Postmenopausal hormone therapy and risk of stroke: A pooled analysis of data from population-based cohort studies

Abstract

BackgroundRecent research indicates a favourable influence of postmenopausal hormone therapy (HT) if initiated early, but not late, on subclinical atherosclerosis. However, the clinical relevance of timing of HT initiation for hard end points such as stroke remains to be determined. Further, no previous research has considered the timing of initiation of HT in relation to haemorrhagic stroke risk. The importance of the route of administration, type, active ingredient, and duration of HT for stroke risk is also unclear. We aimed to assess the association between HT and risk of stroke, considering the timing of initiation, route of administration, type, active ingredient, and duration of HT.Methods and findingsData on HT use reported by the participants in 5 population-based Swedish cohort studies, with baseline investigations performed during the period 1987–2002, were combined in this observational study. In total, 88,914 postmenopausal women who reported data on HT use and had no previous cardiovascular disease diagnosis were included. Incident events of stroke (ischaemic, haemorrhagic, or unspecified) and haemorrhagic stroke were identified from national population registers. Laplace regression was employed to assess crude and multivariable-adjusted associations between HT and stroke risk by estimating percentile differences (PDs) with 95% confidence intervals (CIs). The fifth and first PDs were calculated for stroke and haemorrhagic stroke, respectively. Crude models were adjusted for age at baseline only. The final adjusted models included age at baseline, level of education, smoking status, body mass index, level of physical activity, and age at menopause onset. Additional variables evaluated for potential confounding were type of menopause, parity, use of oral contraceptives, alcohol consumption, hypertension, dyslipidaemia, diabetes, family history of cardiovascular disease, and cohort. During a median follow-up of 14.3 years, 6,371 first-time stroke events were recorded; of these, 1,080 were haemorrhagic. Following multivariable adjustment, early initiation (<5 years since menopause onset) of HT was associated with a longer stroke-free period than never use (fifth PD, 1.00 years; 95% CI 0.42 to 1.57), but there was no significant extension to the time period free of haemorrhagic stroke (first PD, 1.52 years; 95% CI −0.32 to 3.37). When considering timing as a continuous variable, the stroke-free and the haemorrhagic stroke-free periods were maximal if HT was initiated approximately 0–5 years from the onset of menopause. If single conjugated equine oestrogen HT was used, late initiation of HT was associated with a shorter stroke-free (fifth PD, −4.41 years; 95% CI −7.14 to −1.68) and haemorrhagic stroke-free (first PD, −9.51 years; 95% CI −12.77 to −6.24) period than never use. Combined HT when initiated late was significantly associated with a shorter haemorrhagic stroke-free period (first PD, −1.97 years; 95% CI −3.81 to −0.13), but not with a shorter stroke-free period (fifth PD, −1.21 years; 95% CI −3....

Sex and gender: modifiers of health, disease, and medicine

“…However, initiation of therapy early after menopause decreases stroke risk. 96 Additionally, some stroke risk factors are common to both sexes but the frequency of each risk factor, and the population-attributable risk, differs between the sexes. As shown in the international INTERSTROKE case-control study, 97 hypertension, abdominal obesity, and adverse lipid profiles are the most impactful causes of stroke in women worldwide.…”

Age-Related Changes and Sex-Related Differences in Brain Iron Metabolism

“…Increasing experimental and clinical evidence concerning iron metabolism support the idea that healthy aging processes, as well as neurological disorders, differ between women and men, suggesting the existence of different underlying mechanisms involved in the iron homeostasis and the pathogenesis of diseases (Figure 3) [16][17][18][19][20][21][22]161]. Age and sex are important co-factors to consider when establishing the differences between the pathological neurodegeneration from healthy aging.…”

An Appraisal of the Role of Previously Reported Risk Factors in the Age at Menopause Using Mendelian Randomization

“…Menopause is normally defined as the cessation of spontaneous menses for 12 months, marking the end of the reproductive phase of life; it includes functional ovarian failure and a change of hormone profiles (Nelson, 2008). Estrogen decline in the postmenopausal period is associated with numerous pathophysiological conditions, including osteoporosis, depressive symptoms, coronary disease, and stroke (Ahlborg et al, 2003;Vivian-Taylor and Hickey, 2014;Muka et al, 2016;Carrasquilla et al, 2017). Thus, early age at natural menopause (ANM), which shortens the period of exposure to estrogen, is an important problem in women's health and quality of life (Hernandez-Angeles and Castelo-Branco, 2016).…”