Endocr J. 2017 Feb 27;64(2):221-227. doi: 10.1507/endocrj.EJ16-0170.

Gradually increasing ethinyl estradiol for Turner syndrome may produce good final height but not ideal BMD

Yukihiro Hasegawa

Division of Endocrinology and Metabolism, Tokyo Metropolitan Children’s Medical Center.

Corresponding Author:

Yukihiro Hasegawa, M.D. and Ph.D.

2-8-29 Musashi-dai, Fuchu, Tokyo, Japan 183-8561

Division of Endocrinology and Metabolism

Tokyo Metropolitan Children€™s Medical Center


Disclosure statement: Nothing to declare



Estrogen replacement therapy in Turner syndrome should theoretically mimic the physiology of healthy girls. The objective of this study was to describe final height and bone mineral density (BMD) in a group of 17 Turner syndrome patients (group E) who started their ethinyl estradiol therapy with an ultra-low dosage (1-5 ng/kg/day) from 9.8~13.7 years. The subjects in group E had been treated with GH 0.35 mg/kg/week since the average age of 7.4 years. The 30 subjects in group L, one of the historical groups, were given comparable doses of GH, and conjugated estrogen 0.3125 mg/week ~0.3125 mg/day was initiated at 12.2-18.7 years. The subjects in group S, the other historical group, were 21 patients who experienced breast development and menarche spontaneously. Final height (height gain < 2 cm/year) in group E was 152.4 +/- 3.4 cm and the standard deviation (SD) was 2.02 +/- 0.62 for Turner syndrome. The final height in group L was 148.5 +/- 3.0 cm with a SD of 1.30 +/- 0.55, which was significantly different from the values for group E. The volumetric BMD of group S (0.290 +/- 0.026 g/cm3) was significantly different from that of group L or E (0.262 or 0.262 g/cm3 as a mean, respectively). This is the first study of patients with Turner syndrome where estrogen was administered initially in an ultra-low dose and then increased gradually. Our estrogen therapy in group E produced good final height but not ideal BMD.

PMID: 27916781



Turner syndrome (TS) is one of the most common sex chromosome aneuploidies and one of the main treatable symptoms is delayed puberty. Estrogen replacement for TS should ideally mimic a physiology of healthy girls; hence treatment should begin with an ultra-low dosage and gradually increase. However, no studies to date have examined the merits of this kind of therapy. We administered EE2 to 17 patients with TS (Early-group; group E) to imitate physiological pubertal development.

This is the first study of patients with TS where estrogen was administered initially in an ultra-low dose and then increased gradually. The initial dose of EE2, 1-5 ng/kg in group E, was extremely low (cf. adult dose is roughly 200~400 ng/kg). Additionally, this is the first study of TS, where volumetric BMD (vBMD) was also taken into consideration in terms of the timing and method of exogenous estrogen administration. One of the representative cases is shown in Figure 1.

In this study, the higher vBMD values contrasting with the lower final height in group S (Spontaneous puberty-group), compared with the corresponding values for group E, should be noted. Estrogen administration in group E should have been started earlier than done in this study in order to achieve adequate BMD in patients with TS who are not expected to experience regular menstruation. One of our previous studies reported a decrease in actual BMD as measured by quantitative computed tomography in TS patients not only during, but also before puberty. The decline started as early as 7-10 years of age [1]. It is classically speculated that less estrogen is needed to maintain bone mineral density than to maintain and develop pubertal/adult physical change [2].

Since it is commonly believed that transdermal estradiol could be more physiological treatment than others [3-5], the future study should be ideally done with transdermal estradiol, titrated starting at an ultra-low dose and at earlier ages. The endpoints should consist of not only height and bone parameters but also uterus size, lipid and coagulation profiles, and QOL evaluations.



Figure 1. One of the representative cases who started ultra-low EE2 at an early age. Her final height was 159.2 cm (0.1 SD for Japanese girls) and DXA value at lumbar 2-4 at the final height was -0.1 SD.




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