Research Article|Articles in Press

The effect of the rate of increase of estrogen replacement therapy on bone mineral density accrual in young patients with Turner syndrome.

Published:March 17, 2023DOI:



      Turner syndrome (TS) is caused by partial/complete X-chromosome monosomy with variable phenotypes, characterized by hypogonadism and short stature. To achieve pubertal changes, up to 50-79% of patients with TS require estrogen replacement therapy (ERT) and 80% have low bone mineral density (BMD). Studies show that pubertal delays are associated with decreased BMD. Currently, guidelines suggest ERT start at 12 years, increasing slowly, simulating pubertal progression. Many studies show that ERT increases BMD in TS adolescents, but uncertainty remains as to how the rate of increase in ERT affects BMD.


      IRB approval was obtained from our institution for this retrospective chart review from 1991-2020. Charts were requested for the database using ICD 9-10 codes for TS and patients undergoing dual-energy X-ray absorptiometry (DEXA). Biometric data, medical and treatment histories were extracted from charts. Multilevel random effects models were constructed to assess the time dependent associations between ERT and bone density parameters. The primary independent variable of interest was the rate at which patients went from initiating ERT to reaching final doses. The primary dependent variables measured were total body BMD (tbBMD) and corresponding z-scores, calculated using DEXA techniques. Analyses were done with SAS software (version 9.4, Cary, NC).


      28 patients met inclusion criteria. Mean age of TS diagnosis was 6.9 years; 8 patients had monosomy X, 16 had mosaic karyotypes, 4 had unknown karyotypes. The average age for starting HRT was 14.1 years. 13 patients had spontaneous pubertal onset before starting HRT. tbBMD increased significantly with age (p = 0.03). However, change in BMD by age does not vary between patients who reached final adult doses of ERT within 0-2.5 years, compared to patients who took 2.5-5.5 years (p=0.7). Patients who took 2.5-5.5 years to reach final adult doses of ERT had a more negative trend in z-scores (-2.144) in comparison to patients who took 0-2.5 years (-1.776), although this difference did not reach statistical significance (p=.15). Future larger studies are needed to better understand the relationship between duration of ERT use and tbBMD.


      BMD in TS adolescents increases with age. Neither absolute tbBMD values nor tbBMD z-scores increased faster when ERT doses were maximized within 2.5 years. This study has identified a cohort of children under 12 years with TS who have not had any ERT or BMD measurements - a potential population for future larger prospective studies.


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        • Gravholt CH
        • Viuff MH
        • Brun S
        • Stochholm K
        • Andersen NH.
        Turner syndrome: mechanisms and management.
        Nat Rev Endocrinol. 2019 Oct; 15: 601-614
        • Itonaga T
        • Koga E
        • Nishigaki S
        • Kawai M
        • Sakakibara H
        • Hasegawa Y.
        A retrospective multicenter study of bone mineral density in adolescents and adults with Turner syndrome in Japan.
        Endocr J. 2020 Oct 28; 67: 1023-1028
        • Cameron-Pimblett A
        • Davies MC
        • Burt E
        • Talaulikar VS
        • La Rosa C
        • King TFJ
        • Conway GS
        Effects of Estrogen Therapies on Outcomes in Turner Syndrome: Assessment of Induction of Puberty and Adult Estrogen Use.
        J Clin Endocrinol Metab. 2019 Jul 1; 104: 2820-2826
        • Webber L
        • Davies M
        • Anderson R
        • Bartlett J
        • Braat D
        • Cartwright B
        • Cifkova R
        • de Muinck Keizer-Schrama S
        • Hogervorst E
        • Janse F
        • Liao L
        • Vlaisavljevic V
        • Zillikens C
        • Vermeulen N.
        • European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI
        ESHRE Guideline: management of women with premature ovarian insufficiency.
        Hum Reprod. 2016 May; 31: 926-937
        • Matthews D
        • Bath L
        • Högler W
        • Mason A
        • Smyth A
        • Skae M.
        Hormone supplementation for pubertal induction in girls.
        Arch Dis Child. 2017 Oct; 102: 975-980
        • Gravholt CH
        • et al.
        International Turner Syndrome Consensus Group. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting.
        Eur J Endocrinol. 2017 Sep; 177: G1-G70
        • Cintron D
        • Rodriguez-Gutierrez R
        • Serrano V
        • Latortue-Albino P
        • Erwin PJ
        • Murad MH.
        Effect of estrogen replacement therapy on bone and cardiovascular outcomes in women with turner syndrome: a systematic review and meta-analysis.
        Endocrine. 2017 Feb; 55: 366-375
        • Chan YM
        • Feld A
        • Jonsdottir-Lewis E.
        Effects of the Timing of Sex-Steroid Exposure in Adolescence on Adult Health Outcomes.
        J Clin Endocrinol Metab. 2019 Oct 1; 104: 4578-4586
        • Jain RK
        • Vokes T.
        BMDs Derived From Total Body DXA are Strongly Correlated With Dedicated Hip and Spine BMD and are Associated With Prior Fractures in NHANES.
        J Clin Densitom. 2022 Jul-Sep; 25: 349-356
        • Donaldson M
        • Kriström B
        • Ankarberg-Lindgren C
        • Verlinde S
        • van Alfen-van der Velden J
        • Gawlik A
        • van Gelder MMHJ
        • Sas T
        on behalf of the European Society for Paediatric Endocrinology Turner Syndrome Working Group. Optimal Pubertal Induction in Girls with Turner Syndrome Using Either Oral or Transdermal Estradiol: A Proposed Modern Strategy.
        Horm Res Paediatr. 2019; 91: 153-163
        • Klein KO
        • Rosenfield RL
        • Santen RJ
        • Gawlik AM
        • Backeljauw PF
        • Gravholt CH
        • Sas TCJ
        • Mauras N
        Estrogen Replacement in Turner Syndrome: Literature Review and Practical Considerations.
        J Clin Endocrinol Metab. 2018 May 1; 103: 1790-1803
      1. Martinez-Millana A, Hulst JM, Boon M, Witters P, Fernandez-Llatas C, Asseiceira I, Calvo-Lerma J, Basagoiti I, Traver V, De Boeck K, Ribes-Koninckx C. Optimisation of children z-score calculation based on new statistical techniques.