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Is Hormone Replacement Safe?

Dr. Adrian Nasager
10 April 2016

Is Hormone Replacement Safe? - A Review

by Adrian Nasager, ND

304 Cole Road,
Guelph Ontario
N1G 3J2

Is Hormone Replacement Safe? - A Review


Every woman—if she lives long enough—will experience menopause. For some, the transition is easy and can even be a relief from the troubles of a regular menstrual cycle. For others, the change is extremely challenging as they struggle to manage frequent “hot flashes,” weight gain, and severe depression. Many of the symptoms of menopause can be directly related to the decreased production of sex hormones— specifically estrogen and progesterone. It seems reasonable that returning these hormones to premenopausal levels should—and often does—reverse the symptoms and lead to a sense of general wellbeing. However, serious concerns about the safety of hormone replacement therapy (HRT), such as the risk of cancers and cardiovascular disease, are justified. Over the past 10 years, new research has led to major changes in the prescription of conventional hormone replacement therapy. Although many women could benefit from the safe use of bioidentical hormone replacement therapy (BHRT), concerns about safety are often a major reason for refusing treatment. This article will demystify the issues of safety around BHRT, and empower women to make educated and informed choices about whether or not hormone therapy is right for them.

What are Bioidentical Hormones?

The term “bioidentical hormone” refers to a supplemental hormone that has the exact chemical structure of human hormones. While there are several bioidentical hormones (such as levothyroxine and insulin) in use, the term most often refers to sex hormones like estrogens, progesterone, and testosterone.

Are Bioidentical Hormones Natural?

Yes and no. Bioidentical hormones are natural in that they are familiar to our bodies and they behave the same way in the body that our own endogenous hormones do. They are unnatural in that they are synthesized outside of our bodies, often from natural precursors like Dioscorea (wild yam). While in most cases, natural is better, there are some exceptions, and I believe BHRT is one such exception. There is a form of estrogen that is not synthesized in a laboratory: it is made by another living being—pregnant horses. The drug Premarin, which was one of the first hormone replacements on the market, is a derivative of pregnant mare urine—hence the name Pre-mar-in! Some might say that this is a more natural form of estrogen replacement and, historically, some doctors have prescribed it for that reason. Regardless of its organic origin, horse estrogen is very different from human estrogen. You don’t need to be a biochemist to see the difference:

Premarin Ethinyl Estradiol Estradiol

The same is true of synthetic forms of estrogen like ethinyl estradiol (EE; right). While ethinyl estradiol behaves somewhat like estrogen, it too has a different chemical structure…

The reason for this is simple; estrogens are actually a class of hormones with similar effects but very different strengths. Consider estradiol and estriol, two human estrogens. Estradiol is more potent than estriol and stimulates the growth of some estrogensensitive tumours, whereas estriol does not increase the risk of breast or uterine cancers.[1]

Hormone Replacement and Cancer Risk Hormone Replacement and Cancer Risk

You may have heard that hormone replacement can increase your risk of breast cancer or cervical cancer. It is true that estrogens, even bioidentical ones, if given improperly, can increase a woman’s risk for breast, endometrial, and cervical cancer. That is because estrogens cause breast, uterine, and cervical tissue to proliferate or grow. Not all estrogens do this to the same extent. While HRT with estradiol alone can increase breast cancer risk by 30%, estriol does not increase this risk. According to an observational study, women with the highest estriol levels had 58% less risk of breast cancer than those with the lowest levels; this suggests that higher levels of estriol may be important for preventing breast cancer. There are two distinct estrogen receptors that estrogen hormones bind on breast cells.[2] This is because estriol binds primarily to different (beta) estrogen receptor in the breast, which inhibits proliferation and cancer development.[3–6]

Fortunately, we have yet another hormone that protects these tissues from the proliferative effects of estrogen: progesterone. The reputation of bioidentical progesterone suffers from the same confusion as estrogens when it comes to natural v. synthetic. The irony is that while natural progesterone has been shown to protect women from breast cancer, progestins (synthetic progesterone) can actually increase this risk more than estrogen alone. A large study of hormone replacement therapy (HRT) in menopausal women showed a highly significant (69%) increased risk of breast cancer in those who used estrogen in combination with synthetic progestins when compared to women who had never used HRT.[7] Numbers like this are obviously concerning to any woman considering HRT for relief of menopausal symptoms. However, for women who used bioidentical progesterone with estrogen, the increased risk of breast cancer was completely eliminated. That is to say HRT that used bioidentical estradiol and bioidentical progesterone had the same risk has no HRT!

Progesterone A progestin
Hormone Replacement and Cardiovascular Health

What about the effects of HRT on heart health? In a landmark trial called the Women’s Health Initiative, researchers reported that adding a synthetic progestin to nonbioidentical estrogen therapy resulted in a substantial increase (about 24%) in the risk of heart attack and stroke in postmenopausal women.[8] Conversely, several trials on bioidentical progesterone have proven it to have beneficial effects on cardiovascular health. One of the clearest demonstrations of the safety of bioidentical hormones is a study that showed women given bioidentical progesterone for only 10 days performed substantially better on an exercise stress test (a standard test used to measure risk of heart disease) than women on progestins. The same women had better blood flow to their heart during the test.[9]

Estrogen and Blood clots

The risk of a blood clot is a serious concern with the use of conventional estrogen replacement therapy, especially when taken orally.[10] In 2007, The ESTHER study clearly showed an astounding 290% increase in risk of blood clots or venous thrombosis in postmenopausal women taking a combination of synthetic estrogen (EE) and progestin (MPA) v. no HRT. This results should not be surprising, considering that women often have a lighter menstrual period when on progestin-containing oral contraceptive, and the risk of blood clots in OCP have been previously demonstrated. This increased risk of blood clots likely accounts for much of the cardiovascular risk. Again, this seems like a major deterrent for using HRT to control menopausal symptoms. Fortunately, much of the risk of blood clots can be minimized by delivering bioidentical estrogen through the skin as opposed to orally. Adding an appropriate dose of bioidentical progesterone results in 30% less risk than women who had never been on HRT! This led the authors to conclude that “transdermal estrogen combined with micronized progesterone is safe” for blood clots.[10]

Why all of the Confusion? Why all of the Confusion?

Part of the problem is that many studies use imprecise language in reporting their methods. They often inaccurately refer to synthetic progestins as “progesterone,” and synthetic estrogen derivatives as “estrogen.” Furthermore, when analysing multiple trials, they combine all trials that study “hormone replacement therapy,” without differentiating what type of HRT; this would be the same as looking at the safety of “pain killers” without differentiating between Tylenol, aspirin, and morphine. By now, it should be clear that not all hormones are created equally and that, with regards to safety, different hormones can have very different effects.

Are There Effective Alternatives?

Even after all of this research, some women are still concerned about the risk of hormone replacement. It is especially understandable for women with a strong risk of estrogenpositive cancers or those with a history of endometriosis or fibrocystic breasts. There are, of course, nonhormonal alternatives to managing the symptoms of menopause. For example, isoflavones from soy or red clover have been shown to reduce hot flashes and protect bones from postmenopausal osteoporosis. A specific extract of rhubarb is available which predominantly binds to the estrogen beta receptor. Although the safety of these agents has been less studied than hormone therapies, they may provide a more reassuring alternative for some women.


Bioidentical hormone replacement offers woman a safe and effective means of managing menopausal symptoms. The risks of breast, cervical, and endometrial cancer associated with conventional HRT are not present when bioidentical hormones are properly prescribed. Heart disease can actually be reduced with appropriate use of bioidentical hormones, as opposed to being increased with conventional HRT. Some naturopathic doctors in Ontario are trained and licenced to prescribe bioidentical hormones and can discuss all of the options for managing the symptoms of menopause.