In the Journals

Low-dose menopausal HT cessation does not affect progression of preclinical atherosclerosis

Virginia Miller
Virginia M. Miller

Menopausal women who discontinued low doses of hormone therapy did not experience accelerated changes in carotid artery intima-media thickness during 3 years of observation, according to follow-up analysis of a study published in Menopause.

In the Kronos Early Estrogen Prevention Study (KEEPS), menopausal women assigned to low doses of conjugated equine estrogens or transdermal estradiol for 4 years saw no differences in carotid intima-media thickness, a measure of preclinical atherosclerosis, Virginia M. Miller, PhD,professor in the department of surgery and department of physiology and director of the Mayo Clinic Women’s Health Resource Center in Rochester, Minnesota, and colleagues wrote in the study background. However, it remains unknown whether the use of menopausal HT during the early years of menopause would affect the trajectory for the development of atherosclerosis after discontinuing therapy.

“There is much confusion and fear regarding the use of menopausal hormone therapy,” Miller told Endocrine Today. “This study provides evidence that women who have used menopausal hormone treatments can stop their use without concerns about a ‘rebound effect’ on increasing damage to their arteries above that normally occurring due to aging.”

Miller and colleagues analyzed data from 76 menopausal women who completed the KEEPS trial and 3-year posttreatment follow-up visit at Mayo Clinic. At the time of enrollment in KEEPS, women were aged 42 to 59 years, in good cardiovascular health and within 5 to 36 months of their last menses (median age at baseline, 53 years; median time since menopause, 1.6 years; all white; all nonsmokers). Women were randomly assigned to oral conjugated equine estrogen 0.45 mg per day, transdermal estradiol 50 µg per day, or placebo pills and patch for 4 years. Women in the active arms of the study were also prescribed oral progesterone 200 mg per day for 12 days each month. Carotid intima-media thickness was measured at baseline, 1, 2, 3 and 4 years during the study, and at the 3-year follow-up visit.

At the 3-year follow-up visit, median age was 60 years and median time past menopause was 8.5 years.

Although researchers observed increases in carotid intima-media thickness in both the transdermal estradiol and placebo groups at follow-up, there were no observed changes in the conjugated equine estrogen group, and they observed no differences in the linear trend across treatment arms (P = .067). All three groups experienced similar increases during the 3-year follow-up period after HT cessation, according to researchers, and there were no differences in linear change from 4 to 7 years or from baseline to 7 years between the groups.

When expressed as percent change across groups, average increase in carotid intima-media thickness was 4.1% at 4 years and 9.1% at 7 years, with a 5.4% increase from year 4 to year 7, according to researchers. The rate of increase in carotid intima-media thickness was greater during the posttreatment period vs. the on-treatment period for both the overall group (mean difference, 0.006; 95% CI, 0.002-0.009) and for the oral conjugated equine estrogen group (mean difference, 0.01; 95% CI, 0.002-0.017), according to researchers. Neither age nor menopausal age was associated with carotid intima-media thickness changes.

“Physicians can use this information to reassure women that risk of cardiovascular disease increases with natural aging, but this risk is not increased if women stop using menopausal hormone treatments,” Miller said.

The researchers noted that both the duration of treatment and follow-up periods were short, and that by limiting the analysis to the subset of women who completed the 7-year study visit, the effect of treatment randomization may have been compromised. However, a sensitivity analysis repeating the longitudinal analysis of on-treatment trends using all KEEPS women for whom carotid intima-media thickness data were available yielded similar results comparable to the primary analysis, according to the researchers.

“More long-term studies are needed regarding how the newer lower doses of estrogen treatments on how they affect cardiovascular risk on women,” Miller said. “The most recent trials have been only 4 to 5 years. Formulations have changed since the Women’s Health Initiative and more research is needed to provide state-of-the-practice evidence.” – by Regina Schaffer

Disclosures: The authors report no relevant financial disclosures.

Virginia Miller
Virginia M. Miller

Menopausal women who discontinued low doses of hormone therapy did not experience accelerated changes in carotid artery intima-media thickness during 3 years of observation, according to follow-up analysis of a study published in Menopause.

In the Kronos Early Estrogen Prevention Study (KEEPS), menopausal women assigned to low doses of conjugated equine estrogens or transdermal estradiol for 4 years saw no differences in carotid intima-media thickness, a measure of preclinical atherosclerosis, Virginia M. Miller, PhD,professor in the department of surgery and department of physiology and director of the Mayo Clinic Women’s Health Resource Center in Rochester, Minnesota, and colleagues wrote in the study background. However, it remains unknown whether the use of menopausal HT during the early years of menopause would affect the trajectory for the development of atherosclerosis after discontinuing therapy.

“There is much confusion and fear regarding the use of menopausal hormone therapy,” Miller told Endocrine Today. “This study provides evidence that women who have used menopausal hormone treatments can stop their use without concerns about a ‘rebound effect’ on increasing damage to their arteries above that normally occurring due to aging.”

Miller and colleagues analyzed data from 76 menopausal women who completed the KEEPS trial and 3-year posttreatment follow-up visit at Mayo Clinic. At the time of enrollment in KEEPS, women were aged 42 to 59 years, in good cardiovascular health and within 5 to 36 months of their last menses (median age at baseline, 53 years; median time since menopause, 1.6 years; all white; all nonsmokers). Women were randomly assigned to oral conjugated equine estrogen 0.45 mg per day, transdermal estradiol 50 µg per day, or placebo pills and patch for 4 years. Women in the active arms of the study were also prescribed oral progesterone 200 mg per day for 12 days each month. Carotid intima-media thickness was measured at baseline, 1, 2, 3 and 4 years during the study, and at the 3-year follow-up visit.

At the 3-year follow-up visit, median age was 60 years and median time past menopause was 8.5 years.

Although researchers observed increases in carotid intima-media thickness in both the transdermal estradiol and placebo groups at follow-up, there were no observed changes in the conjugated equine estrogen group, and they observed no differences in the linear trend across treatment arms (P = .067). All three groups experienced similar increases during the 3-year follow-up period after HT cessation, according to researchers, and there were no differences in linear change from 4 to 7 years or from baseline to 7 years between the groups.

When expressed as percent change across groups, average increase in carotid intima-media thickness was 4.1% at 4 years and 9.1% at 7 years, with a 5.4% increase from year 4 to year 7, according to researchers. The rate of increase in carotid intima-media thickness was greater during the posttreatment period vs. the on-treatment period for both the overall group (mean difference, 0.006; 95% CI, 0.002-0.009) and for the oral conjugated equine estrogen group (mean difference, 0.01; 95% CI, 0.002-0.017), according to researchers. Neither age nor menopausal age was associated with carotid intima-media thickness changes.

“Physicians can use this information to reassure women that risk of cardiovascular disease increases with natural aging, but this risk is not increased if women stop using menopausal hormone treatments,” Miller said.

The researchers noted that both the duration of treatment and follow-up periods were short, and that by limiting the analysis to the subset of women who completed the 7-year study visit, the effect of treatment randomization may have been compromised. However, a sensitivity analysis repeating the longitudinal analysis of on-treatment trends using all KEEPS women for whom carotid intima-media thickness data were available yielded similar results comparable to the primary analysis, according to the researchers.

“More long-term studies are needed regarding how the newer lower doses of estrogen treatments on how they affect cardiovascular risk on women,” Miller said. “The most recent trials have been only 4 to 5 years. Formulations have changed since the Women’s Health Initiative and more research is needed to provide state-of-the-practice evidence.” – by Regina Schaffer

Disclosures: The authors report no relevant financial disclosures.