Effects of Estrogen Therapies on Outcomes in Turner Syndrome

Assessment of Induction of Puberty and Adult Estrogen Use

Antoinette Cameron-Pimblett; Melanie C. Davies; Elizabeth Burt; Vikram Sinai Talaulikar; Clementina La Rosa; Thomas F. J. King; Gerard S. Conway

Disclosures

J Clin Endocrinol Metab. 2019;104(7):2820-2826. 

In This Article

Abstract and Introduction

Abstract

Context: Turner syndrome (TS) is often associated with delayed puberty. To induce puberty, estrogen is administered in incremental doses at an age determined by age of presentation. After puberty, various types of maintenance estrogen replacement therapy (ERT) are used.

Objective: We sought associations between age of induction of puberty and type of ERT on adult health outcomes.

Design: Health surveillance data included blood profiles, bone density, and blood pressure. We assessed interactions between these data and age at first estrogen exposure in women with primary amenorrhea. We also assessed these data according to ERT subgroups [combined oral contraceptive pill (OCP), oral estrogen (OE), and transdermal estradiol (TE)] using data from each of 6679 clinic visits, controlling for age, body mass index, and height.

Setting: Adult TS clinic at University College London Hospital.

Patients: Of 799 women with TS, 624 had primary amenorrhea and 599 had accurate maintenance ERT data.

Main Outcome Measures: Parameters of health surveillance derived from clinical guidelines.

Results: Estrogen start age was negatively correlated with adult bone density (spine: r = −0.20 and hip: r = −0.022; P ≤ 0.001). OCP users had higher blood pressure and an adverse lipid profile compared with other ERT subgroups. TE was associated with elevated liver enzymes and hemoglobin A1c compared with OE (P ≤ 0.01).

Conclusions: An earlier age of induction of puberty may be beneficial for adult bone density. Given the high prevalence of hypertension in TS, the use of OCP for ERT should be limited. OE may be a benefit for steatohepatitis.

Introduction

Turner syndrome (TS) is a genetic condition caused by the complete or partial lack of one X chromosome, affecting approximately 1 in 2500 females at birth.[1] The genetic background of TS is varied, with several karyotype subgroups and levels of mosaicism, leading to a phenotype spectrum.[2,3] Short stature and delayed puberty due to gonadal dysgenesis are common routes to diagnosis from childhood to early adulthood.[4]

Approximately 85% of adolescents with TS experience delayed puberty and primary amenorrhea.[3,5] For this group, puberty must be induced with incremental doses of estrogen to mimic natural development. The aim of induction of puberty in girls with TS is to achieve growth, adult uterine and breast configuration, and monthly withdrawal bleeds.[2,6] A minority of girls experiences spontaneous puberty but then go on to develop secondary amenorrhea later in life.[5]

The clinical practice guidelines for the care of girls and women with TS produced by the 2016 International Consensus Group[7] states that induction of puberty should be initiated at 11 or 12 years, preferably using transdermal estradiol (TE). However, the timing of estrogen exposure may vary because of delayed presentation or differences in local practice. Late diagnosis of TS, often well into the second decade of life, is a common obstacle to timely induction of puberty.[8]

Women with TS who have completed puberty usually require long-term estrogen replacement therapy (ERT) to maintain secondary sex characteristics and overall wellbeing. In addition, ERT in women with TS has been linked to the normalization of raised liver enzymes and improved bone mineral density.[9–12] Several options are available for estrogen administration in adults with TS, including oral contraceptive pills (OCPs) containing ethinyl estradiol, oral preparations containing estradiol or conjugated equine estrogens, and TE.[13] Although TE has gained popularity and has the advantage of direct absorption without first-pass metabolism through the liver, there is a scant evidence base to guide the choice of ERT formulation.[14,15]

A dedicated health surveillance clinic for adults with TS has been in place at University College London Hospital (UCLH) for more than 20 years. Data from this clinic comprise the Turner Syndrome Life Course Project, which aims to document adult outcomes of this condition. Here, we present clinical associations relating to the timing of first exposure to estrogen in those presenting with primary amenorrhea with the type of estrogen replacement in all subjects at each clinic visit.

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