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Hormones and Cardiovascular Disease
Published in Stephen T. Sinatra, Mark C. Houston, Nutritional and Integrative Strategies in Cardiovascular Medicine, 2022
One randomized trial tested the timing hypothesis. Hodis et al. randomized 643 postmenopausal women based on time since menopause (6 years or less versus 10 years or more). Women were treated with oral estradiol and, if they had a uterus, vaginal progesterone gel. They measured carotid intimal-medial thickness every 6 months. They found that early hormone therapy was linked to less progression when given within 6 years of menopause. No benefit was seen 10 years or more post menopause.93
Breast And Reproductive Cancers
Published in Jane M. Ussher, Joan C. Chrisler, Janette Perz, Routledge International Handbook of Women’s Sexual and Reproductive Health, 2019
In more recent years, secondary analyses of the WHI data have been designed to determine conditions where HT might be beneficial, despite other harms and risks. One proposition, known as the timing hypothesis, is based on the idea that younger women, relatively closer to the typical age of menopause, might benefit from hormone therapy, whereas it might not be beneficial for women aged 60 or older. However, these secondary analyses disclosed no significant benefit for younger women (Rossouw et al., 2007). A larger secondary analysis combined results from the WHI controlled trial with the WHI observational component that simply asked women to report their health practices and ongoing or new health conditions. This recombination allowed researchers to compare outcomes among larger numbers of users versus non-users (Prentice et al., 2008). However, the combined secondary analysis indicated even greater risk for breast cancer. Compared with non-users, women who started HT early in menopause had approximately a 50% increase in breast cancer risk when HT was in place for up to five years and double the risk if the regimen was in place for as long as ten years (Prentice et al., 2008). Regardless of age at which HT was begun, users of estrogen alone or combined estrogen+progestin had consistently more cases of stroke than non-users.
The impacts of menopausal hormone therapy on longer-term health consequences of ovarian hormone deficiency
Published in Climacteric, 2023
The Women’s Health Initiative (WHI) study (mean participant age 63 years) demonstrated that menopausal hormone therapy (MHT) employing conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) prevents bone mineral density (BMD) loss and fracture in healthy postmenopausal women [6,7]. However, a significantly increasing time trend in the risk of CHD was found with the number of years since menopause at MHT initiation [8], and the stroke risk was elevated irrespective of the age at recruitment [9,10]. A WHI memory study additionally showed an increase in the dementia risk in older women [11]. Of note, a meta-analysis of prior randomized controlled trials (RCTs) reported that MHT using oral estrogen significantly decreased the CHD risk by 48%, but did not influence the stroke risk in women less than 10 years after menopause [12]. Prospective studies also reported that when MHT is started early after menopause, it might reduce the risk of dementia [13]. Accordingly, a timing hypothesis has been raised for CHD and dementia. Even though OHD is causally associated, current data reveal a limitation of MHT’s efficacy in the prevention of late problems of OHD.
Interactions between estradiol, diabetes, and brain aging and the risk for cognitive impairment
Published in Climacteric, 2021
C. E. Hugenschmidt, T. Duran, M. A. Espeland
Collectively, the trials already described support a ‘timing’ or ‘window of opportunity’ hypothesis, in which the impact of HT on women’s brain health may vary depending on when it is administered relative to the onset of the menopausal transition28–30. HT appears to have overall beneficial effects in both preclinical and clinical research when it is administered in a timeframe at or near the reduction of ovarian hormones. However, administration of HT in late menopause might have neutral or even harmful effects. The timing hypothesis was proposed because of failed trials of HT in people with Alzheimer’s disease (AD), and a parallel hypothesis applies to HT and cardiovascular health31. Emerging evidence suggests that the metabolic effects of estrogen may in part determine the window of opportunity for beneficial effects of HT. If this is the case, diseases and conditions that affect mitochondria and cellular metabolism may also alter the optimal timing of HT administration.
Hormone replacement therapy – where are we now?
Published in Climacteric, 2021
R. D. Langer, H. N. Hodis, R. A. Lobo, M. A. Allison
The 7-year Early vs. Late Intervention Trial with Estradiol (ELITE) is the only clinical trial to directly test the ‘timing hypothesis’. It tested oral micronized estradiol 1 mg daily (plus micronized progesterone vaginal gel in women with an intact uterus) versus placebo in healthy women who were <6 years or >10 years past menopause when randomized. The ELITE found reduced progression of subclinical atherosclerosis (carotid artery intima-media thickness) in women who were <6 years postmenopausal, but no benefit in women >10 years past menopause (p for interaction = 0.007)38. The timing hypothesis was also studied using the Finnish nationwide death registry (1994–2009) comprising 489,105 postmenopausal women with 3.3 million years of HRT exposure; CHD death was evaluated among HRT users according to age at initiation. The CHD standardized mortality ratio was lower among women who initiated estradiol alone or estradiol/progestogen therapy at age <60 years compared to those initiating at older ages. HRT reduced the risk of all-cause mortality in a nearly linear relationship with duration of exposure7. With this in mind, it should be noted that the WHI CEE + MPA trial included 1298 women with pre-existing CVD. The effects of HRT in women with pre-existing CVD could have confounded the CHD results, giving the impression that CEE + MPA increased CHD in primary prevention. A stratified analysis of WHI women by baseline CVD to determine the effects of HRT on CHD in women with and without pre-existing CVD is conspicuously missing from the literature.