Reading: The Truth About Hormone Therapy: Q&A with Dr. JoAnn Manson

About 85% of women experience menopausal symptoms like hot flashes, night sweats, and disrupted sleep, yet by their own admission, many doctors aren’t adequately trained to manage menopause or to discuss the benefits and risks of hormone therapy (HT)*, recognized by several professional medical societies as the most effective treatment for these symptoms. In fact, according to a Mayo Clinic survey from 2017, 20% of primary care medical residents reported not having received any lectures about menopause, and fewer than 10% felt prepared to manage patients going through it. 

Back in 2002, a report from the Women’s Health Initiative (WHI) that estrogen and progesterone therapy increased the risk of breast cancer, stroke, and coronary heart disease in menopausal women led many doctors to stop prescribing HT, in part because of misinterpretation of the study’s results.

“One of the repercussions of the anxiety and fear that arose after the WHI findings was that many training programs were no longer providing education in use of hormone therapy,” says JoAnn Manson, MD, chief of preventive medicine at Brigham and Women’s Hospital in Boston, professor of medicine at Harvard Medical School, and a lead investigator of the WHI. 

Long-term results from the WHI have recently confirmed that women under 60 can take HT to treat symptoms like hot flashes and night sweats without significantly increasing their risk of breast cancer and other diseases. But what about older women? 

Many doctors have remained reluctant to prescribe HT to women 60+, whose age alone puts them at increased risk for heart disease and breast cancer. There are still gaps in research on the safety of HT, particularly for extended durations of use and in women past the age of 65, notes Dr. Manson, though she says a study published last month in the journal Menopause took a step toward closing some of those gaps. The study, which examined the health impact of hormone use in 10 million women on Medicare, suggested that women beyond 65 can safely continue hormone therapy to treat menopausal symptoms. In fact, lower doses and certain formulations of HT were even shown to reduce the risk of heart disease, breast and other cancers, and even mortality. 

So who should — and who shouldn’t — use HT? CoveyClub recently caught up with Dr. Manson, who co-authored an editorial that accompanied the release of the Menopause study, to understand more.

(Interview has been edited for length.)

CoveyClub: The recent study in the journal Menopause on the health impact of hormone therapy in older women suggests that not only is it safe to continue HT in women past age 65, but that doing so may even confer health benefits. Can you discuss the significance of the findings? 

Dr. Manson: There is not a magic age at which hormone therapy needs to be discontinued, and many women are making the choice to continue HT well into their 60s. This study is important in providing information about the association between HT and health outcomes in women of 65 and older. Most of the women in this study would have started hormone therapy in earlier menopause and are taking it now past age 65 and the researchers are finding favorable associations [such as] not seeing increased risk of many of the chronic conditions but rather lower risks of many of the conditions that have been linked to hormone therapy in randomized trials. 

This was an observational study — large in sample size, but not a randomized, clinical trial — so there’s still potential for confounding by other factors. For example, the women who continue to take HT long-term are the women who remain free of adverse events on HT and are free of contraindications. These women are not developing blood clots, stroke, breast cancer, or other cancers. So it’s not that surprising that they tend to do well. It’s important to have more research on the continuation of HT among women into their 60s and past age 65.

[Whether to stay on HT] should be an individual and personalized decision, including shared decision making with the patient, and it will depend on whether the patient continues to have indications for hormone therapy such as symptoms like hot flashes, night sweats, or quality of life issues that are being helped by HT, and whether she continues to be free of contraindications (no prior history of blood clots in the legs or lungs, heart attack, stroke, or breast cancer) and continues to be interested in taking HT. 

CoveyClub: In your editorial, you claim that the underutilization of hormone therapy likely had negative consequences for many menopausal patients. What kind of negative consequences?

Dr. Manson: There could be risks of having disrupted sleep and really impaired quality of life for many years [plus] the stress that comes from that sleep disruption and that could be linked to increased risk for heart disease and other cardiovascular disease. Women who are having distressing hot flashes, night sweats, and disrupted sleep should be seeking treatment, whether it’s a low dose transdermal form of hormone therapy, oral HT, or a nonhormonal treatment. There are many new options … like lower doses transdermally, bioidentical hormones like estradiol and micronized progesterone [and also] nonhormonal treatments like SSRI, SNRI, antidepressants, gabapentin, and the recently FDA-approved fezolinetant. 

CoveyClub: You also mention in your editorial that major gaps persist in research on the safety of HT. What don’t we know? 

Dr. Manson: The WHI tested the most common formulation at the time of the study, in the early 1990s. We now have lower doses, and transdermal delivery of estrogen, and these lower doses and transdermal routes of delivery may be safer and may have a more favorable pattern of risks, but they haven’t been tested in large scale, randomized clinical trials. I think we need a lot more information on the risks and benefits of taking the more commonly used formulations now [of] transdermal, the patch, estradiol, and micronized progesterone. We need to understand the effects of longer duration outcomes. If a woman starts below the age of 60 or within 10 years of menopause onset and is doing well and continues to have symptoms, what is the benefit/risk ratio of continuing past 65? We need that information, as this new paper suggests and our editorial states.

“There is not a magic age at which hormone therapy needs to be discontinued…” — JoAnn Manson, MD

CoveyClub: Why has HT been so underutilized if most of the big organizations — The Menopause Society, The American College of Obstetricians and Gynecologists, the various professional associations of endocrinologists — recognize HT as the most effective treatment for menopause symptoms? 

Dr. Manson: One of the reasons is that training programs are not consistently providing education on menopause management, menopause symptom management, and the use of HT, [including] how to prescribe it [and] how to adjust dosing. Women around the country are having difficulty finding a clinician with the necessary expertise to discuss the benefits and risks of HT with patients. I get calls on a regular basis, like nearly every day, by a woman somewhere in this country asking for my help in finding a local clinician who has expertise in menopause management and can review treatment options for night sweats and hot flashes. Fortunately, the Menopause Society has a website where you can put in your zip code to find a menopause practitioner near you that has special training in menopause management. 

CoveyClub: Many women — and perhaps practitioners — believe that HT increases the risk of breast cancer and heart disease, but this study suggests that certain forms of HT, at least, actually significantly decrease these risks. What accounts for these seemingly contradictory findings? 

Dr. Manson: The goal of the WHI randomized trial was to assess whether hormone therapy should be used for the express purpose of trying to prevent heart disease, stroke, dementia, and other chronic disease. It was not designed to test whether women in their 40s and 50s should be given HT for bothersome or distressing hot flashes or night sweats. The results were extrapolated to women seeking relief from these symptoms even in early menopause, and many women were being denied HT for their menopausal symptoms. The WHI findings should never be used as a reason to deny hormone therapy to women in early menopause who are seeking relief from bothersome hot flashes, night sweats, or other menopausal symptoms leading to impaired quality of life. 

CoveyClub: Can you discuss the different types of HT, and the indications, health benefits, and risks of each? What is the most commonly prescribed formulation? 

Dr. Manson: The most commonly prescribed is estradiol, as opposed to what was tested in WHI (conjugated estrogen). Estradiol is virtually identical to what we make in our own bodies, so is considered bioidentical, and it’s FDA approved. The key point is that women should seek out the FDA-approved products, not the compounded products from compounding pharmacies that are not FDA regulated. Micronized progesterone is another bioidentical — again, similar to what we make — as opposed to the synthetic progestins tested in the WHI study. Micronized progesterone may be less likely to increase risk of breast cancer compared with MPA, the synthetic progestin that was tested in WHI and is in some medications. (Women who have not had a hysterectomy need a progesterone or some way to protect the uterus, as using estrogen alone in women with intact uterus can increase the risk of endometrial or uterine cancer.) There’s been a move to using lower dose and bioidentical formulations and using transdermal delivery for systemic estrogen, generally transdermal patch, spray, or gel, which is less likely to lead to blood clots. 

The vaginal application of low-dose estradiol or other estrogen is prescribed mostly for the genitourinary syndrome of menopause [which refers to] vaginal dryness, pain, or discomfort with sex, and there is minimal if any systemic absorption of the estrogen when given that way. There are different types, including creams [or] tablets that you insert into the vagina, and vaginal rings that slowly release estrogen. It should have fewer risks, but because it doesn’t get absorbed systemically, it’s not recommended for the treatment of hot flashes, night sweats, and other systemic symptoms.  

CoveyClub: Why does vaginal and transdermal administration lower risk of blood clots, whereas oral administration might increase risk? 

Dr. Manson: With the pill form, the medication goes more directly to the liver, where it increases the synthesis of clotting factors and can have adverse effects in terms of blood clotting. When given through skin, similar to hormones being produced by the ovaries, it doesn’t go directly to the liver like something you take by mouth. It is well known that the oral estrogen may be more likely to increase clotting factors made by the liver, and with randomized trials showing increased risk of blood clots with oral HT, there’s been this hope that using transdermal delivery could mitigate that risk. The observational studies support that, but there haven’t been large scale randomized trials. But the [transdermal formulations] still should be favored — especially in women who have risk factors for cardiovascular disease, including women with high blood pressure, high body mass index, and diabetes. Higher body mass index and metabolic syndrome are already risk factors for blood clots in the legs and lungs. You don’t want to exacerbate that by adding a medication that would increase that risk. 

“Women around the country are having difficulty finding a clinician with the necessary expertise to discuss the benefits and risks of HT with patients.” — JoAnn Manson, MD

CoveyClub: If, as this study suggests, certain types of HT are associated with a significant reduction in risk for several common cancers and certain types of heart disease — and even dementia — is there an argument for prescribing HT as a preventive treatment or at least to women at high risk for any of these diseases? 

 Dr. Manson: The WHI looked at a lot of different outcomes, and while some significant benefits were seen, it was still a pattern of benefits and risks that would not support use for prevention of chronic disease. I want to emphasize that the bar is set very high for medications used for prevention purposes. The risks need to be extremely low, because if there’s no clear indication for treatment, then many people using the medication may not get a clear benefit, but they’re still at risk for developing some of those adverse outcomes over time. If a medication is going to be used for long-term prevention, it has to have a very, very favorable risk/benefit profile. 

If HT is used for treatment, say, of moderate to severe hot flashes, and night sweats, there will be an immediate, clear benefit for relieving those symptoms and for improving quality of life, and those benefits are likely to outweigh the small risk of adverse events in women younger than 60. For blood clots and stroke, there is less than 1 extra case per 1,000 women using HT per year. 

In the randomized trials there has been an increased risk of blood clots and strokes, and when started late, an increased risk of dementia. These risks, although small, would offset the benefits among women without an indication for treatment such as bothersome symptoms.

There were benefits for lowering osteoporotic fracture and diabetes, but it’s a complex question whether to use it for fracture prevention. Some women may in fact be candidates if, let’s say, they can’t tolerate — or aren’t candidates for — other osteoporosis treatment, but it really has to be used long-term in order to prevent fractures, because once you stop the hormone therapy, there is rapid dissipation of bone benefits. So if you are treated with HT for decades into the 70s and older, with estrogen and progestin, there could be increased risk for breast cancer and stroke.

The conclusions that hormone therapy should not be used for prevention of heart disease, stroke, dementia and other chronic diseases have remained consistent over time. But HT still remains appropriate, starting before the age of 60 or within 10 years of onset of menopause, for treatments for hot flashes, night sweats, and other systemic symptoms that impact quality of life. If a woman asks should I start taking HT at age 70 to prevent heart disease, stroke, dementia or other chronic diseases, the answer to that is an unequivocal no. [Because] now she’s getting into an age group in which heart disease is a greater risk.

CoveyClub: So should women past age 60 — or past 10 years from starting menopause — not start HT?

Dr. Manson: The ages recommended for starting HT — below 60 and within 10 years of menopause onset — would tend to be the ages when women are most likely to have indications for treatments: symptoms such as moderate-to-severe hot flashes and night sweats and disrupted sleep. That’s when the benefit/risk profile is most favorable. The question being asked in the observational study is: What about continuing past 65? Do you need to stop, or can you continue? 

Generally, starting HT for the first time after 65 would not be recommended in most scenarios, though for those with symptoms, it may be reasonable, on an individual basis. If a woman has low risk for cardiovascular disease and breast cancer, and let’s say, a high risk of osteoporosis, there may be some women — on an individual basis, with personalized decision-making — for whom the benefits would outweigh the risks.

CoveyClub: Some women choose to go on HT as a sort of anti-aging treatment — to preserve sexual health, cognitive acuity, etc. Is there anything to this? 

Dr. Manson: Most professional organizations and clinical guidelines would not recommend starting HT after age 65 to slow the aging process. That is basically what the WHI tested. Use of HT for prevention of chronic disease is not really indicated. 

CoveyClub: What should women who are candidates for HT do if their practitioners write off their symptoms as being “a normal part of aging”?  Or if their practitioners do not offer HT? 

Dr. Manson: If a woman feels that her symptoms are being dismissed, and that she’s not getting answers to her questions or a discussion of options for improving her quality of life, she may want to seek an additional point of view. 

*Once widely referred to as hormone replacement therapy or HRT, hormone therapy or HT is now the more commonly used term to describe the administration of hormones to treat menopausal symptoms.