Oral Contraceptives, Hormone Replacement Therapy, and Stroke Risk

Abstract

BACKGROUND: 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.

Genomic Risk Scores and Oral Contraceptive-Associated Ischemic Stroke Risk

“…In our cohort, OC use was significantly associated with the risk of ischemic stroke, as has been reported previously. [1][2][3] Importantly, the odds ratio for ischemic stroke associated with OC-use was highest in the tertile with highest genomic risk of ischemic stroke. The formal test of interaction, although not statistically significant, is consistent with our hypothesis that the genomic risk score modifies the association of OC use with ischemic stroke.…”

“…4 While many of the cardiovascular risk factors such as hypertension and diabetes often emerge by increasing age, the risk for ischemic stroke is suggested to be highest shortly after initiation of OCs. 2 If a genomic risk score could identify women at latent risk, this could help to reduce the burden of early onset ischemic stroke and associated socioeconomic consequences.…”

“…Combined oral contraceptives (OCs) are associated with an increased risk of ischemic stroke. [1][2][3] Although ischemic strokes are rare in reproductive-aged women, the consequences are often severe. Despite several factors that increase OC-associated ischemic stroke have been identified, including age, smoking, and hypertension, 4 the exact mechanisms remain insufficiently understood.…”

Stroke in Women and Unique Risk Factors

“…However, the time-varying analysis showed an increased hazard of any stroke in the first year of OC use (HR, 2.49 [95% CI, 1.44–4.30]), with no difference in stroke risk between users and nonusers during the remaining years of use and after discontinuation. 18…”

The Impact of Nicotine along with Oral Contraceptive Exposure on Brain Fatty Acid Metabolism in Female Rats

“…Ample literature has shown that longterm exposure to HRT or OC affects blood clotting, lipid and lipoprotein metabolism, and endothelial function [5]. In contrast, a recent study shows that both OC use and HRT were associated with an increased risk of stroke, especially during the first year of use, possibly due to immediate changes in hemostatic balance [6]. It is also documented that OC exposure makes females more susceptible to stress hormone effects on episodic memory, fear conditioning, and cognitive emotion regulation [7][8][9][10].…”