Hormone Therapy + Menopause: How an Effective Treatment Got a Bad Rap

Medically reviewed by Dr. Mindy Goldman MD

At the Cusp, we want to make sure our clients have the straight scoop on the most effective treatments for managing their menopause. Some of the most common—and most vexing—symptoms of this transition are hot flashes/night sweats, mood changes, and brain fog (a groggy, slow-motion state of mind that feels not unlike a reaction to allergy meds). While there are a lot of treatment options available for each of these, by far, the most effective treatment for all of them together is hormone therapy (HRT). So why aren’t more women choosing it?

Unfortunately, HRT got a bad rap over the years, thanks to the media’s skewed reporting on the results of a massive hormone study called The Women’s Health Initiative (WHI)1. And because of the resulting press, many women developed strong opinions about it. But in the medical community, the controversies over HRT are not so much about its use for treating peri/menopause symptoms, but more about its role in disease prevention—especially heart disease. 

Where did all the controversy come from?  

It started when scientists started looking at cardiac outcomes in various studies that were collecting medical data. These are called “observational” studies, as they’re just measuring outcomes, not attempting to affect them with a treatment. In this case, the scientists started seeing a correlation between HRT and a lower incidence of heart disease. Based on that correlation, by the 1980s and 90s doctors started encouraging women with risk factors for heart disease—hypertension, obesity, smoking—to consider HRT after they reached menopause (the 1-year anniversary of their last period). 

Then in the 1990s, the first quality studies came out, looking at women who had already had a cardiac event to see if HRT prevented a secondary cardiac event. Results showed that it did not2. But scientists still wanted to know if HRT prevented heart disease in the first place in healthy postmenopausal women.

That’s the question that led to the WHI.1 This study, which started in 1993, is considered the “gold standard” of all hormone studies. It was a huge randomized controlled trial (RCT), enrolling over 161,000 women between the ages of 50-79. RCTs are studies that randomly place participants into different treatment groups, and give one group an intervention (e.g. hormone therapy) and the other group a placebo. Then the outcomes between the two groups are compared.

One the many questions WHI was hoping to answer was whether the use of HRT protected against heart disease in healthy, postmenopausal women. For this portion of the trial, they looked at 27,347 women. Of these, 10,739 women had undergone a hysterectomy and were randomized to receive either estrogen (E) alone or a placebo. The other 16,608 women still had a uterus and were randomized to receive either a combination of estrogen and progestin (E+P) or a placebo. 

Why the two different interventions? Generally, estrogen is the component of HRT that eases menopause symptoms like hot flashes and night sweats. But in the 1980s, scientists discovered that taking estrogen alone increases the risk of uterine cancer. So women who still have their uterus need to take some form of progestin along with the estrogen to protect their uterus. But women who have had a hysterectomy can take estrogen alone, because there’s no uterus to protect.

Now, there are two important details about this study that it’s crucial to keep in mind when looking at the data: 

The Hormones Prescribed

The type of estrogen prescribed in the study was conjugated equine estrogen (trade name: Premarin). The progestin included medroxyprogesterone acetate (trade name: Prempro), a synthetic product that acts like progesterone.

These hormones were used because they were the most commonly prescribed types in those days. Also, the drug company that made them helped sponsor the study, because they anticipated finding a positive benefit with respect to heart disease. The important bit is that these are not bioidentical hormones, like the types of hormones prescribed by knowledgeable doctors today, such as Vivelle and Climera patches and micronized progesterone. 

The Age of Participants

Since the WHI was looking at heart disease as the major outcome, they chose to look at an older population, with an average age of 63. But the average age of menopause is 51, and typically the women asking for hormones to treat their hot flashes are in their 40’s and 50’s, not their 60’s. 

The WHI study was scheduled to continue until 2005, but the E+P (Prempro) arm of the study was stopped short in 2002, when results showed that it didn’t protect against heart disease and increased the risk of breast cancer3. The E (Premarin) arm of the study did not find an increased risk of breast cancer, but stopped in 2004, when results showed that it did not protect against heart disease and it increased the risk of stroke4.

Because of these findings and the onslaught of negative press they generated, many women stopped their HRT5, worried that the risks of HRT were greater than the benefits of relief from their menopausal symptoms.

We’ve learned many things since the original publication of the WHI—one of the most important being that the findings from the study differ depending on the age of the women studied.

Only 10% of subjects in the WHI were under 60. And of those women, the ones who took estrogen alone showed a lower risk of heart disease3. The ones who took estrogen + progestin showed a slightly higher risk of heart disease (2.5 women per 1000)3, which may have been related to the form of progestin used. Both E and E+P were associated with a lower risk of all-cause mortality. 

But for women in the study who were older than age 60, the results were different. In that group, E+P was found to significantly increase the risk of heart disease. But still, E alone did not6. So, you can see that the original published results that got all the press attention were not telling the whole story. 

Since the WHI was published, some study participants have agreed to be followed in extension studies from 2005-2010 and from 2010-2020. The data from the WHI has been evaluated in many different ways, and there are more than 1400 articles that have been published in the medical literature that pertain to these original studies! 

WHI Results Show that Timing is Key

Currently, in 2020, it’s generally accepted in the medical community that there’s a “timing hypothesis” when it comes to the use of hormone therapy. For women over age 60, long-term hormone therapy has more risks than benefits. But for women under age 60, the benefits may outweigh any of the risks. Though long-term use of E+P may increase the risk of breast cancer by 3 cases per 1000 women taking the medication over 5 years.  

So, where does this leave you? If you’re under the age of 60 and having significant symptoms like hot flashes/night sweats, mood changes, and brain fog, and they disrupt your quality of life, HRT is the most effective treatment. And it may provide health benefits, including lower risks of bone loss, diabetes, and all-cause mortality, as well as lower risk of heart disease, if you’re taking estrogen alone. But all drugs have risks and benefits. It’s important to discuss your own personal risks with a menopause specialist when making decisions about the use of HRT.

Sources

1. Design of the Women’s Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group. Control. Clin. Trials 19, 61–109 (1998)

2. Grady, D. et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 288, 49–57 (2002)

3. Manson, J. E. et al. Estrogen plus progestin and the risk of coronary heart disease. N. Engl. J. Med. 349, 523–534 (2003)

4. Anderson, G. L. et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 291, 1701–1712 (2004)

5. Landmark trial overstated HRT risk for younger women | CMAJ News

6. Rossouw, J. E. et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 297, 1465–1477 (2007)

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