	Drug: Transdermal 17Beta-estradiol, progesterone Drug: Ethinyl Estradiol + Desogestrel Dietary Supplement: Sham Comparator
Enrollment	121

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	Estrogen Patch	Estrogen Pill	Control
Arm/Group Description	17Beta-estradiol transdermal patch ...	One pill containing estrogen and pr...	Elemental calcium 1200 mg and Vit D...
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
Reason Not Completed
Lost to Follow-up	6	11	9
Withdrawal by Subject	10	7	3
Did not start medication	2	0	0

Baseline Characteristics

Arm/Group Title		Estrogen Patch	Estrogen Pill	Control	Total
Arm/Group Description		17Beta-estradiol transdermal patch ...	One pill containing estrogen and pr...	Elemental calcium 1200 mg and Vit D...	Total of all reporting groups
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 Number of Baseline Participants		43	40	38	121
Baseline Analysis Population Description		...
Baseline Analysis Population Description		Athletes with amenorrhea
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	43 participants	40 participants	38 participants	121 participants
		19.86 (0.40)	20.30 (0.44)	19.35 (0.38)	19.84 (0.41)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	43 participants	40 participants	38 participants	121 participants
	Female	43 100.0%	40 100.0%	38 100.0%	121 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	43 participants	40 participants	38 participants	121 participants
	Hispanic or Latino	0 0.0%	0 0.0%	2 5.3%	2 1.7%
	Not Hispanic or Latino	43 100.0%	40 100.0%	36 94.7%	119 98.3%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	43 participants	40 participants	38 participants	121 participants
	American Indian or Alaska Native	1 2.3%	0 0.0%	0 0.0%	1 0.8%
	Asian	4 9.3%	0 0.0%	1 2.6%	5 4.1%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	White	37 86.0%	38 95.0%	35 92.1%	110 90.9%
	More than one race	1 2.3%	2 5.0%	2 5.3%	5 4.1%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment Measure Type: Number Unit of measure: Participants
United States	Number Analyzed	43 participants	40 participants	38 participants	121 participants
United States		43	40	38	121
BMI Mean (Standard Deviation) Unit of measure: Kg/m^2
	Number Analyzed	43 participants	40 participants	38 participants	121 participants
		20.45 (0.35)	20.80 (0.39)	20.75 (0.34)	20.67 (0.36)

Outcome Measures

1.Primary Outcome


Title	Change in Lumbar Bone Mineral Density
Description	Change in bone density with transdermal estrogen versus oral estrogen ...
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 ...	One pill containing estrogen and pr...	Elemental calcium 1200 mg and Vit D...
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
Overall Number of Participants Analyzed	25	22	26
Mean (Standard Error) Unit of Measure: 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	[Not Specified]
	Type of Statistical Test	Other
	Comments	Least square means

Statistical Test of Hypothesis	P-Value	0.039
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

2.Secondary Outcome


Title	Change in Total Volumetric Bone Mineral Density (Tibia)
Description	Change in total volumetric bone density at the tibia with transdermal ...
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 ...	One pill containing estrogen and pr...	Elemental calcium 1200 mg and Vit D...
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
Overall Number of Participants Analyzed	24	24	27
Mean (Standard Error) Unit of Measure: 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	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.018
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]

Adverse Events

Time Frame	1 year
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	Estrogen Patch		Estrogen Pill		Control
Arm/Group Description	17Beta-estradiol transdermal patch ...		One pill containing estrogen and pr...		Elemental calcium 1200 mg and Vit D...
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 (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/43 (0.00%)		0/40 (0.00%)		0/38 (0.00%)
Serious Adverse Events Serious Adverse Events
	Estrogen Patch		Estrogen Pill		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/43 (6.98%)		0/40 (0.00%)		1/38 (2.63%)
Endocrine disorders
Fractures or sprains ^†	3/43 (6.98%)	3	0/40 (0.00%)	0	0/38 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Sinus surgery ^†	0/43 (0.00%)	0	0/40 (0.00%)		1/38 (2.63%)	1
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0.1%
	Estrogen Patch		Estrogen Pill		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/43 (23.26%)		13/40 (32.50%)		1/38 (2.63%)
Endocrine disorders
Breast tenderness ^†	1/43 (2.33%)	1	1/40 (2.50%)	1	0/38 (0.00%)	0
Early menses ^†	0/43 (0.00%)	0	1/40 (2.50%)	1	0/38 (0.00%)	0
Gastrointestinal disorders
Nausea ^†	0/43 (0.00%)	0	2/40 (5.00%)	2	0/38 (0.00%)	0
Gastritis ^†	1/43 (2.33%)	1	0/40 (0.00%)	0	0/38 (0.00%)	0
Diarrhea ^†	1/43 (2.33%)	1	0/40 (0.00%)	0	0/38 (0.00%)	0
General disorders
Fatigue ^†	0/43 (0.00%)	0	1/40 (2.50%)	1	0/38 (0.00%)	0
Bloating ^†	2/43 (4.65%)	2	0/40 (0.00%)	0	0/38 (0.00%)	0
Generalized discomfort ^†	1/43 (2.33%)	1	0/40 (0.00%)	0	0/38 (0.00%)	0
Infections and infestations
Yeast infection ^†	0/43 (0.00%)	0	1/40 (2.50%)	1	0/38 (0.00%)	0
Mononucleosis ^†	0/43 (0.00%)	0	1/40 (2.50%)	1	0/38 (0.00%)	0
Investigations
Electrolyte changes ^†	0/43 (0.00%)	0	1/40 (2.50%)	1	0/38 (0.00%)	0
Metabolism and nutrition disorders
Fluid retention ^†	0/43 (0.00%)	0	1/40 (2.50%)	1	0/38 (0.00%)	0
Nervous system disorders
Headache ^†	2/43 (4.65%)	2	1/40 (2.50%)	1	0/38 (0.00%)	0
Product Issues
Mood swings ^†	0/43 (0.00%)	0	1/40 (2.50%)	1	0/38 (0.00%)	0
Psychiatric disorders
Worsening depression ^†	1/43 (2.33%)	1	1/40 (2.50%)	1	0/38 (0.00%)	0
Reproductive system and breast disorders
Decreased libido ^†	0/43 (0.00%)	0	1/40 (2.50%)	1	0/38 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Upper respiratory symptoms ^†	0/43 (0.00%)	0	0/40 (0.00%)	0	1/38 (2.63%)	1
Skin and subcutaneous tissue disorders
Skin rash ^†	1/43 (2.33%)	1	0/40 (0.00%)	0	0/38 (0.00%)	0
Skin tags ^†	0/43 (0.00%)	0	1/40 (2.50%)	1	0/38 (0.00%)	0
Vascular disorders
Dizziness ^†	1/43 (2.33%)	1	0/40 (0.00%)	0	0/38 (0.00%)	0
Vasovagal response ^†	0/43 (0.00%)	0	2/40 (5.00%)	2	0/38 (0.00%)	0
† Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

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

Layout table for Results Point of Contact information

Name/Title:	Madhu Misra, MD; Chief, Pediatric Endocrine
Organization:	Massachusetts General Hospital and Harvard Medical School
Phone:	6177245602
EMail:	mmisra@mgh.harvard.edu

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

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.

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.

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.

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.

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.

Layout table for additonal information

Responsible Party:	Madhusmita Misra, Massachusetts General Hospital
ClinicalTrials.gov Identifier:	NCT00946192
Other Study ID Numbers:	2009P000353 R01HD060827-01A1 ( U.S. NIH Grant/Contract )
First Submitted:	July 22, 2009
First Posted:	July 24, 2009
Results First Submitted:	February 15, 2020
Results First Posted:	March 18, 2020
Last Update Posted:	June 11, 2020

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