Changes in marrow adipose tissue in relation to changes in bone parameters following estradiol replacement in adolescent and young adult females with functional hypothalamic amenorrhea

doi:10.1016/j.bone.2021.115841

. 2021 Apr:145:115841.

doi: 10.1016/j.bone.2021.115841. Epub 2021 Jan 6.

Changes in marrow adipose tissue in relation to changes in bone parameters following estradiol replacement in adolescent and young adult females with functional hypothalamic amenorrhea

Vibha Singhal¹, Nazanin Hazhir Karzar², Amita Bose³, Colleen Buckless⁴, Kathryn E Ackerman⁵, Miriam A Bredella⁶, Anne Klibanski⁷, Madhusmita Misra⁸

Affiliations

¹ Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States; Division of Pediatric Endocrinology, Mass General Hospital for Children and Harvard Medical School, Boston, MA, United States; MGH Weight Center, Massachusetts General Hospital, Boston, MA, United States. Electronic address: Vsinghal1@partners.org.
² Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States. Electronic address: nhazhirkarzar@mgh.harvard.edu.
³ Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States. Electronic address: Abose1@mgh.harvard.edu.
⁴ Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States. Electronic address: Cbuckless@mgh.harvard.edu.
⁵ Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States. Electronic address: Kathryn.ackerman@childrens.harvard.edu.
⁶ Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States. Electronic address: mbredella@mgh.harvard.edu.
⁷ Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States. Electronic address: aklibanski@partners.org.
⁸ Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States; Division of Pediatric Endocrinology, Mass General Hospital for Children and Harvard Medical School, Boston, MA, United States. Electronic address: mmisra@mgh.harvard.edu.

PMID: 33418100
PMCID: PMC8022869
DOI: 10.1016/j.bone.2021.115841

Changes in marrow adipose tissue in relation to changes in bone parameters following estradiol replacement in adolescent and young adult females with functional hypothalamic amenorrhea

Vibha Singhal et al. Bone. 2021 Apr.

. 2021 Apr:145:115841.

doi: 10.1016/j.bone.2021.115841. Epub 2021 Jan 6.

Authors

Vibha Singhal¹, Nazanin Hazhir Karzar², Amita Bose³, Colleen Buckless⁴, Kathryn E Ackerman⁵, Miriam A Bredella⁶, Anne Klibanski⁷, Madhusmita Misra⁸

Affiliations

¹ Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States; Division of Pediatric Endocrinology, Mass General Hospital for Children and Harvard Medical School, Boston, MA, United States; MGH Weight Center, Massachusetts General Hospital, Boston, MA, United States. Electronic address: Vsinghal1@partners.org.
² Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States. Electronic address: nhazhirkarzar@mgh.harvard.edu.
³ Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States. Electronic address: Abose1@mgh.harvard.edu.
⁴ Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States. Electronic address: Cbuckless@mgh.harvard.edu.
⁵ Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States. Electronic address: Kathryn.ackerman@childrens.harvard.edu.
⁶ Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States. Electronic address: mbredella@mgh.harvard.edu.
⁷ Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States. Electronic address: aklibanski@partners.org.
⁸ Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States; Division of Pediatric Endocrinology, Mass General Hospital for Children and Harvard Medical School, Boston, MA, United States. Electronic address: mmisra@mgh.harvard.edu.

PMID: 33418100
PMCID: PMC8022869
DOI: 10.1016/j.bone.2021.115841

Abstract

Context: Low energy availability causes disruption of hypothalamic gonadotropin-releasing hormone secretion leading to functional hypothalamic amenorrhea (FHA) and hypoestrogenism, which in turn contributes to decreased bone mineral density (BMD) and increased bone marrow adipose tissue (MAT). Transdermal estradiol administration in physiologic doses increases BMD in adolescents and adults with FHA. However, the impact of estrogen replacement on MAT in relation to changes in BMD has not been studied in adolescents and young adults. We hypothesized that physiologic estrogen replacement would lead to decreases in MAT, associated with increases in BMD.

Methods and materials: We studied 15 adolescent and young adult females with FHA (14-25 years). All participants received a17β- estradiol transdermal patch at a dose of 0.1 mg/day (applied twice weekly) for 12 months. Participants also received cyclic progestin for 10-12 days each month. We quantified MAT (lipid/water ratio) of the fourth lumbar (L4) vertebral body and femoral diaphysis by single proton (1H)-magnetic resonance spectroscopy, and compartmental volumetric BMD of the distal radius and tibia using high-resolution peripheral quantitative computed tomography.

Results: Transdermal estradiol therapy over 12 months resulted in a decrease in MAT at the lumbar (L4) vertebra from 0.92 ± 0.55 at baseline to 0.63 ± 0.29 at 12-months (p = 0.008), and an increase in radial and tibial cortical vBMD (p = 0.006, p = 0.0003). Changes in L4 MAT trended to be inversely associated with changes in radial cortical vBMD (rho = -0.47, p = 0.08).

Conclusion: We show that in adolescent and young adult girls with FHA, MAT decreases following transdermal estrogen therapy and these changes are associated with increased cortical vBMD.

Keywords: Adolescents; Bone mineral density; Estrogen replacement; Marrow adipose tissue; Unsaturated marrow adipose tissue.

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Conflict of interest statement

Disclosure summary: All authors state that they have no conflict of interest.

Figures

**Figure 1:**
Marrow adipose tissue in the lumbar vertebrae at baseline and 12-months. Marrow adipose tissue decreased over 12 months of transdermal estradiol administration. * p<0.05

See this image and copyright information in PMC

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References

1. Shufelt CL, Torbati T, Dutra E. Hypothalamic Amenorrhea and the Long-Term Health Consequences. Semin Reprod Med. 2017;35(3):256–62. - PMC - PubMed
1. Gordon CM, Ackerman KE, Berga SL, Kaplan JR, Mastorakos G, Misra M, et al. Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2017;102(5):1413–39. - PubMed
1. Meczekalski B, Podfigurna-Stopa A, Warenik-Szymankiewicz A, Genazzani AR. Functional hypothalamic amenorrhea: current view on neuroendocrine aberrations. Gynecol Endocrinol. 2008;24(1):4–11. - PubMed
1. Faje AT, Fazeli PK, Miller KK, Katzman DK, Ebrahimi S, Lee H, et al. Fracture risk and areal bone mineral density in adolescent females with anorexia nervosa. Int J Eat Disord. 2014;47(5):458–66. - PMC - PubMed
1. Cano Sokoloff N, Eguiguren ML, Wargo K, Ackerman KE, Baskaran C, Singhal V, et al. Bone parameters in relation to attitudes and feelings associated with disordered eating in oligo-amenorrheic athletes, eumenorrheic athletes, and nonathletes. Int J Eat Disord. 2015;48(5):522–6. - PMC - PubMed

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[1] Shufelt CL, Torbati T, Dutra E. Hypothalamic Amenorrhea and the Long-Term Health Consequences. Semin Reprod Med. 2017;35(3):256–62. - PMC - PubMed

[2] Shufelt CL, Torbati T, Dutra E. Hypothalamic Amenorrhea and the Long-Term Health Consequences. Semin Reprod Med. 2017;35(3):256–62. - PMC - PubMed

[3] Gordon CM, Ackerman KE, Berga SL, Kaplan JR, Mastorakos G, Misra M, et al. Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2017;102(5):1413–39. - PubMed

[4] Gordon CM, Ackerman KE, Berga SL, Kaplan JR, Mastorakos G, Misra M, et al. Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2017;102(5):1413–39. - PubMed

[5] Meczekalski B, Podfigurna-Stopa A, Warenik-Szymankiewicz A, Genazzani AR. Functional hypothalamic amenorrhea: current view on neuroendocrine aberrations. Gynecol Endocrinol. 2008;24(1):4–11. - PubMed

[6] Meczekalski B, Podfigurna-Stopa A, Warenik-Szymankiewicz A, Genazzani AR. Functional hypothalamic amenorrhea: current view on neuroendocrine aberrations. Gynecol Endocrinol. 2008;24(1):4–11. - PubMed

[7] Faje AT, Fazeli PK, Miller KK, Katzman DK, Ebrahimi S, Lee H, et al. Fracture risk and areal bone mineral density in adolescent females with anorexia nervosa. Int J Eat Disord. 2014;47(5):458–66. - PMC - PubMed

[8] Faje AT, Fazeli PK, Miller KK, Katzman DK, Ebrahimi S, Lee H, et al. Fracture risk and areal bone mineral density in adolescent females with anorexia nervosa. Int J Eat Disord. 2014;47(5):458–66. - PMC - PubMed

[9] Cano Sokoloff N, Eguiguren ML, Wargo K, Ackerman KE, Baskaran C, Singhal V, et al. Bone parameters in relation to attitudes and feelings associated with disordered eating in oligo-amenorrheic athletes, eumenorrheic athletes, and nonathletes. Int J Eat Disord. 2015;48(5):522–6. - PMC - PubMed

[10] Cano Sokoloff N, Eguiguren ML, Wargo K, Ackerman KE, Baskaran C, Singhal V, et al. Bone parameters in relation to attitudes and feelings associated with disordered eating in oligo-amenorrheic athletes, eumenorrheic athletes, and nonathletes. Int J Eat Disord. 2015;48(5):522–6. - PMC - PubMed

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Changes in marrow adipose tissue in relation to changes in bone parameters following estradiol replacement in adolescent and young adult females with functional hypothalamic amenorrhea

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Changes in marrow adipose tissue in relation to changes in bone parameters following estradiol replacement in adolescent and young adult females with functional hypothalamic amenorrhea

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