J Menopausal Med.  2019 Apr;25(1):49-54. 10.6118/jmm.2019.25.1.49.

The Effects of Menopausal Hormone Therapy on Serum Level of C-reactive Protein in Postmenopausal Korean Women

• Shin W
• Kim SE
• Lee JY
• Seo JW
• Hyun HS
• Suh JH
• Choi D
• Yoon BK

• KMID: 2443627
• DOI: http://doi.org/10.6118/jmm.2019.25.1.49

Abstract

OBJECTIVES
Inflammation is a major mechanism underlying coronary heart disease (CHD) and C-reactive protein (CRP) is a marker of inflammation. When administered soon after menopause, menopausal hormone therapy (MHT) prevents CHD. This study was conducted to examine the impact of estrogen by administration route on CRP in postmenopausal Korean women using micronized progesterone (MP4) for endometrial protection.
METHODS
This retrospective cohort study included 129 healthy women without CHD risk factors. Eighty-nine women took oral estrogen (conjugated equine estrogen, 0.625 mg/day or equivalent), and 40 women applied a 1.5-mg/day 0.1% percutaneous estradiol gel. MP4 was added in 82 women with an intact uterus. The CRP level was measured at baseline and three and six months after initiation of MHT.
RESULTS
The baseline characteristics were comparable between the MHT groups except current age and age at menopause. After controlling for age, menopausal age, body mass index, and basal CRP, no significant change in CRP was observed in the oral estrogen group (n = 29). Follow-up CRP levels were also similar to the baseline in the percutaneous estrogen group (n = 18). However, three-month CRP was significantly lower than six-month CRP, and there was a significant time trend within the percutaneous estrogen group. However, the group difference did not reach statistical significance. CRP also did not differ by addition of MP4 in either group.
CONCLUSIONS
In postmenopausal Korean women, no change in CRP was observed with oral estrogen, while percutaneous estrogen might decrease CRP. The estrogenic impacts were not influenced by adding MP4.

Keyword

C-reactive protein; Hormone replacement therapy; Progesterone; Postmenopause; Drug administration routes

MeSH Terms

Body Mass Index
C-Reactive Protein*
Cohort Studies
Coronary Disease
Drug Administration Routes
Estradiol
Estrogens
Female
Follow-Up Studies
Hormone Replacement Therapy
Humans
Inflammation
Menopause
Postmenopause
Progesterone
Retrospective Studies
Risk Factors
Uterus
C-Reactive Protein
Estradiol
Estrogens
Progesterone

Reference

1. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000; 342:836–843. PMID: 10733371.

2. Ridker PM, Hennekens CH, Rifai N, Buring JE, Manson JE. Hormone replacement therapy and increased plasma concentration of C-reactive protein. Circulation. 1999; 100:713–716. PMID: 10449692.

3. Haverkate F, Thompson SG, Pyke SD, Gallimore JR, Pepys MB. Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Lancet. 1997; 349:462–466. PMID: 9040576.

4. Tracy RP, Lemaitre RN, Psaty BM, Ives DG, Evans RW, Cushman M, et al. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol. 1997; 17:1121–1127. PMID: 9194763.

5. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997; 336:973–979. PMID: 9077376.

6. Kuller LH, Tracy RP, Shaten J, Meilahn EN. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Multiple Risk Factor Intervention Trial. Am J Epidemiol. 1996; 144:537–547. PMID: 8797513.

7. Buckley DI, Fu R, Freeman M, Rogers K, Helfand M. C-reactive protein as a risk factor for coronary heart disease: a systematic review and meta-analyses for the U.S. Preventive Services Task Force. Ann Intern Med. 2009; 151:483–495. PMID: 19805771.

8. Reslan OM, Khalil RA. Vascular effects of estrogenic menopausal hormone therapy. Rev Recent Clin Trials. 2012; 7:47–70. PMID: 21864249.

9. Korean Statistical Information Service (KOSIS). The top 50 of the most common disease mortality rate [Internet]. Daejeon: KOSIS;2018. cited by 2018 April 1. Available from: http://kosis.kr/statHtml/statHtml.do?orgId=101&tblId=DT_1B34E13&vw_cd=MT_ZTITLE&list_id=D11&seqNo=&lang_mode=ko&language=kor&obj_var_id=&itm_id=&conn_path=MT_ZTITLE.

10. Yilmazer M, Fenkci V, Fenkci S, Sonmezer M, Aktepe O, Altindis M, et al. Hormone replacement therapy, C-reactive protein, and fibrinogen in healthy postmenopausal women. Maturitas. 2003; 46:245–253. PMID: 14625121.

11. Wenger NK, Speroff L, Packard B. Cardiovascular health and disease in women. N Engl J Med. 1993; 329:247–256. PMID: 8316269.

12. Mosca L. The role of hormone replacement therapy in the prevention of postmenopausal heart disease. Arch Intern Med. 2000; 160:2263–2272. PMID: 10927722.

13. Mosca L. Hormone replacement therapy in the prevention and treatment of atherosclerosis. Curr Atheroscler Rep. 2000; 2:297–302. PMID: 11122757.

14. Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Willett WC, Rosner B, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med. 1996; 335:453–461. PMID: 8672166.

15. Atkins CD. Postmenopausal hormone therapy and mortality. N Engl J Med. 1997; 337:1390–1391.

16. Sellers TA, Mink PJ, Cerhan JR, Zheng W, Anderson KE, Kushi LH, et al. The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer. Ann Intern Med. 1997; 127:973–980. PMID: 9412302.

17. Boardman HM, Hartley L, Eisinga A, Main C, Roqué i, Bonfill Cosp X, et al. Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst Rev. 2015; (3):CD002229. PMID: 25754617.

18. Koh KK. Effects of estrogen on the vascular wall: vasomotor function and inflammation. Cardiovasc Res. 2002; 55:714–726. PMID: 12176121.

19. 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; 107:3165–3169. PMID: 12796135.

20. Koh KK, Ahn JY, Jin DK, Yoon BK, Kim HS, Kim DS, et al. Effects of continuous combined hormone replacement therapy on inflammation in hypertensive and/or overweight postmenopausal women. Arterioscler Thromb Vasc Biol. 2002; 22:1459–1464. PMID: 12231566.

21. Vehkavaara S, Silveira A, Hakala-Ala-Pietilä T, Virkamäki A, Hovatta O, Hamsten A, et al. Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women. Thromb Haemost. 2001; 85:619–625. PMID: 11341495.

22. 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; 288:321–333. PMID: 12117397.

23. Rosano GM, Webb CM, Chierchia S, Morgani GL, Gabraele M, Sarrel PM, et al. Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women. J Am Coll Cardiol. 2000; 36:2154–2159. PMID: 11127455.

24. Yousuf O, Mohanty BD, Martin SS, Joshi PH, Blaha MJ, Nasir K, et al. High-sensitivity C-reactive protein and cardiovascular disease: a resolute belief or an elusive link? J Am Coll Cardiol. 2013; 62:397–408. PMID: 23727085.

25. Modena MG, Bursi F, Fantini G, Cagnacci A, Carbonieri A, Fortuna A, et al. Effects of hormone replacement therapy on C-reactive protein levels in healthy postmenopausal women: comparison between oral and transdermal administration of estrogen. Am J Med. 2002; 113:331–334. PMID: 12361820.

26. Frazier-Jessen MR, Kovacs EJ. Estrogen modulation of JE/monocyte chemoattractant protein-1 mRNA expression in murine macrophages. J Immunol. 1995; 154:1838–1845. PMID: 7836768.

27. Caulin-Glaser T, Watson CA, Pardi R, Bender JR. Effects of 17beta-estradiol on cytokine-induced endothelial cell adhesion molecule expression. J Clin Invest. 1996; 98:36–42. PMID: 8690801.

28. Vongpatanasin W, Tuncel M, Wang Z, Arbique D, Mehrad B, Jialal I. Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women. J Am Coll Cardiol. 2003; 41:1358–1363. PMID: 12706932.

29. Choi DS, Lee DY, Yoon BK. Effects of transdermal estrogen gel in postmenopausal Korean women. J Korean Soc Menopause. 2012; 18:113–118.

30. Scott RT Jr, Ross B, Anderson C, Archer DF. Pharmacokinetics of percutaneous estradiol: a crossover study using a gel and a transdermal system in comparison with oral micronized estradiol. Obstet Gynecol. 1991; 77:758–764. PMID: 2014092.

31. Kao PC, Shiesh SC, Wu TJ. Serum C-reactive protein as a marker for wellness assessment. Ann Clin Lab Sci. 2006; 36:163–169. PMID: 16682512.

32. Saito I, Maruyama K, Eguchi E. C-reactive protein and cardiovascular disease in East asians: a systematic review. Clin Med Insights Cardiol. 2015; 8(Suppl 3):35–42. PMID: 25698882.

33. Furness S, Roberts H, Marjoribanks J, Lethaby A. Hormone therapy in postmenopausal women and risk of endometrial hyperplasia. Cochrane Database Syst Rev. 2012; (8):CD000402. PMID: 22895916.

34. L'hermite M, Simoncini T, Fuller S, Genazzani AR. Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review. Maturitas. 2008; 60:185–201. PMID: 18775609.

35. L'Hermite M. HRT optimization, using transdermal estradiol plus micronized progesterone, a safer HRT. Climacteric. 2013; 16(Suppl 1):44–53. PMID: 23848491.