Menopausal HRT and Cardiovascular Disease

MENOPAUSAL HORMONE CHANGES ARE ASSOCIATED WITH INCREASED CARDIOVASCULAR DISEASE RISK 

Estrogen provides a protective effect against heart disease in women. It lowers blood pressure by increasing blood flow and dilating small arteries, improves cholesterol by lowering LDL and increasing HDL, protects against atherosclerosis, and even helps prevent low vitamin D levels and osteoporosis, two factors that are associated with an increase in cardiac events. It’s no wonder then, that during menopause when estrogen levels drop, a woman’s risk of cardiovascular disease increases. Remember that menopause is the cessation of ovarian hormone cycles and fertility in women that occurs anywhere from age 40-58, with the average age being 51.   

WHAT IS MENOPAUSAL HRT? 

Menopausal HRT is a collection of prescription hormone receptor agonists (synthetic or bioidentical hormones) used in menopause to reduce or eliminate symptoms of menopause.  It generally refers to the prescription of estrogens and progestogens , although other hormones are sometimes used in post-menopausal women. 

MHRT is not currently approved for the prevention or treatment of cardiovascular disease, but it is approved for the following: 

• Moderate to severe vasomotor symptoms (VMS) 
• Moderate to severe vulvovaginal symptoms: vaginal atrophy (VVA) and dyspareunia  
• Prevention of osteoporosis in postmenopausal women  
• Hypoestrogenism from hypogonadism, surgical menopause (bilateral oophorectomy), or premature ovarian insufficiency (POI) 

It is important to note that there are many forms of estrogens available: conjugated equine estrogens (CEEs), synthetic conjugated estrogens, esterified estrogens, synthetic ethinyl estradiol, and bioidentical estradiol (17β-estradiol; often simply referred to as E2). 

Likewise, there are many forms of progestogens available. Progestogen is an umbrella term that includes synthetic and bioidentical forms. Progestins are synthetic progestogens. Progesterone is a bioidentical progestogen. Progestogens are combined with estrogens in women with a uterus to reduce the risk of endometrial hyperplasia that occurs with estrogen. 

There are various contraindications to MHRT. The cardiovascular-related contraindications include history of: 

Venous thromboembolism (VTE), as seen with deep vein thrombosis (DVT) or pulmonary embolism (PE)  

• Stroke 
• Myocardial infarction (heart attack) 
• Coronary heart disease (CHD)  
• Blood clotting disorders 

It is interesting to note that there is some evidence that stroke, heart attack, and clotting risk is improved with estrogen therapy depending on the formulation, route of administration, and health of the patient. 

THE WOMEN’S HEALTH INITIATIVE 

The most prominent study on HRT is the Women’s Health Initiative (WHI). It was a randomized controlled trial (RCT) looking at women aged 50-79 . This study used only oral conjugated equine estrogens (CEEs) and oral synthetic progestin, medroxyprogesterone acetate (MPA). CEEs alone were used in women without a uterus and CEEs + MPA in women with a uterus . The study DID NOT use bioidentical estradiol (E2) or bioidentical progesterone. 

The initial interpretation of the WHI hurt the public perception of MHRT, as initial negative results were heavily publicized.  However, subsequent careful analysis demonstrated the WHI had many positive findings, especially for women aged 50-59 (the most common type of MHRT patient), and all cardiovascular risks were considered rare. For example, when combining the data from both oral CEE + MPA (average use 5.6 years) and oral CEE alone (average 7.2 years) groups after a median of 18 years follow-up, the WHI outcomes for women aged 50-59 found no increased CVD mortality, reduced coronary heart disease (CHD), and a reduction in all-cause mortality!  

Women aged 50-59 taking oral CEE had an increased incidence of VTE, however, and women taking oral CEE + MPA additionally had an increased incidence coronary heart disease (CHD) and stroke. As stated earlier, although these risks were identified, the risk increases remained “rare” at <10/10,000 women per year. Despite these incidents remaining in the “rare” category, subjects taking oral MPA, the synthetic progestin, had double the risk of VTE and significantly greater CVD risk than those who did not take MPA. Subsequently, oral MPA has been linked to increased thrombogenesis (increased clotting factors) where oral bioidentical progesterone has not. 

It is now over 20 years since the WHI, and continued follow-up and data analysis found that the MHRT used in the study has more health benefits than risks when initiating in women aged 50-59 or within 10 years of menopause. Combining the data from the WHI and other studies, it has been found that the oral route for estrogens and synthetic progestins are thrombogenic, and age as well as baseline health should be considered. Therefore, most major associations conclude that the rare risks identified may be mitigated by appropriate CVD screening and using safer formulations and routes of administration (e.g., transdermal E2 instead of oral CEE and bioidentical progesterone instead of MPA, which will be discussed next). 

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