Menopause Live - IMS Updates

Date of release: 11 November, 2013

The importance of HT dose, formulation and route of delivery

A new analysis from the WHI observational study addresses the potential differences in risk for cardiovascular disease (CVD) associated with different doses, formulations and routes of administration of postmenopausal hormone therapy (HT) [1)]. As a reminder, the WHI observational trial was a multicenter, prospective cohort study that was conducted at 40 US sites. Analyses included 93,676 postmenopausal women aged 50–79 years at study entry, with a mean follow-up of 10.4 years. In direct comparisons, oral estradiol was associated with lower hazard ratios (HRs) for stroke than oral conjugated equine estrogens (CEE; HR 0.64; 95% CI 0.40–1.02), but statistical power was limited. Similarly, transdermal estradiol was associated with a moderate but non-significantly lower risk of coronary heart disease (CHD) compared with oral CEE (HR 0.63; 95% CI 0.37–1.06). For other outcomes, comparisons revealed no appreciable differences by estrogen doses, formulations, or routes of delivery. Absolute risks of CVD events and all-cause mortality were markedly lower in younger women compared with older women.


As always, one should try to read beyond the written text. First, the WHI investigators understand that the continuous combined regimen used by most American women (CEE 0.625 mg/medroxyprogesterone acetate 5 mg) may not be ideal from the metabolic and cardiovascular perspectives. Also, they acknowledge the importance of the time since menopause by including in the analyses a group of women characterized by being in early menopause at start of treatment (< 5 years in menopause). Indeed, they were able to show that different doses and formulations, and certainly years since menopause at initiation of HT, may be associated with different adverse consequences. Unfortunately, the relatively small numbers of women taking either low-dose CEE, or oral or transdermal estradiol (only 2000–3000 in each group) made it almost impossible to get significant results. Yet, the data presented in the tables clearly show that low-dose CEE and transdermal estradiol are associated with lesser risk for CHD, CVD and stroke, although not significant as confidence intervals included 1. A figure in the article presented the absolute numbers of clinical events divided according to recency of menopause. It demonstrated that women who initiated therapy less than 5 years since menopause had only about 10% the number of events detected in women who initiated therapy more than 20 years past menopause: 12 vs. 129 major CHD events/10,000 women-years; 11 vs. 131 stroke events/10,000 women-years. Certainly, this reflects the mere fact that women in their fifties have a very low basal incidence of CVD and points at the good safety of HT cardiac-wise and stroke-wise in this age group. So actually, nothing is really surprising, except for the fact that the WHI investigators soften their approach to HT as more time elapses since the first publication of WHI results in 2002. 
I picked several key messages in the Discussion section: … 'oral estradiol may be associated with a lower risk of stroke, and transdermal HT and low-dose oral CEE may be linked to a lower risk of CHD, compared with conventional-dose oral CEE.' 'Our data add to emerging evidence suggesting that transdermal estrogen delivery may have advantages in minimizing the risk of CVD events associated with HT.' 'The timing of HT initiation in relation to proximity to menopause has been recognized as a potentially important predictor of CVD outcomes.' 'Our data support a growing body of literature suggesting that the transdermal route of delivery and/or lower doses of estrogen may avoid the excess risk of certain CVD events associated with HT.' If the WHI people say so, there is no need for me to add anything further.

Amos Pines
Department of Medicine T, Ichilov Hospital, Tel-Aviv, Israel


  1. Shufelt CL, Merz CN, Prentice RL, et al. Hormone therapy dose, formulation, route of delivery, and risk of cardiovascular events in women: findings from the Womens Health Initiative Observational Study. Menopause 2013 Sep 16. Epub ahead of print