AACE/ACE Updated Position Statement on Menopause

The American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) recently published an updated position statement regarding menopause treatment.¹ Although the updated statement does not change the recommendations outlined in the AACE/ACE 2011 clinical practice guideline on the topic, the authors have added 8 new recommendations based on evidence that has emerged in the interim.² The recommendations and selected highlights are summarized here.

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.

Although the Women’s Health Initiative trial published in 2002 showed a negative effect of hormone replacement therapy (HRT) on cardiovascular risk in postmenopausal women, the sample had a mean age of 63 years.³ The results of trials conducted since then have explored the possibility that the timing of estrogen therapy (based on age) affects related cardiovascular outcomes.

The Kronos Early Estrogen Prevention Study (KEEPS) trial (n=728; ages 42-58 years) found no difference in the progression of carotid intima media thickness between postmenopausal women treated with either 0.45 mg conjugated oral equine estrogens or 50 µg transdermal estradiol, both combined with 200 mg micronized progesterone for 12 days per month, or placebo.⁴ Findings from the Early versus Late Intervention Trial with Estradiol (ELITE) show that carotid intima media thickness progressed more slowly in a younger (median age, 55.4 years) estrogen-treated group compared with both placebo and an older group (median age, 63.6 years) of postmenopausal women.⁵

Recommendation: The use of transdermal estrogen preparations should be considered as less likely to produce thrombotic risk, and perhaps the risk for stroke and CAD. 

In a meta-analysis of observational studies, users of oral estrogen had an odds ratio of first-time venous thromboembolism of 2.5 (95% CI, 1.9-3.4) compared with 1.2 (95% CI, 0.9-1.7) in users of transdermal estrogen. The relative risk for venous thromboembolism in oral estrogen users was 2.1 (95% CI, 1.4-3.1).⁶

Recommendation: When the use of progesterone is necessary, micronized progesterone is considered the safer alternative. 

A cohort study of 80,308 postmenopausal women reported an increased thrombotic risk with norpregnanes (HR, 1.8) vs progesterone (HR, 0.9), pregnanes (HR, 1.3), and 19-nortestosterone derivatives (HR, 1.4).⁷ Compared with micronized progesterone, medroxyprogesterone acetate generally “seems to have greater risk with regard to multiple outcomes, including cardiovascular effects, blood pressure, [venous thromboembolism], probably stroke and breast cancer,” say the authors, although use for a duration of less than 5 years does not appear to be linked to increased risk.

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

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

Considering the evidence suggesting a potential increase in cardiovascular and stroke risk related to HRT, and because this risk is higher in HRT-treated women with metabolic syndrome, “caution should be exercised in treatment of this subgroup of women, with or without overt diabetes,” the authors advise.⁸

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

The US Food and Drug Administration provided testimony to the Senate Special Committee in 2007 expressing concern about inaccurate claims pertaining to the safety and efficacy of such products, for which evidence is still lacking, as noted in the 2011 AACE/ACE practice guideline.

Recommendation: In symptomatic menopausal women who are at significant risk from the use of HRT, the use of selective serotonin reuptake inhibitors and possibly other nonhormonal agents may offer significant symptom relief.

Pooled data from 3 trials (n = 899) demonstrate that both venlafaxine 75 mg and escitalopram 10 to 20 mg reduced vasomotor symptoms as well as 0.5 estradiol.⁹

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. 

As noted in a recent review by the Comité, when considering selective serotonin reuptake inhibitor use in patients with breast cancer taking tamoxifen, fluoxetine and paroxetine should be avoided because of their inhibiting action on the effect of tamoxifen.¹⁰

Summary: The updated AACE/ACE position statement reaffirms recommendations made in their 2011 clinical practice guidelines and considers relevant evidence that has emerged since its publication.

References

1. Cobin RH, Goodman NF; AACE Reproductive Endocrinology Scientific Committee. American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement on Menopause-2017 update. Endocr Pract. 2017;23:869-880.
2. Goodman NF, Cobin RH, Ginzburg SB, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for diagnosis and treatment of menopause. Endocr Pract. 2011;17(suppl 6):1-25.
3. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.
4. Wharton W, Gleason CE, Mill VM, Asthana S.  Rationale and design of the Kronos Early Estrogen Prevention Study (KEEPS) and the KEEPS cognitive and affective sub study (KEEPS Cog). Brain Res. 2013;1514:12-17.
5. Hodis HN, Mack WJ, Henderson VW, et al. Vasuclar effects of early versus late postmenopausal treatment with estradiol. N Engl J Med. 2016;374:1221-1231.
6. Canonico M, Plu-Bureau G, Lowe G, Scarabin PY. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ. 2008;336:1227-1231.
7. Stanczyk FZ, Bhavnani BR. Reprint of “Use of medroxyprogesterone acetate for hormone therapy in postmenopausal women: Is it safe?” J Steroid Biochem Mol Biol. 2015;153:151-159.
8. Stuenkel CA. Menopause hormone therapy and diabetes. Climacteric. 2017;20(1):11-21.
9. Guthrie KA, LaCroix AZ, Ensrud KE, et al. Pooled analysis of six pharmacologic and nonpharmacologic interventions for vasomotor symptoms. Obstet Gynecol. 2015;126(2):413-422.
10. Binkhorst L, Mathijssen RH, van Herk-Sukel MP, et al. Unjustified prescribing of CYP2D6 inhibiting SSRIs in women treated with tamoxifen. Breast Cancer Res Treat. 2013;139(3):923-929.