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

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


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

In This Article

Formulation, Dosing, Route of Administration, and Safety


Estrogens. The estrogens most commonly prescribed are CEE, synthetic conjugated estrogens, micronized 17(β-estradiol, and ethinyl estradiol. Conjugated equine estrogen, used in the WHI, is isolated from the urine of pregnant mares and comprised of estrone sulfate (weaker than estradiol) and mixtures of more than 10 minor components of different active forms of estrogens (weak estrogen agonists). Conjugated equine estrogens and estradiol are rapidly metabolized into weaker estrogens such as estrone. Thus, there may be differences in the types of concentrations of estrogens or interactions with ERs in different target tissues.

Meta-analysis of FDA-approved estrogen trials found no evidence of a significant difference in effectiveness between estradiol and CEE in treating VMS. Findings with regard to adverse events (AEs) were inconsistent,[4] despite more hepatic protein production with CEE.[5] However, there were differences in cognitive outcomes between types of estrogen and the brain serotonergic system, with estradiol providing more robust anxiolytic and antidepressant effects.[6,7]

Progestogen indication: need for endometrial protection. Chronic unopposed endometrial exposure to estrogen increases the risk for endometrial hyperplasia or cancer.[8,9] The primary menopause-related indication for progestogen use is to prevent endometrial overgrowth and the increased risk of endometrial cancer during ET use. Progestins commonly used include MPA, norethindrone acetate, and native progesterone. Women with an intact uterus using systemic ET should receive adequate progestogen unless they are taking CEE combined with bazedoxifene.[10–12]

Progestogen dose and duration of use are important in ensuring endometrial protection. When adequate progestogen is combined with estrogen, the risk of endometrial neoplasia is not higher than in untreated women. In the WHI, use of continuous oral CEE + MPA daily was associated with a risk of endometrial cancer similar to placebo (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.48–1.36),[13] with significant reduction of risk after a median 13 years' cumulative follow-up.[14]

A higher incidence of breast cancer was seen in the WHI for CEE + MPA compared with placebo, but a reduced incidence with CEE alone (Figure 1).[14] Observational studies have suggested that the risk of breast cancer may be less with the use of micronized progesterone (MP) compared with synthetic progestogens,[15,16] but the bioavailability of oral and transdermal progesterone is poor.

Figure 1.

Absolute risks of health outcomes by 10-year age groups in the Women's Health Initiative Hormone Therapy Trials during the intervention phase. CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate. From Manson et al. Reproduced with permission of the American Medical Association ©American Medical Association. All rights reserved.

Micronized progesterone needs to be adequately dosed for endometrial protection.[17–19] Improperly formulated or dosed or delivery issues with estrogen plus MP combinations have potentially serious health consequences, including increased risk of endometrial neoplasia.[20] In women using EPT, unscheduled bleeding occurring more than 6 months after initiation should be investigated.

Tissue-selective Estrogen Complex

Bazedoxifene, a selective ER modulator (SERM; estrogen agonist or antagonist), has been combined with CEE to form a tissue-selective estrogen complex. The combination provides endometrial protection without the need for a progestogen.[21]


Estrogen therapy. The therapeutic goal should be to use the most appropriate, often lowest, effective dose of systemic ET consistent with treatment goals. The appropriate dose of progestogen is added to provide endometrial protection if a woman has a uterus, unless CEE is combined with bazedoxifene.

Progestogen therapy. Progestogen dosing-regimen options that provide for endo-metrial safety are dependent on the potency of the progestogen and vary with the estrogen dose. Different types and doses of progestogens, routes of administration, and types of regimen (sequential or continuous-combined) may have different health outcomes.[22]

Routes of Administration

Systemic estrogens can be prescribed as oral drugs; trans-dermal patches, sprays, and gels; or as vaginal rings. Low-dose vaginal estrogen is available as a cream, tablet, ring, and in some countries, a pessary. Progestogens are available as oral drugs, combination patches with estrogen, intrauterine systems, injectables, and vaginal gels or tablets.

Nonoral routes of administration (transdermal, vaginal, and intrauterine systems) may offer potential advantages because nonoral routes bypass the first-pass hepatic effect; however, there are no head-to-head RCTs to validate this supposition.

Safety Considerations

Contraindications for HT include unexplained vaginal bleeding, severe active liver disease, prior estrogen-sensitive breast or endometrial cancer, coronary heart disease (CHD), stroke, dementia, personal history or inherited high risk of thromboembolic disease, porphyria cutanea tarda, or hyper-triglyceridemia, with concern that endometriosis might reactivate, migraine headaches may worsen, or leiomyomas may grow.

More common AEs include nausea, bloating, weight gain, fluid retention, mood swings (progestogen-related), breakthrough bleeding, headaches, and breast tenderness.

Potential risks of HT initiated in women aged younger than 60 years or who are within 10 years of menopause onset include the possible risk of breast cancer with combined EPT, endometrial hyperplasia and cancer if estrogen is unopposed or inadequately opposed, venous thromboembolism (VTE), and biliary issues. Additional risks across ages include myocardial infarction (MI), stroke, and dementia.

Key Points

  • Different HTs, even within the same HT class, may have different effects on target organs, potentially allowing options to minimize risk.

  • The appropriate, often lowest, effective dose of systemic ET consistent with treatment goals that provides benefits and minimizes risks for the individual woman should be the therapeutic goal.

  • The appropriate formulation, dose, and route of administration of progestogen is needed to counter the proliferative effects of systemic estrogen on the endometrium.

  • Formulation, dose, and route of administration for HT should be determined individually and reassessed periodically.

  • Potential risks of HT for women aged younger than 60 years or who are within 10 years of menopause onset include the rare risk of breast cancer with combined EPT, endometrial hyperplasia and cancer with inadequately opposed estrogen, VTE, and biliary issues. Additional risks across ages include MI, stroke, and dementia.