The 2017 Hormone Therapy Position Statement of The North American Menopause Society

The North American Menopause Society 2017 Hormone Therapy Position Statement Advisory Panel

Disclosures

The North American Menopause Society (NAMS). 2018;24(7):728-753. 

In This Article

Cardiovascular Disease and All-cause Mortality

Newer observational data and reanalysis of older studies by age or time since menopause, including the WHI, suggest that for healthy, recently menopausal women, the benefits of HT (estrogen alone or with a progestogen) outweigh its risks, with fewer CVD events in younger versus older women.[14,172–182]

Initiation Fewer Than 10 Years After Menopause Onset

Surrogate markers. Some earlier studies suggested benefit on coronary artery calcification,[183–185] whereas more recent RCTs in younger, recently postmenopausal women have not.[106,186] In the Early versus Late Intervention Trial With Estradiol, HT (oral 17β-estradiol 1mg/d plus progesterone vaginal gel 45mg administered sequentially for women with a uterus) reduced carotid artery intima-media thickness (CIMT) progression after a median of 5 years when initiated within 6 years of menopause onset but not when initiated 10 or more years after menopause onset.[106] The Kronos Early Estrogen Prevention Study in healthy postmenopausal women aged 42 to 58 years who received HT (oral CEE 0.45 mg/d; transdermal estradiol patch 50µg/wk, each with cyclic oral MP 200mg for 12d/mo) found no effect on CIMT progression.[186]

Meta-analysis of clinical outcomes. A 2015 Cochrane review of RCT data found that HT initiated fewer than 10 years after menopause onset lowered CHD in postmenopausal women (RR, 0.52; 95% CI, 0.29–0.96).[177] It also found a reduction in all-cause mortality (RR, 0.70; 95% CI, 0.52–0.95) and no increased risk of stroke but an increased risk of VTE (RR, 1.74; 95% CI, 1.11–2.73), similar to the findings of a prior meta-analysis of studies in women who initiated HT within 10 years of menopause onset and/or in women aged younger than 60 years.[180]

Women's Health Initiative. For CEE alone, CHD, total MI, and coronary artery bypass grafting or percutaneous coronary intervention showed a lowered HR in women aged younger than 60 years and fewer than 10 years since menopause onset, even in intention-to-treat analyses.[14] Age-group analysis in the WHI CEE + MPA trial was an outlier. In the 50- to 59-year-old age group, the HR for CHD was elevated but not statistically significant at 1.34 (95% CI, 0.82–2.19) for CEE + MPA.

Initiation More Than 10 Years From Menopause Onset or in Women Aged Older Than 60 Years

For women who initiated HT more than 10 years from menopause onset or when aged older than 60 years, a meta-analysis of studies found no evidence that HT reduced or had an effect on CHD (RR, 1.07; 95% CI, 0.96–1.20) or all-cause mortality (RR, 1.06; 95% CI, 0.95–1.18).[177] Risks included an increased risk of stroke (RR, 1.21; 95% CI, 1.06–1.38) and VTE (RR, 1.96; 95% CI, 1.37–2.80).

Initiation Across All Ages

When HT is initiated across all ages, there is no evidence for primary or secondary prevention of all-cause mortality, CV death, nonfatal MI, angina, or revascularization.[177] Compared with placebo, HT use was associated with an extra 6 strokes per 10,000 women (RR, 1.24; 95% CI, 1.10–1.41), 8 cases of VTE per 10,000 women (RR, 1.92; 95% CI, 1.36–2.69), and 4 cases of pulmonary embolism (PE) per 10,000 women (RR, 1.81; 95% CI, 1.32–2.48).

Attributable Risk of Stroke in Women Aged Younger Than 60 Years or Who Were Within 10 Years of Menopause Onset

A meta-analysis of studies found no increased risk of stroke in women aged younger than 60 years or who were fewer than 10 years from menopause onset.[177] In subgroup analysis, the attributable risk of stroke in the WHI for women who initiated HT when aged younger than 60 years and/or who were within 10 years of menopause onset was rare (< 1/1,000 person-years) and statistically nonsignificant for CEE + MPA, with an absolute risk of 5 per 10,000 person-years in women aged younger than 60 years or within 10 years of initiation,[181] similar to other studies.[172,181]

For CEE alone in the WHI, findings were inconsistent. For women aged 50 to 59 years at randomization, a decrease of 1 per 10,000 person-years was seen for stroke, whereas for women fewer than 10 years from menopause onset, an increase in 13 strokes per 10,000 person-years was seen (Figure 1).[14]

Based only on observational studies, lower doses of either oral[187] or transdermal[188] estrogen may have less risk of stroke; no clear association with age has been found. No head-to-head data comparing oral to transdermal are available.

Venous Thromboembolism

In a meta-analysis of trials of women who began HT treatment fewer than 10 years after menopause onset or who were aged younger than 60 years, strong evidence of increased risk of VTE was found in the HT group compared with placebo (RR 1.74; 95% CI, 1.11–2.73).[177] Lower doses of oral ET may confer less VTE risk than higher doses,[189] but comparative RCT data are lacking. Micronized progesterone may be less thrombogenic than other progestins.[190] Limited observational data suggest less risk with transdermal HT than oral.[188,190,191] No excess risk has been seen with vaginal estrogen.

Area of Scientific Uncertainty and Need for Randomized, Controlled Trial Data

Although newer observational data are consistent with older observational data, caution is recommended when considering the data that suggest reduced CHD and all-cause mortality when HT is initiated in women aged younger than 60 years and/or who are within 10 years of menopause onset. Clinical decisions need to be individualized by reviewing the data and taking all specific circumstances into account on a case-by-case basis.

Key Points

Coronary heart disease.

  • Hormone therapy represents a safe and effective option for the treatment of menopause symptoms when initiated in healthy postmenopausal women aged younger than 60 years or are within 10 years of menopause onset; however, the effects of HT on CHD may vary depending on when HT is initiated in relation to a woman's age and/or time since menopause onset.

  • There are older and newer observational data; the Early versus Late Intervention Trial With Estradiol surrogate markers; the Danish Osteoporosis Prevention Study data; and meta-analyses that suggest reduced risk of CHD in women who initiate HT when aged younger than 60 years and/or who are within 10 years of menopause onset.

  • In women who initiate HT more than 10 years from menopause onset, and clearly by 20 years, there is potential for increased risk of CHD. The WHI found that both CEE alone and CEE + MPA increased risk of CHD, with potentially greater risk with CEE + MPA, which was significant when initiated in women who were more than 20 years from menopause onset.

Mortality.

  • Meta-analyses of RCTs report a significant reduction in all-cause mortality in women who initiate HT when aged younger than 60 years and/or who are within 10 years from menopause onset. However, no protective effect was found in women with initiation more than 10 years from menopause onset.

Stroke.

  • A meta-analysis of RCTs of women who initiate HT found no increased risk of stroke in women aged younger than 60 years or who were within 10 years of menopause onset, whereas observational study findings are mixed.

  • In subgroup analysis, both the WHI CEE + MPA and CEE-alone studies found a rare, absolute risk of stroke (< 1/1,000 woman-years) in women who initiated HT when aged younger than 60 years, with an increase in women on CEE alone who were within 10 years of menopause onset.

  • A meta-analysis of RCTs found an increased risk of stroke in women who initiate HT when aged older than 60 years and/or who are more than 10 years from menopause onset.

  • Observational studies across all ages, including metaanalyses, suggest that compared with standard-dose oral HT, lower-dose oral as well as lower-dose transdermal therapy has less effect on risk of stroke, although RCT data are lacking.

Venous thromboembolism.

  • Data from the WHI across all ages show increased risk of VTE with oral CEE-alone and CEE + MPA therapy, with higher risk seen in the first 1 to 2 years. For women who initiated HT when aged younger than 60 years, the absolute risk of VTE was rare but significantly increased, as shown in a meta-analysis of studies.

  • A meta-analysis of RCTs found higher absolute risks of VTE (with risk of PE) in women initiating HT more than 10 years from menopause onset.

  • A meta-analysis of observational studies across all ages suggests that, compared with standard-dose oral HT, transdermal HT as well as lower doses of oral or transdermal HT have less effect on risk of VTE; however, RCT data are lacking.

  • There is no evidence of increased risk of VTE with low-dose vaginal ET used for genitourinary symptoms.

Conclusions.

  • For healthy symptomatic women aged younger than 60 years or who are within 10 years of menopause onset, the more favorable effects of HT on CHD and all-cause mortality should be considered against potential rare increases in risks of breast cancer, VTE, and stroke. Hormone therapy is not FDA indicated for primary or secondary cardioprotection.

  • Women who initiate HT when aged older than 60 years and/or who are more than 10 years, and clearly by 20 years, from menopause onset are at higher absolute risks of CHD, VTE (risk of PE), and stroke than women initiating HT in early menopause.

  • Personal and familial risk of CVD, stroke, and VTE should be considered when initiating HT.

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