Questions and Answers About Menopause Therapy with Dr. Denise Black

By Denise Black, MD, FRCSC

Assistant Professor,
Department of Obstetrics, Gynecology and Reproductive Sciences,
University of Manitoba


What is the “timing hypothesis” and how does it affect my patients?

The “timing hypothesis” was created to reconcile two pieces of seemingly contradictory data in the field of menopause care. Long term observational studies (such as the Nurses’ Health Study) showed that women who took menopausal hormone therapy (MHT) had lower cardiovascular risk as they aged. The Women’s Health Initiative (WHI), which was a RCT, showed increased cardiovascular risk among MHT users.

It was speculated that the differences seen were primarily because of the ages of the participants. Women in the Nurses’ Health Study started MHT closer to the time of menopause, whereas women in the WHI were often remote from menopause at initiation of MHT. The “timing hypothesis” purports a window of opportunity where the benefits of MHT outweigh the risks, and that this window for initiation of MHT is close to the time of the final menstrual period.

What is the optimal time to initiate estrogen therapy?

It is felt that to avoid the negative effects of systemic estrogen (softening and destabilization of existing plaque) MHT should be initiated prior to the age of 60, or less than 10 years from the final menstrual period. Initiation of MHT outside of these parameters may adversely alter the risk/benefit ratio.

How does estrogen therapy affect your patient’s cardiovascular health?

Prescribed within the window of opportunity, estrogen is thought to contribute to cardiovascular health in a number of ways. Favourable alteration of lipids (lower LDL and higher HDL) occurs. Estrogen therapy favourably alters glucose metabolism, with fewer new cases of Type 2 DM diagnosed in post-menopausal women using supplemental estrogen.

Perhaps the most important effect of estrogen is on maintaining the integrity of the vascular endothelium. There are estrogen receptors in many vessels, and stimulating these receptors may reduce reactivity to vasoactive peptides. A healthy endothelium will be less likely to develop plaque and consequently vascular obstruction. Two recent RCTs have looked at the CV effects of MHT. The Kronos Early Estrogen Prevention Study (KEEPS) looked at carotid intima media thickness (CIMT) among women less than 36 months from their final menstrual period. Over the 48 months of the study, CV safety of MHT was confirmed. The Early Versus Late Intervention Trial With Estradiol (ELITE) showed a 50% reduction in progression of CIMT among women in the early group (<6 years since menopause) who used MHT over the 6 years of the trial.

What is the recommended duration of MHT use?

The SOGC 2014 Guideline states that there is no clear recommended duration of therapy, and that each woman has the choice of when to stop MHT. The indication for MHT is management of symptoms related to menopause. Hot flushes are the most common symptom, and it is estimated that 15% of the population will have flushing for more than 15 years. Women need to be counseled that breast cancer risk may rise marginally after 4-5 years of therapy with estrogen-progestin, or after 8 years with estrogen alone therapy.


1. Grodstein F, Manson JE, Colditz GA, et al. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000; 133(12):933-41.

2. Nelson HD, Humphrey LL, Nygren P, et al. Postmenopausal hormone replacement therapy: scientific review. JAMA 2002; 288(7):872-1.

3. Harman SM, Black DM, Naftolin F, et al. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Ann Intern Med 2014; 161(4):249-60.

4. Hodis HN, Collins P, Mack WJ, et al. The timing hypothesis for coronary heart disease prevention with hormone therapy: past, present and future in perspective. Climacteric 2012; 15(3):217-28.

5. Reid R, Abramson BL, Blake J, et al. Managing menopause. J Obstet Gynaecol Can 2014; 36(9):830-8.

Development of this article was sponsored by Merck Canada Inc. The author had complete editorial independence in the development of this article and is responsible for its accuracy. The sponsor exerted no influence in the selection of content or material published.