In the JournalsPerspective

HT plays ‘pivotal role’ in treatment of Turner syndrome

Among Danish women with Turner syndrome, those prescribed hormone therapy were less likely to develop diabetes, sustain an osteoporotic fracture or be hospitalized for stroke during nearly 4 decades of follow-up when compared with those not prescribed HT, according to findings published in The Journal of Clinical Endocrinology & Metabolism.

Mette H. Viuff

“No studies have so far evaluated the effect of hormone replacement therapy in Turner syndrome or other conditions of premenopausal hypogonadism,” Mette H. Viuff, MD, a doctoral student in the department of internal medicine and endocrinology at Aarhus University Hospital, Denmark, told Endocrine Today. “It is unlikely that proper randomized, placebo-controlled trials with HT as the active drug will ever be conducted because that would clearly be unethical. Therefore, we were interested in other ways of investigating the effects of HT on morbidity and mortality. We took advantage of the Danish registries where we could follow all individuals diagnosed with Turner syndrome and compare them with a large, age-matched control group of women.”

Viuff and colleagues analyzed data from 1,156 women who were diagnosed with Turner syndrome between 1960 and 2014, identified via the Danish Cytogenetic Central Registry, as well as 115,577 age-matched women without Turner syndrome identified via Statistics Denmark, who served as controls. Data from all the women were linked with person-level data from the National Patient Registry and the Medication Statistics Registry. Researchers compared mortality, hospitalizations and prescriptions among patients with and without Turner syndrome.

To assess the health effects of HT use among women with Turner syndrome, researchers analyzed data from 329 women with the 45,X karyotype in Turner syndrome who were aged 18 to 60 years at any time between 1994 and 2014. Among women with the 45,X karyotype, 285 were prescribed HT.

During follow-up (1977-2014), 14% of women with Turner syndrome in the overall cohort and 8% of controls died. Among women with Turner syndrome, mortality was almost fivefold increased, with an HR of 4.7 (95% CI, 3.7-6) when compared with controls. Endocrine and cardiovascular mortality and morbidity were significantly increased in the women with Turner syndrome vs. controls.

Researchers observed a trend toward lower mortality among women with Turner syndrome prescribed HT vs. those who were not treated, although the finding did not rise to significance (HR = 0.83; 95% CI, 0.38-1.79). Among HT-treated women with Turner syndrome, researchers observed a reduction in risk for hospital admission for stroke and lower risks for type 1 and type 2 diabetes, thyroid disorders, hypertension and osteoporotic fractures vs. women with Turner syndrome who were nottreated. Supporting the finding, researchers also observed lower use of thyroid hormone and antihypertensive medications among HT-treated women with Turner syndrome, and a “clear trend” toward lower use of bisphosphonates.

The researchers noted the findings demonstrate that HT plays a “pivotal role” in the general health of women with Turner syndrome.

“It turned out that a surprisingly large group of women with Turner syndrome did not receive HT, which allowed us to investigate the effects of HT,” Viuff said. “Treatment with estrogen in combination with progesterone seems to have a beneficial effect on several endocrine conditions in women with Turner syndrome, in particular, diabetes mellitus, thyroid disorders and osteoporotic fractures. Furthermore, it seems to decrease the risk for hypertension and stroke.”

Viuff said the findings stress the necessity of proper treatment and the importance of estrogen on general health in women with Turner syndrome.

“Surprisingly, we discovered that 13% of women with a 45,X karyotype never received estrogen treatment, underscoring that the international guidelines on clinical care of women with Turner syndrome are not followed in all instances,” Viuff said. “It emphasizes the need for specialized clinics caring for women with Turner syndrome to increase proper adherence to HT. We hope to enlighten other clinicians about the importance of continuous treatment.” – by Regina Schaffer

For more information:

Mette H. Viuff , MD, can be reached at Aarhus University, Department of Internal Medicine and Endocrinology, Palle-Juul Jensens Boulevard 99, 8200 Aarhus N, Denmark; email: metteviuff@clin.au.dk.

Disclosures: The authors report no relevant financial disclosures.

Among Danish women with Turner syndrome, those prescribed hormone therapy were less likely to develop diabetes, sustain an osteoporotic fracture or be hospitalized for stroke during nearly 4 decades of follow-up when compared with those not prescribed HT, according to findings published in The Journal of Clinical Endocrinology & Metabolism.

Mette H. Viuff

“No studies have so far evaluated the effect of hormone replacement therapy in Turner syndrome or other conditions of premenopausal hypogonadism,” Mette H. Viuff, MD, a doctoral student in the department of internal medicine and endocrinology at Aarhus University Hospital, Denmark, told Endocrine Today. “It is unlikely that proper randomized, placebo-controlled trials with HT as the active drug will ever be conducted because that would clearly be unethical. Therefore, we were interested in other ways of investigating the effects of HT on morbidity and mortality. We took advantage of the Danish registries where we could follow all individuals diagnosed with Turner syndrome and compare them with a large, age-matched control group of women.”

Viuff and colleagues analyzed data from 1,156 women who were diagnosed with Turner syndrome between 1960 and 2014, identified via the Danish Cytogenetic Central Registry, as well as 115,577 age-matched women without Turner syndrome identified via Statistics Denmark, who served as controls. Data from all the women were linked with person-level data from the National Patient Registry and the Medication Statistics Registry. Researchers compared mortality, hospitalizations and prescriptions among patients with and without Turner syndrome.

To assess the health effects of HT use among women with Turner syndrome, researchers analyzed data from 329 women with the 45,X karyotype in Turner syndrome who were aged 18 to 60 years at any time between 1994 and 2014. Among women with the 45,X karyotype, 285 were prescribed HT.

During follow-up (1977-2014), 14% of women with Turner syndrome in the overall cohort and 8% of controls died. Among women with Turner syndrome, mortality was almost fivefold increased, with an HR of 4.7 (95% CI, 3.7-6) when compared with controls. Endocrine and cardiovascular mortality and morbidity were significantly increased in the women with Turner syndrome vs. controls.

Researchers observed a trend toward lower mortality among women with Turner syndrome prescribed HT vs. those who were not treated, although the finding did not rise to significance (HR = 0.83; 95% CI, 0.38-1.79). Among HT-treated women with Turner syndrome, researchers observed a reduction in risk for hospital admission for stroke and lower risks for type 1 and type 2 diabetes, thyroid disorders, hypertension and osteoporotic fractures vs. women with Turner syndrome who were nottreated. Supporting the finding, researchers also observed lower use of thyroid hormone and antihypertensive medications among HT-treated women with Turner syndrome, and a “clear trend” toward lower use of bisphosphonates.

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The researchers noted the findings demonstrate that HT plays a “pivotal role” in the general health of women with Turner syndrome.

“It turned out that a surprisingly large group of women with Turner syndrome did not receive HT, which allowed us to investigate the effects of HT,” Viuff said. “Treatment with estrogen in combination with progesterone seems to have a beneficial effect on several endocrine conditions in women with Turner syndrome, in particular, diabetes mellitus, thyroid disorders and osteoporotic fractures. Furthermore, it seems to decrease the risk for hypertension and stroke.”

Viuff said the findings stress the necessity of proper treatment and the importance of estrogen on general health in women with Turner syndrome.

“Surprisingly, we discovered that 13% of women with a 45,X karyotype never received estrogen treatment, underscoring that the international guidelines on clinical care of women with Turner syndrome are not followed in all instances,” Viuff said. “It emphasizes the need for specialized clinics caring for women with Turner syndrome to increase proper adherence to HT. We hope to enlighten other clinicians about the importance of continuous treatment.” – by Regina Schaffer

For more information:

Mette H. Viuff , MD, can be reached at Aarhus University, Department of Internal Medicine and Endocrinology, Palle-Juul Jensens Boulevard 99, 8200 Aarhus N, Denmark; email: metteviuff@clin.au.dk.

Disclosures: The authors report no relevant financial disclosures.

    Perspective
    Ondrej Soucek

    Ondrej Soucek

    In this paper by Viuff and colleagues, the authors described the positive effect of estrogen replacement therapy on mortality and morbidity in Turner syndrome. This interesting paper clearly shows that hormone replacement prevents osteoporotic fractures in women with Turner syndrome with the classical karyotype (45,X), where one of the sex chromosomes is missing. Although it has been shown by several previous studies that HT preserves bone density in this condition, where ovarian failure is one of the main characteristic features, this is the first retrospective, longitudinal, nationwide study confirming the positive effect on fracture rate.

    In particular, whereas the osteoporotic fracture rate among hormone-substituted women with Turner syndrome with the 45,X karyotype did not differ from the rate among healthy controls, it was significantly lower compared with the rate among untreated women with the 45,X kerotype. This is in line with our own study showing a comparable rate of clinically significant fractures among children with Turner syndrome treated with growth hormone and estrogens and healthy girls (Soucek O, et al. J Clin Endocrinol Metab. 2018; doi:10.1210/jc.2017-02381.).

    In addition, HT prevented women with the 45,X karyotype from experiencing stroke and the need for treatment of hypertension and lowered the risk for developing type 2 diabetes and hypothyroidism. Altogether, these findings underline the importance of life-long HT in Turner syndrome and clearly show the beneficial effect on skeletal and CV complications of the disease.

    • Ondrej Soucek, MD, PhD
    • Department of Pediatrics, Second Faculty of Medicine
      Charles University and Motol University Hospital
      Prague

    Disclosures: Soucek reports no relevant financial disclosures.