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Summary

The Kronos Early Estrogen Prevention Study (KEEPS) was a randomized, double-blind, placebo-controlled trial designed to determine the effects of menopausal hormone treatments (MHTs) on the progression of carotid intima-medial thickness (CIMT) in recently menopausal women) [1]. Participants less than 3 years from menopause and without a history of overt cardiovascular disease (CVD), defined as no clinical CVD events and coronary artery calcium < 50 Agatston units, received either oral conjugated equine estrogens (CEE, 0.45 mg/day) or transdermal 17β-estradiol (50 µg/day), both with progesterone (200 mg/day for 12 days/month), or placebo pills and patches for 4 years. The authors found that although MHT did not decrease the age-related increase in CIMT, yet both MHTs versus placebo reduced the severity of menopausal symptoms and maintained bone density, but differed in efficacy regarding mood/anxiety, sleep, sexual function, and deposition of β-amyloid in the brain. Additionally, genetic variants in enzymes for metabolism and uptake of estrogen affected the efficacy of MHT for some aspects of symptom relief. The authors concluded that the KEEPS provides important information for use of MHT in clinical practice, including type, dose, and mode of delivery of MHT recently after menopause, and how genetic variants in hormone metabolism may affect MHT efficacy on specific outcomes. However, the debate MHT regarding the “windows of opportunity” is still open.

Commentary

Age and time since menopause in terms of MHT initiation are two of the most critical factors influencing the effects of MHT on the risk of chronic disease. Many authors support the idea that the moment of menopause onset is especially important because it is the time spent in the absence of the effects of estrogen on the endothelium that makes the difference in terms of atherosclerotic risk [2]. After the menopause onset, there is a loss of the inhibitory effect of estrogens on the growth and proliferation of vascular smooth muscle cells [3]. This leads to an acceleration of the atherosclerosis process and the production of pro-inflammatory cytokines and adipokines in visceral adipose tissue [4,5]. The blood lipid profile tends to become atherogenic in women within a year of the final menstrual period (FMP) with significant increases in total cholesterol, LDL-cholesterol, and apolipoprotein B (ApoB), independent of ethnicity, age or weight [6]. Increases in HDL-cholesterol levels are paradoxically associated with a more significant progression of CIMT [7]. Moreover, blood pressure levels tend to rise in the postmenopause [8].

In the proximity of the menopause, women still have healthy arteries and present a “window of opportunity” for MHT to produce beneficial cardiovascular effects. Ageing arteries, however, become less responsive to the beneficial effects of estrogens, possibly due to a down-regulation of estrogen receptors [9]. Estrogens produce different effects on arteries, depending on the stage of the atherosclerotic process. At an early stage, these steroids inhibit or slow down the development of the atherosclerotic plaque by preventing the accumulation of foam cells in the endothelium. At later stages, they exacerbate inflammation, precipitate rupture of vulnerable plaques, by increasing expression of matrix metalloproteinases (MMPs), and promote thrombo-occlusive events [10]. Considerable increases in MMPs lead to excessive remodeling and disruption of existing atheromatous plaques [11]. Thus, the prior endothelial condition of a woman is the real determining factor of MHT cardiovascular outcome. The vast majority of the women included in the original trial probably had a severely diseased vasculature due to age, the number of years since menopause, and pre-existing cardiovascular risk factors (obesity, HDL-cholesterol, and hypertension). In the WHI, those women who started MHT early after the menopause showed better cardiovascular outcomes, having quite seemingly less advanced atherosclerosis. Indeed, in the WHI-CACS, approximately 8.7 years after randomization, women aged 50-59 years receiving CEE-only presented a lower prevalence and quantity of coronary-artery calcium, a marker of atherosclerosis progression, than those receiving placebo [12].

Based on this hypothesis, a group of researchers designed the Early versus Late Intervention Trial (ELITE), a randomized, placebo-controlled, double-blind prospective trial aimed at evaluating the effects of MHT on the progression of atherosclerosis, having a CIMT and coronary arterial calcification (CAC) as the outcomes [13]. The aim of the ELITE study was specifically to test the timing hypothesis of MHT, by comparing these outcomes in women early in postmenopause (<6 years past menopause) and in women late in postmenopause (≥ 10 years past menopause) [13]. CIMT measurements every six months, and cardiac computed tomography were carried out on 643 healthy postmenopausal women, randomized to MHT or placebo for 6 to 7 years. The rate of progression of atherosclerosis by CIMT was similar in the estradiol and placebo groups in women ≥ 10 years past menopause. At the same time, it was slower in the group of women <6 years past menopause for women on MHT compared with placebo. Computed tomography did not reveal differences for CAC, total stenosis, and plaque between the estradiol and placebo-treated women in either the menopausal age group. This may be attributed to the short trial duration in regards to the long incubation period of CAC [14], therefore the study may not have lasted long enough to observe a change [13]. Moreover, the post-trial analysis of the ELITE data revealed that with higher plasma E2 levels, achieved through the therapy, the CIMT progression rate was decreased among women in early postmenopause but increased among women in late postmenopause. These data are perfectly in line with the timing hypothesis [1]. KEEPS was also designed to focus on the healthy younger women by recruiting subjects within 3 years of menopause and by excluding those with known clinical and subclinical atherosclerosis [15]. In the KEEPS, CIMT increased comparably among treatment and placebo-treated women in a similar fashion over the 4 study years. The misalignment between the KEEPS results of no benefit on CIMT progression and the results of the ELITE trial may be explained by a dose-response effect of estradiol or a time-dependent effect [13,16]. Indeed, treatment consisted of CEE 0.45 mg/day or transdermal estradiol 50 mcg/day, both with oral progesterone (200 mg/day for 12 days/month), or placebo pills and patches. Circulating levels of E2 and E1, although both increased with both treatments versus placebo, differed between women assigned to transdermal Eor oral CEE. Moreover, the duration of the study, 4 years, was shorter than that of the ELITE study.

CIMT was evaluated after a 3-year period of stopping MHT or placebo in a subgroup of 76 participants from KEEPS. No accelerated changes occurred in arterial thickness and no differences between treatment groups over time, although for women randomized to oral estradiol, there was a significant increase in CIMT post-treatment regarding the years of active treatment [15]. A recent report from the Finnish nationwide prescription register reported that MHT reduces death risk related to coronary heart disease, the earlier MHT is initiated [17].

Andrea Giannini, MD
Tommaso Simoncini MD, PhD
Department of Clinical and Experimental Medicine
University of Pisa, Pisa Italy

References

  1. Miller VM, Taylor HS, Naftolin F, et al. Lessons from KEEPS: the Kronos Early Estrogen Prevention Study. Climacteric. 2021;24(2):139-145.
    https://pubmed.ncbi.nlm.nih.gov/32880220/
  2. Tuomikoski P, Mikkola TS. Postmenopausal hormone therapy and coronary heart disease in early postmenopausal women. Ann Med. 2014;46(1):1–7.
    https://pubmed.ncbi.nlm.nih.gov/24266727/
  3. Mendelsohn ME. Mechanisms of estrogen action in the cardiovascular system. J Steroid Biochem Mol Biol. 2000;74(5):337-43.
    https://pubmed.ncbi.nlm.nih.gov/11162942/
  4. Pou KM, Massaro JM, Hoffmann U, et al. Visceral and subcutaneous adipose tissue volumes are cross-sectionally related to markers of inflammation and oxidative stress: the Framingham Heart Study. Circulation. 2007;116(11):1234-41.
    https://pubmed.ncbi.nlm.nih.gov/17709633/
  5. Lee CG, Carr MC, Murdoch SJ, et al. Adipokines, inflammation, and visceral adiposity across the menopausal transition: a prospective study. J Clin Endocrinol Metab. 2009;94(4):1104-10.
    https://pubmed.ncbi.nlm.nih.gov/19126626/
  6. Matthews KA, Crawford SL, Chae CU, et al. Are Changes in Cardiovascular Disease Risk Factors in Midlife Women due to Chronological Aging or to the Menopausal Transition? J Am Coll Cardiol. 2009;54(25):2366-73.
    https://pubmed.ncbi.nlm.nih.gov/20082925/
  7. El Khoudary SR, Wang L, Brooks MM, Thurston RC, Derby CA, Matthews KA. Increase HDL-C level over the menopausal transition is associated with greater atherosclerotic progression. J Clin Lipidol. 2016;10(4):962-969.
    https://pubmed.ncbi.nlm.nih.gov/27578129/
  8. Taddei S. Blood pressure through aging and menopause. Climacteric. 2009;12 Suppl 1:36-40.
    https://pubmed.ncbi.nlm.nih.gov/19811239/
  9. Smiley DA, Khalil RA. Estrogenic compounds, estrogen receptors and vascular cell signaling in the aging blood vessels. Curr Med Chem. 2009;16(15):1863–1887. https://pubmed.ncbi.nlm.nih.gov/19442151/
  10. Khalil RA. Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease. Biochem Pharmacol. 2013;86(12):1627–1642.
    https://pubmed.ncbi.nlm.nih.gov/24099797/
  11. Wingrove CS, Garr E, Godsland IF, Stevenson JC. 17beta-oestradiol enhances release of matrix metalloproteinase-2 from human vascular smooth muscle cells. Biochim Biophys Acta. 1998 Mar 5;1406(2):169-74.
    https://pubmed.ncbi.nlm.nih.gov/9573355/
  12. Manson JE, Allison MA, Rossouw JE, et al.; WHI and WHI-CACS Investigators. Estrogen therapy and coronary-artery calcification. N Engl J Med. 2007;356(25):2591-602.
    https://pubmed.ncbi.nlm.nih.gov/17582069/
  13. Hodis HN, Mack WJ, Henderson VW, Shoupe D, Budoff MJ, Hwang-Levine J, Li Y, Feng M, Dustin L, Kono N, Stanczyk FZ, Selzer RH, Azen SP. ELITE Research Group. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med. 2016;374:1221–1231.
    https://pubmed.ncbi.nlm.nih.gov/27028912/
  14. Loria CM, Liu K, Lewis CE, et al. Early adult risk factor levels and subsequent coronary artery calcification: the CARDIA Study. J Am Coll Cardiol. 2007;49:2013–2020.
    https://pubmed.ncbi.nlm.nih.gov/17512357/
  15. Miller VM, Black DM, Brinton EA, et al. Using basic science to design a clinical trial: baseline characteristics of women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). J Cardiovasc Transl Res. 2009;2(3):228-39.
    https://pubmed.ncbi.nlm.nih.gov/19668346/
  16. Sriprasert I, Hodis HN, Karim R, et al. Differential Effect of Plasma Estradiol on Subclinical Atherosclerosis Progression in Early vs Late Postmenopause. J Clin Endocrinol Metab. 2019;104(2):293‐300.
    https://pubmed.ncbi.nlm.nih.gov/30272234/
  17. Savolainen-Peltonen H, Tuomikoski P, Korhonen P, et al. Cardiac death risk in relation to the age at initiation or the progestin component of hormone therapies. J Clin Endocrinol Metab. 2016;101:2794–801.
    https://pubmed.ncbi.nlm.nih.gov/27172432/

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