No 'Rebound' Arterial Effect Seen With HRT Cessation

Nancy A. Melville

July 25, 2018

The cessation of low-dose menopausal hormone therapy after several years of treatment during menopause shows no "rebound" effect on the progression of atherosclerosis, with changes similar to what is expected with normal aging, according to new research.

"These data provide evidence regarding changes in a relatively short (3-year) timeframe after cessation and provide the evidence that cessation of the particular hormone treatments does not accelerate development of cardiovascular disease compared to what might be expected with chronological aging," first author Virginia M. Miller, PhD, of the Department of Surgery at the Mayo Clinic, in Rochester, Minnesota, told Medscape Medical News.

Some previous studies have suggested estrogen-containing menopausal hormone therapy provides cardiovascular benefits, and although the clinical significance of those effects is the subject of ongoing debate, the authors sought to investigate whether cessation of hormone therapy is linked to any "rebound" effect of arterial thickening.

For the new study, published online July 16 in Menopause, they identified a subset of 76 women (out of 727 women) who had participated in the Kronos Early Estrogen Prevention Study (KEEPS), which compared low doses of oral conjugated equine estrogens (CEE), transdermal 17β-estradiol (transdermal patch), or placebo. The main results from KEEPS showed that, despite improvements in some cardiovascular markers over 4 years of treatment, there were no overall differences between the groups in the progression of atherosclerosis.

The 76 women in this new follow-up study were among 118 women at the Mayo Clinic who took part in KEEPS and agreed to a 3-year follow-up after cessation of treatment.

Mean rates of increase in carotid intima-media thickness (CIMT), a key measure of subclinical atherosclerosis, in the CEE group (n = 20) were significantly higher in the post-cessation period compared with the 4-year on-treatment period (0.010 mm/year; P = .014); similar changes were not observed in the placebo (n = 33; 0.006 mm/year; P = .072) or transdermal patch (n = 23) groups (0.002 mm/year; P = 0.312).

The linear trends across the intervals, however, showed no significant differences between the treatment groups (P = .524)

Over the initial 4 years of treatment, the CEE group did not have significant changes in CIMT, whereas CIMT did increase over that period in the transdermal patch and placebo groups, but again, there were no significant differences in the measure of linear trends among the three groups (P = .067).

"All three groups had similar increases over the 3 years after treatment cessation, and there were no significant differences in linear change from 4 to 7 years or from baseline to 7 years among groups," the authors reported.

In the KEEPS study, women at baseline were 42 and 58 years of age and within 6 to 36 months of their last menses, and in addition to the CEE (Premarin, Pfizer; 0.45 mg/day) or transdermal 17β-estradiol (Climara, Bayer; 50 mg/day, skin patch), each active treatment group also received oral progesterone (Prometrium, AbbVie; micronized progesterone, 200 mg/day) for 12 days each month.

Among those in the follow-up study, median age at baseline was 53.3 years and median time since menopause was 1.6 years. At the final 3-year follow-up visit, median age was 60.2 years and median time since menopause was 8.5 years.

The average changes in CIMT from baseline in the three groups combined were 4.1% at year 4 and 9.1% at year 7, with a 5.4% increase from year 4 to 7.

The increases are consistent with arterial thickening shown in other studies, the authors note, and there were no significant associations between age or menopausal age at time of randomization and rate of increase in CIMT.

Those results are notable in light of findings from the Early Versus Late Intervention Trial With Estradiol (ELITE) trial, which provided strong evidence for the "timing hypothesis," with CEE therapy shown to be associated with less progression of subclinical atherosclerosis, measured by CIMT, compared with placebo when therapy was initiated within 6 years of menopause but not 10 years or more after menopause (N Engl J Med. 2016;374:1221-1231).

Miller said, however, that the ELITE study used oral estradiol and that differences in formulations complicate comparisons. "Formulation and dose matter," she said. "This makes it difficult to come to general conclusions regarding hormone treatment and cardiovascular disease."

Other results from the new study were somewhat perplexing: a decrease in high-density lipoprotein cholesterol (HDL-C) observed in the two treatment groups after 4 years in the KEEPS study had returned to pretreatment levels after 3 years of cessation. And baseline low-density lipoprotein cholesterol (LDL-C) levels sustained over the initial 4 years decreased after 3 years.

"The changes in HDL-C and LDL-C in this subset of women while on and after use of menopausal hormone therapy were unexpected and somewhat inconsistent with the changes found in the full cohort of women completing KEEPS," Miller and colleagues write.

"These differences most likely reflect the subset of women who participated in this follow-up study, the use of lipid-lowering medications, and perhaps differences in assays used to assess the lipids for the entire cohort at the end of the study compared with the follow-up timepoint," they speculate.

In other findings, the CEE group also showed greater swings in triglycerides and high-sensitivity C-reactive protein (hs-CRP) levels compared with the other two groups. Whereas triglycerides in the CEE group increased from a mean of 85 mg/dL at baseline to 115 mg/dL at the end of 4 years of treatment, levels dropped to a mean of 104 mg/dL at the 3-year follow-up. In the placebo group, triglycerides significantly increased from a mean of 77 mg/dL at baseline to 99 mg/dL after 4 years (P < .05), and levels declined to 97 mg/dL at the 3-year follow-up.

And hs-CRP levels in the CEE group nearly tripled from a mean of 1.3 mg/dL at baseline to 3.5 mg/dL after 4 years, but decreased to 1.9 mg/dL at the follow-up. There were no significant changes in the transdermal patch or placebo groups in those measures.

In addition to the clear limitation of a small number of patients, some other important caveats include the potential confounder of the use of other medications during the follow-up period. The placebo group, for instance, had a greater use of antihypertensive medication, and there was a trend in higher use of lipid-lowering medications in the treated groups compared with placebo, the authors noted.

Furthermore, the women were all white and nonsmokers, and importantly, some reported using hormone therapy during the 3-year cessation period.

The findings provide some important insights, however, supporting the suggestion that any effects of low-dose hormone therapy on the vascular system and cells in the vascular wall are likely reversible, the authors explain.

"The temporal relationships among the various activational (reversible) effects...have not been studied in detail relative to cell type and ongoing structural changes in various vascular beds," they write.

"The results of this study provide a reference point for such studies and should provide some useful information to women deciding about timing of cessation of menopausal hormone therapy."

The latest North American Menopause Society (NAMS) position statement on menopausal hormone therapy does not endorse menopause hormones for the prevention of cardiovascular disease, and in commenting on the study, NAMS executive director JoAnn Pinkerton, MD noted the inconsistency with the ELITE trial findings.

"In the KEEPS trial, low doses of hormone therapy (oral or transdermal) given for 4 years close to menopause did not improve CIMT, and this study shows no rebound effect on progression of CIMT after stopping the hormones," Pinkerton said in a statement.

"In contrast, the ELITE trial found benefits on CIMT when hormone therapy was given early but not when started more than 10 years from menopause," she said.

Pinkerton underscored that "the primary indication for the use of hormone therapy should be for relief of bothersome menopause symptoms or for those at elevated risk of bone loss."

"There may be beneficial effects on reduction of heart disease, but it should not be used for its prevention."

The study was supported by grants from the Aurora Foundation to the Kronos Longevity Research Institute, American Heart Association, and Mayo Foundation. The authors have reported no relevant financial relationships. Pinkerton has served as a consultant for Pfizer and an investigator for TherapeuticsMD.

Menopause. Published online July 16, 2018. Abstract

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