Safety and benefit considerations for menopausal hormone therapy

ABSTRACT

Introduction: While benefits and risks of hormone therapy (HT) have been shown in rigorous randomized, controlled trials, clinical use and further study have discovered effects of age, time of HT initiation, and differential effects of various regimens and administration routes on its safety profile.

Areas covered: The safety of HT with regard to cardiovascular disease, thrombosis, the endometrium, the breast, and cognition was reviewed. Differential safety effects of estradiol versus conjugated equine estrogens, and progesterone versus synthetic progestins are reported.

Expert opinion: Perceived safety of HT has evolved based on data from observational studies, the Women’s Health Initiative and its subsequent analyses, more recent randomized, controlled trials, and studies examining the differences between different estrogens and between different progestogens. Unexpected safety concerns with HT became apparent with release of the first results from WHI. Differences between estrogen-alone versus estrogen-progestogen therapies, estradiol versus conjugated equine estrogens, and progesterone versus progestins were found in subsequent WHI analyses and studies examining components of various regimens. The decision to use HT depends on balancing risks and benefits for each individual and determining the most appropriate choice of therapy, dosing, and route of administration, while also considering the safety evidence of different estrogens and progestogens.

KEYWORDS:

• Conjugated equine estrogens
• estradiol
• menopause
• progesterone
• progestins
• safety

Article highlights

• The perceived safety of menopausal hormone therapy (HT) has evolved over the past few decades based on observational data, initial and follow-up analyses of the Women’s Health Initiative, more recent randomized, controlled studies, and studies evaluating variations between different estrogens and progestogens.

• Randomized, controlled, double-blind, head-to-head trials examining the differences between estradiol and conjugated estrogens, or progesterone and synthetic progestins, or comparing transdermal versus oral routes of administration, are limited.

• Cardiovascular risk with estrogens and estrogens-progestogen are neutral to beneficial for the most part in women <60 years of age or <10 years from menopause.

• In the WHI, CEE alone did not increase risk of breast cancer, unlike CEE/MPA.

• Decisions to use HT depend on balancing individual risks and benefits and determining the most appropriate choice of therapy, dosing, and route of administration, while considering the safety evidence of different estrogens and progestogens.

This box summarizes key points contained in the article.

Acknowledgments

The authors acknowledge the medical review by TherapeuticsMD.

Declaration of interest

J Pickar has received consultant fees from Wyeth/Pfizer, Radius Health Inc, TherapeuticsMD, and Shionogi Inc; and has stock options with TherapeuticsMD (but was not paid for his role as an author on this paper). DF Archer (within the past 3 years) has received research support from Actavis (previously Allergan, Watson Pharmaceuticals, Warner Chilcott), Bayer Healthcare, Endoceutics, Glenmark, Merck (previously Schering Plough, Organon), Radius Health Inc, Shionogi Inc, and TherapeuticsMD; and has served as a consultant to Abbvie (previously Abbott Laboratories), Actavis (previously Allergan, Watson Pharmaceuticals, Warner Chilcott), Agile Therapeutics, Bayer Healthcare, Endoceutics, Exeltis (previously CHEMO), InnovaGyn, Merck (previously Schering Plough, Organon), Pfizer, Radius Health Inc, Sermonix Pharmaceuticals, Shionogi Inc, Teva Women’s Healthcare, and TherapeuticsMD. R Kagan has received research grants and support from Therapeutics MD (paid to Sutter Health), and has served as a consultant to Amgen, Noven, Pfizer, Shionogi Inc, Sprout, Valeant, Merck, Palatin, AMAG, Allergan, Juniper, Azure, and Heptares. J Pinkerton has received grants and research support (paid to the University of Virginia) from TherapeuticsMD, and has received consultant fees (paid to the University of Virginia) from Pfizer, and in-kind editorial support from Pfizer Inc, Noven Pharmaceuticals Inc, TherapeuticsMD, and Shionogi Inc. H Taylor has received grant support (paid to Yale University) from Pfizer and OvaScience; and served as a consultant to Abbvie, Obseva, Bayer Healthcare, and Euroscreen. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

Funding was received from TherapeuticsMD for medical writing assistance provided by Kathleen Ohleth, and Laura Ninger of Precise Publications, LLC. The authors directed all content and were fully responsible for content and editorial decisions for this manuscript.