Elsevier

Endocrine Practice

Volume 23, Issue 7, July 2017, Pages 869-881
Endocrine Practice

Position Statement
American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement on Menopause–2017 Update

https://doi.org/10.4158/EP171828.PSGet rights and content

Executive Summary

This American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) Position Statement is designed to update the previous menopause clinical practice guidelines published in 2011 but does not replace them. The current document reviews new clinical trials published since then as well as new information regarding possible risks and benefits of therapies available for the treatment of menopausal symptoms. AACE reinforces the recommendations made in its previous guidelines and provides additional recommendations on the basis of new data. A summary regarding this position statement is listed below:

  • New information available from randomized clinical trials and epidemiologic studies reported after 2011 was critically reviewed.

  • No previous recommendations from the 2011 menopause clinical practice guidelines have been reversed or changed.

  • Newer information enhances AACE's guidance for the use of hormone therapy in different subsets of women.

  • Newer information helps to support the use of various types of estrogens, selective estrogen-receptor modulators (SERMs), and progesterone, as well as the route of delivery.

  • Newer information supports the previous recommendation against the use of bioidentical hormones.

  • The use of nonhormonal therapies for the symptomatic relief of menopausal symptoms is supported.

  • Newer information enhances AACE's guidance for the use of hormone therapy in different subsets of women.

  • Newer information helps to support the use of various types of estrogens, SERMs, and progesterone, as well as the route of delivery.

  • Newer information supports the previous recommendation against the use of bioidentical hormones.

  • The use of nonhormonal therapies for the symptomatic relief of menopausal symptoms is supported.

New recommendations in this position statement include:

  • 1. Recommendation: the use of menopausal hormone therapy in symptomatic postmenopausal women should be based on consideration of all risk factors for cardiovascular disease, age, and time from menopause.

  • 2. Recommendation: the use of transdermal as compared with oral estrogen preparations may be considered less likely to produce thrombotic risk and perhaps the risk of stroke and coronary artery disease.

  • 3. Recommendation: when the use of progesterone is necessary, micronized progesterone is considered the safer alternative.

  • 4. Recommendation: in symptomatic menopausal women who are at significant risk from the use of hormone replacement therapy, the use of selective serotonin re-uptake inhibitors and possibly other nonhormonal agents may offer significant symptom relief.

  • 5. Recommendation: AACE does not recommend use of bioidentical hormone therapy.

  • 6. Recommendation: AACE fully supports the recommendations of the Comité de l'Évolution des Pratiques en Oncologie regarding the management of menopause in women with breast cancer.

  • 7. Recommendation: HRT is not recommended for the prevention of diabetes.

  • 8. Recommendation: In women with previously diagnosed diabetes, the use of HRT should be individualized, taking in to account age, metabolic, and cardiovascular risk factors.

Abbreviations: AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; BMI = body mass index; CAC = coronary artery calcification; CEE = conjugated equine estrogen; CEPO = Comité de l'Évolution des Pratiques en Oncologie; CAD = coronary artery disease; CIMT = carotid intima media thickness; CVD = cardiovascular disease; FDA = Food and Drug Administration; HDL = high-density lipoprotein; HRT = hormone replacement therapy; HT = hypertension; KEEPS = Kronos Early Estrogen Prevention Study; LDL = low-density lipoprotein; MBS = metabolic syndrome; MPA = medroxyprogesterone acetate; RR = relative risk; SERM = selective estrogen-receptor modulator; SSRI = selective serotonin re-uptake inhibitor; VTE = venous thrombo-embolism; WHI = Women's Health Initiative

Section snippets

INTRODUCTION

The most recent American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) clinical practice guidelines for the treatment of menopause was published in 2011 (1). This AACE/ACE Position Statement was produced in accordance with the “American Association of Clinical Endocrinologists and American College of Endocrinology Protocol for Standardized Production of Clinical Practice Guidelines, Algorithms, and Checklists – 2014 Update.” Each recommendation was

KEEPS Trial

This randomized controlled clinical trial was based on the hypothesis that a critical window of time exists when cardiovascular risk may not be increased, and perhaps may actually be decreased, by the administration of HRT, particularly estrogen-only replacement. The study randomized 728 women at 9 sites, age 42 to 58 years, 6 to 36 months postmenopausal and in good health, with extensive exclusion criteria:

  • prior or current cardiovascular disease (CVD), including myocardial infarction, angina,

Danish Osteoporosis Study

Additional reassuring data comes from the Danish Osteoporosis Prevention Study. A total of 502 young (age 45 to 58 years) recently menopausal women were randomized to treatment with triphasic estradiol and norethisterone acetate or with 2 mg estradiol only, if prior hysterectomy, and matched to 504 untreated women. An intervention phase lasted 11 years, and further observation continued up to 16 years. The primary endpoint was a composite of death, admission to hospital for heart failure, and

Post HOC Analysis of the WHI: CVD Outcomes

Recognizing the difference in clinical outcomes following HRT reported by the WHI when women were stratified by age and time from menopause, the WHI committee has created a risk stratification model for HRT, suggesting that there is a group of women for whom HRT offers less risk of CVD (7) (Table 1).

Several characteristics that modify risk for CVD events in women while on HRT have been identified. As reviewed below, optimal candidates for HRT use include women of younger age (<60 years), recent

The Effect of Vasomotor Symptoms on Outcomes

Although it had been postulated in the past that the presence of vasomotor symptoms might reflect better vascular integrity, and therefore the exclusion of these women in the WHI might have biased results toward the development of CVD, this theory has not been supported by data. In fact, in the population of relatively young, early menopausal women screened for participation in the KEEPS study, neither estrogen levels nor vasomotor symptoms predicted baseline CAC or CIMT (10). Vasomotor

Menopausal Estrogen Replacement: Effect of Delivery Route: VTE/Cerebrovascular Accident (CVA)

Since the publication of the last AACE/ACE menopause guidelines, further evidence has accumulated which tends to support the use of transdermal over oral estrogen replacement.

VTE

Meta-analyses of observational studies revealed a higher risk of clinical thromboembolic events with the use of oral as compared with transdermal estrogen. Compared with nonusers of estrogen, the odds ratio of first time VTE in current users of oral estrogen was 2.5 (95% CI, 1.9 to 3.4) and in current users of transdermal estrogen was 1.2 (95% CI, 0.9 to 1.7), with the risk being greatest in the first year of use compared with more than 1 year of use. Past use of oral estrogen did not confer

CVA/CAD

In the WHI review, oral estradiol compared with CEE showed a significantly lower HR for stroke, with limited statistical power in the analysis.

Transdermal estradiol was associated with a moderate but insignificantly lower risk of CAD compared with oral CEE (HR, 0.63; 95% CI, 0.37 to 1.06). For other outcomes, comparisons revealed no appreciable differences by estrogen doses, formulations, or routes of delivery. Absolute risks of CVD events and all-cause mortality were markedly lower in younger

Breast Studies

The WHI follow-up study for cumulative events over 13 years (5.6 years of intervention, remainder observation only) confirmed the intervention phase data for breast cancer risk in HRT treated women (i.e., that there was a significant risk of combined conjugated estrogen/medroxyprogesterone acetate therapy compared with placebo, with HRs of 1.24 in the intervention phase and 1.28 for cumulative events). With conjugated estrogen alone, however, the HR for treated women compared with placebo was

The Role of Progesterone in Risk/Benefit of HRT Endometrial Protection

Studies have shown that the best protection against endometrial hyperplasia and carcinoma is with continuous rather than cyclic progestogen, regardless of the chemical nature of the progestogen (24). There are, however, conflicting data regarding the relative endometrial safety of different types of progestogens.

In a large European multi-site epidemiologic survey, users of estrogen-only therapy, compared with never users, were at increased the risk of endometrial cancer (HR, 2.52; 95% CI, 1.77

CVD/VTE

Various progestins may have different impact on thromboembolic risk. For example, in the in the E3N cohort study of 80,308 postmenopausal women, with an average follow-up of 10.1 years (29), there was a significantly increased thrombotic risk with norpregnanes (HR, 1.8) compared with progesterone (HR, 0.9), pregnanes (HR, 1.3), and 19-nortestosterone derivatives (HR, 1.4). In general, MPA use seems to have greater risk with regard to multiple outcomes, including cardiovascular effects, blood

Breast Cancer

Epidemiologic data on postmenopausal HT have consistently reported that the addition of any progestin to estrogen increases the risk of breast cancer diagnosis compared with estrogen alone. In a study by Kerlikowske et al (31), use of estrogen and progestin for greater than 5 years was associated with a greater risk of breast cancer diagnosis (RR, 1.49; 95% CI, 1.36 to 1.63), with no increased risk compared with nonusers and estrogen-only users. This relationship was confirmed by a

Cognitive Function

A study of 1,768 women revealed that the use of hormone therapy within 5 years of menopause was associated with a 30% reduction in the risk of developing Alzheimer disease later in life, especially if the duration of use was 10 years or longer. This is in contrast to the increase in the risk of Alzheimer disease in women who use hormone replacement later in life (35).

The ongoing KEEPS Cognitive and Affective study, with 700 women enrolled, is the first multi-site, randomized,

Diabetes and Glucose Tolerance

While spontaneous menopause has not been associated with an increased risk of diabetes, MBS/insulin resistance is known to increase with age. Some studies have suggested that premature menopause or premenopausal oophorectomy increases the risk of type 2 diabetes.

In observational studies, treatment with HRT has resulted in either neutral or beneficial effects on glucose levels in patients with pre-existent type 2 diabetes. Both oral and transdermal estrogen conferred this effect, although in

Bioidentical Hormones

The most recent version of the AACE/ACE menopause guidelines cautioned against the use of bioidentical hormone replacement, noting that there is no evidence to support superior safety with these products and that there is often lack of consistency in the content of compounded products, leading to either less or greater amounts of biologically active hormone being received (Table 3). Authorities have noted that there are no controlled trials which support claims for better efficacy, and most

Combination Selective Estrogen-Receptor Modulator (SERM)/CEE

Bazedoxifene, a SERM with efficacy in preventing and treating postmenopausal osteoporosis, is available in combination with CEE. The SERM alone is similar to raloxifene in fracture prevention but is associated with a risk of hot flashes and deep vein thrombosis. There seems to be no effect on the endometrium, and animal data suggest no increase in breast cancer risk, but no robust human data are yet available. The combination of SERM/CEE decreased the incidence of hot flashes and improved

Selective Serotonin Re-Uptake Inhibitors (SSRIs)

SSRIs have been used with moderate success in the treatment of hot flashes in women who are unable or unwilling to use estrogen. Pooled individual-level data from three randomized clinical trials including 899 perimenopausal and postmenopausal women with at least 14 bothersome vasomotor symptoms per week compared 0.5 mg estradiol with venlafaxine 75 mg or 10 to 20 mg escitolapram and three nonpharmacologic interventions, with both SSRIs performing as well as estrogen. To reduce placebo effect,

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    DISCLOSURE

    The authors have no multiplicity of interest to disclose.

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