The Women’s Health Initiative (WHI) postmenopausal hormone therapy trials were a landmark investigation of the safety of menopausal hormone therapy (MHT). The trials aimed to assess the risks and benefits of MHT in order to evaluate its appropriateness for chronic disease prevention. Two frequently used hormone formulations at the time were compared against placebo: conjugated equine oestrogens alone and in combination with medroxyprogesterone acetate. Early WHI trials results were dramatic, with the combined arm ending after an average of five years largely due to increased breast cancer risk. Similarly, the oestrogen-only arm was ended after seven years due to an increased risk of stroke. Long-term post-treatment follow-up has been conducted over 14 years. This article provides an overview of some of the major outcomes assessed in the WHI trials and outlines the current understanding of the impact of MHT.

Cardiovascular disease

The effect of MHT on coronary heart disease (CHD) differed between the two trials. Combined-MHT was associated with a non-significant increase in coronary events during treatment, with an additional six coronary events for every 10 000 women treated per year. However, over long-term follow up, the data suggest a dissipation of risk shortly after treatment cessation.^{1 2 3}

The effect on CVD risk appears to be unrelated to patient age. However, a more harmful effect on cardiovascular health is demonstrated in those further from menopause, although the results are only significant when initiated in women more than 20 years since menopause onset.^{4 5 6}

Oestrogen-only MHT demonstrates a more favourable cardiovascular risk profile, with CVD risk remaining neutral throughout intervention and follow-up.⁷

Overall, there appears to be no significant increase in CVD risk with MHT use in healthy women aged less than 60 years and within 10 years of menopause for up to six years of treatment. Recent observational data suggest transdermal oestrogen preparations may be associated with reduced risk of CVD events, but this has not been examined by higher-level studies.⁸

Breast cancer

Combined-MHT is associated with a significantly increased risk of breast cancer. During treatment, an additional nine breast cancers occurred per 10 000 women treated with combined-MHT beyond five years of use. Furthermore, malignancies tended to be more advanced at diagnosis, possibly because combined therapy increases breast density, thereby increasing the potential for abnormal mammography.^{9 10 11} Long-term follow-up demonstrates an attenuated risk with each year after treatment cessation.^{12 13 14}

The effect on breast cancer risk appears independent of patient age. However, observational data suggest increased risk when combined-MHT is initiated within five years of menopause.^{15 16 17 18} This is in contrast to the evidence regarding venous thromboembolism (VTE), stroke and coronary CHD, all demonstrating greater safety in younger postmenopausal women.

The oestrogen-only arm of the WHI trials demonstrated no increase in breast cancer risk for seven years of treatment and a significantly reduced risk over long-term follow up.^{19 20} This effect was consistent across all age groups and independent of menopause onset. More recent observational data suggest similar safety with up to five years of therapy.²¹ These results contradict observational data from the Million Women Study,²² and may be due to different oestrogen preparations, MHT use prior to enrolment and differing baseline participant characteristics.²³

The clear difference in breast cancer risk between hormonal regimens supports research on the carcinogenic potential of progesterone on breast tissue.²⁴ However, the effect on risk profiles between various progestins and cyclical versus continuous progesterone therapy has not been assessed in high-level studies.

Stroke

The risk of stroke was significantly increased in both WHI trials. The risk of ischaemic stroke was increased by 37 per cent and 35 per cent with combined-MHT and oestrogen-only therapy, respectively, reflecting an additional 9–11 strokes per 10 000 women treated per year. The risk of haemorrhagic stroke was unchanged.^{25 26} Data from long-term follow-up suggest dissipation of this risk after treatment cessation.^{27 28 29}

The excess risk conferred by MHT appears independent of time since menopause and is only significant for women aged older than 60 years.³⁰ Furthermore, the absolute risk for stroke in women under 60 years is low and is a clinically important consideration for symptomatic women considering MHT. Observational data suggest low-dose transdermal preparations may not be associated with an increased risk of stroke.^{31 32}

VTE

The WHI trials demonstrated a significantly increased risk of VTE in both hormonal regimens. During treatment with combined-MHT, the risk of pulmonary embolism (PE) doubled and the risk of deep vein thrombosis (DVT) was increased by 87 per cent. Oestrogen-only MHT demonstrated an increase in DVT of almost 50 per cent and a non-significant increase in PE. The effect of MHT on VTE risk did not appear to be age related.³³

Long-term follow up shows the increased risk of VTE dissipates rapidly following cessation of treatment.^{34 35} No difference in risk profile has been demonstrated between various progestogens and observational data suggest transdermal preparations may not be associated with increased VTE risk.^{36 37 38}

Fracture

Both WHI trials hormonal regimens demonstrated 33 per cent reductions in hip fracture when compared to placebo, reflecting six fewer fractures per 10 000 women treated per year. Although this effect is reduced after cessation of therapy, some benefit persists for up to 13 years following combined-MHT.³⁹ While MHT is not first-line management for osteoporosis, current guidelines support its use in premature (age less than 40 years) or early (age less than 45 years) menopause for bone preservation.^{40 41}

Conclusion

The use of MHT for menopausal symptoms requires an individual and holistic approach with considerations of personal risk factors and quality of life. The risk-benefit profile appears less favourable for combined-MHT and generally more favourable in younger, more recently postmenopausal women. On balance, MHT appears to be safe for healthy women under 60 years, and within 10 years of menopause, for less than five years of therapy. Current data do not support the use of MHT in chronic disease prevention. Current menopause guidelines advise against the use of MHT in women at high risk of, or with established risk factors for, the major adverse events outlined.^{42 43}

1. Heiss G, Wallace R, Anderson GL. Health Risks and Benefits 3 Years After Stopping Randomized Treatment With Estrogen and Progestin. JAMA. 2008;299(9):1036-1045.
2. LaCroix AZ, Chlebowski RT, Manson JE, et al. Health Risks and Benefits after Stopping the Women’s Health Initiative Trial of Conjugated Equine Estrogens in Postmenopausal Women with Prior Hysterectomy. JAMA. 2011;305(13):
   1305-1314.
3. Manson JE, Chlebowski RT, Stefanick ML, et al. The Women’s Health Initiative Hormone Therapy Trials: Update and Overview of Health Outcomes During the Intervention and Post-Stopping Phases. JAMA. 2013;310(13):1353-1368.
4. Manson JE, Chlebowski RT, Stefanick ML, et al. The Women’s Health Initiative Hormone Therapy Trials: Update and Overview of Health Outcomes During the Intervention and Post-Stopping Phases. JAMA. 2013;310(13):1353-1368.
5. Prentice RL, Manson JE, Langer RD, et al. Benefits and Risks of Postmenopausal Hormone Therapy When It Is Initiated Soon After Menopause. American Journal of Epidemiology. 2009;170(1):12-23.
6. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. Journal of the American Medical Association. 2007;297(13):1465-1477.
7. Manson JE, Chlebowski RT, Stefanick ML, et al. The Women’s Health Initiative Hormone Therapy Trials: Update and Overview of Health Outcomes During the Intervention and Post-Stopping Phases. JAMA. 2013;310(13):1353-1368.
8. Shufelt CL, Merz CNB, Prentice RL et al. Hormone Therapy Dose, Formulation, Route of Delivery, and Risk of Cardiovascular Events in Women: findings from the Women’s Health Initiative Observational Study. Menopause 2014;21(3):260-266.
9. Manson JE, Chlebowski RT, Stefanick ML, et al. The Women’s Health Initiative Hormone Therapy Trials: Update and Overview of Health Outcomes During the Intervention and Post-Stopping Phases. JAMA. 2013;310(13):1353-1368.
10. Chlebowski RT, Rohan TE. Changing Concepts: Menopausal Hormone Therapy and Breast Cancer. Journal of the National Cancer Institute. 2012;104(7):517-527.
11. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women: the Women’s Health Initiative Randomized Trial. JAMA. 2003;289(24):3243-3253.
12. Heiss G, Wallace R, Anderson GL. Health Risks and Benefits 3 Years After Stopping Randomized Treatment With Estrogen and Progestin. JAMA. 2008;299(9):1036-1045.
13. Manson JE, Chlebowski RT, Stefanick ML, et al. The Women’s Health Initiative Hormone Therapy Trials: Update and Overview of Health Outcomes During the Intervention and Post-Stopping Phases. JAMA. 2013;310(13):1353-1368.
14. Chlebowski RT, Rohan TE, Manson JE, et al. Breast Cancer After Use of Estrogen Plus Progestin and Estrogen Alone: Analyses of Data From 2 Women’s Health Initiative Randomized Clinical Trials. JAMA Oncol. 2015;1(3):296-305.
15. Prentice RL, Manson JE, Langer RD, et al. Benefits and Risks of Postmenopausal Hormone Therapy When It Is Initiated Soon After Menopause. American Journal of Epidemiology. 2009;170(1):12-23.
16. Beral V, Reeves G, Bull D, et al. Breast Cancer Risk in Relation to the Interval Between Menopause and Starting Hormone Therapy. Journal of the National Cancer Institute. 2011;103(4):296-305.
17. Fournier A, Mesrine S, Boutron-Ruault M, et al. Estrogen-Progestogen Menopausal Hormone Therapy and Breast Cancer: does delay from menopause onset to treatment initiation influence risks? Journal of Clinical Oncology. 2009;27(31);5138-5143.
18. Prentice RL, Chlebowski RT, Stefanick ML, et al. Conjugated Equine Estrogens and Breast Cancer Risk in the Women’s Health Initiative Clinical Trial and Observational Study. American Journal of Epidemiology. 2008;167(12):1407-1415.
19. LaCroix AZ, Chlebowski RT, Manson JE, et al. Health Risks and Benefits after Stopping the Women’s Health Initiative Trial of Conjugated Equine Estrogens in Postmenopausal Women with Prior Hysterectomy. JAMA. 2011;305(13):1305-1314.
20. Manson JE, Chlebowski RT, Stefanick ML, et al. The Women’s Health Initiative Hormone Therapy Trials: Update and Overview of Health Outcomes During the Intervention and Post-Stopping Phases. JAMA. 2013;310(13):1353-1368.
21. Santen RJ, Allred DC, Ardoin SP, et al. Postmenopausal Hormone Therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab. 2010;95(7 suppl 1)s1-66.
22. Beral V et al for Million Women Study Collaborators. Breast Cancer and Hormone-Replacement Therapy in the Million Women Study. Lancet. 2003;362:419-427.
23. North American Menopause Society. The 2012 Hormone Therapy Position Statement of the North American Menopause Society. Menopause. 2012;19(3),257-271.
24. Beral V, Reeves G, Bull D, et al. Breast Cancer Risk in Relation to the Interval Between Menopause and Starting Hormone Therapy. Journal of the National Cancer Institute. 2011;103(4):296-305.
25. Manson JE, Chlebowski RT, Stefanick ML, et al. The Women’s Health Initiative Hormone Therapy Trials: Update and Overview of Health Outcomes During the Intervention and Post-Stopping Phases. JAMA. 2013;310(13):1353-1368.
26. Hendrix SL, Wassertheil-Smoller S, Johnson KC, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women’s Health Initiative. Circulation. 2006;113:2425-2434.
27. Heiss G, Wallace R, Anderson GL. Health Risks and Benefits 3 Years After Stopping Randomized Treatment With Estrogen and Progestin. JAMA. 2008;299(9):1036-1045.
28. LaCroix AZ, Chlebowski RT, Manson JE, et al. Health Risks and Benefits after Stopping the Women’s Health Initiative Trial of Conjugated Equine Estrogens in Postmenopausal Women with Prior Hysterectomy. JAMA. 2011;305(13):1305-1314.
29. Manson JE, Chlebowski RT, Stefanick ML, et al. The Women’s Health Initiative Hormone Therapy Trials: Update and Overview of Health Outcomes During the Intervention and Post-Stopping Phases. JAMA. 2013;310(13):1353-1368.
30. Olie V, Plu-Bureau G, Conard J, et al. Hormone Therapy and Recurrence of Venous Thromboembolism Among Postmenopausal Women. Menopause.2011;18(5):488-493.
31. Shufelt CL, Merz CNB, Prentice RL et al. Hormone Therapy Dose, Formulation, Route of Delivery, and Risk of Cardiovascular Events in Women: findings from the Women’s Health Initiative Observational Study. Menopause 2014;21(3):260-266.
32. Renoux C, Dell’Aniello S, Garbe E, et al. Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study. MJ.2010;340:c2519. Available from: www.bmj.com/content/340/bmj.c251
33. Manson JE, Chlebowski RT, Stefanick ML, et al. The Women’s Health Initiative Hormone Therapy Trials: Update and Overview of Health Outcomes During the Intervention and Post-Stopping Phases. JAMA. 2013;310(13):1353-1368.
34. Heiss G, Wallace R, Anderson GL. Health Risks and Benefits 3 Years After Stopping Randomized Treatment With Estrogen and Progestin. JAMA. 2008;299(9):1036-1045.
35. LaCroix AZ, Chlebowski RT, Manson JE, et al. Health Risks and Benefits after Stopping the Women’s Health Initiative Trial of Conjugated Equine Estrogens in Postmenopausal Women with Prior Hysterectomy. JAMA. 2011;305(13):1305-1314.
36. Olie V, Plu-Bureau G, Conard J, et al. Hormone Therapy and Recurrence of Venous Thromboembolism Among Postmenopausal Women. Menopause. 2011;18(5):488-493.
37. Bergandal A, Kieler H, Sundström, A, et al. Risk of Venous Thromboembolism Associated with Local and Systemic Use of Hormone Therapy in Peri- and Postmenopausal Women and in Relation to Type and Route of Administration. Menopause. 2016;23(6),593-599.
38. Laliberte F, Dea K, Duh MS, et al. Does the Route of Administration for Estrogen Hormone Therapy Impact the Risk of Venous Thromboembolism? Estradiol Transdermal System Versus Oral Estrogen-Only Hormone Therapy. Menopause. 2011;18(10):1052-1059.
39. Manson JE, Chlebowski RT, Stefanick ML, et al. The Women’s Health Initiative Hormone Therapy Trials: Update and Overview of Health Outcomes During the Intervention and Post-Stopping Phases. JAMA. 2013;310(13):1353-1368.
40. North American Menopause Society. The 2012 Hormone Therapy Position Statement of the North American Menopause Society. Menopause. 2012;19(3),257-271.
41. Stuenkel CA, Davis SR, Gompel A, et al. Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100(11),3975-4011.
42. North American Menopause Society. The 2012 Hormone Therapy Position Statement of the North American Menopause Society. Menopause. 2012;19(3),257-271.
43. Stuenkel CA, Davis SR, Gompel A, et al. Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100(11),3975-4011.