Adrenal and Gonadal Hormone Replacement in Anorexia Nervosa

NCT ID: NCT00310791

Last Updated: 2018-04-11

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2/PHASE3

Total Enrollment

80 participants

Study Classification

INTERVENTIONAL

Study Start Date

2004-04-30

Study Completion Date

2010-12-31

Brief Summary

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This study seeks to gain new information on why young women with anorexia nervosa are predisposed to early bone loss and osteoporosis. Through a randomized treatment trial in which participants will receive either combined therapy with the adrenal hormone, dehydroepiandrosterone (DHEA) and estrogen replacement therapy or placebo, we will determine the effects of an 18-month treatment course on bone mass, circulating markers of bone turnover, and serum levels of a factor, insulin-like growth factor I (IGF-I). We are also studying if these therapies change bone structure to increase skeletal strength compared to placebo, as assessed through cross-sectional geometric analysis of our bone density data by dual-energy x-ray absorptiometry (DXA).

Detailed Description

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Profound osteopenia is a frequent and often irreversible complication of anorexia nervosa (AN). Adolescents with AN often have a reduced peak bone mass and are at increased risk for early osteoporosis and fractures. These young women have subnormal serum levels of gonadal steroids and the adrenal androgen dehydroepiandrosterone (DHEA) that may be associated with their low bone mineral density (BMD). Low DHEA levels are accompanied by decreased levels of insulin-like growth factor I (IGF-I), estrogen, and testosterone. Previous data from our group indicate that oral DHEA therapy in young women with AN: increases lean body mass, serum levels of bone formation markers and insulin-like growth factor I (IGF-I), and decreases urinary markers of bone resorption. We also found that standard hormonal replacement therapy (HRT) significantly decreased bone resorption markers. Information on the effects of these therapies on bone strength and ultimate fracture risk is lacking.

In this project, we will test the hypothesis that combined therapy with DHEA and estrogen/progestin will enhance bone mass in patients with AN through anabolic and antiosteolytic mechanisms. We will test the hypothesis that 18 months of DHEA + HRT will increase bone mineral density (BMD) and markers of bone formation, while decreasing bone resorption markers in these patients. The proposed study will examine whether restoring normal levels of DHEA and estrogen in these young women will increase bone mass during a critical period for bone accretion. The study will also examine whether DHEA's anabolic effects on bone are mediated through the skeletal IGF-I regulatory system. Using cross-sectional analyses of dual energy x-ray absorptiometry (DXA) data, we will also measure indices of bone structural geometry to determine if mechanical strength is compromised in these young women, and if strength is restored in response to combined anabolic/antiresorptive therapy.

To gain new information on the mechanisms underlying bone loss and fracture risk in young women with AN, our research goals are:

Specific Aim I: Through a randomized controlled trial, to measure the effects of an 18-month course of DHEA + HRT on bone mass, markers of bone turnover, and serum levels of IGF-I compared to placebo. Specific Aim II: To determine whether combined therapy with adrenal and gonadal steroid replacement changes bone structure to increase strength compared to placebo, as assessed through cross-sectional geometric analysis of DXA data.

Conditions

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Anorexia Nervosa

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Participants Caregivers Investigators

Study Groups

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Sugar Pill

Placebo (sugar pill); identical to treatment medication capsule

Group Type PLACEBO_COMPARATOR

Placebo (Sugar Pill)

Intervention Type OTHER

Placebo (sugar pill)

DHEA + Hormone replacement therapy (estrogen/progestin)

Combined therapy of dehydroepiandrosterone (DHEA) and hormone replacement therapy (ERT). Patients randomized to the DHEA + HRT arm will receive micronized oral DHEA in a dose of 50 mg daily + HRT (0.3 mg Premarin, 1 tablet daily for 3 months, follow by Alesse (20 mg ethinyl estradiol + 0.1 mg levonorgestrel for 15 months). The estrogen/progestin component of the regimen has been chosen to maximize patient compliance, as patients with AN may experience bloating or nausea if higher estrogen doses (\> 20 g) are initiated too rapidly. The DHEA capsule strength will be 50 mg, the total daily dose to be studied in combination with HRT. The micronized DHEA preparation achieves more constant DHEA and DHEA-S levels. Fifty milligrams appears to be a physiological replacement dose for these young women, determined both from our pilot (10) and longitudinal studies (7).

Group Type EXPERIMENTAL

Hormone replacement therapy (estrogen/progestin)

Intervention Type DRUG

Hormone replacement therapy (estrogen/progestin). 0.3 mg conjugated estrogens x 3 months, followed by 9 months of oral contraceptive (20 mg ethinyl estradiol + 0.1 mg levonorgestrel)

Dehydroepiandrosterone (DHEA)

Intervention Type DRUG

50 mg tablet, 1 daily

Interventions

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Hormone replacement therapy (estrogen/progestin)

Hormone replacement therapy (estrogen/progestin). 0.3 mg conjugated estrogens x 3 months, followed by 9 months of oral contraceptive (20 mg ethinyl estradiol + 0.1 mg levonorgestrel)

Intervention Type DRUG

Placebo (Sugar Pill)

Placebo (sugar pill)

Intervention Type OTHER

Dehydroepiandrosterone (DHEA)

50 mg tablet, 1 daily

Intervention Type DRUG

Other Intervention Names

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Alesse (20 mg ethinyl estradiol + 0.1 mg levonorgestrel) Premarin (conjugated estrogens) Placebo Sugar pill Prasterone

Eligibility Criteria

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Inclusion Criteria

* Age 15 - 30 years
* Anorexia nervosa by psychiatric criteria
* Amenorrhea for at least 3 months

Exclusion Criteria

* Receiving no medications known to affects bone metabolism
* No other chronic medical conditions
Minimum Eligible Age

15 Years

Maximum Eligible Age

30 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

No

Sponsors

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United States Department of Defense

FED

Sponsor Role collaborator

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

NIH

Sponsor Role collaborator

Boston Children's Hospital

OTHER

Sponsor Role lead

Responsible Party

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Catherine M. Gordon

Catherine Gordon, MD, MSc

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Catherine M. Gordon, MD

Role: PRINCIPAL_INVESTIGATOR

Boston Children's Hospital

Locations

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Children's Hospital Boston

Boston, Massachusetts, United States

Site Status

Countries

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United States

References

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Vajapeyam S, Ecklund K, Mulkern RV, Feldman HA, O'Donnell JM, DiVasta AD, Rosen CJ, Gordon CM. Magnetic resonance imaging and spectroscopy evidence of efficacy for adrenal and gonadal hormone replacement therapy in anorexia nervosa. Bone. 2018 May;110:335-342. doi: 10.1016/j.bone.2018.02.021. Epub 2018 Feb 26.

Reference Type BACKGROUND
PMID: 29496516 (View on PubMed)

Divasta AD, Feldman HA, Brown JN, Giancaterino C, Holick MF, Gordon CM. Bioavailability of vitamin D in malnourished adolescents with anorexia nervosa. J Clin Endocrinol Metab. 2011 Aug;96(8):2575-80. doi: 10.1210/jc.2011-0243. Epub 2011 Jun 1.

Reference Type RESULT
PMID: 21632810 (View on PubMed)

Divasta AD, Feldman HA, Gordon CM. Vertebral fracture assessment in adolescents and young women with anorexia nervosa: a case series. J Clin Densitom. 2014 Jan-Mar;17(1):207-11. doi: 10.1016/j.jocd.2013.02.011. Epub 2013 Apr 3.

Reference Type RESULT
PMID: 23562364 (View on PubMed)

DiVasta AD, Feldman HA, Beck TJ, LeBoff MS, Gordon CM. Does hormone replacement normalize bone geometry in adolescents with anorexia nervosa? J Bone Miner Res. 2014 Jan;29(1):151-7. doi: 10.1002/jbmr.2005.

Reference Type RESULT
PMID: 23744513 (View on PubMed)

DiVasta AD, Mulkern RV, Gordon CM, Ecklund K. MR Imaging in a case of severe anorexia nervosa: the 'flip-flop' effect. Pediatr Radiol. 2015 Apr;45(4):617-20. doi: 10.1007/s00247-014-3145-3. Epub 2014 Aug 17.

Reference Type RESULT
PMID: 25129340 (View on PubMed)

Donaldson AA, Feldman HA, O'Donnell JM, Gopalakrishnan G, Gordon CM. Spinal Bone Texture Assessed by Trabecular Bone Score in Adolescent Girls With Anorexia Nervosa. J Clin Endocrinol Metab. 2015 Sep;100(9):3436-42. doi: 10.1210/jc.2015-2002. Epub 2015 Jun 24.

Reference Type RESULT
PMID: 26108094 (View on PubMed)

DiVasta AD, Feldman HA, O'Donnell JM, Long J, Leonard MB, Gordon CM. Effect of Exercise and Antidepressants on Skeletal Outcomes in Adolescent Girls With Anorexia Nervosa. J Adolesc Health. 2017 Feb;60(2):229-232. doi: 10.1016/j.jadohealth.2016.10.003. Epub 2016 Dec 6.

Reference Type RESULT
PMID: 27939877 (View on PubMed)

DiVasta AD, Feldman HA, O'Donnell JM, Long J, Leonard MB, Gordon CM. Skeletal outcomes by peripheral quantitative computed tomography and dual-energy X-ray absorptiometry in adolescent girls with anorexia nervosa. Osteoporos Int. 2016 Dec;27(12):3549-3558. doi: 10.1007/s00198-016-3685-5. Epub 2016 Jul 8.

Reference Type RESULT
PMID: 27392467 (View on PubMed)

Bialo SR, Gordon CM. Underweight, overweight, and pediatric bone fragility: impact and management. Curr Osteoporos Rep. 2014 Sep;12(3):319-28. doi: 10.1007/s11914-014-0226-z.

Reference Type RESULT
PMID: 24986712 (View on PubMed)

Ecklund K, Vajapeyam S, Mulkern RV, Feldman HA, O'Donnell JM, DiVasta AD, Gordon CM. Bone marrow fat content in 70 adolescent girls with anorexia nervosa: Magnetic resonance imaging and magnetic resonance spectroscopy assessment. Pediatr Radiol. 2017 Jul;47(8):952-962. doi: 10.1007/s00247-017-3856-3. Epub 2017 Apr 22.

Reference Type RESULT
PMID: 28432403 (View on PubMed)

Other Identifiers

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R01HD043869

Identifier Type: NIH

Identifier Source: secondary_id

View Link

Anorexia04

Identifier Type: -

Identifier Source: org_study_id

NCT01343771

Identifier Type: -

Identifier Source: nct_alias

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