To determine the risk of stroke associated with oral and transdermal routes of administration of hormone replacement therapy.
Population based nested case-control study. Setting About 400 general practices in the United Kingdom contributing to the General Practice Research Database. Participants Cohort of all women in the database aged 50-79 years between 1 January 1987 and 31 October 2006 who were members of a practice that fulfilled predefined quality criteria and without a diagnosis of stroke before cohort entry. For each case of stroke occurring during follow-up, up to four controls were selected from among the cohort members in the risk sets defined by the case. Exposure to hormone replacement therapy (HRT) was categorised into oestrogens only, oestrogens plus progestogen, progestogen only, and tibolone. Oestrogens were further subdivided according to the route of administration (oral v transdermal) and dose (high v low). Main outcome measures Rate ratio of stroke associated with current use of oral and transdermal HRT compared with no use. Current use was considered as a prescription whose duration included the index date.
There were 15,710 cases of stroke matched to 59 958 controls. The rate of stroke in the cohort was 2.85 per 1000 per year. The adjusted rate ratio of stroke associated with current use of transdermal HRT was 0.95 (95% CI 0.75 to 1.20) relative to no use. The risk of stroke was not increased with use of low oestrogen dose patches (rate ratio 0.81(0.62 to 1.05)) compared with no use, whereas the risk was increased with high dose patches (rate ratio 1.89 (1.15 to 3.11)). Current users of oral HRT had a higher rate of stroke than non-users (rate ratio 1.28 (1.15 to 1.42)) with both low dose and high dose.
The use of transdermal HRT containing low doses of oestrogen does not seem to increase the risk of stroke. The presence of residual confounding, however, cannot be entirely excluded in the interpretation of this finding.
"There are no trial data directly comparing stroke risk with varying types and doses of estrogen as existing clinical trials were based on single regimens of HRT. Data from available observational studies are conflicting since some of them indicate a similar stroke risk between subjects using high and low doses of estrogen while other studies show a dose–response association [132–134]. Clinical trial results show that the use of either estrogen plus progestin or estrogen alone (taken orally) increases stroke risk in post-menopausal women [134–136]. "
[Show abstract][Hide abstract] ABSTRACT: Migraine is a predominantly female disorder. Menarche, menstruation, pregnancy, and menopause, and also the use of hormonal contraceptives and hormone replacement treatment may influence migraine occurrence. Migraine usually starts after menarche, occurs more frequently in the days just before or during menstruation, and ameliorates during pregnancy and menopause. Those variations are mediated by fluctuation of estrogen levels through their influence on cellular excitability or cerebral vasculature. Moreover, administration of exogenous hormones may cause worsening of migraine as may expose migrainous women to an increased risk of vascular disease. In fact, migraine with aura represents a risk factor for stroke, cardiac disease, and vascular mortality. Studies have shown that administration of combined oral contraceptives to migraineurs may further increase the risk for ischemic stroke. Consequently, in women suffering from migraine with aura caution should be deserved when prescribing combined oral contraceptives.
Electronic supplementary material
The online version of this article (doi:10.1007/s10194-012-0424-y) contains supplementary material, which is available to authorized users.
The Journal of Headache and Pain 02/2012; 13(3):177-89. DOI:10.1007/s10194-012-0424-y · 2.80 Impact Factor
"Furthermore, the type of progestin may also and again be a determinant factor since combinations with 19-norpregnanes were found to be associated with an increased VTE risk even when the oestrogen is given by the transdermal route (Canonico et al., 2007). More recently, transdermal HT did not appear to increase the risk of stroke in another independent case/control study, especially with regimens using low doses of oestrogens (Renoux et al., 2010). Thus, although these findings should be confirmed by randomized clinical trials, they strongly suggest that both the route of oestrogen administration and the type of progestin may be important determinants of the overall benefit–risk profile of HT. "
[Show abstract][Hide abstract] ABSTRACT: The ancestral status of oestrogen receptor (ER) in the family of the steroid receptors has probably contributed to the pleiotropic actions of oestrogens, and in particular, that of 17β-oestradiol (E2). Indeed, in addition to their well-described role in sexual development and reproduction, they influence most of the physiological processes. The pathophysiological counterpart of these actions includes prevention of osteoporosis, atheroma and type 2 diabetes, and also the promotion of uterus and breast cancer growth. Thus, the major challenge consists in uncoupling some beneficial actions from other deleterious ones, that is, selective ER modulation. Tamoxifen and raloxifene are already used, as they prevent the recurrence of breast cancer and mimic oestrogen action mainly on bone. Both E2 and tamoxifen exhibit a proliferative and, thus, a protumoural action on the endometrium. Activation of ERα and ERβ regulates target gene transcription (genomic action) through two independent activation functions, AF-1 and AF-2, but can also elicit rapid membrane-initiated steroid signals. In the present review, we attempted to summarize recent advances provided by the in vivo molecular 'dissection' of ERα, allowing the uncoupling of some of its actions and potentially paving the way to optimized selective ER modulators.
British Journal of Pharmacology 06/2011; 165(1):57-66. DOI:10.1111/j.1476-5381.2011.01538.x · 4.84 Impact Factor
"One additional report from the WHI ancillary study of coronary artery calcium showed that women with vasomotor symptoms who were given estrogen more immediately after the onset of menopause and for a shorter duration had a reduced calcified-plaque burden (Allison et al., 2010). Finally, a new large case-control study based on UK general practices showed that estrogen alone or combined with a progestogen is not a risk factor for stroke if the estrogen is used at low doses and administered transdermally (Renoux et al., 2010). "
[Show abstract][Hide abstract] ABSTRACT: The neuroprotective effects of estrogen have been demonstrated consistently in cellular and animal studies but the evidence in women remains conflicted. We explored the window of opportunity hypothesis in relation to cognitive aging and dementia. In particular, we reviewed existing literature, reanalyzed some of our data, and combined results graphically. Current evidence suggests that estrogen may have beneficial, neutral, or detrimental effects on the brain depending on age at the time of treatment, type of menopause (natural versus medically or surgically induced), or stage of menopause. The comparison of women who underwent bilateral oophorectomy with referent women provided evidence for a sizeable neuroprotective effect of estrogen before age 50 years. Several case-control studies and cohort studies also showed neuroprotective effects in women who received estrogen treatment (ET) in the early postmenopausal stage (most commonly at ages 50-60 years). The majority of women in those observational studies had undergone natural menopause and were treated for the relief of menopausal symptoms. However, recent clinical trials by the Women's Health Initiative showed that women who initiated ET alone or in combination with a progestin in the late postmenopausal stage (ages 65-79 years) experienced an increased risk of dementia and cognitive decline regardless of the type of menopause. The current conflicting data can be explained by the window of opportunity hypothesis suggesting that the neuroprotective effects of estrogen depend on age at the time of administration, type of menopause, and stage of menopause. Therefore, women who underwent bilateral oophorectomy before the onset of menopause or women who experienced premature or early natural menopause should be considered for hormonal treatment until approximately age 51 years.
Brain research 10/2010; 1379:188-98. DOI:10.1016/j.brainres.2010.10.031 · 2.84 Impact Factor
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