Effect of Sex Steroid Use on Cardiovascular Risk in Transsexual Individuals
Effect of Sex Steroid Use on Cardiovascular Risk in Transsexual Individuals
Initial search of the literature yielded 341 publications, of which 64 were potentially relevant to this review based on titles and abstracts (Fig. 1). After full-text review, we found 15 eligible studies, selected with near-perfect agreement across reviewers (kappa statistic = 0·9; 95% CI = 0·8-1·0). Data from an unpublished study was kindly offered by one of the primary authors contacted (Schneiders et al., unpub. obs.) Four studies, fulfilling our inclusion criteria, had overlapping patient populations with other included studies, which was confirmed by author contact, and were not included to avoid duplicating individuals. We also excluded studies in which participants used sex steroids for less than 3 months or measured cardiovascular risk factors of unclear significance, e.g. leptin, homocysteine and vascular reactivity.
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Figure 1.
The process of study selection.
Table 1 summarizes the characteristics of eligible studies. Twelve studies included groups of MF and 10 studies had FM groups; overall, the literature reviewed included 1471 MF and 651 FM individuals. Patients averaged 31 years of age. MF individuals used various regimens that mainly included oral, intramuscular or transdermal oestrogens with less frequent use of cyproterone acetate, goserelin acetate or spironolactone. FM individuals used various regimens of testosterone that were mainly administered intramuscularly with infrequent use of oral preparations. No transdermal testosterone was used. Progestins were added if menses did not cease.
We successfully contacted all of the corresponding authors (another author in two studies) by electronic mail. All authors either contributed missing data (where these data had been collected but not reported in the format we needed for analyses) or confirmed study characteristics, quality assessments and data as collected.
Table 2 summarizes the methodological quality of the 16 included studies. Studies were uncontrolled or self-controlled observational studies, one of which included a nested trial (randomizing MF individuals to oral or transdermal oestrogen preparations). Medical records were the most frequent method of ascertaining exposure to hormonal therapy and assessing outcomes.
Patient Important Outcomes. There were very few reported cardiovascular events across the trials, with varied length of follow-up. Figure 2 shows the proportion of participants in each eligible study who had reported cardiovascular events.
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Figure 2.
Proportions of cardiovascular outcomes in included studies. Each study is represented by a circle. F/U, follow-up; FM, female-to-male individuals; MF, male-to-female individuals; MI, myocardial infarction; VTE, venous thromboembolism.
Serum Lipids and Blood Pressure.Table 3 and Table 4 represent pooled data for the lipid parameters and blood pressure measurements in MF and FM individuals after sex steroid use, respectively.
All feasible subgroup interaction analyses are shown in Table 5 and Table 6 . In MF individuals, significant interaction existed in HDL level-route of hormonal administration, showing a higher serum level after oral administration than the transdermal route. The same was observed with triglycerides levels. In FM individuals, we found insufficient data to compare the route of administration of hormonal therapy (intramuscularly vs. orally). Subgroups defined by individuals followed up for more than 1 year vs. less than 1 year, showed significant increase in cholesterol and triglycerides in studies with follow-up period of more than 1 year. All other subgroup analyses were nonsignificant.
In terms of sensitivity analyses, pooling studies with a cross-over study design separately did not show any significant change in measured lipid fractions. The exclusion of unpublished data decreased between study heterogeneity and drove the statistically significant decrease in HDL and increase in systolic blood pressure towards the null, although a strong trend continued to exist (P = 0·05 and 0·06; respectively).
Results
Study Identification
Initial search of the literature yielded 341 publications, of which 64 were potentially relevant to this review based on titles and abstracts (Fig. 1). After full-text review, we found 15 eligible studies, selected with near-perfect agreement across reviewers (kappa statistic = 0·9; 95% CI = 0·8-1·0). Data from an unpublished study was kindly offered by one of the primary authors contacted (Schneiders et al., unpub. obs.) Four studies, fulfilling our inclusion criteria, had overlapping patient populations with other included studies, which was confirmed by author contact, and were not included to avoid duplicating individuals. We also excluded studies in which participants used sex steroids for less than 3 months or measured cardiovascular risk factors of unclear significance, e.g. leptin, homocysteine and vascular reactivity.
(Enlarge Image)
Figure 1.
The process of study selection.
Study Characteristics
Table 1 summarizes the characteristics of eligible studies. Twelve studies included groups of MF and 10 studies had FM groups; overall, the literature reviewed included 1471 MF and 651 FM individuals. Patients averaged 31 years of age. MF individuals used various regimens that mainly included oral, intramuscular or transdermal oestrogens with less frequent use of cyproterone acetate, goserelin acetate or spironolactone. FM individuals used various regimens of testosterone that were mainly administered intramuscularly with infrequent use of oral preparations. No transdermal testosterone was used. Progestins were added if menses did not cease.
Author Contact
We successfully contacted all of the corresponding authors (another author in two studies) by electronic mail. All authors either contributed missing data (where these data had been collected but not reported in the format we needed for analyses) or confirmed study characteristics, quality assessments and data as collected.
Study Quality
Table 2 summarizes the methodological quality of the 16 included studies. Studies were uncontrolled or self-controlled observational studies, one of which included a nested trial (randomizing MF individuals to oral or transdermal oestrogen preparations). Medical records were the most frequent method of ascertaining exposure to hormonal therapy and assessing outcomes.
Meta-analyses
Patient Important Outcomes. There were very few reported cardiovascular events across the trials, with varied length of follow-up. Figure 2 shows the proportion of participants in each eligible study who had reported cardiovascular events.
(Enlarge Image)
Figure 2.
Proportions of cardiovascular outcomes in included studies. Each study is represented by a circle. F/U, follow-up; FM, female-to-male individuals; MF, male-to-female individuals; MI, myocardial infarction; VTE, venous thromboembolism.
Serum Lipids and Blood Pressure.Table 3 and Table 4 represent pooled data for the lipid parameters and blood pressure measurements in MF and FM individuals after sex steroid use, respectively.
Subgroup and Sensitivity Analyses
All feasible subgroup interaction analyses are shown in Table 5 and Table 6 . In MF individuals, significant interaction existed in HDL level-route of hormonal administration, showing a higher serum level after oral administration than the transdermal route. The same was observed with triglycerides levels. In FM individuals, we found insufficient data to compare the route of administration of hormonal therapy (intramuscularly vs. orally). Subgroups defined by individuals followed up for more than 1 year vs. less than 1 year, showed significant increase in cholesterol and triglycerides in studies with follow-up period of more than 1 year. All other subgroup analyses were nonsignificant.
In terms of sensitivity analyses, pooling studies with a cross-over study design separately did not show any significant change in measured lipid fractions. The exclusion of unpublished data decreased between study heterogeneity and drove the statistically significant decrease in HDL and increase in systolic blood pressure towards the null, although a strong trend continued to exist (P = 0·05 and 0·06; respectively).
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