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Summary

Recently Taylor et al [1] have assessed the controversies regarding hormone replacement therapy (HRT) for primary prevention of cardiovascular in postmenopausal women, a situation that has been ongoing for the past several decades. They reviewed important research studies of HRT in postmenopausal women with respect to its safety and efficacy for the primary prevention of cardiovascular disease. Although in the 80’s observational studies suggested that HRT had a benefit for primary cardiovascular disease prevention, randomized controlled studies performed in the 90’s suggested a potential harm. Due to these discrepancies, recommendations from authorities and various international societies regarding its use have varied, indicating that the timing of HRT initiation related to the onset of menopause, also known as the “timing hypothesis”, is the crucial factor that could explain the differences observed in these studies.
Some recent investigations have concluded that HRT initiated in postmenopausal women near the onset of menopause confers a cardioprotective benefit, while others simply showed that HRT does not cause harm. There has been an expansion in research in order to evaluate alternative doses, preparations, routes, and formulations, including the use of selective estrogen receptor modulators, to demonstrate their suitability for the purpose of treating women with symptoms.

Commentary

There is no doubt that HRT has a positive effect on climacteric symptoms such as hot flashes or the genitourinary syndrome. However, the effect that this therapy has on chronic diseases is still widely discussed. The review of Taylor et al [1] focuses on cardiovascular risk, and addresses the same controversies that HRT had in recent decades. We still remember when in 1960, HRT was the best option for women to always stay beautiful and healthy. In relation to this last aspect, health and diseases, many observational studies analyzed the effect of estrogen deprivation on one of the main causes of death in women, cardiovascular diseases. One of these studies, the Framingham, reported a 2.6 higher risk of cardiovascular events in postmenopausal women when compared to premenopausal ones [2]. Similarly, another study observed that women with surgical menopause had a 2.7 higher cardiovascular risk than women of the same age without surgical menopause [3]. These studies suggested that HRT, by counteracting postmenopausal hypoestrogenism, could have a positive effect on the primary prevention of cardiovascular disease.

Nevertheless, the point of view regarding the positive cardiovascular effect of estrogens was completely reversed after the publication of the results of the Women’s Health Initiative (WHI), which showed an increase in cardiovascular risk with HRT use [4]. However, subsequent sub-analysis publications of the WHI itself and by other groups such as the DOPS, KEEPS and ELITE, showed that the initial negative results of the WHI could not be extrapolated to women of any age, at all doses or all types of estrogens. As a result, the “window of opportunity” theory emerged. HRT initiated in women within the first 10 years of menopause did not involve cardiovascular risks and could even be cardioprotective; in older women, on the other hand, it may increase cardiovascular risk [5].

The positive effect of HRT on cardiovascular health can be understood from its metabolic effects. Thus, estrogen affects substances such as endothelial nitric oxide synthetase, superoxide dismutase, cyclooxygenase 1 and 2, angiotensin, thromboxane and endothelin 1, which have vasodilator, antioxidant and anti-inflammatory properties [6]. Conversely, hypoestrogenism alters the intestinal microbiota, which is associated with obesity, fatty liver and chronic inflammation, factors associated with cardiovascular risk. Furthermore, orally administered estrogen increases thrombotic risk and the instability of atherosclerotic plaques, increasing cardiovascular risk in older postmenopausal women [7].
Eighteen years have passed since the publication of the results of the WHI and the risk of thromboembolism is a limiting factor for the use of HRT as primary cardiovascular prevention. A meta-analysis of several studies that compared oral vs transdermal HRT found that the risk of thrombosis in women who used the oral route was 2.5 fold (1.9-3.4) compared to 1.2 (0.9-1.7) observed in those who used the transdermal route [8]. This could be explained because transdermal HRT prevents the hepatic passage and its consequent effect on coagulation factors. Therefore, it is not correct to extrapolate the cardiovascular effects of oral estrogens to transdermal estrogens.

In conclusion, although HRT is currently prescribed mainly for the treatment of vasomotor symptoms, its effect on cardiovascular risk would be beneficial as long as initiated early in postmenopausal women. Since most of the current information refers to oral estrogens, long-term studies of transdermal estrogens are required to evaluate their cardiovascular effects.

María S. Vallejo, MD
Clínica Quilín, Facultad de Medicina
Universidad de Chile, Santiago de Chile, Chile

References

  1. Taylor JE, Baig MS, Helmy T, Gersh F. Controversies Regarding Post-Menopausal Hormone Replacement Therapy for Primary Cardiovascular Disease Prevention in Women. Cardiol Rev. 2020 Nov 6. doi: 10.1097/CRD.0000000000000353. Epub ahead of print. PMID: 33165087.
    https://pubmed.ncbi.nlm.nih.gov/33165087/
  2. Kannel WB, Hjortland MC, McNamara PM, Gordon T. Menopause and risk of cardiovascular disease: the Framingham study. Ann Intern Med. 1976;85(4):447-52.
    https://pubmed.ncbi.nlm.nih.gov/970770/
  3. Gordon T, Kannel WB, Hjortland MC, McNamara PM. Menopause and coronary heart disease. The Framingham Study. Ann Intern Med. 1978;89(2):157-61.
    https://pubmed.ncbi.nlm.nih.gov/677576/
  4. Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-33.
    https://pubmed.ncbi.nlm.nih.gov/12117397/
  5. Nudy M, Chinchilli VM, Foy AJ. A systematic review and meta-regression analysis to examine the ‘timing hypothesis’ of hormone replacement therapy on mortality, coronary heart disease, and stroke. Int J Cardiol Heart Vasc. 2019;22:123-131.
    https://pubmed.ncbi.nlm.nih.gov/30705938/
  6. Fredette NC, Meyer MR, Prossnitz ER. Role of GPER in estrogen-dependent nitric oxide formation and vasodilation. J Steroid Biochem Mol Biol. 2018;176:65-72.
    https://pubmed.ncbi.nlm.nih.gov/28529128/
  7. Chen KL, Madak-Erdogan Z. Estrogens and female liver health. Steroids. 2018;133:38-43.
    https://pubmed.ncbi.nlm.nih.gov/29100781/
  8. Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ. 2008;336(7655):1227-31.
    https://pubmed.ncbi.nlm.nih.gov/18495631/
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