Cardiac Death Risk in Relation to the Age at Initiation or the Progestin Component of Hormone Therapies

The Mikkola Group shows that the earlier postmenopausal hormone therapy (HT) is initiated the smaller is the cardiovascular mortality risk. The various progestin components of HT do not significantly modify this effect.

Altogether, 489,105 Finnish women used estradiol-based HT, either estradiol only (ET) or estradiol combined with progestin (EPT), during 3.7 million person-years during 1994-2009. Of EPT users 48 % had used norethisterone acetate (NETA), 35 % medroxyprogesterone acetate (MPA), and 17 % dydrogesterone. Women using other progestins were combined, and tibolone users were considered as a separate group. There was a follow-up of these women from the therapy initiation to death, or to the end of year 2009. The risk of coronary heart disease (CHD) death in hormone users was compared with that in the age-matched background population using standardized mortality ratio with 95% confidence intervals.

It was found that in women younger than 60 years of age the cardiac death risk was significantly (54-77 %) lower than in the background population. The different EPT preparations did not differ in this regard. In all hormone users, the cardiac mortality risk was smaller, the earlier the use of ET or EPT had started. Also in women older than 60 years of age, the cardiac mortality risk was lower (26-54%) than in the background population.

Epidemiological studies during the 1980-1990´s indicated that postmenopausal HT is cardioprotective. However, the results were not confirmed in the large placebo-controlled trials both for secondary (HERS) and primary prevention (Women’s Health Initiative Study, WHI) of CHD events. Later analyses of the WHI indicated that postmenopausal HT with conjugated equine oestrogen (CEE) alone or in combination with medroxyprogesterone acetate (MPA) is protective against cardiovascular diseases only, if initiated before 60 years of age, but possibly deleterious if initiated later. This phenomenon is called the “window hypothesis”. The study by Savolainen-Peltonen et al. shows that 60 years of age is not a definitive limit as regards cardiovascular effects of estradiol. Instead, the sooner after the onset of menopause HT is initiated the better it protects against cardiac death risk.

Hormone therapy regimens used in Finland contain exclusively estradiol, whereas CEE was used in the WHI study. An increasing body of evidence indicates that natural estradiol may be safer for the vascular bed than CEE, and furthermore, it has been hypothesized that other progestins than MPA could have a more favourable vascular risk profile. However, no large-scale comparisons with different progestins have been carried out. In the study by Savolainen-Peltonen et al. the various progestins, such as MPA, NETA, dydrogestone, or some other progestins as complements to estradiol show no differences in cardiac death risk.

Coronary heart disease is the main cause of death in women. Therefore, the decreased cardiac death risk in HT users is significant information both for women using postmenopausal HT and for physicians initiating hormone therapies.

Original study:

Savolainen-Peltonen H, Tuomikoski P, Korhonen P, Hoti F, Vattulainen P, Gissler M, Ylikorkala O, Mikkola TS. Cardiac Death Risk in Relation to the Age at Initiation or the Progestin Component of Hormone Therapies. J Clin Endocrinol Metab 101: 2794-2801, 2016