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Original Article EP161622.OR ORAL VERSUS TRANSDERMAL ESTROGEN IN TURNER SYNDROME: A SYSTEMATIC REVIEW AND META-ANALYSIS Feras Zaiem MD1, Fares Alahdab MD1, Alaa Al Nofal MD2 , Mohammad Hassan Murad MD, MPH1 , Asma Javed MBBS3 From: 1 Evidence-based Practice Center, Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, 200 1st Street SW, Rochester MN 55905; 2 Pediatric Endocrinology, Department of Pediatrics, Sanford Children Specialty Clinic, University of South Dakota, Sioux Falls SD; 3 Pediatric and Adolescent Gynecology, Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester MN.
Running title: OE vs TDE in Turner Syndrome
Correspondence address: Asma Javed, MBBS, Division of Pediatrics and Adolescent Gynecology, Mayo Clinic, 200 First St SW, Rochester, MN 55902 Email:
[email protected]
DOI:10.4158/EP161622.OR © 2016 AACE.
Running title: Oral vs Transdermal Estrogen in Turner Syndrome Disclosure Summary: The authors have nothing to disclose. No. of tables: 3 No. of figures: 3 No. of supplemental figures: 4 No. of supplemental appendix: 1 Key terms: Turner syndrome, estrogen therapy, oral estrogen, transdermal estrogen
DOI:10.4158/EP161622.OR © 2016 AACE.
Abstract Objective: To conduct a systematic review and meta-analysis comparing transdermal estrogens (TDE) versus oral estrogens (OE) in Turner syndrome (TS). Method: Randomized trials and observational comparative studies with a minimal follow up of 6 months for skeletal and metabolic outcomes and serum hormone changes. Outcomes were pooled with a random effects model and were reported as mean difference between OE and TDE groups and 95% confidence interval (CI). Result: Of 845 candidate references, 4 studies were included. Both OE and TDE were associated with an increase in whole body BMD z-score with TDE therapy displaying a greater increase. OE were associated with higher fasting glucose and total cholesterol. Both OE and TDE reduced LDL-C and increased HDLC with OEs providing a more favorable effect. The use of 17 beta estradiol was associated with a higher total cholesterol and lower LDL-C than TDE. No statistically significant difference was found between OEs and TDEs in body mass index, fat mass, fat free mass, insulin growth factor 1, insulin growth factor binding protein 3, fasting insulin, triglycerides, estradiol or estrone levels. Conclusion: In girls with TS, TDE may be associated with a more beneficial effect on fasting glucose, cholesterol and whole body bone mineral density. However, OE has a more favorable impact on LDL-C and HDL-C. 17 Beta estradiol has a more favorable effect on LDL-C.
Abbreviations: BMI = body mass index; BMD = bone mineral density; CI = confidence interval; FM = fat mass; FMM = fat-free mass; HDL-C = high density lipoprotein- cholesterol; IGF-1 = insulin-like growth factor 1; IGF-BP3 = insulin-like growth factor binding protein 3; LDL-C = low density lipoprotein- cholesterol; LFT= liver function test; MD = mean difference; OE = oral estrogen; RCT = randomized controlled trial; TDE = transdermal estrogen; TS = Turner syndrome.
DOI:10.4158/EP161622.OR © 2016 AACE.
Introduction Turner syndrome (TS) is one of the most common chromosomal abnormalities, occurring approximately in 1/2000 female infants 1. The disease is characterized by complete or partial absence of one set of genes from the short arm of the X chromosome. The cardinal manifestations of TS include short stature and reduced ovarian reserve with almost all patients eventually developing ovarian failure 2. A variety of additional symptoms can occur such as osteoporosis 3 and aortic root dilation with risk of dissection 4. Estrogen replacement therapy, along with growth hormone, is the standard treatment for patients with TS. The main goal of estrogen therapy is to induce puberty, maintain healthy secondary sexual development and to deliver other important physiological effects of estrogen like uterine maturation and bone mineralization 5. A previous systematic review showed that in patients with Turner syndrome, estrogen replacement therapy may lead to improvements in bone mineral density and high density lipoprotein cholesterol.6 In the United States, oral equine estrogens have been the most widely used form of estrogen in girls with TS 7, which has more than 100 individual estrogenic compounds of different biologic potency. However, transdermal estrogen (TDE) is steadily gaining popularity 8. The main advantage of TDE over oral estrogen includes the direct absorption into the circulation without first pass hepatic effects which results in allowing a sustained therapeutic level of estrogen 9. Few studies in the literature supported the superiority of TDE over oral conjugated estrogen in regards to bone density, IGF-1 concentrations 9, fat versus lean mass and uterine maturation in patients with TS. Because of all reasons mentioned above, many experts recommend TDE as a mode of estrogen replacement for induction of puberty and estrogen replacement in girls with TS 10 . However, whether differences in the mode of estrogen therapy will ultimately have meaningful clinical differences in TS is still unknown. The aim of this systematic review and meta-analysis is to compare TDE vs OE in patients with TS in terms of metabolic and skeletal outcomes.
DOI:10.4158/EP161622.OR © 2016 AACE.
Materials and Methods This meta-analysis was reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. 11
Database Search A comprehensive search of several databases from each database’s inception to May 15th, 2015, any language was conducted. The databases included Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus. The search strategy was designed and conducted by an experienced librarian with input from the study’s principle investigator. Controlled vocabulary supplemented with keywords was used to search for comparative studies of estrogen use in Turner’s syndrome. The actual search strategy is available in appendix. The comprehensive search was for all randomized clinical trials and observational studies irrespective of language. We included children and adults with a clinical or genetic diagnosis of TS. The interventions of interest were transdermal and oral estrogen therapy in all their different forms. The outcomes of interest were liver function tests (LFTs), lipids panel, glucose, insulin, IGF-1, estradiol, estrone, BMI, fractures, bone mineral content and density. We excluded uncontrolled studies, case series, cross sectional studies, and studies with short follow up duration of less than 6 months.
Study Selection Two independent reviewers screened the titles and abstracts to determine eligibility for inclusion. Full texts were then retrieved and screened independently in pairs. Disagreements between the reviewers were resolved by consensus. An online reference management system was used for this phase (DistillerSR; Evidence Partners, Inc.). Inter-reviewer agreeability (Cohen’s kappa) was calculated to assess agreement between the reviewers. Data extraction Two independent reviewers extracted data from relevant studies using a web-based predesigned and piloted extraction form. Data on patients’ baseline characteristics, interventions, comparisons, and outcomes were systematically extracted from each report. Disagreements were discussed until a consensus decision was reached.
DOI:10.4158/EP161622.OR © 2016 AACE.
Risk of bias assessment and quality of evidence We used the Cochrane tool for risk of bias tool to evaluate randomized controlled trials. Risk of bias assessment was carried out by independent reviewers working in duplicates, also using an online piloted form. Several items were evaluated in the RCTs including randomization, allocation concealment, completeness of follow-up, and use of intention-to-treat analysis. Disagreements were resolved by referring to the trial report, correspondence with the authors of the report and discussions and involvement of a third reviewer. The quality of evidence was evaluated using the Grading of Recommendations assessment, Development and Evaluation (GRADE) approach.12,13
Statistical Analysis All of the outcomes of interest in this systematic review and meta-analysis were continuous variables. We presented results using the mean differences (MD) as the effect measure. A metaanalysis was conducted by pooling the MDs across the studies. We used the I2 statistic to estimate the percentage of total between-study variation due to heterogeneity rather than chance (ranging from 0-100%) 14,15. I2 values of 25%, 50%, and 75% are consistent with low, moderate, and high heterogeneity, respectively. Statistical analyses were carried out using OpenMeta[Analyst] 16. A two-tailed P
