Sex Hormone Replacement Therapy in Turner Syndrome

Impact on Morbidity and Mortality

Mette H. Viuff; Agnethe Berglund; Svend Juul; Niels H. Andersen; Kirstine Stochholm; Claus H. Gravholt

Disclosures

J Clin Endocrinol Metab. 2020;105(2) 

In This Article

Abstract and Introduction

Abstract

Context: The long-term effects of female hormone replacement therapy (HRT) in Turner syndrome (TS) are unknown.

Objective: To examine morbidity, mortality and medicinal use in TS and the impact of HRT in 45,X women.

Design and Setting: National cohort study, following all TS individuals ever diagnosed in Denmark from 1977 to 2014.

Patients and Methods: In the Danish Cytogenetic Central Registry, we identified 1156 females diagnosed with TS from 1960 to 2014, and, subsequently, Statistics Denmark randomly identified 115 577 age-matched female controls. TS women and their matched controls were linked with person-level data from the National Patient Registry and the Medication Statistics Registry, and they were compared concerning mortality, hospitalizations, and medical prescriptions. Among 329 45,X women, 44 had never been HRT treated, and 285 had been treated at some point. HRT treated women were compared with untreated concerning mortality, hospitalizations, and medical prescriptions.

Results: Endocrine and cardiovascular mortality and morbidity were significantly increased in TS compared with the matched controls. Comparing HRT treated with nontreated 45,X women, we found a similar mortality (hazard ratio 0.83, 95% confidence interval 0.38–1.79). Among the HRT-treated 45,X women, we found a significantly lower use of antihypertensives, antidiabetics, and thyroid hormones and significantly reduced hospitalization rates for stroke and osteoporotic fractures.

Conclusion: Women with TS have an increased overall mortality and morbidity. HRT seems to have a beneficial effect on endocrine conditions, hypertension, and stroke in women with 45,X karyotype, with no clear impact on mortality.

Introduction

Turner syndrome (TS) is a sex chromosomal abnormality in females, characterized by complete or partly lack of one X chromosome, providing a 45,X karyotype or a mosaic form. It is present in about 40 to 60 per 100 000 female live births.[1–3] TS is diagnosed at all ages, from intrauterine life, through childhood and adolescence into adult life, with a median age of 15 years.[2,4–7] Short stature, ovarian dysgenesis, infertility, and cardiovascular malformations are classic traits in TS, but the phenotypical spectrum is wide.

TS is associated with an increased morbidity due to an increased occurrence of type 1 and type 2 diabetes (DM), thyroid disorders, autoimmune diseases, osteoporosis, fractures, ischemic heart disease, and aortic dissection as well as congenital heart disease such as coarctation of the aorta, abnormal anatomy of the coronary arteries, and bicuspid aortic valve.[2,8–12] Women with TS suffer from premature ovarian failure and subsequent estrogen deficiency. Hence, they have a similar comorbidity pattern as postmenopausal women, just occurring at a younger age. Mortality is 3-fold higher in TS women than in the female background population.[13]

Spontaneous pubertal development is seen in women with TS,,[14,15] but menarche is present in few (6%–9%) 45,X women, of whom about one-third continue to have regular menstrual bleedings (2%–3%).[16,17] In contrast, 20% to 40% of women with mosaic TS and no structural abnormalities of the second X present with spontaneous menarche, but the great majority proceed to premature ovarian failure.[17] Although rare, natural pregnancies occur in TS women. According to TS guidelines, hormone replacement therapy (HRT) should be initiated in TS women with primary or secondary amenorrhea, preferably starting between 11 and 12 years of age and continuing until the normal age of natural menopause.[18] HRT is necessary to induce puberty, to maintain secondary sex characteristics, and to facilitate uterine growth, appropriate peak bone mass, and possibly the neurocognitive function, and it improves the metabolic profile via a positive influence on body composition.[19] However, empiric data on the long-term effects of HRT in women with TS are limited, especially concerning the impact on endocrine conditions, cardiovascular diseases, and mortality. Some have raised concerns that HRT in TS women may induce the development of deep venous thrombosis and pulmonary embolism.[20]

Here we link data concerning karyotype with mortality, hospital admissions, and medications to study the health of women with TS, compared to age-matched controls, in a nationwide registry study. We further study the effect of HRT on health outcomes in women with TS.

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