North American Menopause Society

North American Menopause Society


Kling JM. S-13. Presented at: North American Menopause Society Annual Meeting; Sept. 22-25, 2021 (hybrid meeting).

Disclosures: Kling reports receiving consultant fees from Procter & Gamble.
September 30, 2021
4 min read

Consider benefits, risks when prescribing menopausal hormone therapy


Kling JM. S-13. Presented at: North American Menopause Society Annual Meeting; Sept. 22-25, 2021 (hybrid meeting).

Disclosures: Kling reports receiving consultant fees from Procter & Gamble.
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Menopausal hormone therapy is safe and effective for many women experiencing bothersome symptoms like hot flashes, but treatment should be individualized for people with certain risk factors, according to a speaker.

“Our patients are coming to see us, and they just want to feel better,” Juliana M. Kling, MD, MPH, NCMP, FACP, associate professor of medicine and chair of the division of women’s health internal medicine at Mayo Clinic Arizona, said during a plenary presentation at the North American Menopause Society annual meeting. “But they also bring with them the myths, the misinformation they heard from a friend, from television or from Twitter about hormones and menopause. Our goal is to work through shared decision-making to find a plan that is safe and effective.”

Kling is an associate professor of medicine and chair of the division of women’s health internal medicine at Mayo Clinic Arizona.

Most guidelines now state that for women younger than 60 years within 10 years of their last menstrual cycle, the benefits of menopausal HT outweigh the risks, Kling said. Vasomotor symptoms can last on average from 7 to 10 years and can effectively be treated with HT; however, there are challenges when women also have chronic comorbidities.

“When you recognize that 80% of women over 55 have at least one chronic medical condition, that is where it starts to get tricky,” Kling said.

CV considerations

On July 9, 2002, investigators leading the landmark Women’s Health Initiative study closed the estrogen and progestin arm early after researchers observed an increased risk for invasive breast cancer, as well as increases in coronary heart disease, stroke and pulmonary embolism in the HT group compared with placebo.

“That caused a lot of smart scientists and clinicians to scratch their heads,” Kling said. “Isn’t menopausal HT good for the heart?”

Menopause represents a period of increasing risk for CVD and declining endothelial function for women, Kling said. Animal models and observational studies show menopausal HT reduced CVD incidence and all-cause mortality by nearly half among postmenopausal women, and estrogens improve a wide variety of known and suspected risk factors for atherosclerosis, she said.

Explaining the “timing hypothesis,” Kling said researchers found that risks that may accompany menopausal HT have to do with the timing of initiation of hormones. If initiating HT early — at age 60 years or younger or less than 10 years after the final menstrual period — risks are low. If initiating HT later, as was done in the WHI, risks are higher.

“Indeed, when you look at the 18-year follow-up from the WHI, sub-analyzed by age category, women between the ages of 50 to 59 years started on HT had lower all-cause mortality, CV mortality and cancer mortality vs. women given placebo,” Kling said. “[Data are] similar when you combine other studies in meta-analyses. ... Women starting HT early had reduced coronary heart disease risk and reductions in all-cause mortality compared with placebo.”

For women with hypertension, current evidence supports no significant deleterious effect of HT on blood pressure. Oral estrogen has also been shown to decrease LDL cholesterol and triglycerides and increase HDL cholesterol levels.

However, for women with obesity, type 2 diabetes or other risk factors, Kling recommended ordering a lipid panel and calculating atherosclerotic CVD risk.

“If her risk is above 10%, then you want to focus on shared decision-making to pick the safest option,” Kling said. “You may also want to consider a test like coronary artery calcium score to see if she has existing plaque.”

Cognitive concerns

When prescribed early in menopause, HT most likely does not increase risk for dementia, Kling said, though women may express such concerns to their health care provider.

In the WHI Memory study, researchers observed an increased risk for dementia for women started on HT older than 65 years.

In three randomized controlled trials assessing women early in menopause — the Kronos Early Estrogen Prevention Study (KEEPS), the Early vs. Late Intervention Trial with Estradiol (ELITE) study, and the WHI Memory Study of Younger Women — menopausal HT did not cause deleterious effects on cognition when assessed, on average, 4, 5 and 7.2 years after the trials, respectively, Kling said.

“There is no randomized controlled data that supports this similar timing hypothesis or critical window hypothesis, but there are prospective studies that do suggest [timing] may be the issue,” Kling said. “In KEEPS, researchers found that women on transdermal estradiol had less amyloid-beta plaque deposition in their brain, particularly among high-risk women who were APOE e4 carriers, compared with those receiving placebo, so there may be something there.”

Breast cancer data ‘complicated’

Differences in risk for breast cancer with menopausal HT are likely based on many things, including the type, formulation and route of HT administration, Kling said.

“Oftentimes in medicine, we present things as black and white, good or bad, such as that all hormones are bad for breast cancer risk, but in fact, that is not the case,” Kling said. “It turns out the relationship of menopausal HT and breast cancer is complicated.”

Risks for women can vary between estrogen therapy vs. estrogen plus progestin, or oral conjugated equine estrogen combined with bazedoxifene, which is a tissue-selective estrogen modulator like tamoxifen, Kling said.

WHI findings show women who had a hysterectomy and were given estrogen alone had less breast cancer risk and lower breast cancer mortality if they did develop breast cancer compared with placebo.

Women on both oral conjugated equine estrogen and medroxyprogesterone acetate did have a higher risk for breast cancer, but there was no significant difference in breast cancer mortality.

“Breast cancer risk for women on combined therapy was rare, less than one additional case per 1,000 years of use,” Kling said. “It is less than the risk of two glasses of wine per day, or similar to risk with obesity or a sedentary lifestyle. I share that with you so you can reassure your patients. If she is having significant symptoms that the benefit of HT will outweigh the risks, she can implement everyday lifestyle habits to help reduce her risk for breast cancer in conjunction with HT.”

Individualize treatment

The Hormone Therapy Position Statement, issued by NAMS in 2017, provides evidence-based and current best clinical practice recommendations for HT use in menopause and is helpful to address misconception about HT with patients, Kling said.

“It is important to let [patients] know that HT is the most effective treatment for vasomotor symptoms of menopause. Understanding the risks and benefits of HT by organ and system will allow us to counsel our patients appropriately. Overall, the benefits of HT in healthy, symptomatic women generally outweigh the risk under age 60 years for most women.”


NAMS 2017 Hormone Therapy Position Statement Advisory Panel. Menopause. 2017;doi:10.1097/GME.0000000000000921.