Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women
Open accessAbstract
Objectives We investigated whether the route of estrogen replacement therapy (ET) is the major determinant of C-reactive protein (CRP) in postmenopausal women.Background Recent studies demonstrated that oral ET causes a sustained increase in CRP, implicating a proinflammatory effect. Because CRP is synthesized in the liver, we hypothesized that estrogen-induced CRP elevation is related to first-pass hepatic metabolism.Methods In 21 postmenopausal women, we conducted a randomized, crossover, placebo-controlled study to compare the effects of transdermal versus oral ET on CRP and inflammatory cytokines. We measured CRP, interleukin (IL)-1-beta, IL-6, and tumor necrosis factor-alpha before and after eight weeks of transdermal estradiol (E(2)) (100 microg/day), oral conjugated estrogen (CEE) (0.625 mg/day), or placebo. Insulin-like growth factor-1 (IGF-1), a hepatic-derived anabolic peptide, was also measured.Results Transdermal E(2) had no effect on CRP or IGF-1 levels. In contrast, eight weeks of oral conjugated estrogens caused a more than twofold increase in CRP and a significant reduction in IGF-1 (p < 0.01) in the same women. The magnitude of increase in CRP was inversely correlated to the decrease in IGF-1 (r = -0.49, p = 0.008). Neither transdermal E(2) nor oral CEE had any effects on the plasma concentrations of cytokines that promote CRP synthesis.Conclusions In postmenopausal women, oral but not transdermal ET increased CRP by a first-pass hepatic effect. An increase in CRP levels is accompanied by a reduction in IGF-1, an anti-inflammatory growth factor. Because CRP is a powerful predictor of an adverse prognosis in otherwise healthy postmenopausal women, the route of administration may be an important consideration in minimizing the adverse effects of ET on cardiovascular outcomes.
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Transdermal estrogen has not been reported to increase proinflammatory cytokines and procoagulant factors.
“Transdermal estrogen, on the other hand, has not been reported to increase proinflammatory cytokines and procoagulant factors [118–120].”
From Estrogen and thrombosis: a bench to bedside review (2020) · cites this paper as [120]
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Cites
Writing Group for the Women's Health Initiative Investigators (2002) · JAMA: The Journal of the American Medical Association · doi:10.1001/jama.288.3.321 · Cited by 15,889 · see citing works
Hulley, S. (1998) · JAMA · doi:10.1001/jama.280.7.605 · Cited by 6,216 · see citing works
Ridker, P. M., Hennekens, C. H., Buring, J. E., & Rifai, N. (2000) · New England Journal of Medicine · doi:10.1056/nejm200003233421202 · Cited by 5,850 · see citing works
The Design and Analysis of Clinical Experiments
Fleiss, J. L. (1999) · Wiley eBooks · doi:10.1002/9781118032923 · Cited by 4,819 · see citing works
Ridker, P. M., Rifai, N., Rose, L., Buring, J. E., & Cook, N. R. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa021993 · Cited by 3,604 · see citing works
Direct Proinflammatory Effect of C-Reactive Protein on Human Endothelial Cells
Pasceri, V., Willerson, J. T., & Yeh, E. T. H. (2000) · Circulation · doi:10.1161/01.cir.102.18.2165 · Cited by 1,941 · see citing works
Effects of Estrogen Replacement on the Progression of Coronary-Artery Atherosclerosis
Herrington, D. M., Reboussin, D. M., Brosnihan, K. B., Sharp, P. C., Shumaker, S. A., Snyder, T. E., Furberg, C. D., Kowalchuk, G. J., Stuckey, T. D., Rogers, W. J., et al. (2000) · New England Journal of Medicine · doi:10.1056/nejm200008243430801 · Cited by 1,242 · see citing works
Verma, S., Wang, C., Li, S., Dumont, A. S., Fedak, P. W. M., Badiwala, M. V., Dhillon, B., Weisel, R. D., Li, R., Mickle, D. A. G., et al. (2002) · Circulation · doi:10.1161/01.cir.0000029802.88087.5e · Cited by 1,052 · see citing works
Venugopal, S. K., Devaraj, S., Yuhanna, I. S., Shaul, P. W., & Jialal, I. (2002) · Circulation · doi:10.1161/01.cir.0000033116.22237.f9 · Cited by 849 · see citing works
Self-citationInflammatory Biomarkers, Hormone Replacement Therapy, and Incident Coronary Heart Disease
Pradhan, A. D., Manson, J. E., Rossouw, J. E., Siscovick, D. S., Mouton, C. P., Rifai, N., Wallace, R. B., Jackson, R. D., Pettinger, M. B., & Ridker, P. M. (2002) · JAMA · doi:10.1001/jama.288.8.980 · Cited by 680 · see citing works
Cushman, M., Legault, C., Barrett-Connor, E., Stefanick, M. L., Kessler, C., Judd, H. L., Sakkinen, P. A., & Tracy, R. P. (1999) · Circulation · doi:10.1161/01.cir.100.7.717 · Cited by 660 · see citing works
C-Reactive Protein in the Arterial Intima
Torzewski, M., Rist, C., Mortensen, R. F., Zwaka, T. P., Bienek, M., Waltenberger, J. L., Köenig, W., Schmitz, G., Hombach, V., & Torzewski, J. (2000) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.20.9.2094 · Cited by 581 · see citing works
WEISSBERGER, A. J., HO, K. K. Y., & LAZARUS, L. (1991) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-72-2-374 · Cited by 514 · see citing works
Hormone Replacement Therapy and Increased Plasma Concentration of C-Reactive Protein
Ridker, P. M., Hennekens, C. H., Rifai, N., Buring, J. E., & Manson, J. E. (1999) · Circulation · doi:10.1161/01.cir.100.7.713 · Cited by 442 · see citing works
Barrett-Connor, E. L. (1998) · BMJ · doi:10.1136/bmj.317.7156.457 · Cited by 402 · see citing works
Sesmilo, G., Biller, B. M. K., Llevadot, J., Hayden, D., Hanson, G., Rifai, N., & Klibanski, A. (2000) · Annals of Internal Medicine · doi:10.7326/0003-4819-133-2-200007180-00010 · Cited by 257 · see citing works
van Baal, M., Kenemans, P., van der Mooren, M. J., van Kessel, H. I., EMEIS, J. J., & Stehouwer, C. D. A. (1999) · Thrombosis and Haemostasis · doi:10.1055/s-0037-1614600 · Cited by 140 · see citing works
DeCensi, A., Omodei, U., Robertson, C., Bonanni, B., Guerrieri‐Gonzaga, A., Ramazzotto, F., Johansson, H. A., Mora, S., Sandri, M. T., Cazzaniga, M., et al. (2002) · Circulation · doi:10.1161/01.cir.0000028463.74880.ea · Cited by 119 · see citing works
Sesmilo, G., Fairfield, W. P., Katznelson, L. J., Pulaski, K., Freda, P. U., Bonert, V. S., Dimaraki, E. V., Stavrou, S., Vance, M. L., Hayden, D., et al. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.87.4.8364 · Cited by 116 · see citing works
Wakatsuki, A., Okatani, Y., Ikenoue, N., & Fukaya, T. (2002) · Circulation · doi:10.1161/hc1202.105945 · Cited by 97 · see citing works
Inflammatory cardiovascular risk markers in women with hypopituitarism
Sesmilo, G., Miller, K. K., Hayden, D., & Klibanski, A. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.12.8087 · Cited by 97 · see citing works
Jeschke, M. G., Barrow, R. E., & Herndon, D. N. (2000) · Annals of Surgery · doi:10.1097/00000658-200002000-00014 · Cited by 92 · see citing works
Sattar, N. A., Perera, M., SMALL, M. P., & Lumsden, M.-A. (1999) · The Lancet · doi:10.1016/s0140-6736(99)02079-6 · Cited by 84 · see citing works
Lou, H. X., Kodama, T., Zhao, Y. J., et al. (1996) · Circulation · doi:10.1161/01.cir.94.12.3355 · Cited by 62 · see citing works
Skouby, S. O., Gram, J., Andersen, L. F., Sidelmann, J. J., Petersen, K. R., & Jespersen, J. (2002) · American Journal of Obstetrics and Gynecology · doi:10.1067/mob.2002.122414 · Cited by 56 · see citing works
Giltay, E. J., Gooren, L. J., EMEIS, J. J., Kooistra, T., & Stehouwer, C. D. A. (2000) · Thrombosis and Haemostasis · doi:10.1055/s-0037-1614026 · Cited by 33 · see citing works
Changes in serum concentration and mRNA level of rat C-reactive protein
Wataru, N., Takakuwa, Y., & Higashi, T. (1994) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/0925-4439(94)90109-0 · Cited by 26 · see citing works
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Estrogen and thrombosis: a bench to bedside review
Abou-Ismail, M. Y., Citla Sridhar, D., & Nayak, L. (2020) · Thrombosis Research · doi:10.1016/j.thromres.2020.05.008 · Cited by 261 · see citing works
Goldstein, Z., Khan, M., Reisman, T., & Safer, J. D. (2019) · Journal of Blood Medicine · doi:10.2147/jbm.s166780 · Cited by 63 · see citing works
Effects of high dose oestrogen therapy on circulating inflammatory markers
Wilson, R., Spiers, A., Ewan, J., Johnson, P., Jenkins, C., & Carr, S. (2009) · Maturitas · doi:10.1016/j.maturitas.2009.01.009 · Cited by 59 · see citing works
Yildiz, M. F., Kumru, S., Godekmerdan, A., & Kutlu, S. (2005) · International Journal of Gynecology & Obstetrics · doi:10.1016/j.ijgo.2005.05.005 · Cited by 56 · see citing works
“Since intranasal and transdermal administrations of the estrogens did not elevate serum hs-CRP concentrations, it has been suggested that oral, but not transdermal, estrogens increased CRP by a firstpass hepatic effect [15].”
BackgroundD'Anna, R., Baviera, G., Corrado, F., Cancellieri, F., Crisafulli, A., & Squadrito, F. (2005) · Acta Obstetricia Et Gynecologica Scandinavica · doi:10.1111/j.0001-6349.2005.00661.x · Cited by 52 · see citing works
- Authors
- Vongpatanasin, W., Tuncel, M., Wang, Z., Arbique, D., Mehrad, B., & Jialal, I.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- University of California Davis Medical Center (US)
- Corresponding author
- Vongpatanasin, Wanpen
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2003-04
- Volume
- 41
- Issue
- 8
- Pages
- 1358-1363
- ISSN
- 0735-1097 (ISSN-L)
- OpenAlex
- W2137796794
- Cited by
- 153
- References
- 27
- Citations by year
- 2026: 5 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 5 · 2019: 2 · 2018: 2 · 2017: 3 · 2016: 3 · 2015: 3 · 2014: 8 · 2013: 2 · 2012: 5
- FWCI
- 13.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1k23rr016321-01a1)
- U.S. Public Health Service (M01-RR00633)
- National Center for Research Resources (M01RR000633, K23RR16321, M01 RR00633)
- NIH Clinical Center
- National Center for Complementary and Integrative Health (K-24AT00596, K24AT000596)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Keywords
- estrogen replacement therapy, transdermal estradiol, C-reactive protein, postmenopausal women, insulin-like growth factor I, inflammatory cytokines, hepatic first-pass metabolism, route of administration, inflammation, cardiovascular risk
- MeSH terms
- Administration, Cutaneous, Administration, Oral, Analysis of Variance, C-Reactive Protein, Estrogens, Female, Humans, Insulin-Like Growth Factor I, Lipids, Liver, Menopause, Middle Aged, Estrogen Replacement Therapy, Cross-Over Studies
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