C-Reactive Protein and Hormone Replacement Therapy
To the Editor:
Two recent articles in Circulation1 2 described increases in C-reactive protein (CRP) concentration with hormone replacement therapy (HRT) that consisted of oral estrogen or estrogen plus progestin preparations. The authors argued that such a proinflammatory effect of HRT may help to explain the increased risk of cardiovascular disease in the first year of treatment with HRT, as observed in the recent HERS trial (Heart and Estrogen-progestin Replacement Study).
In contrast, in related research, we have found that in a double-blind trial of 33 women with type 2 diabetes, a combination of transdermal estradiol (80 μg) and continuous oral norethisterone (1 mg) significantly reduced CRP concentrations relative to placebo after 6 months of therapy.3 What could be the reasons for the discordant results observed?
There were differences in design between the studies. The PEPI study1 was a 3-year randomized trial, whereas Ridker et al presented cross-sectional results from the Women’s Health Study (WHS).2 In addition, the women in our study were all diabetics, and CRP levels are known to be significantly raised in diabetics. Our sample size was smaller than the American studies. Nonetheless, we propose that beyond methodological issues, there are important biological explanations for the differences in the direction of CRP after HRT.
First, in our study, the estrogen component was delivered transdermally (not orally1 2 ), thus bypassing the hepatic first-pass metabolism effect. This may be critical, because plasma CRP concentrations are thought to reflect increased hepatic synthesis rather than systemic clearance. Second, the progestogen used in our study was oral norethisterone, a 19 nortestosterone progestin. This preparation has both progestogenic and androgenic effects. This is noteworthy because both progestogens and androgens generally display anti-inflammatory effects in other tissues.4 It is conceivable that similar effects occur in the liver.
Interestingly, triglyceride concentrations are also reduced with oral norethisterone (in general, the progestin effect may be triglyceride neutral, and androgens diminish circulating triglyceride concentrations), whereas oral estrogens increase hepatic triglyceride synthesis.5 In support of a net progestogenic/androgenic hepatic effect in our study, triglyceride concentrations were significantly reduced.
We suggest that not all HRTs are alike in their effect on CRP concentrations. The route of delivery of the estrogen, the relative androgenicity of the progestogen, and the chronicity of use might be important in this respect. It would be interesting to examine whether HRT preparations, which reduce CRP concentrations, avoid a transient increase in cardiovascular risk potentially associated with preparations containing oral estrogens. If so, this route of delivery might be more desirable for women with existing coronary heart disease who are considering HRT.
- Copyright © 2000 by American Heart Association
Cushman M, Legault C, Barrett-Connor E, et al. Effect of postmenopausal hormones on inflammation-sensitive proteins: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Study. Circulation. 1999;100:717–722.
Ridker PM, Hennekens CH, Rifai N, et al. Hormone replacement therapy and increased plasma concentration of C-reactive protein. Circulation. 1999;100:713–716.
We thank Sattar and colleagues for their letter concerning our article.R1 We were intrigued by their report of transdermal estradiol plus oral norethisterone in women with type 2 diabetes; however, these preliminary results should be interpreted cautiously. Although not statistically significant, among the 33 women studied, baseline C-reactive protein concentration was higher in the estrogen group than in the placebo group (4.97 versus 4.13 mg/L). This difference may have led to bias toward a reduction of C-reactive protein in the treatment group. Nonetheless, we agree with Sattar et al that their data support a hypothesis that the rise in C-reactive protein with oral estrogens, now observed in several experimental studies,R1 R2 R3 R4 might relate to first-pass effects in the liver.
Synthesis of C-reactive protein in the liver is primarily regulated by interleukin-6 (IL-6). Adipocytes provide a major source of IL-6, supporting the importance of further study of type 2 diabetes and obesity in relation to inflammation, hormones, and coronary heart disease risk. One preliminary report confirmed a rise in C-reactive protein with estrogen, and this was associated with a nonsignificant increase in plasma IL-6.R4 This suggests against a first-pass liver effect on C-reactive protein. Further study of the effects of different hormone therapies on IL-6 and other cytokines may shed light on this issue, and diabetic women should be included in such studies.
In the PEPI trial and in our cross-sectional report from the Cardiovascular Health Study (CHS),R5 there was insufficient power to detect differences in C-reactive protein by orally administered hormone therapy among diabetics. Since the latter report, C-reactive protein was measured in the entire CHS cohort, so we can provide further insight into the relationship of hormone therapy and inflammation among diabetics. Among 1464 women aged 65 years and older who had diabetes or impaired glucose tolerance, the 172 women using oral postmenopausal estrogen had a geometric mean C-reactive protein concentration of 2.89 mg/L compared with 2.30 mg/L in nonusers (P=0.003). Among diabetics, comparing the 62 users and 572 nonusers, respective mean C-reactive protein was 3.55 versus 2.85 mg/L (P=0.07). Therefore, for oral administration in this cross-sectional analysis of long-term users, associations of hormone therapy and C-reactive protein appear to be similar in diabetics and nondiabetics.
Cushman M, Legault C, Barrett-Connor E, et al. Effect of postmenopausal hormones on inflammation-sensitive proteins: the Postmenopausal Estrogen/Progestin Interventions (PEPI) study. Circulation. 1999;100:717–722.
de Valk-de Roo GW, Stehouwer CDA, Meijer P, et al. Both raloxifene and estrogen reduce major cardiovascular risk factors in healthy postmenopausal women: a 2-year, placebo-controlled study. Arterioscler Thromb Vasc Biol. 1999;19:2993–3000.
Cox DA, Sashegyi A, Paul S, et al. Effects of raloxifene and hormone replacement therapy on markers of inflammation in healthy postmenopausal women. Circulation. 1999;100(suppl I):I-826. Abstract.
Cushman M, Meilahn EN, Psaty BM, et al. Hormone replacement therapy, inflammation, and hemostasis in elderly women. Arterioscler Thromb Vasc Biol. 1999;19:893–899.