Heidi D. Nelson, MD, MPH; Miranda Walker, MA; Bernadette Zakher, MBBS; Jennifer Mitchell, BA
Disclaimer: The findings and conclusions in this document are those of the authors, who are
responsible for its content, and do not necessarily represent the views of AHRQ. No statement in this report
should be construed as an official position of AHRQ or of the U.S. Department of Health and Human
Acknowledgment: The authors thank Andrew Hamilton, MLS, MS, for conducting literature
searches; Rongwei Fu, PhD, for statistical assistance; and Amanda Brunton, BS, for assistance with preparing
Grant Support: By contract HHSA-290-2007-10057-I-EPC3, task order 3, from the AHRQ.
Potential Conflicts of Interest: Dr. Nelson: Grant (money to institution):
Agency for Healthcare Research and Quality; Support for travel to meetings for the study or other
purposes (money to institution): Agency for Healthcare Research and Quality. Ms. Walker:
Grant (money to institution): Agency for Healthcare Research and Quality. Disclosures can
be also viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-3020.
Requests for Single Reprints: Heidi D. Nelson, MD, MPH, Oregon Evidence-based Practice
Center, Oregon Health & Science University, Mailcode BICC, 3181 Southwest Sam Jackson Park Road,
Portland, OR 97239-3098; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Nelson, Ms. Walker, Dr. Zakher, and Ms. Mitchell: Oregon Health
& Science University, Mailcode BICC, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239-3098.
Author Contributions: Conception and design: H.D. Nelson, M. Walker.
Analysis and interpretation of the data: H.D. Nelson, M. Walker, B. Zakher, J. Mitchell.
Drafting of the article: H.D. Nelson, M. Walker, B. Zakher.
Critical revision of the article for important intellectual content: H.D. Nelson, M. Walker, B. Zakher.
Final approval of the article: H.D. Nelson, M. Walker, B. Zakher.
Provision of study materials or patients: H.D. Nelson.
Statistical expertise: H.D. Nelson.
Obtaining of funding: H.D. Nelson.
Administrative, technical, or logistic support: H.D. Nelson, M. Walker, J. Mitchell.
Collection and assembly of data: H.D. Nelson, M. Walker, B. Zakher.
This article has been corrected. The original version (PDF) is appended to this article as a
Menopausal hormone therapy to prevent chronic conditions is currently not recommended because of its
To update evidence about the effectiveness of hormone therapy in reducing risk for chronic conditions and
adverse effects, and to examine whether outcomes vary among women in different subgroups.
MEDLINE (January 2002 to November 2011), Cochrane Central Register of Controlled Trials and Cochrane
Database of Systematic Reviews (through the 3rd quarter of 2011), Scopus, and reference lists.
Randomized, placebo-controlled trials of menopausal hormone therapy published in English since 2002 that
assessed primary prevention of chronic conditions.
Investigators extracted data on participants, study design, analysis, follow-up, and results; 2
investigators independently rated study quality by using established criteria.
9 fair-quality trials met the inclusion criteria. The Women's Health Initiative reported most of the
results, had 11 years of follow-up, and had data most applicable to postmenopausal women in the United
States. It showed that estrogen plus progestin therapy reduced fractures (46 fewer per 10 000
woman-years) and increased invasive breast cancer (8 more per 10 000 woman-years), stroke (9 more per
10 000 woman-years), deep venous thrombosis (12 more per 10 000 woman-years), pulmonary embolism
(9 more per 10 000 woman-years), lung cancer death (5 more per 10 000 woman-years), gallbladder
disease (20 more per 10 000 woman-years), dementia (22 more per 10 000 woman-years), and urinary
incontinence (872 more per 10 000 woman-years). Estrogen-only therapy reduced fractures (56 fewer per
10 000 woman-years), invasive breast cancer (8 fewer per 10 000 woman-years), and death (2 fewer
per 10 000 woman-years) and increased stroke (11 more per 10 000 woman-years), deep venous
thrombosis (7 more per 10 000 woman-years), gallbladder disease (33 more per 10 000 woman-years),
and urinary incontinence (1271 more per 10 000 woman-years). Outcomes did not consistently differ by
age or comorbid conditions.
Limitations of the trials included low adherence, high attrition, inadequate power to detect risks for some
outcomes, and evaluation of few regimens.
Estrogen plus progestin and estrogen alone decreased risk for fractures but increased risk for stroke,
thromboembolic events, gallbladder disease, and urinary incontinence. Estrogen plus progestin increased risk
for breast cancer and probable dementia, whereas estrogen alone decreased risk for breast cancer.
Agency for Healthcare Research and Quality.
Analytic framework and key questions.
Summary of evidence search and selection.
EMS = Estrogen Memory Study; ESPRIT = Oestrogen in the Prevention of Reinfarction Trial; HERS = Heart and
Estrogen/Progestin Replacement Study; ULTRA = Ultra–Low-Dose Transdermal Estrogen Assessment; WHI =
Women's Health Initiative; WHIMS = Women's Health Initiative Memory Study; WHISCA = Women's Health
Initiative Study of Cognitive Aging; WISDOM = Women's International Study of Long-Duration Oestrogen After
* Includes the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic
† Includes reference lists, Scopus, and studies suggested by experts.
‡ Studies that met the inclusion criteria for the key questions included in this systematic
Appendix Table. Randomized, Controlled Trials Included in This Update
Table 1. Baseline Characteristics of WHI Trial Participants
Table 2. Results of the WHI Trials
Table 3. Summary of Evidence
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Teresa Schaer, MD, FACP, Associate Clinical Professor, Internal Medicine
UMDNJ- Robert Wood Johnson Medical School, New Brunswick, NJ
August 20, 2012
To the Editor:
In reading the article on Menopausal Hormone Therapy by Nelson and colleagues (1), I was concerned to find that the “systematic review” is far from comprehensive. In particular, the review did not include the many studies that show how the human, non-pharmacologically altered form of progesterone—sometimes referred to as “natural” or “bioidentical” progesterone—is beneficial for the treatment and prevention of many chronic conditions, including neurologic disorders such as dementia, and stroke (2) (3), cardiovascular disease (4) (5), and osteoporosis (6) (7), in addition to breast cancer (8) (9).
It is true that progestin, the pharmacologically altered form of progesterone, has been associated with many negative health effects, as cited in the article. However studies comparing human progesterone with progestins have found that the two molecules cannot be equated. For example, a 2005 review of the literature by Compagnoli, et al, (8) in which the two hormones were compared, the authors concluded that progestin increases the risk of breast cancer while human progesterone (called “natural progesterone” by the authors) “does not have a detrimental effect on breast tissue.” In addition, a prospective study by Fournier, et al, (9) followed a group of over 80,000 women on hormone replacement therapies (HRTs), and found that over an eight year period there was an increase risk of breast cancer found only in the groups taking estrogen alone or estrogen with progestins, but no such increase in those on estrogen with progesterone.
The studies cited below, and many others as well, show similar differences in the effects of the two hormones. It’s critical that we not confuse the negative impacts of progestin on health with the overwhelmingly positive effects of taking progesterone. This important point should not be lost in reviewing the studies on hormones, or else it could discourage women from starting or continuing treatment with the safer, beneficial version of the hormone.
Teresa M. Schaer MD, FACP
(1) Nelson, HD et al. Menopausal Hormone Therapy for the primary Prevention of Chronic Conditions: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendations. Ann Intern Med. 2012;157:104-113.
(2) Brinton RD, et al. Progesterone Receptors: Form and Function in Brain. Front Neuroendocrinol. 2008 May; 29(2): 313–339.
(3) Stein D. The Case for Progesterone. Ann NY Acad Sci. 2005; 1052:152-169.
(4) Rosano GMC, et al. Natural Progesterone, but Not Medroxyprogesterone Acetate, Enhances the Beneficial Effect of Estrogen on Exercise-Induced Myocardial Ischemia in Postmenopausal Women. J Am Coll Cardiol 2000; 36: 2154-2159.
(5) Hermsmeyer RK, et al. Prevention of Coronary Hyperractivity in Preatherogenic Menopausal Rhesus Monkeys by Transdermal Progesterone. Arterioscler Thromb Vasc Biol 2004; 24:955-961.
(6) Seifert-Klauss V and Prior JC. Review article, Progesterone and Bone: Actions Promoting Bone Health in Women. J Osteoporos. 2010; 2010: 845180.
(7) Heersche JNM, Bellows, CG, Ishida Y. The decrease in bone mass associated with aging and menopause. J Prosthet dent 1998;79:14-16
(8)Campagnoli C, et al. Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. J Steroid Biochem & Molec Bio 2005: 96;95-108.
(9) Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2008; 107:103-111
Heidi D. Nelson MD, MPH
Oregon Health & Science University
September 19, 2012
Dr. Schaer is correct that studies of the human non-pharmacologically altered form of progesterone were not included in our systematic review of menopausal hormone therapy for the primary prevention of chronic conditions (1). Although all types of hormone therapy were included in our searches of reference databases, studies of progesterone were not included in the systematic review because they did not meet the inclusion criteria detailed in the methods section of the article and technical report (2). The inclusion criteria were developed to identify the strongest available evidence to address the key questions of the review (i.e., the benefits and harms of menopausal hormone therapy when used to prevent chronic conditions, and the variability of outcomes in population subgroups). The systematic review included only randomized controlled trials that enrolled postmenopausal women and compared hormone therapy against placebo. Trials were included if they evaluated the primary prevention of new conditions and reported predetermined health outcomes rather than intermediate outcomes (e.g., fractures not bone density). None of the studies of progesterone met these criteria. In the discussion section of the review, we acknowledged the limitations of this approach and called for additional trials of other hormonal agents.
Heidi D. Nelson MD, MPH Oregon Health & Science University
1. Nelson, HD, Walker MW, Zakher B, Mitchell J. Menopausal hormone therapy for the primary prevention of chronic conditions: A systematic review to update the U.S. Preventive Services Task Force recommendations. Ann Intern Med. 2012;157:104-113.
2. Nelson, HD, Walker MW, Zakher B, Mitchell J. Menopausal Hormone Therapy for the Primary Prevention of Chronic Conditions: A Systematic Review to Update the 2002 and 2005 U.S. Preventive Services Task Force Recommendations. Contract HHSA-290-2007-10057-1-EPC3, task order 3, Rockville, MD: Agency for Healthcare Research and Quality; 2012.
Nelson HD, Walker M, Zakher B, Mitchell J. Menopausal Hormone Therapy for the Primary Prevention of Chronic Conditions: A Systematic Review
to Update the U.S. Preventive Services Task Force Recommendations. Ann Intern Med. 2012;157:104-113. doi: 10.7326/0003-4819-157-2-201207170-00466
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Published: Ann Intern Med. 2012;157(2):104-113.
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