Is there a time limit for systemic menopausal hormone therapy?

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Compared with estrogen-progestin therapy, estrogen-only therapy has a more favorable risk profile in terms of coronary heart disease and breast cancer, although stroke risk remains elevated in users of conjugated equine estrogen with or without medroxyprogesterone acetate.

There is limited evidence directly comparing different formulations of hormone therapy, although they all effectively treat vasomotor symptoms.1

Oral vs transdermal formulations

Canonico et al,21 in a meta-analysis of observational studies, found that oral estrogen was associated with a higher risk of venous thromboembolism than transdermal estrogen:

  • Relative risk with oral estrogen 2.5, 95% CI 1.9–3.4
  • Relative risk with transdermal estrogen 1.2, 95% CI 0.9–1.7.

The Estrogen and Thromboembolism Risk (ESTHER) study22 was a multicenter case-control study of women ages 45 to 70 that assessed risk of venous thromboembolism in oral vs transdermal estrogen users. Compared with women not taking hormone therapy, current users of oral estrogen had a significantly higher risk of venous thromboembolism, while transdermal estrogen users did not:

  • Odds ratio with oral estrogen 4.2, 95% CI 1.5–11.6
  • Odds ratio with transdermal estrogen 0.9, 95% CI 0.4–2.1.

The Kronos Early Estrogen Prevention Study (KEEPS)23 did not support these findings. This 4-year randomized controlled trial, published in 2014, was designed to assess the risk of atherosclerosis progression with early menopause initiation of placebo vs low-dose oral hormone therapy (conjugated equine estrogen 0.45 mg daily with cyclical micronized progesterone) or transdermal hormone therapy (estradiol 50 µg/week with cyclical micronized progesterone).

In the 727 women in the study, there was one transient ischemic attack in the oral hormone therapy group, one unconfirmed stroke in the transdermal hormone therapy group, and one case of venous thromboembolism in each group, findings that were underpowered for statistical significance. Both oral and transdermal hormonal therapy had neutral effects on atherosclerosis progression, as assessed by arterial imaging. Transdermal hormone therapy was associated with improvements in markers of insulin resistance and was not associated with an increase in triglycerides, C-reactive protein, or sex hormone-binding globulin, as would be expected with transdermal circumvention of the first-pass hepatic effect.


The most effective treatment for vasomotor symptoms in women at any age is hormone therapy, and the benefits are more likely to outweigh risks when initiated before age 60 or within 10 years of menopause.7 The Women’s Health Initiative randomized study was limited to 5.6 to 7.2 years of hormone therapy (13 years of cumulative follow-up), and the Danish Osteoporosis Study was limited to 11 years of use (16 years cumulative follow-up).

The coronary heart disease outcomes for longer durations of therapy remain uncertain. There is a small but statistically significant increased risk of stroke and venous thromboembolism with oral hormone therapy, and breast cancer risk is associated with long-term estrogen-progestin use.

Patients on hormone therapy should be evaluated annually regarding the need for ongoing therapy. Persistent moderate-severe vasomotor symptoms, quality of life benefits of hormone therapy, contraindications to its use (Table 2), and patient preference need to be assessed as well as baseline risks of cardiovascular disease, breast cancer, and fracture.

Risk calculators may facilitate the shared decision-making process. Examples are:

  • The Gail model for breast cancer risk26 (
  • MenoPro, a menopause decision-support algorithm and companion mobile app developed by NAMS to help direct treatment decisions based on the 10-year risk of atherosclerotic cardiovascular disease (
    The discussion of the risks of hormone therapy with patients should incorporate the perspective of absolute risk. For example, a woman wishing to continue estrogen-progestin therapy should be told that the Women’s Health Initiative data suggest that, after 5 years of use, breast cancer risk may be increased by 8 additional cases per 10,000 users per year. According to the World Health Organization, this magnitude of risk is defined as rare (less than 1 event per 1,000 women).28

A strategy of prescribing the lowest dose to achieve the desired clinical benefits is prudent and recommended.1–3Table 3 outlines the estrogen formulations now available in the United States, with their doses and formulations.

Unless contraindications develop (Table 2), patients may elect to continue hormone therapy if its benefits outweigh its risks. The American College of Obstetricians and Gynecologists (ACOG) 2014 practice recommendations for management of menopausal symptoms31 and the 2015 NAMS statement both recommend that hormone therapy not be discontinued based solely on a woman’s age.29

Hormone therapy is on the Beer’s list of potentially inappropriate medications for older adults,30 which remains a hurdle to its long-term use and seems to be at odds with these ACOG and NAMS statements.

Patients who choose to discontinue hormone therapy need to be monitored for persistent bothersome vasomotor symptoms, bone loss, osteoporosis, and the genitourinary syndrome of menopause (previously referred to as vulvovaginal atrophy)31 and offered alternative therapies if needed.

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