‘Early start is key to menopausal hormone therapy’

Treatment recommended within 10 years of menopause or before 60

Breast cancer and thrombosis risks may vary by progestogen

Menopausal hormone therapy (MHT) strategies are shifting toward an approach that comprehensively takes into account treatment timing, the characteristics of individual therapies and patient-specific risk factors.

Experts say it is important to initiate treatment relatively early after menopause and that patients who begin MHT at an appropriate time do not necessarily need to discontinue treatment solely because of age. Evidence also suggests that even among MHT regimens, breast cancer and cardiovascular safety profiles may vary depending on the type of progestogen used with estrogen.

Seong-wook Chun, Professor of Obstetrics and Gynecology at Inje University Haeundae Paik Hospital, presented the latest MHT treatment paradigms and guidelines at Abbott Korea’s Femoston Media Session in Seoul on Sept. 18.

Chun said, “Most recent global and Korean guidelines emphasize when treatment is initiated but are moving away from imposing a uniform limit on treatment duration. Starting treatment for the first time after age 65 requires caution, but a patient who has been receiving treatment since age 50 does not necessarily have to stop simply because she has turned 65.”

He added, “This does not apply to all hormone therapies. The benefits and risks can vary depending on the type and formulation of hormones, dose, route of administration, timing of treatment initiation and the progestogen used in combination.”

Overview of the Femoston media session.

Treating menopausal symptoms remains the primary goal…risks vary by timing

MHT is used to replace estrogen that declines with menopause and relieve vasomotor symptoms such as hot flashes and night sweats. It can also improve genitourinary symptoms associated with menopause and help prevent bone loss.

Because long-term estrogen monotherapy in women with a uterus can increase the risk of endometrial hyperplasia and endometrial cancer, a progestogen is generally administered together with estrogen.

Chun cited vasomotor symptoms, genitourinary syndrome of menopause (GSM), prevention and treatment of osteoporosis, and premature menopause as major indications for MHT. He explained that in clinical practice, however, the most common reason for treatment is to relieve menopausal symptoms severe enough to affect daily life.

Chun said, “Most women experience a range of symptoms after menopause, although their severity varies. The problem is that even when symptoms are severe enough to interfere with daily life, relatively few women actually consult a healthcare professional and receive treatment.”

Safety concerns surrounding MHT intensified following publication of the Women’s Health Initiative (WHI) study in 2002. The trial was stopped early after concerns emerged over coronary heart disease and breast cancer in the estrogen-plus-progestin group, leading to a sharp decline in MHT prescriptions worldwide.

However, as follow-up evidence accumulated, the so-called “timing hypothesis,” that the benefits and risks of treatment may differ depending on when therapy is initiated, gained traction.

Chun explained that atherosclerosis is often absent or still at an early stage shortly after menopause, whereas women who are many years beyond menopause are more likely to have established atherosclerosis.

Estrogen can have favorable cardiovascular effects, including lowering LDL cholesterol, but initiating hormone therapy after atherosclerotic plaques have already developed may produce different outcomes.

Chun said, “The average age of women enrolled in the WHI study was over 60, and many participants were already well past menopause. The concept is now well established that it is important to initiate treatment relatively early, such as within 10 years of menopause or before age 60.”

MHT is not, however, recommended specifically for the prevention of cardiovascular disease. The distinction is between initiating therapy at an appropriate time to treat menopausal symptoms and starting it for the first time many years after menopause.

Seong-wook Chun, Professor of Obstetrics and Gynecology at Inje University Haeundae Paik Hospital

Chun said, “The timing of treatment initiation matters. Starting MHT for the first time more than 10 years after menopause or after age 60 may increase risks, but patients who have continued treatment since shortly after menopause can maintain therapy based on their individual condition, including by lowering the dose or changing the formulation, rather than stopping solely because of age.”

The regulatory environment is also changing. The U.S. Food and Drug Administration (FDA) has moved to revise boxed warnings concerning cardiovascular disease, breast cancer, and dementia that have been applied to MHT products.

The previous approach of using “the lowest effective dose for the shortest duration” is also giving way to a more individualized strategy in which dose and treatment duration are adjusted based on symptoms, risk factors and treatment response.

MHT profiles differ by regimen…progestogen choice in focus

Differences among progestogens used with estrogen were another major focus of the session.

Femoston is a combination of estradiol and dydrogesterone. Sequential or continuous combined regimens can be selected depending on the stage of menopause and treatment needs, while multiple dose strengths allow treatment to be tailored to individual patients.

Chun stressed that progestogens should not be evaluated as a single, uniform drug class.

He said, “The risks of MHT can vary not only according to the type, dose, duration, route of administration and timing of treatment, but also according to which progestogen is used,” he said.

He noted that some observational studies have found relatively lower risks of breast cancer and venous thromboembolism with micronized progesterone or dydrogesterone, which are structurally closer to natural progesterone, compared with certain other synthetic progestogens.

The French E3N cohort study found differences in breast cancer risk depending on the progestogen combined with estrogen. Estrogen plus dydrogesterone was associated with a relatively lower risk than combinations involving some other synthetic progestogens.

Abbott Korea also presented findings from a study using a U.K primary care database. In the analysis, estradiol/dydrogesterone was not associated with an increase in cardiovascular events such as myocardial infarction, thrombotic stroke and venous thromboembolism compared with some other MHT regimens.

Also, a study using Korean real-world clinical data was presented, showing differences in cardiovascular outcomes according to the type of progestogen used.

However, most of these findings are based on observational studies rather than randomized controlled trials, meaning it cannot be concluded that a specific ingredient directly reduces the risk of breast cancer or cardiovascular disease.

Abbott Korea said, “The observational findings should not be interpreted as showing that dydrogesterone prevents disease, but rather as evidence that safety profiles may differ according to the characteristics of individual progestogens.”

Femoston is used to relieve menopausal symptoms and prevent bone loss. In sequential combined therapy, dydrogesterone is added after estradiol has been administered for a specified period, while continuous combined therapy involves taking both ingredients every day.

Abbott also presented clinical evidence related to the prevention of bone mineral density loss as well as vasomotor symptoms including hot flashes and night sweats. Both sequential and continuous regimens have been shown to suppress bone loss or improve bone mineral density in the lumbar spine and hip in postmenopausal women, the company said.

Chon said MHT is likely to evolve toward a more individualized approach rather than applying the same criteria to all postmenopausal women.

He said, “A patient’s symptoms, stage of menopause, health status and risk factors all need to be considered together. The question is moving beyond whether or not to use MHT to determining who should receive it, when it should be started, and which therapy and dose should be selected.”