The effects of estrogen and hormone replacement therapy on platelet activity: a review.

Am J Blood Res 2022;12(1):33-42 www.AJBlood.us /ISSN:2160-1992/AJBR0140145 Review Article The effects of estrogen and hormone replacement therapy on platelet activity: a review Mehrnoosh Hashemzadeh1,2, Fathima Haseefa1, Lee Peyton2,4, Shery Park2,3, Mohammed Reza Movahed1,3 University of Arizona, College of Medicine, Phoenix, AZ, USA; 2Pima College, Tucson, AZ, USA; 3University of Arizona, Tucson, AZ, USA; 4Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine and Science, Rochester, MN, USA 1 Received October 27, 2021; Accepted January 24, 2022; Epub February 15, 2022; Published February 28, 2022 Abstract: Many studies have shown that an increase in cardiovascular disease in women is related to hormonal changes occurring particularly after menopause with increasing age. While the results of large clinical trials reporting no benefit of hormone replacement therapy (HRT) in cardiovascular disease have been known for some time, there is an increasing body of knowledge regarding the various mechanisms by which estrogen modulates platelet function that could in part explain the higher cardiovascular risk occurring in postmenopausal women and potential benefits of HRT on cardiovascular health. Our review summarizes our current knowledge regarding the effect of endogenous and exogenous estrogen on platelet activity, which can help researchers design future studies. We collected information from 21 peer-reviewed articles published from 1993 to 2021. Studies have indicated that postmenopausal women have higher platelet activity than premenopausal women, which can increase the risk of thrombo-embolic events and cardiovascular disease. Although some studies have reported pro-thrombotic effects of estrogen replacement therapy such as increased platelet activation and adhesion, other studies demonstrated decreased platelet aggregation by inhibiting GP IIb/IIIa receptor expression. This is mediated by estrogen receptors on the platelet membrane in a non-genomic manner and suggests an opportunity for the usage of estrogen replacement therapy with subtle changes in the formulation and route, particularly if started early after menopause. The effect of estrogen on platelet activity is promising as an important factor in reducing the risk of cardiovascular events, warranting further investigation. Keywords: Cardiovascular disease, coronary artery disease, atherosclerosis, menopause, estrogen, hormone replacement therapy, estradiol, estrone, estriol, E2, HDL, osteoporosis, platelet aggregation, GP IIb/IIIa, antiplatelet therapy, estrogen receptor Introduction Atherosclerosis can be caused by numerous factors such as age, risk factors, lifestyle, and diet. Both males and females share most of the classic risk factors for the development of cardiovascular disease (CVD). According to numerous studies, the onset of CVD in women lags roughly 10 years behind that of men [1]. These studies have also indicated that the pathophysiology of CVD in women by way of atherosclerosis is correlated with age and decreasing levels of the sex hormone estrogen seen in menopausal women [2]. Cardiovascular disease in women has strongly been associated with the loss of endogenous estradiol [1]. Due to the large number of women affected by CVD each year, increasing research has begun to deduce a possible mechanism by which estrogen might convey possible cardiovascular protection for women. However, hormone replacement therapy in large, randomized trials has failed to show any cardiovascular benefit unless it is started early [3, 4]. Hormone replacement therapy (HRT) in the form of conjugated equine estrogens (CEE) or synthetic conjugated estrogens have been around for numerous years to help alleviate the symptoms of menopause such as hot flashes, sleep disturbances, and mood lability. Research has also indicated a possible secondary benefit of HRT, namely the suppression of CVD in postmenopausal women. Basic science and Effects of estrogen and HRT on platelet activity discrepancy is not known. In fact, HRT reduces risk factors partially due to its beneficial effects on lipoproteins [5]. Figure 1. Flow diagram of articles selected for the review. animal studies have suggested that estrogen therapy could be beneficial. The female cynomolgus monkey has many reproductive characteristics similar to female humans such as a 28-day menstrual cycle with cyclic changes in plasma concentrations of estradiol, folliclestimulating hormone, luteinizing hormone, and progesterone and the occurrence of menopause. Compared to their male counterparts, premenopausal cynomolgus monkeys present significantly higher plasma concentrations of HDL cholesterol, much like premenopausal women. In addition, the likelihood of coronary artery atherosclerosis in male versus female monkeys is analogous to that of humans. When premenopausal female monkeys had oral contraceptives added to their experimental diet based on their body weight and caloric requirements, like humans, these monkeys had less atherosclerosis and a lower incidence of thrombosis. Postmenopausal monkeys receiving HRT did not have an increased incidence of arterial thrombosis compared to untreated controls. However, the effect of HRT in humans has been negative in protecting from cardiovascular events as mentioned earlier. The cause of this 34 The purpose of this review is to summarize the available literature regarding the effects of naturally occurring endogenous estrogen and the addition of exogenous estrogen on platelet activity in postmenopausal women which may explain the favorable cardiovascular effects seen with early estrogen replacement in post hoc analyses of large clinical trials. This paper will discuss in detail the mechanism of estrogen’s interaction with platelets and platelet receptors such as glycoprotein IIb/IIIa (GP IIb/IIIa) that can lead to decreased platelet activation and aggregation based on findings from basic science and clinical studies. Methods A review of the literature was performed by searching the PubMed database using the following keywords alone or in combination: “estrogen”, “hormone replacement therapy”, “platelets”, “cardiovascular disease”, “thromboembolism”, and “postmenopausal”. Inclusion criteria for this review consisted of peerreviewed articles published from January 1, 1993 to September 30, 2021 (Figure 1). Articles that were not in English and/or not relevant to the effects of HRT on platelet activity and cardiovascular health of postmenopausal women were excluded. Information was synthesized from 21 peer-reviewed articles, including previous literature reviews as well as experimental and observational studies, and key findings were extracted by the researchers (Tables 1 and 2). The role of platelet binding in cardiovascular disease Cardiovascular disease begins as atherosclerosis. Atherosclerosis is a process of accumula- Am J Blood Res 2022;12(1):33-42 Effects of estrog (...truncated)