Boston, MA - A new observational study suggests that early use of hormone replacement therapy (HRT), when a woman is close to the menopause, might lower the risk of coronary heart disease (CHD) [1]. This is in contrast to warnings issued following the Women's Health Initiative (WHI) and the Heart Estrogen/Progestin Replacement Study (HERS) a few years ago, which found that hormone use increased the risk of CHD.

The new data from the Nurses' Health Study, reported by Dr Francine Grodstein (Harvard Medical School, Boston, MA) and colleagues in the January/February 2006 issue of the Journal of Women's Health, show that women who began HRT near to menopause had an approximately 30% reduced risk of CHD compared with women who didn't use HRT. This benefit was lost in older women, however, including subgroups who started HRT at least 10 years after menopause and those who began taking hormones after the age of 60.

"These data support the possibility that timing of HRT initiation in relation to menopause onset or age might influence coronary risk," say Grodstein et al.

Dr Thomas B Clarkson (Wake Forest University School of Medicine, Winston-Salem, NC) coauthor of an accompanying editorial [2] with Dr Tomi S Mikkola (Helsinki University Central Hospital, Finland), told heartwire that there has been much debate about the findings of WHI and the aftermath, which led to the mistaken concept that hormones were bad for everybody.

"A large number of us have focused on the fact that the women [in WHI] were about 18 years postmenopausal when the HRT was begun. We believe that estrogens may be beneficial in the early stages of atherosclerosis but may become harmful when it has progressed to a fairly complicated stage."

All of this discussion prompted Grodstein and her coauthors—one of whom, Dr JoAnn E Manson (Harvard Medical School), was lead researcher on the original WHI report—"to take a new look at the Nurses' Health Study," says Clarkson. "Although this is an exciting and intriguing finding, this is still an observational study, and people will never accept it as more than that." Two new studies, the Kronos Early Estrogen Protection Study (KEEPS) and the Early versus Late Intervention Trial with Estradiol (ELITE), which are still at the recruitment stage, will more definitively answer the questions about HRT, the timing of initiation of therapy, and CHD risk, he says.

Grodstein and colleagues prospectively examined the risk of CHD according to the timing of initiation of hormone therapy relative to age and time since menopause among participants in the Nurses' Health Study, with follow-up from 1976 to 2000.

They found that women beginning HRT near menopause had a significantly reduced risk of CHD (relative risk [RR]=0.66 for estrogen alone, RR=0.72 for estrogen plus progestin). In the subgroup of women demographically similar to those in the WHI (who began taking hormone therapy 10 years after menopause), they found no significant relation between HRT and CHD, and in those who started HRT at an older age (60+ years) they also found no relation.

Grodstein et al say the problem in analyzing these new data and comparing them with the WHI study is that there were relatively few older women in this current analysis and in WHI there were relatively few women randomized soon after menopause.

While Clarkson acknowledges this, he says there was an almost significant benefit of estrogen only on CHD risk in women aged 50 to 59 in WHI and "no significant worsening" in those aged 50 to 59 taking estrogen and progestin combined.

During the intervening years, many organizations—including the American College of Obstetricians and Gynecologists—have softened their recommendations on HRT prescribing, he points out. "Most OB/GYN doctors now accept this timing hypothesis," he says.

Currently, the general recommendations are to use HRT for menopausal symptoms only at or around the time of menopause, to limit therapy to a maximum of five years in general, and to use the lowest dose of estrogen possible, he adds.

Interestingly, Grodstein et al found nearly identical relative risks of CHD associated with 0.3 mg and 0.625 mg of estrogen and concluded, "Substantially more data are needed on the cardiovascular effects of 0.3-mg estrogen as this dose has . . . become standard in clinical practice." Clarkson told heartwirethat 0.459 mg of estrogen is also often used now.

The current recommendations are not to use HRT for the primary or secondary prevention of coronary heart disease, Clarkson notes, "although we are leaving the door open that this may change."

"Fortunately, two clinical trials have been initiated in the US to test the timing hypothesis," he and Mikkola explain in their editorial, as well as one in Finland. The KEEPS trial will include only women in early menopause who are treated with lower-dose conjugate equine estrogen (CEE; 0.459 mg/day with oral micronized progesterone). ELITE will contrast the effects of oral micronized estradiol (1 mg/day with intravaginal progesterone) given to women less than six years past menopause vs women 10 years or more postmenopausal.

For both KEEPS and ELITE, the primary end point will be change in carotid artery intima-media thickness. The Finnish trial—SYMPTOM—will compare vascular and cardiac function in recently menopausal women with or without severe vasomotor symptoms and will also look at vascular response to oral vs transdermal HRT.

Manson herself, together with others, has written a "personal perspective" in the January/February 2006 issue of Menopause: the Journal of the North American Menopause Society [3], in which she concludes that these randomized trials will answer unresolved clinical issues.

Mikkola and Clarkson conclude by saying that the increasing body of evidence indicates "that cardiovascular benefits from HRT may outweigh the risks if treatment is started at early menopause, but that the risks may outweigh benefits if treatment is started at a later age."

Until the results of ongoing trials are known, treatment decisions about HRT "should be made on an individual basis, taking into account troubling climacteric symptoms and HRT-associated risk factors."