美国凯撒医疗大型队列中，使用雌激素的跨性别女性血栓和中风发生率更高

跨性别者使用异性激素与急性心血管事件：一项队列研究

Authors: Darios Getahun, Rebecca Nash, W. Dana Flanders, Tracy C. Baird, Tracy A. Becerra-Culqui, Lee Cromwell, Enid Hunkeler, Timothy L. Lash, Andrea Millman, Virginia P. Quinn, Brandi Robinson, Douglas Roblin, Michael J. Silverberg, Joshua Safer, Jennifer Slovis, Vin Tangpricha, Michael Goodman
Journal: Annals of Internal Medicine
Year: 2018
Source: https://doi.org/10.7326/M17-2785

Summary

Researchers used Kaiser Permanente health records to follow about 5,000 trans adults and nearly 100,000 matched non-trans men and women. They looked at blood clots in the veins, strokes from a blocked blood vessel, and heart attacks. Trans women had clearly more blood clots than either comparison group, and the gap grew over time. In those who started estrogen during the study, clots rose after about 2 years and strokes after about 6 years. Heart attack rates were similar to non-trans men. For trans men there were too few cases to conclude anything. The authors said estrogen raises the risk of clots and probably stroke, and doctors should watch for this long term. The study is large and well matched, but follow-up was short, people were young, and hormone use outside Kaiser was often unknown, so the real risks are probably higher.

Key findings

该研究纳入了2,842名跨性别女性和2,118名跨性别男性，与来自Kaiser Permanente三个地区的48,686名非跨性别男性和48,775名非跨性别女性比较。
跨性别女性有61例血栓、54例中风和33例心脏病发作；跨性别男性分别有23例、16例和9例。
与非跨性别男性相比，跨性别女性在2年后每1,000人多约4例血栓，8年后多约17例；与非跨性别女性相比，分别多约3例和14例。
在研究期间开始使用雌激素的跨性别女性中，血栓发生率在约2年后拉开差距，中风发生率在约6年后拉开差距。这比绝经后使用激素替代治疗的非跨性别女性出现得更晚。
跨性别女性的心脏病发作比非跨性别女性更常见，但与非跨性别男性大致相同。
跨性别男性的数据不足。作者指出，使用睾酮可能有更多心脏病发作的迹象，但非常不确定。
人们平均只被随访了约4年，因此随着年龄增长的长期风险仍然未知。

Abstract

BACKGROUND: Venous thromboembolism (VTE), ischemic stroke, and myocardial infarction in transgender persons may be related to hormone use. OBJECTIVE: To examine the incidence of these events in a cohort of transgender persons. DESIGN: Electronic medical record-based cohort study of transgender members of integrated health care systems who had an index date (first evidence of transgender status) from 2006 through 2014. Ten male and 10 female cisgender enrollees were matched to each transgender participant by year of birth, race/ethnicity, study site, and index date enrollment. SETTING: Kaiser Permanente in Georgia and northern and southern California. PATIENTS: 2842 transfeminine and 2118 transmasculine members with a mean follow-up of 4.0 and 3.6 years, respectively, matched to 48 686 cisgender men and 48 775 cisgender women. MEASUREMENTS: VTE, ischemic stroke, and myocardial infarction events ascertained from diagnostic codes through the end of 2016 in transgender and reference cohorts. RESULTS: Transfeminine participants had a higher incidence of VTE, with 2- and 8-year risk differences of 4.1 (95% CI, 1.6 to 6.7) and 16.7 (CI, 6.4 to 27.5) per 1000 persons relative to cisgender men and 3.4 (CI, 1.1 to 5.6) and 13.7 (CI, 4.1 to 22.7) relative to cisgender women. The overall analyses for ischemic stroke and myocardial infarction demonstrated similar incidence across groups. More pronounced differences for VTE and ischemic stroke were observed among transfeminine participants who initiated hormone therapy during follow-up. The evidence was insufficient to allow conclusions regarding risk among transmasculine participants. LIMITATION: Inability to determine which transgender members received hormones elsewhere. CONCLUSION: The patterns of increases in VTE and ischemic stroke rates among transfeminine persons are not consistent with those observed in cisgender women. These results may indicate the need for long-term vigilance in identifying vascular side effects of cross-sex estrogen. PRIMARY FUNDING SOURCE: Patient-Centered Outcomes Research Institute and Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Conclusion

The patterns of increases in VTE and ischemic stroke rates among transfeminine persons are not consistent with those observed in cisgender women. These results may indicate the need for long-term vigilance in identifying vascular side effects of cross-sex estrogen. In the discussion the authors state that cross-sex estrogen is a risk factor for VTE and probably ischemic stroke among transfeminine persons, that evidence for transmasculine persons was insufficient (with a possible signal for myocardial infarction), and that the risk must be weighed against the benefits of treatment.

Methodological limitations

Hormone use often unknown: The researchers could not tell who got hormones outside Kaiser Permanente. So the trans groups mix people who did and did not take hormones, which hides some of the hormone effect and left no clean untreated group to compare with.
Short follow-up in young people: People were followed for about 4 years on average, but the extra strokes linked to estrogen only appeared after about 6 years. That is too short to see the long-term risk to blood vessels.
Very few cases: Only 9 heart attacks happened in trans men and 4 in the group who started estrogen during the study. So finding no difference in heart attacks, or for trans men, does not show these are safe, as the authors themselves stress.
Illnesses taken from billing codes: Blood clots, strokes and heart attacks were found from diagnosis codes in the records, not by doctors checking each case. Some cases may have been missed or wrongly counted.
Other causes not fully accounted for: There was no data on cholesterol drugs or many other health conditions. A published letter (Goldstein, Streed and others, Annals of Internal Medicine 2019) argued that HIV, serious mental distress and poor use of preventive care were not accounted for. The authors replied that these would have to affect trans women and trans men differently to explain the results, and an extra check suggested the blood clot finding held up.
Time cut-offs chosen after looking at the data: The researchers split the results at 2 years for blood clots and 6 years for stroke after looking at the curves. Choosing cut-offs this way, after the fact, can make the risk in a given period look bigger than it is.
No comparison of hormone types: There were too few people to compare types, doses or ways of taking estrogen, or different testosterone-blocking drugs. Recorded estrogen doses (about 4 mg a day by mouth at the highest) were higher than in European studies, so results may not apply to patches, gels or lower doses.
Some health measures filled in: Weight, blood pressure and cholesterol were missing for some people, and the researchers estimated the missing values using statistics.
Many comparisons made: The study looked at three illnesses, two comparison groups, several time points and many subgroups without adjusting for doing so many tests. This raises the chance that some findings are flukes.
May not apply to everyone: Everyone was an insured member of one US health system in three states. The start date was the first record of being transgender, not the date hormones began.
Authors' viewpoint: The team included well-known gender clinic doctors (such as Joshua Safer and Vin Tangpricha). No financial conflicts were declared and funding came from US government research bodies (PCORI and NICHD). But the conclusion says the risks must be weighed against benefits that this study did not measure.

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Summary

Key findings

Abstract

Conclusion