Effect of estrogen replacement therapy on bone and cardiovascular outcomes in women with turner syndrome: a systematic review and meta-analysis

Abstract

Patients with Turner syndrome have adverse bone and cardiovascular outcomes from chronic estrogen deficiency. Hence, long-term estrogen replacement therapy is the cornerstone treatment. The estimates of its effect and optimal use, however, remain uncertain. We aimed to summarize the benefits and harms of estrogen replacement therapy on bone, cardiovascular, vasomotor and quality of life outcomes in patients with Turner syndrome. A comprehensive search of four databases was performed from inception through January 2016. Randomized clinical trials and observational cohort studies studying the effect of estrogen replacement therapy in patients with Turner syndrome under the age of 40 were included. Independently and in duplicate reviewers selected studies, extracted data and assessed risk of bias. Subgroup analyses were based on route of administration and type of estrogen formulation. Twenty-five studies at moderate to high risk of bias (12 randomized trials, 13 cohort studies) with 771 patients were included. Using random-effects models, estrogen replacement therapy showed an increase in bone mineral density [weighted mean change from baseline 0.09 g/cm2 (0.04-0.14)] that differed by type of estrogen but not route of administration. Oral estrogen replacement therapy showed a higher increase in high density lipoprotein cholesterol levels when compared to transdermal [weighted mean difference 9.33 mg/dl (4.82-13.85)] with no significant effect on other lipid fractions. The current evidence suggests possible benefit of estrogen replacement therapy on bone mineral density and high density lipoprotein cholesterol. Whether this improvement translates into changes in patient important outcomes (cardiovascular events or fractures) remains uncertain. Larger randomized clinical trials with direct comparisons on patient important outcomes are necessary.

Estrogen-based hormone therapy in women with primary ovarian insufficiency: a systematic review

“…A previous systematic review and meta-analysis including only women with Turner syndrome showed that HT was associated with increased BMD and HDL cholesterol when compared to baseline values, with minimal reporting of patient important outcomes such as fractures, cardiovascular mortality or vasomotor symptoms [11]. Other etiologies of POI, however, are increasing in prevalence.…”

“…Data on patients with hypergonadotropic hypogonadism in women with Turner syndrome were summarized separately[11] and excluded from this systematic review. A post-hoc search was performed April 2017 in clinicaltrials.gov to evaluate for ongoing trials addressing the same population and intervention ( APPENDIX 2 ).…”

Hormone replacement therapy in Turner syndrome is important—a new meta-analysis points at many shortcomings in the available literature

“…Just considering the lengthy discussions concerning the WHI study and the possibility that the timing hypothesis for ERT exists and that the timing of start with ERT may therefore be of great importance [1]. In addition ascertainment bias is a problem in TS research, since less than two-thirds of all TS are ever diagnosed [2], decreasing the validity of clinical studies of TS.A new meta-analysis and systematic review takes a critical view at effects of ERT on bone and cardiovascular outcome in TS and includes all randomized clinical trials (RCT) on the subject [3]. Not surprisingly, only 9 RCTs could be included in quantitative assessment of effects and furthermore there were pronounced differences in the drugs used, the duration of studies spanning from 2 to 66 months, the age of the TS in the different studies and the route of administration.…”

“…A new meta-analysis and systematic review takes a critical view at effects of ERT on bone and cardiovascular outcome in TS and includes all randomized clinical trials (RCT) on the subject [3]. Not surprisingly, only 9 RCTs could be included in quantitative assessment of effects and furthermore there were pronounced differences in the drugs used, the duration of studies spanning from 2 to 66 months, the age of the TS in the different studies and the route of administration.…”

“…The authors of the meta-analysis prudently notes that we still need "prospective long follow up trials that include assessment of fracture events, BMD values adjusted for height, as current measurements do not correct for bone and body size, a concern in patients with TS who have shorter stature and smaller bones; comparative effectiveness studies of ERT types and routes of administration and earlier ERT interventions given that 90% of women's peak BMD is reached by 18 years of age" [3].…”