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Oral Contraceptive Use, Hormone Replacement Therapy, and Stroke Risk
TAKE-HOME MESSAGE
- In this UK Biobank analysis including 257,194 women, a substantially higher stroke event rate (HR, 2.49) was observed in women during the first year of oral contraceptive use compared with nonusers, but the risks were comparable (HR, 1.00) thereafter. Hormone replacement therapy was also associated with higher risks of any stroke and cause-specific stroke within the first year, with persistently higher risks of any stroke after the first year of use (HR, 1.18) and after discontinuation (HR, 1.16).
- These data show that both oral contraceptive use and hormone replacement therapy are associated with a substantially increased risk of stroke, with the risk primarily being evident during the first year.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
Millions of women worldwide use exogenous hormones as oral contraceptives or hormone replacement therapy. Still, time-dependent and long-term consequences of exogenous hormones on stroke risk remains unclear.
METHODS
We examined the association between self-reported oral contraceptive and hormone replacement therapy use and stroke risk in 257 194 women from the UK Biobank, born between 1939 and 1970. Outcomes included any type of stroke, ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. Exposures were analyzed as time-varying variables in Cox regression models.
RESULTS
During first year of oral contraceptive use, an increased event rate of any stroke was observed (hazard ratio [HR], 2.49 [95% CI, 1.44-4.30]), while the hazards were found to be comparable during remaining years of use (HR, 1.00 [95% CI, 0.86-1.14]), compared with nonusers. Similarly, first year of hormone replacement therapy use was associated with higher hazard rates of any stroke (HR, 2.12 [95% CI, 1.66-2.70]), as well as cause-specific stroke, including ischemic stroke (HR, 1.93 [95% CI, 1.05-3.57]) and subarachnoid hemorrhage (HR, 2.17 [95% CI, 1.25-3.78]), which remained increased for any stroke during remaining years of use (HR, 1.18 [95% CI, 1.05-1.31]), and after discontinuation (HR, 1.16 [95% CI, 1.02-1.32]).
CONCLUSIONS
Oral contraceptive use and hormone replacement therapy were associated with an increased risk of stroke, especially during the first year of use, possibly due to immediate changes in hemostatic balance. This study provides new insights on the effects of hormone exposure on stroke risk and provide evidence of not only an overall risk but also a pronounced effects seen in the beginning of treatment.
Additional Info
Disclosure statements are available on the authors' profiles:
Oral Contraceptives, Hormone Replacement Therapy, and Stroke Risk
Stroke 2022 Jun 23;[EPub Ahead of Print], T Johansson, P Fowler, WE Ek, A Skalkidou, T Karlsson, Å JohanssonFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Are women at increased risk of stroke from oral contraceptives or hormone replacement therapy?
There have always been concerns about causing harm with hormone therapies, be it oral contraceptives (OC) or hormone replacement therapies (HRT). The authors of this study pointed out that hormones can have a prothrombotic effect; hence, there is a theoretical risk of increasing blood clot-type diseases such as stroke. It would be difficult to do a randomized prospective study on this topic. This study looked at 257,194 women in the UK Biobank. There were 3007 stroke diagnoses in the database. The authors divided the analysis into two parts. The first part looked at the first year after starting hormonal therapy and the second part looked at the remaining years of therapy.
There was an increase in stroke rate, with a hazard ratio of 2.49 in the first year of starting OC. For the remaining years, there was no difference observed in the stroke rate, with a hazard ratio of 1.00. For patients who discontinued the OC therapy, there were no differences in the stroke rate, with a hazard ratio of 0.93.
We can speculate as to why this is. Maybe we doubled up on the hormones. The OC is providing hormones in addition to the natural hormones in the patient; could these higher levels be causing the prothrombotic effect? Presumably, over time, the body no longer produces hormones, and hence, the OC hormones are the only hormones available and so the risk goes back to normal. Another possible explanation might be that the patients that will have strokes had them in the first year and after that, there won’t be any difference in stroke incidence. It is like giving peanut butter to a group of people – individuals who are allergic to peanuts will be identified early and thereafter there would be no more allergic reactions.
For HRT, there was an increase in the stroke rate in the first year, with a hazard ratio of 2.12. Because this is an older population, there were more stroke incidences; therefore, the authors looked at ischemic and hemorrhagic strokes separately as well. For ischemic stroke, in the first year, the rate increased, with a hazard ratio of 1.93 and this makes sense from the prothrombotic effect of HRT.
However, the incidence of subarachnoid hemorrhage was also increased with a hazard ratio of 2.17. The authors speculated that cerebral vasodilation along with a transient elevation in blood pressure could cause rupture of pre-existing aneurysms. This is more of a stretch but nonetheless, there is a real risk for hemorrhagic stroke.
For the HRT group, after the first year, the hazard ratio was still elevated for any stroke at 1.18. And even after the discontinuation of HRT, the HRT group continued to have a higher hazard ratio for any stroke (HR, 1.16). Therefore, for the HRT group, there is still an increased risk for stroke during the remainder of the years albeit much smaller than in the first year.
This study does make us think about the risk and benefits of OC and HRT. Should we do studies on hormone levels and try to not over-replace them? Or perhaps we should give smaller amounts of hormones so that there is not a big dump of hormones into the system? Or perhaps we need to look at the type of hormones that were used. This study did not identify which OC or HRT was used in the stroke patients. Perhaps that would be a useful exercise. Or perhaps we should look at the stroke risk factors in our patients and try to reduce them before starting OC or HRT? So if they are smokers, then get them off smoking. In other words, control the vascular risk factors before starting OC and HRT. This path and starting with lower doses might be a path until such time that we have more data to know exactly what to do.