Women's Hormone Replacement Therapy, What Are the Risks?

By: Zachary Lott

12/11/2023

Where does the fear stem from?

Women's Hormone replacement therapy (HRT)  is widely misunderstood by both healthcare providers and healthcare consumers alike. Much of this misunderstanding stems from a research study that was conducted about 20 years ago called the Women’s Health Initiative (WHI). In the WHI Hormone Trials, postmenopausal women were enrolled in a research study that investigated the use of non-isomolecular, commonly referred to as “synthetic” hormones. The term non-isomolecular literally means non, same, molecule. The two hormones investigated in the study were conjugated equine estrogens (CEE or Premarin) and medroxyprogesterone acetate (Provera). Now, the drug name Premarin stems from a combination of words: Pre (PREgnant), mar (MARe or horse), and in (urINe) - Pregnant horse urine - the drug is primarily hormones derived from the urine of pregnant horses. Medroxyprogesterone acetate sounds a lot like progesterone, but it unfortunately does not act enough like the hormone progesterone in the body. To sum up the WHI study, women who were typically less than 10 years in to menopause did generally well and a reevaluation of the trial data showed some possible benefit that included a 22% reduction in incidence of breast cancer, in those woman diagnosed with breast cancer while on hormone; and a greater than 40% reduction in mortality. Now, when the drug Provera was added in to the story, that’s when things became more dangerous and the study was halted for safety reasons because of an increase in risks such as breast cancer, heart attacks, vascular dementia, and blood clots.

What does the “bioidentical” hormone replacement therapy research show?

Subsequent research, that has investigated the use of isomolecular (same-molecule), also referred to as “bioidentical,” hormones, such as oral estradiol and oral micronized progesterone, have shown safety, efficacy, and even benefit. The following is a list of resources that I often reference regarding HRT:

CORA (Coronary Risk Factors for Atherosclerosis) - this study showed that hormone replacement therapy (HRT) may be beneficial, and is NOT associated with an increased risk for coronary heart disease (CHD). This study also showed that oral estradiol did not increase the risk of blood clots. 

DOPS (Danish Osteoporosis Prevention Study) - This study showed a reduction in cardiovascular disease (CVD) with oral estradiol, this was one of the longest high-level studies looking at oral estradiol to date and lasted more than 10 years. This also showed no increased risk of blood clots.

ELITE (Early vs Late Intervention Trial with oral Estradiol) - This study showed that treating women with hormones early after menopause, rather than later, provided better cardiovascular protection as evidenced by a reduction in atherosclerosis (plaque in the arteries). This also showed a positive safety profile with oral estradiol.

EPAT (Estrogen in the Prevention of Atherosclerosis Trial) - This study looked at the effects of 1 mg oral estradiol, it showed that it was safe, caused no increase in blood clots, but the most significant finding was the reduction in carotid intima-media thickness (CIMT), this is the thickness of the lining of the blood vessels. In other terms, oral estradiol at just 1 mg/day decreased arterial age.

EPIC (The European Prospective Investigation into Cancer and Nutrition) - This is a broad ongoing study since 1993, the significant finding for women was that oral micronized progesterone (‘bioidentical’ progesterone) is safer than Provera regarding breast cancer. 

ESTHER (Estrogen and Thromboembolism Risk) - This was an observational trial so it shows less reliable results than some of the others above but still gives us favorable data. This study looked at oral estradiol, versus transdermal (cream or patch) estradiol, with blood clot risk. The study also looked at micronized progesterone. The study showed that any increase in blood clot incidence was attributable to an increased body mass index (BMI). The study also showed that micronized progesterone does not increase blood clots.

PEPI (Postmenopausal Estrogen/Progestin Interventions Trial) - This study looked at a number of different things regarding different hormone treatment regimens’ effects on the female body but what I thought was important to pull from this study is that oral estradiol decreases CVD risk. 

WEST (Women’s Estrogen for Stroke Trial) - This study looked at HRT and stroke. After 3 years on 1 mg of oral estradiol alone, there was no increased risk for stroke, blood clots, or breast cancer. There was interestingly a significant reduction in the incidence of Alzheimer’s disease.

Summary of hormone replacement therapy for women

There are 8 reliable research studies above, using “bioidentical” hormones that show a reduction in many types of health risk that women fear most. But; most importantly, these studies demonstrate safety with hormone replacement therapy for women. The greatest aspect of HRT for women, that is not demonstrated in this research, is the profound impact that HRT can have on a woman’s quality of life. 

According to the North American Menopause Society (NAMS), hormone replacement therapy (HRT) “remains the most effective treatment” for hot flashes, night sweats, and the genitourinary syndrome of menopause (GSM [e.g., vulvovaginal atrophy, dryness, irritation, painful intercourse, urgency and urinary tract infections]), and has been shown to prevent bone loss and fractures. Women’s hormone replacement therapy “treatment should be individualized to identify the most appropriate type, dose, formulation, route of administration, and duration of use, using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of the benefits and risks of continuing or discontinuing.”

If you have questions or concerns about women's hormone replacement therapy please contact our of fice to see if we can help answer your questions. 

*All information subject to change. Images may contain models. Individual results are not guaranteed and may vary.