The four different study regimens did not lead to any significant changes in the augmentation index, and the responses were similar in women with intolerable and tolerable hot flushes. Similarly, the changes in Te and TR before nitroglycerin were unaffected by both hot flush status and treatment regimens. Changes in the levels of E1 or E2 or the time since menopause were not associated with these variables. However, significant interaction between hot flush status and the effect of treatment was found with both changes in Te (P=.009) and TR (P=.006) after the nitroglycerin challenge. Therefore, separate analyses were carried out for women with intolerable and tolerable hot flushes. No significant treatment effect was detected in women with intolerable hot flushes. However, in women with tolerable hot flushes, the use of oral E2 alone was associated with significant reductions in both Te and TR after nitroglycerin (Fig. 2). With oral E2 use, Te was decreased by 13.2% (to 86.8±5.0% from baseline, P=.028), and TR was decreased by 8.4% (to 91.6±3.2% from baseline, P=.018) when compared with placebo (108.3±4.4% and 106.0±3.4%, respectively). The time to the reflected wave (dependent on pulse wave velocity) after nitroglycerin was decreased by 8.4% (to 91.6±3.2% from baseline, P=.018) when compared with placebo (108.3±4.4% and 106.0±3.4%, respectively). The changes caused by oral E2 were also significantly different from those associated with transdermal E2 (Te 111.2±4.1% and TR 106.1±2.1%) or oral E2 plus medroxyprogesterone acetate (Te 111.6±8.4% and TR 107.4±4.8%) (Fig. 2). These changes in Te and TR after nitroglycerin were not associated with time since menopause or the changes in levels of E1 and E2.
Our data show that hot flush status affects vascular responses to HT and that only in women with tolerable hot flushes oral E2 leads to less receptive vasculature. We compared the vascular responses, as assessed by pulse–wave analysis, to various forms of HT in recently menopausal women with intolerable or tolerable hot flushes. Women in our study were considered to represent either those likely to initiate HT (intolerable hot flushes) or those not likely to use HT (tolerable hot flushes) in clinical practice. We have recently shown that women with intolerable hot flushes have prolonged Te and TR after a nitroglycerin challenge,14 and this was confirmed in the present study. It is possible that women with troublesome hot flushes have an elevated sympathetic tone, because the autonomic nervous system regulates both left ventricular ejection and aortic smooth muscle tone. This explanation is further supported by our present data indicating that this baseline difference vanished after HT treatment, when hot flushes were alleviated or disappeared. Obviously we cannot rule out the possibility that 6-month HT treatment could also result in structural and not only functional changes in the vasculature. However, since these changes were seen only in women with tolerable hot flushes, hot flush status appears to be a determinant of the vascular reaction to HT in recently menopausal women.
The use of oral E2 alone in women with tolerable, but not with intolerable, hot flushes was accompanied by a decrease of the rapid phase of ventricular ejection and an earlier return of the reflected wave after nitroglycerin challenge. These findings in women with tolerable hot flushes are potentially unfavorable, since a more rapid return of the reflected wave indicates acceleration of wave velocity and decreased vasodilatation—in other words less compliant vasculature.28 This effect was not seen during the transdermal use of E2 or during the combined use of oral E2 and medroxyprogesterone acetate. It is possible that the higher circulating estrogen levels, especially those of E1, during the use of oral rather than transdermal E2 are involved. This could result in differences in the up-regulation of estrogen receptors in the vascular wall29 or hepatic modulation of the renin-angiotensin system30 or vasoactive agents, such as nitric oxide and endothelin-1.31 Of these explanations, the activation of hepatic and/or gastrointestinal regulation of various biological factors by oral estrogen may be a key factor. Furthermore, these effects could be mediated by cytokines or inflammatory markers32 stimulated by oral HT. Oral33,34 but not transdermal35,36 estrogen therapy has been shown to increase the concentrations of various inflammatory markers (eg, C-reactive protein [CRP]), although the HT-related increase in CRP is most likely to be a result of metabolic hepatic activation rather than being a sign of an acute-phase vascular response.37 Whether this is also the case with other inflammatory markers is not clear, but it has been shown that hot flush status among premenopausal, perimenopausal, and postmenopausal women influences interleukin-8 levels.38
It has been suggested that vascular responses to E2 with and without medroxyprogesterone acetate differ, although this has not been clearly confirmed in all clinical trials.39–41 Our data support the concept of medroxyprogesterone acetate–related vascular differences, since we detected less compliant vasculature in women with tolerable hot flushes when receiving oral E2 but not when it was accompanied by medroxyprogesterone acetate. We cannot deduce the exact mechanisms behind this difference, but one possibility is that medroxyprogesterone acetate counteracts the effect of oral estrogen treatment. This is supported by the results of a study showing that oral estrogen alone or in combination with low-dose medroxyprogesterone acetate (2.5 mg) increased the levels of CRP and serum amyloid A protein, but not if oral estrogen was accompanied by a higher dose (5.0 mg) of medroxyprogesterone acetate.34 Similar results have also been shown when high-dose (20 mg) cyclic medroxyprogesterone acetate was used.42 Synthetic progestins such as medroxyprogesterone acetate also have androgenic40,43 properties, and thus, medroxyprogesterone acetate may reduce the strength of estrogen-mediated vascular effects. Therefore, in addition to dose, medroxyprogesterone acetate–related vascular effects may also be dependent on hot flush status.
Our study has some limitations. First, we studied only lean, white women, and thus, our results may not be generalizable to obese women or women of other ethnic origins. Second, we used hot flush diaries, and therefore, the number and severity of hot flushes are subjective. However, when women consider using HT, it is commonly based on their subjective experience of the severity of hot flushes. In addition, this method of classifying self-reported hot flushes into three categories according to the severity of sweating has been shown to be reliable.16 Third, an exposure time of more than 6 months could have been needed to reveal additional differences, although 3- to 6-month HT treatments have been commonly used in vascular function studies.29 Finally, we had a limited number of women in the subgroups, and thus, it is possible that in a larger study population more robust differences could have been revealed.
Assuming that our two study groups were representative of HT users and non-users in long-term observational studies, our findings support the claim that women with and without hot flushes are not comparable in their vascular responses to HT. Based on our results, it appears that women without troublesome hot flushes are susceptible to unfavorable vascular effects brought about by oral E2 treatment, resulting in less compliant vasculature. This could partly explain the divergent results between observational studies1,2 and randomized clinical trials in which HT-related cardiovascular disease effects have been assessed, since in observational studies, women were likely to have experienced hot flushes when initiating HT, whereas women entering clinical trials did not have troublesome hot flushes. Thus, in future studies assessing HT and cardiovascular disease end-points, hot flush status should be considered as a potential confounding factor.
1. Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016–37.
2. Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000;133:933–41.
3. Hodis HN, Mack WJ. Postmenopausal hormone therapy and cardiovascular disease in perspective. Clin Obstet Gynecol 2008;51:564–80.
4. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) research group. JAMA 1998;280:605–13.
5. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women’s health initiative randomized controlled trial. JAMA 2002;288:321–33.
6. Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349:523–34.
7. van der Schouw YT, Grobbee DE. Menopausal complaints, oestrogens, and heart disease risk: an explanation for discrepant findings on the benefits of post-menopausal hormone therapy. Eur Heart J 2005;26:1358–61.
8. Mendelsohn ME, Karas RH. HRT and the young at heart. N Engl J Med 2007;356:2639–41.
9. Freedman RR. Pathophysiology and treatment of menopausal hot flashes. Semin Reprod Med 2005;23:117–25.
10. Deecher DC, Dorries K. Understanding the pathophysiology of vasomotor symptoms (hot flushes and night sweats) that occur in perimenopause, menopause, and postmenopause life stages. Arch Womens Ment Health 2007;10:247–57.
11. Thurston RC, Sutton-Tyrrell K, Everson-Rose SA, Hess R, Matthews KA. Hot flashes and subclinical cardiovascular disease: findings from the Study of Women’s Health Across the Nation Heart Study. Circulation 2008;118:1234–40.
12. Gast GC, Grobbee DE, Pop VJ, Keyzer JJ, Wijnands-van Gent CJ, Samsioe GN, et al. Menopausal complaints are associated with cardiovascular risk factors. Hypertension 2008;51:1492–8.
13. Crandall CJ, Zheng Y, Crawford SL, Thurston RC, Gold EB, Johnston JM, et al. Presence of vasomotor symptoms is associated with lower bone mineral density: a longitudinal analysis. Menopause 2009;16:239–46.
14. Tuomikoski P, Ebert P, Groop PH, Haapalahti P, Hautamäki H, Rönnback M, et al Evidence for a role of hot flushes in vascular function in recently postmenopausal women. Obstet Gynecol 2009;113:902–8.
15. Notelovitz M, Lenihan JP, McDermott M, Kerber IJ, Nanavati N, Arce J. Initial 17beta-estradiol dose for treating vasomotor symptoms. Obstet Gynecol 2000;95:726–31.
16. Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, Lavasseur BI, Windschitl H. Methodologic lessons learned from hot flash studies. J Clin Oncol 2001;19:4280–90.
17. Panay N, Ylikorkala O, Archer DF, Gut R, Lang E. Ultra-low-dose estradiol and norethisterone acetate: Effective menopausal symptom relief. Climacteric 2007;10:120–31.
18. Rönnback M, Lampinen K, Groop PH, Kaaja R. Pulse wave reflection in currently and previously preeclamptic women. Hypertens Pregnancy 2005;24:171–80.
19. Nelson RE, Grebe SK, OKane DJ, Singh RJ. Liquid chromatography-tandem mass spectrometry assay for simultaneous measurement of estradiol and estrone in human plasma. Clin Chem 2004;50:373–84.
20. Wilkinson IB, Hall IR, MacCallum H, Mackenzie IS, McEniery CM, van der Arend BJ, et al. Pulse-wave analysis: clinical evaluation of a noninvasive, widely applicable method for assessing endothelial function. Arterioscler Thromb Vasc Biol 2002;22:147–52.
21. Mackenzie IS, Wilkinson IB, Cockcroft JR. Assessment of arterial stiffness in clinical practice. QJM 2002;95:67–74.
22. O’Rourke MF, Adji A. An updated clinical primer on large artery mechanics: implications of pulse waveform analysis and arterial tonometry. Curr Opin Cardiol 2005;20:275–81.
23. Davies JI, Struthers AD. Pulse wave analysis and pulse wave velocity: a critical review of their strengths and weaknesses. J Hypertens 2003;21:463–72.
24. Wilkinson IB, MacCallum H, Cockcroft JR, Webb DJ. Inhibition of basal nitric oxide synthesis increases aortic augmentation index and pulse wave velocity in vivo. Br J Clin Pharmacol 2002;53:189–92.
25. Wilkinson IB, Mohammad NH, Tyrrell S, Hall IR, Webb DJ, Paul VE, et al. Heart rate dependency of pulse pressure amplification and arterial stiffness. Am J Hypertens 2002;15:24–30.
26. Hayward CS, Kraidly M, Webb CM, Collins P. Assessment of endothelial function using peripheral waveform analysis: a clinical application. J Am Coll Cardiol 2002;40:521–8.
27. Törmälä R, Appt S, Clarkson TB, Groop PH, Rönnback M, Ylikorkala O, et al. Equol production capability is associated with favorable vascular function in postmenopausal women using tibolone; no effect with soy supplementation. Atherosclerosis 2008;198:174–8.
28. Nichols WW. Clinical measurement of arterial stiffness obtained from noninvasive pressure waveforms. Am J Hypertens 2005;18:3S–10S.
29. Teede HJ. Sex hormones and the cardiovascular system: effects on arterial function in women. Clin Exp Pharmacol Physiol 2007;34:672–6.
30. Koledova VV, Khalil RA. Sex hormone replacement therapy and modulation of vascular function in cardiovascular disease. Expert Rev Cardiovasc Ther 2007;5:777–89.
31. Najjar SS, Scuteri A, Lakatta EG. Arterial aging: is it an immutable cardiovascular risk factor? Hypertension 2005;46:454–62.
32. Lakoski SG, Herrington DM. Effects of hormone therapy on C-reactive protein and IL-6 in postmenopausal women: a review article. Climacteric 2005;8:317–26.
33. Pradhan AD, Manson JE, Rossouw JE, Siscovick DS, Mouton CP, Rifai N, et al. Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women’s Health Initiative observational study. JAMA 2002;288:980–7.
34. Wakatsuki A, Okatani Y, Ikenoue N, Fukaya T. Effect of medroxyprogesterone acetate on vascular inflammatory markers in postmenopausal women receiving estrogen. Circulation 2002;105:1436–9.
35. Saucedo R, Rico G, Basurto L, Ochoa R, Zarate A. Transdermal estradiol in menopausal women depresses interleukin-6 without affecting other markers of immune response. Gynecol Obstet Invest 2002;53:114–7.
36. Sumino H, Ichikawa S, Kasama S, Takahashi T, Kumakura H, Takayama Y, et al. Different effects of oral conjugated estrogen and transdermal estradiol on arterial stiffness and vascular inflammatory markers in postmenopausal women. Atherosclerosis 2006;189:436–42.
37. Silvestri A, Gebara O, Vitale C, Wajngarten M, Leonardo F, Ramires JA, et al. Increased levels of C-reactive protein after oral hormone replacement therapy may not be related to an increased inflammatory response. Circulation 2003;107:3165–9.
38. Yasui T, Uemura H, Tomita J, Miyatani Y, Yamada M, Kuwahara A, et al. Association of interleukin-8 with hot flashes in premenopausal, perimenopausal, and postmenopausal women and bilateral oophorectomized women. J Clin Endocrinol Metab 2006;91:4805–8.
39. Clarkson TB, Appt SE. MPA and postmenopausal coronary artery atherosclerosis revisited. Steroids 2003;68:941–51.
40. Sitruk-Ware R. New hormonal therapies and regimens in the postmenopause: routes of administration and timing of initiation. Climacteric 2007;10:358–70.
41. Yeboah J, Reboussin DM, Waters D, Kowalchuk G, Herrington DM. Effects of estrogen replacement with and without medroxyprogesterone acetate on brachial flow-mediated vasodilator responses in postmenopausal women with coronary artery disease. Am Heart J 2007;153:439–44.
42. Skouby SO, Gram J, Andersen LF, Sidelmann J, Petersen KR, Jespersen J. Hormone replacement therapy: estrogen and progestin effects on plasma C-reactive protein concentrations. Am J Obstet Gynecol 2002;186:969–77.
43. Hermsmeyer RK, Thompson TL, Pohost GM, Kaski JC. Cardiovascular effects of medroxyprogesterone acetate and progesterone: a case of mistaken identity? Nat Clin Pract Cardiovasc Med 2008;5:387–95.