Timing Of Hormone Therapy Initiation Research Articles

Lifetime estrogen exposure and cognition in late life: the Cache County Study.

Prevalence of Alzheimer's disease (AD) is higher for women, possibly influenced by sex-dependent effects of the estrogen. We examined the association between estrogen and cognitive decline in over 2,000 older adult women in a 12-year population-based study in Cache County, Utah. The baseline sample included 2,114 women (mean age = 74.94 y, SD = 6.71) who were dementia-free at baseline and completed a women's health questionnaire, asking questions regarding reproductive history and hormone therapy (HT). Endogenous estrogen exposure (EEE) was calculated taking the reproductive window (age at menarche to age at menopause), adjusted for pregnancy and breastfeeding. HT variables included duration of use, HT type (unopposed; opposed), and time of HT initiation. A modified version of the Mini-Mental State Examination (3MS) was administered at four triennial waves to assess cognitive status. Linear mixed-effects models examined the relationship between estrogen exposure and 3MS score over time. EEE was positively associated with cognitive status (β = 0.03, P = 0.054). In addition, longer duration of HT use was positively associated with cognitive status (β = 0.02, P = 0.046) and interacted with age; older women had greater benefit compared with younger women. The timing of HT initiation was significantly associated with 3MS (β = 0.55, P = 0.048), with higher scores for women who initiated HT within 5 years of menopause compared with those initiating HT 6-or-more years later. Our results suggest that longer EEE and HT use, especially in older women, are associated with higher cognitive status in late life.

The route of administration, timing, duration and dose of postmenopausal hormone therapy and cardiovascular outcomes in women: a systematic review.

The effect of postmenopausal hormone therapy (HT) on cardiovascular disease (CVD) risk remains controversial. We aimed to systematically review the evidence regarding the role of dose, route of hormone administration, timing of initiation and duration of HT on cardiovascular risk among postmenopausal women. The electronic databases Medline Ovid, Web of Science and Cochrane Central were systematically searched to identify studies published before 30 January 2018. Reference lists, using Elsevier's Scopus, of the included studies were searched for further identification of relevant studies. Clinical trials and observational studies that assessed clinical and subclinical cardiovascular outcomes in relation to dose, route of administration, duration of use, or timing of HT initiation among postmenopausal women were included. Data were extracted by independent reviewers using a pre-designed data collection form. The Cochrane Collaboration's tool and the Newcastle-Ottawa Scale were used by two independent investigators to assess the risk of bias in RCTs and in prospective observational studies, respectively. In total, 33 unique studies (6 trials and 27 prospective observational studies) were identified, including a total of 2 588 327 women. The synthesis of the existing knowledge on this topic was challenging due to inconsistent findings between some studies, caused by substantial diversity in scientific rigor and quality across the available literature. Overall, the evidence did not support the concerns that oral or transdermal HT increases heart disease risk. Contrary, observational data showed that a beneficial cardioprotective effect can be observed even with use of low doses of oral HT (effect of 0.3 mg/day of oral conjugated equine estrogen was similar to that seen with the standard dose of 0.625 mg/day), but clinical trials to support a cardioprotective benefit of HT in primary prevention have not been identified. Furthermore, the current data suggested that oral and transdermal HT, in dose-dependent manner and irrespective of HT formulation, may increase thromboembolic risk, as well as risk of stroke. However, transdermal estrogen with <50 μg/day of estrogen combined with micronized progesterone appears to be the safer choice with respect to thrombotic and stroke risk. Also, vaginal HT administration may play a role in myocardial infarction and stroke risk prevention, but this is based on limited evidence and requires further investigation. The timing of HT initiation and duration may be important factors to consider when prescribing HT especially in women with adverse cardiometabolic profile and pre-existing conditions such as coronary/carotid atherosclerosis, which are at risk of developing, and thus progressing to CVD. The quality of evidence was generally low or moderate and the findings were based mostly on observational data. Use of low-dose oral and transdermal HT appears to be safe with regard to CVD risk in women in menopausal transition and within the first years (e.g. 10 years) after menopause onset. In women with increased baseline thromboembolic risk, alternative non-hormonal medications are suggested as first-line treatment and transdermal estradiol alone or with micronized progesterone only should be considered when these options are not effective. When HT is initiated >10 years since the menopause onset (>60 years old), due to greater absolute risks of coronary heart disease, stroke and venous thromboembolism, HT should be used for the shortest time possible and in lowest possible dose and preferably transdermal administration should be recommended. However, an individualized treatment approach including baseline CVD risk assessment should be applied when prescribing HT. The majority of studies included in the current review are from North American and European populations, which might limit the generalizability of the findings of this review to the other populations. Finally, the quality of evidence included in this review was generally low or moderate, highlighting a need for more rigorous research to help us better understand HT and cardiovascular health.

Evaluating the Role of Hormone Therapy in Postmenopausal Women with Alzheimer's Disease.

Hormone therapy (HT) is prescribed during or after menopausal transition to replace the decline in estrogen and progesterone levels. While some studies indicate that estrogen and progesterone depletion in postmenopausal women might carry a significant risk for developing sporadic Alzheimer's disease (sAD), which may be reduced by HT, recent clinical trials oppose this beneficial effect. This review points to possible reasons for these mixed data by considering the issues of both preclinical and clinical trials, in particular, the representativeness of animal models, timing of HT initiation, type of HT (different types of estrogen compounds, estrogen monotherapy vs. estrogen-progesterone combined therapy), mode of drug delivery (subcutaneous, transdermal, oral, or intramuscular), and hormone dosage used, as well as the heterogeneity of the postmenopausal population in clinical trials (particularly considering their sAD stage, anti-AD therapy, and hysterectomy status). Careful planning of future preclinical and clinical HT interventional studies might help to elucidate the effect of HT on cognitive status in postmenopausal women with sAD, which will eventually contribute to more effective sAD prevention and treatment.

Does menopausal hormone therapy reduce myocardial infarction risk if initiated early after menopause? A population-based case-control study.

This study aims to assess whether the timing of menopausal hormone therapy initiation in relation to onset of menopause and hormone therapy duration is associated with myocardial infarction risk. This study was based on the Stockholm Heart Epidemiology Program, a population-based case-control study including 347 postmenopausal women who had experienced a nonfatal myocardial infarction and 499 female control individuals matched for age and residential area. Odds ratios (with 95% CIs) for myocardial infarction were calculated using logistic regression. Early initiation of hormone therapy (within 10 y of onset of menopause or before age 60 y), compared with never use, was associated with an odds ratio of 0.87 (95% CI, 0.58-1.30) after adjustments for lifestyle factors, body mass index, and socioeconomic status. For late initiation of hormone therapy, the corresponding odds ratio was 0.97 (95% CI, 0.53-1.76). For hormone therapy duration of 5 years or more, compared with never use, the adjusted odds ratio was 0.64 (95% CI, 0.35-1.18). For hormone therapy duration of less than 5 years, the odds ratio was 0.97 (95% CI, 0.63-1.48). Neither the timing of hormone therapy initiation nor the duration of therapy is significantly associated with myocardial infarction risk.

Postmenopausal Hormone Therapy and Breast Cancer

IN 2002, THE WOMEN’S HEALTH INITIATIVE (WHI) RANdomized trial of placebo vs hormone therapy with estrogen and progestin was stopped early because of evidence of harm. Sales of combined estrogen-progestin plummeted 32% between the period immediately before the study’s release and the analogous period 1 year later, as the WHI trial had shown that hormone therapy increased a woman’s risk of breast cancer and myocardial infarction. The finding contradicted decades of case-control and observational cohort studies that had suggested that hormone therapy was associated with strong protective effects on the cardiovascular system. The WHI results also undermined a long and successful campaign by hormone replacement advocates to present hormone therapy as a panacea against heart disease, loss of femininity, and other perils of aging. In the scientific community, the WHI results became “exhibit 1” for critics of observational studies, who argued that this latest upheaval of conventional medical knowledge proved (once again) that only randomized studies can yield useful insights into cause and effect. Eight years hence, and many subgroup analyses later, a more nuanced explanation for the study’s findings has emerged. Among the few women in the WHI who enrolled around the time of their menopause, hormone therapy with both estrogen and progestin did not increase the risk of cardiovascular disease and may have reduced it slightly. However, most women in the study were well past menopause at enrollment (the average age was 63 years), and the negative effects of hormone therapy, which increase with more elapsed time after menopause, exceeded any small benefits that might have been experienced by the younger women in the study. In addition, the WHI documented numerous other negative effects of hormone therapy, including an increased risk of stroke and pulmonary embolism, which are not strongly associated with the timing of hormone therapy initiation. Ultimately, the only long-term benefit of hormone therapy that the US Food and Drug Administration (FDA) allows the manufacturer to claim is reduction of risk of osteoporotic fractures. That breast cancer rates in the WHI increased among women receiving hormone therapy was not surprising. Epidemiological and biological studies had anticipated the effect, although the magnitude of risk was not known until the WHI, which showed that the effect of hormone therapy on breast cancer risk was about the same as the deleterious effect on cardiovascular health. In each case, 42 more of approximately 8000 women in the hormone therapy group than the placebo group experienced the adverse outcome. Put in a population perspective, this means that the absolute increase in risk was only approximately 0.5% over the course of the study. But what may seem like a small effect in the study apparently turned out to be an enormous effect in the population. Several years after use of hormone therapy plummeted in the United States, breast cancer incidence also declined. Other questions lingered. What, if at all, is the effect of hormone therapy on the type of breast cancer a woman develops? Are there differences in the aggressiveness or in the potential treatability of cancers caused by hormone therapy? Several observational studies suggested that hormone therapy had counterbalancing actions in that it caused more breast cancers, but on average those cancers were less advanced and had more favorable prognostic features, such as being more often estrogen receptor positive. This potential trade-off made the ultimate effect of the increase in incidence on the rate of death from breast cancer uncertain. Other questions involved the relation between duration of use of hormone therapy and increase in breast cancer risk. Would shorter periods of hormone therapy be associated with less risk? Would the risk decrease after cessation of hormone therapy or remain elevated for a sustained period? In this issue of JAMA, Chlebowski et al report results of an 11-year follow-up of WHI estrogen-progestin trial participants that address many of these questions. The

Hormone Therapy and Coronary Heart Disease: The Role of Time since Menopause and Age at Hormone Initiation

Apparently discrepant findings have been reported by the Women's Health Initiative (WHI) trial compared with observational studies of postmenopausal hormone therapy (HT) and coronary heart disease (CHD). We prospectively examined the relation of HT to CHD, according to timing of hormone initiation relative to age and time since menopause. Participants were postmenopausal women in the Nurses' Health Study, with follow-up from 1976 to 2000. Information on hormone use was ascertained in biennial, mailed questionnaires. We used proportional hazards models to calculate multivariable adjusted relative risks (RR) and 95% confidence intervals (CI). We also conducted sensitivity analyses to determine the possible influence of incomplete capture of coronary events occurring shortly after initiation of HT. Women beginning HT near menopause had a significantly reduced risk of CHD (RR = 0.66, 95% CI 0.54-0.80 for estrogen alone; RR = 0.72, 95% CI 0.56-0.92 for estrogen with progestin). In the subgroup of women demographically similar to those in the WHI, we found no significant relation between HT and CHD among women who initiated therapy at least 10 years after menopause (RR = 0.87, 95% CI 0.69-1.10 for estrogen alone; RR = 0.90, 95% CI 0.62-1.29 for estrogen with progestin). Among women who began taking hormones at older ages, we also found no relation between current use of estrogen alone and CHD (for women aged 60+ years, RR = 1.07, 95% CI 0.65-1.78), although there was a suggestion of possible reduced risk for combined HT (RR = 0.65, 95% CI 0.31-1.38). In sensitivity analyses, we found that the incomplete capture of coronary events occurring shortly after initiation of HT could not explain our observation of a reduced risk of coronary disease for current users of HT. These data support the possibility that timing of HT initiation in relation to menopause onset or to age might influence coronary risk.

Estrogen-containing hormone therapy and Alzheimer’s disease risk: Understanding discrepant inferences from observational and experimental research

Estrogen has the potential to influence brain processes implicated in Alzheimer’s disease pathogenesis. With the loss of ovarian estrogen production after menopause, estrogen-containing hormone therapy might be expected to influence the risk of Alzheimer’s disease. Observational data link use of hormone therapy to reductions in Alzheimer risk, but experimental evidence from the Women’s Health Initiative Memory Study trial demonstrates that oral estrogen, with or without a progestin, increases the incidence of dementia for postmenopausal women age 65 years or older. Mechanisms of harm in this setting are unknown. Bias and unrecognized confounding in observational research are leading candidates for discrepant results between observational studies and the Women’s Health Initiative Memory Study trial. Studies are also distinguished by differences in outcome measures, hormone therapy formulations, prevalence of menopausal symptoms among study participants, and participant age. Finally, Women’s Health Initiative Memory Study findings may not generalize to estrogen use by relatively young women during the menopausal transition or early postmenopause, a class of women who were ineligible for the Women’s Health Initiative Memory Study trial. In observational studies, hormone therapy exposure often included use by younger women for menopausal vasomotor symptoms. Although there is no clinical trial evidence that hormone therapy at any age protects against Alzheimer’s disease, it remains to be determined whether the age at which hormone exposure occurs or the timing of hormone therapy initiation in relation to the menopause (the critical window hypothesis) modifies treatment outcomes on dementia risk.