No increased risk of stroke with early post-menopausal hormone therapy

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Post-menopausal hormone therapy is not associated with increased risk of stroke, provided that it is started early, according to a report from Karolinska Institutet in Sweden.

Roughly three in ten women in the menopause transition are afflicted by symptoms that seriously affect their wellbeing, such as hot flushes, dry mucosa and insomnia. However, although the symptoms can be treated effectively with female sex hormones, prescriptions have been low over the past 15 years as researchers have demonstrated a link between such therapy and an increased risk of certain diseases, including stroke.

There is still, however, a need for more research on the issue, as the risk can be influenced by the time of the treatment and other factors, reasons Karin Leander, researcher at Karolinska Institutet’s Institute of Environmental Medicine.

“New research shows us that hormone therapy actually has a positive effect on blood vessels if initiated early on in the menopause, but not if initiated late,” says Leander. “So there was reason to re-examine whether hormone therapy is linked to the risk of stroke, taking, of course, the time of administering into consideration.”

Leander and her colleagues have now analysed data on post-menopausal hormone therapy from five Swedish cohort studies covering a total of 88,914 women, combined with data from national registries on diagnoses and causes of death during a follow-up period.

Hormone therapy was not linked to increased risk of stroke (ischemic and haemorrhagic stroke combined) if the therapy was initiated within five years of menopausal onset, regardless of means of administration (oral, via the skin or vaginal), type of therapy (combination or oestrogen only), active substance and treatment duration.

In sub-analyses, however, there was an observable increase in risk for haemorrhagic stroke (the less common form) if the therapy contained the active substance conjugated equine oestrogens. Drugs containing oestradiol, on the other hand, were not associated with a higher risk. A higher risk was also seen for both ischemic and haemorrhagic stroke if the treatment was initiated later than five years after the onset of menopause and contained conjugated equine oestrogens.

“The risk of stroke seems virtually eradicable if treatment commences early, but it’s naturally important to take account of the increase in risk that exists under certain circumstances,” says Leander. “These results provide doctors with a better scientific base on which to take decisions on treatment for menopausal symptoms.”

Abstract
Background: Recent research indicates a favourable influence of post-menopausal 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 findings: Data 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 −3.11 to 0.68) than never use. Given the observational nature of this study, the possibility of uncontrolled confounding cannot be excluded. Further, immortal time bias, also related to the observational design, cannot be ruled out.
Conclusions: When initiated early in relation to menopause onset, HT was not associated with increased risk of incident stroke, regardless of the route of administration, type of HT, active ingredient, and duration. Generally, these findings held also for haemorrhagic stroke. Our results suggest that the initiation of HT 0–5 years after menopause onset, as compared to never use, is associated with a decreased risk of stroke and haemorrhagic stroke. Late initiation was associated with elevated risks of stroke and haemorrhagic stroke when conjugated equine oestrogen was used as single therapy. Late initiation of combined HT was associated with haemorrhagic stroke risk.

Authors
Germán D Carrasquilla, Paolo Frumento, Anita Berglund, Christer Borgfeldt, Matteo Bottai, Chiara Chiavenna, Mats Eliasson, Gunnar Engström, Göran Hallmans, Jan-Håkan Jansson, Patrik K. Magnusson, Peter M Nilsson, Nancy L Pedersen, Alicja Wolk, Karin Leander

Karolinska Institutet material
PLOS Medicine abstract


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