Postmenopausal hormone therapy: an Endocrine Society scientific statement

Abstract

Objective: Our objective was to provide a scholarly review of the published literature on menopausal hormonal therapy (MHT), make scientifically valid assessments of the available data, and grade the level of evidence available for each clinically important endpoint. PARTICIPANTS IN DEVELOPMENT OF SCIENTIFIC STATEMENT: The 12-member Scientific Statement Task Force of The Endocrine Society selected the leader of the statement development group (R.J.S.) and suggested experts with expertise in specific areas. In conjunction with the Task Force, lead authors (n = 25) and peer reviewers (n = 14) for each specific topic were selected. All discussions regarding content and grading of evidence occurred via teleconference or electronic and written correspondence. No funding was provided to any expert or peer reviewer, and all participants volunteered their time to prepare this Scientific Statement.

Evidence: Each expert conducted extensive literature searches of case control, cohort, and randomized controlled trials as well as meta-analyses, Cochrane reviews, and Position Statements from other professional societies in order to compile and evaluate available evidence. No unpublished data were used to draw conclusions from the evidence.

Consensus process: A consensus was reached after several iterations. Each topic was considered separately, and a consensus was achieved as to content to be included and conclusions reached between the primary author and the peer reviewer specific to that topic. In a separate iteration, the quality of evidence was judged using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system in common use by The Endocrine Society for preparing clinical guidelines. The final iteration involved responses to four levels of additional review: 1) general comments offered by each of the 25 authors; 2) comments of the individual Task Force members; 3) critiques by the reviewers of the Journal of Clinical Endocrinology & Metabolism; and 4) suggestions offered by the Council and members of The Endocrine Society. The lead author compiled each individual topic into a coherent document and finalized the content for the final Statement. The writing process was analogous to preparation of a multiauthored textbook with input from individual authors and the textbook editors.

Conclusions: The major conclusions related to the overall benefits and risks of MHT expressed as the number of women per 1000 taking MHT for 5 yr who would experience benefit or harm. Primary areas of benefit included relief of hot flashes and symptoms of urogenital atrophy and prevention of fractures and diabetes. Risks included venothrombotic episodes, stroke, and cholecystitis. In the subgroup of women starting MHT between ages 50 and 59 or less than 10 yr after onset of menopause, congruent trends suggested additional benefit including reduction of overall mortality and coronary artery disease. In this subgroup, estrogen plus some progestogens increased the risk of breast cancer, whereas estrogen alone did not. Beneficial effects on colorectal and endometrial cancer and harmful effects on ovarian cancer occurred but affected only a small number of women. Data from the various Women's Health Initiative studies, which involved women of average age 63, cannot be appropriately applied to calculate risks and benefits of MHT in women starting shortly after menopause. At the present time, assessments of benefit and risk in these younger women are based on lower levels of evidence.

Fig. 1.

Improvement in BMD with E+P therapy: a meta-analysis of 57 studies. The bars and numbers on the right indicate aspects that are improved by MHT. Illustrated on the bar is the mean of the RR (middle portion of the bar) with the CI limits indicated by the numbers at the end of the bar. None of the bars are on the left, which would indicate that the placebo was favored. Data from women receiving MHT or placebo for 1 or 2 yr are indicated. [Data were reproduced with permission from G. Wells et al.: Endocr Rev 23:529–539, 2002 (74 ).]

Fig. 2.

Increase in BMD in postmenopausal women treated with alendronate or estrogen, alone or in combination. PLO, Placebo; ALN, alendronate; CE, conjugated estrogen. [Reproduced with permission from H. G. Bone et al. J Clin Endocrinol Metab 85:720–726, 2000 (75). © The Endocrine Society.]

Fig. 3.

RR of vertebral fracture after treatment with MHT. The left side of the vertical bar indicates that the therapy favors MHT. The right side represents data favoring controls. The horizontal bars represent the mean (middle portion of bar), and the ends of each bar represent the CIs. The studies included are Lufkin, Greenespan, Winalawansa, Alexandersen, and a pooled estimate. [Data were reproduced from G. Wells et al.: Endocr Rev 23:529–539, 2002 (74 ). © The Endocrine Society.]

Fig. 4.

RR of breast cancer as observed in the NHS as a function of BMI. One line represents women with a BMI of less than 25 kg/m² and the other, 25 kg/m² or greater. Each point on the line represents the mean RR of breast cancer for women taking E alone as MHT for 2 yr to more than 20 yr. Figure was constructed from the data reported in the study of Chen et al. (109 ).

Fig. 5.

A, Risks and benefits of MHT in women starting MHT between the ages of 50 and 59 yr or less than 10 yr after the start of menopause. Data are expressed as the attributable (excess) risk or benefit for a woman taking E alone as MHT for 5 yr. B, Number of women per 1000 taking MHT for 5 yr who are expected to have improvement of symptoms of vaginal atrophy or hot flashes. Design of panels A and B is the same. Note that the data regarding risks and benefits in the bottom of panel B represent those illustrated in panel A, where they are illustrated in expanded form so that they can be clearly seen. The purpose of reproducing these data in the bottom of panel B is to compare the number of women benefiting from relief of symptoms of hot flashes and vaginal atrophy with the number of women experiencing other risks and benefits. Fig. 5B is based on data in Refs. , and . Solid black bars, E alone; hatched bars, E+P.