Hormone Therapy, Demystified

Medically reviewed by Dr. Tamara Neuhaus MD

What do pulverized cow ovaries, pregnant women’s urine, and pregnant mare’s urine have in common? Aside from a certain ick factor, they all have been used at one time or another to treat perimenopause symptoms, in the form of Hormone Therapy. 

Ah, Hormone Therapy (HRT); possibly the most hotly contested topic in women’s health. The effectiveness of our current generation of HRT treatments (including many which are completely urine-free) isn’t in question. Evidence shows this stuff works. It’s the research on their role in preventing disease and their side-effects that has taken women, physicians and scientists on a veritable roller coaster ride for the past several decades. As a result, many women are afraid to consider HT—or over-cautiously advised against it—when they’re looking for relief from sometimes debilitating perimenopause symptoms. But a closer look at the data shows that depending on a woman’s age, symptoms, and health history, the benefits of responsibly prescribed HT may far outweigh its risks. Now, nothing sounds quite as boring as “a closer look at the data.” Not to worry; HRT’s story is far from boring. And you may be surprised by where it leads. 

Our Story Begins

The quest for a way to refill dwindling estrogen coffers began 120 years ago (enter pulverized cow ovaries). But it started to get interesting is in the 1960s. Doctors had been prescribing an FDA-approved drug called Premarin to treat hot flashes, mood swings, and other perimenopause symptoms for about twenty years—this is the one derived from pregnant mare’s urine (you can see it right there in its name: PREgnant MARe’s urINe). And the first hormonal birth control pill was starting to get traction. So HRT was successfully solving problems at both ends of the fertility timeline. Everybody was winning. 

Then a gynecologist—Dr. Robert A. Wilson—came along in 1966 and published a book called Feminine Forever. Citing an uncontrolled study of 304 women age 40-70, and funded by companies making HRT drugs, he asserted that hot flashes and mood swings were just the tip of HRT’s curative iceberg. He then proceeded to shame women in menopause, whom he described as “castrates,” into considering the therapy. Its benefits, he claimed, included preventing a woman’s sex organs from “shriveling” and making her “much more pleasant to live with” and less likely to become “dull and unattractive.” The book became a bestseller. 

If your mouth is hanging open right now, you’re probably not alone. Take the time you need to collect yourself.

Over the next nine years, estrogen sales doubled—tripled—quadrupled as doctors prescribed Premarin to their female patients in mid-life, for all manner of symptoms that may or may not be related to menopause. Then in 1975, new research surfaced saying that women who take estrogen have an increased risk of a type of uterine cancer called endometrial cancer. 

Boom. Women discontinued their estrogen use in droves, either at the advice of their doctors or on their own.

By the early 80s (think: shoulder pads and baggy jeans) scientists had found a way to protect the endometrium from the elevated cancer risk. And that was to combine progestin—a synthetic form of the body’s naturally occurring hormone, progesterone—and estrogen in HT. The most common combo prescribed was Premarin (for the estrogen) and Provera (for the progestin). So HT was back in good graces again. At the same time, reports started to come out pointing to other benefits of hormone therapy. The National Institutes of Health (NIH) issued a statement in 1984 saying that taking estrogen can reduce bone loss. Other research suggested that estrogen could even prevent cardiovascular disease (CVD). So women and doctors started to weigh the risks versus the benefits when considering HT.

The Plot Thickens

If that was the interesting part, here comes the really interesting part. The part that has contributed the most confusion to the HT debate. It centers around a massive study launched in 1993 called the Women's Health Initiative (WHI). WHI is still considered the gold standard of menopause research because of its scale (161,808 women). 

The very first thing you need to know about this study is that it was designed to evaluate whether hormone therapy (or dietary modifications or vitamin D and Calcium supplements) reduce the risk of age-related disease, particularly heart disease (a.k.a. CVD). It was not designed to see whether hormones helped treat menopause symptoms. 

Now, most women seeking HRT to treat their perimenopause symptoms are in their 40s and 50s. But since the WHI study was only interested in the prevention of age-related disease, the women it studied were significantly older. The average age of participants in the study was 63. And 63-year-olds tend to be more prone to age-related disease by nature of...their age. Unfortunately, the study extrapolated the results—which were not favorable—to all women, including healthy 40- to 50-year-olds looking for relief from headaches and hot flashes.

“As a result of this poorly designed study,” says Dr. Louann Brizendine, Neuropsychiatrist, author of the bestselling book, The Female Brain and advisor to The Cusp’s clinical team, “is that a generation of women has been deprived of a powerful and vital treatment option.”

Here’s how the WHI study went down. Women were separated into two groups: those with a uterus, and those without a uterus (post-hysterectomy). Women with a uterus took a combination of estrogen and progestin in the form of Premarin and Provera, called PremPro. Those without a uterus took estrogen (Premarin) alone—because if you don’t have a uterus, you don’t have an endometrium, so you can’t get endometrial cancer. The intent was to follow these women for 12 years to track the incidence of heart disease, bone fractures due to osteoporosis, and breast cancer. 

In 2002, WHI cut short the portion of the study looking at women with a uterus, taking both estrogen and progestin. Their data showed that the hormones did not protect against heart disease, and the study had surpassed the risk threshold for breast cancer. The other part of the study, looking at women without a uterus who were taking only estrogen, stopped short in 2004 because it exceeded the risk threshold for strokes.

Again, women and prescribing doctors were thrown into turmoil by these findings that painted HT as 1.) not helpful in preventing age-related disease (though that’s not what it was developed or being used for) and 2.) harmful. Interestingly, doctors were aware of the breast cancer risk prior to the WHI study, but it hadn’t stopped them from prescribing it. 

Here’s where we take that closer look at the data. And when we do, we see that it’s much more nuanced than what the media and many doctors shared. The results, it turns out, are quite different for younger women than for those over age 60. Specifically:

Women under 60, or within ten years of clinical menopause have

  • no increased risk of heart disease

  • a clinically insignificant increased risk of stroke

  • lower risk of diabetes if taking a combination of estrogen + progestin

  • no increased risk of breast cancer if only taking estrogen

  • lower overall risk of dying from anything

For women who are older than 60 

  • hormone therapy does not protect against the risk of heart disease

  • there is a slight increased risk for breast cancer if taking a combination of estrogen + progestin

  • there is a slight increased risk for strokes if taking only estrogen

“This is where the art of prescribing hormone therapy comes in,” says Dr. Mindy Goldman, Director of the Gynecology Center for Cancer Survivors and At-Risk Women Program at UCSF, and co-creator of The Cusp’s proprietary guidelines for natural and medical menopause treatment. “You need enough estrogen to address symptoms and just enough progesterone to protect the uterus but not have adverse effects on the breasts.” 

But Dr. Goldman points out that there’s even more complexity to the results than that. “In the years since both arms of the WHI study were cut short, researchers have found that the type of progestin prescribed for the participants—Provera—may have been more harmful than the bioidentical progestins like Prometrium and Crinone prescribed by most U.S. doctors today.” Recall, it’s the progestin that the WHI study linked to increased breast cancer risk. New studies that have been conducted since the WHI suggest that different progestins may have different risks. There also has been a move away from Premarin and toward Estradiol, which is a bioidentical estrogen derived from soy and yams. This is the hormone found in commonly prescribed medicines like Estrace, Vivelle, Vagifem and many others. In 2009, the NIH issued a statement saying that bioidentical hormones are associated with lower risks of breast cancer and cardiovascular disease, and are more effective than their synthetic and animal-derived counterparts.

Wait. Bioidentical? It’s easy to confuse the word “Bioidentical” with “Natural.” But they’re two different things. Bioidentical hormones are derived from plants (natural) and synthesized into hormones that are identical in molecular structure to the hormones human bodies produce. Premarin can also be considered natural, since it’s derived from pregnant mare’s urine. But its molecular structure is not identical to human estrogen. So it’s not a bioidentical hormone.

Epilogue...So Far

Today, hormone therapy is much more individualized and used mainly for treating symptoms as opposed to preventing disease. For women in perimenopause who still are menstruating, HRT often comes in the form of hormonal birth control pills. It works by taking the ovaries out of the driver’s seat when it comes to managing monthly hormonal cycles. It also has the added benefit for some women of preventing unplanned pregnancy.

For women who have reached clinical menopause (the one year anniversary of their last period), there are various forms of HRT that can be used. Studies suggest that Estrogen patches have a better safety profile because they’re absorbed into the skin. This means they bypass the GI tract and liver where they would be metabolized in ways that may lead to higher risks of blood clots, stroke, or cholesterol problems. “A lot of menopause experts feel like the most evidence-based way to practice is to prescribe transdermal formulations, like a patch or vaginal ring,” explains Dr. Goldman.

Meanwhile, the WHI study is still running, collecting self-reported data from the original participants, and monitoring their health outcomes. Updates come out every 5 years (the latest update in 2020 contains more good news) and to this day, the estrogen-only arm of the study still shows no increase in breast cancer risk.

Now, in August 2019 The Lancet published findings on how the type and timing of HRT impacts breast cancer risk. It used existing data from multiple studies, including WHI, to make its determination that all HRT types, except vaginal estrogens, were associated with increased breast cancer risks for women who started HRT in their 40s or 50s. And those risks were greater for estrogen-progestin combinations than estrogen-only preparations. This was different from the WHI study, where the estrogen-only arm of the study didn’t show an increased risk of breast cancer. But the Lancet study used data from many published and unpublished data sets, many of which were from years ago and used formulations of hormones that are not regularly prescribed now. They also relied on observational studies which are prone to bias. So, although this paper received a lot of press, it really didn’t provide new information and reinforced the “scare factor” of hormone therapy.

For doctors with a deeper understanding of the WHI study results, the generally accepted protocol is to prescribe the lowest effective dose, and transdermally when possible, for women in their 40s or 50s whose perimenopause symptoms are diminishing their quality of life. Women with a uterus are prescribed a combination of bioidentical estrogen and progesterone. Women without a uterus are prescribed bioidentical estrogen alone. For women over 60, most doctors agree that the risks of HRT—particularly, the risk of stroke—outweigh the benefits. The silver lining is that by age 60, many menopause symptoms are likely to have dissipated or gone away completely. 

The decision of whether or not to use hormone therapy to treat perimenopause symptoms is deeply personal. Even with all of the knowledge above, some women who would be candidates for HRT may still find the notion scary or uncomfortable. And if that’s you, you need to pay attention to that. The last thing you need right now is to add more discomfort to your life! For others, this knowledge may open the door to a science-based conversation about the topic with their doctor. If you fall into that camp, we strongly recommend consulting a doctor who specializes in menopause care and has taken a deep look into the WHI data. Candidly, not all gynecologists have. If you feel like you’re running into a brick wall, The Cusp’s clinical team of menopause experts is also here to help you weigh your many treatment options. None of which includes pulverized cow ovaries.

About Us

The Cusp provides personalized menopause care. Our doctors have deep expertise and a broad treatment toolkit, offering natural and medical therapies to help you feel better.