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Study Finds No Association Between Oral Contraceptives and Postmenopausal Hormone Therapy and Aneurysmal Subarachnoid Hemorrhage

​The use of oral contraceptives and postmenopausal hormone therapy were not associated with the incidence of aneurysmal subarachnoid hemorrhage, a study published in Neurology on March 29 found.

“Subarachnoid hemorrhage from cerebral aneurysm rupture remains a devastating disease with high mortality and morbidity," wrote lead study author Pui Man Rosalind Lai, MD, of the department of neurosurgery at Brigham and Women's Hospital and department of medicine at Harvard Medical School in Boston, and colleagues. “Post-menopausal women have a higher incidence of aneurysmal subarachnoid hemorrhage (aSAH) and subsequent complications, including cerebral vasospasm, than pre-menopausal women."

However, it remains unclear why the rate of subarachnoid hemorrhage is higher in post-menopausal women. To investigate the association, the researchers analyzed the data of 97,398 participants from the Nurses' Health Study. Of those, 138 had experienced a documented aSAH. Each participant had reproductive life span data and was followed for 38 years to 2018.

The study cohort included only women who had undergone natural menopause or surgical menopause due to bilateral oophorectomy. The investigators used multivariable stratified proportional hazard models to study  reproductive life span, age at menarche, and age at menopause with the incidence of aSAH. The models were adjusted for age, race, smoking, hysterectomy, hypertension, hyperlipidemia, body mass index, hormone therapy use, oral contraceptive use, and parity.

The researchers reported that, overall, a shorter duration of a woman's reproductive life span and a younger age at menopause were associated with a higher risk of aSAH, supporting a role of estrogens in the pathogenesis of aSAH.

A shorter reproductive lifespan (≤35 years) was associated with a twofold higher incidence of aSAH after multivariable adjustment (HR=2.0). Early age at menopause (age <45) was similarly associated with a higher risk of aSAH (HR=2.1), but age at menarche was not. The study authors noted that these associations remained significant even after adjusting for medical comorbidities and lifestyle factors.

However, the researchers did not find any associations for age at menarche, oral contraceptive use, or postmenopausal therapy use. They also noted no association of aSAH with pregnancy, the number of births, age at pregnancy, or age at first birth.

“The production of estrogen dramatically declines with menopause, which has been postulated to explain the increased development of cerebral aneurysms in women after their fourth and fifth decades of life," wrote the study authors. “Murine models support this theory and have demonstrated increased intracranial aneurysm development with the loss of estrogen by ovariectomy, and the restoration of its protective affect after the administration of estrogen agonists."

“However, the study of estrogens and aneurysmal subarachnoid hemorrhage is more complex and insufficient in humans," they added.

Limitations of the study include the relatively small number of aSAHs in the study cohort, the high percentage of participants with European ancestry, and the exclusion of individuals with undiagnosed or unruptured cerebral aneurysms. In addition, the study authors did not account for factors known to be associated to aSAH or evaluate the risks associated with hormone therapy and aSAH in women who were assigned male sex at birth or intersex individuals.

No disclosures were reported.


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Lai P, Jimenez M, Du R, et al. Association of reproductive life span and age at menopause with the risk of aneurysmal subarachnoid hemorrhage. Neurology 2022; Epub 2022 Mar 29.