Progestins affect mechanism of estrogen-induced C-reactive protein stimulation.
OBJECTIVE
To determine whether the mechanisms of C-reactive protein production differ depending on the presence or absence of a progestin in the regimen.


METHODS
We examined data from the Postmenopausal Estrogen Progestin Intervention (PEPI) study, a 5-group (3 different combined estrogen-progestin regimens, conjugated equine estrogen-only, and placebo) randomized clinical trial. This substudy included 221 postmenopausal women assigned to active treatment groups who took at least 80% of pills and had stored plasma specimens available to assess 12-month changes in estrone, sex hormone binding globulin, interleukin (IL)-6, and C-reactive protein levels.


RESULTS
All treatments resulted in increases in estrone, sex hormone binding globulin, and C-reactive protein at 12 months compared with baseline values. In all progestin-containing groups, 12-month change in IL-6 was positively correlated with 12-month change in C-reactive protein (r between 0.34 and 0.65, each P <.010). By contrast, in the conjugated equine estrogen-only group, 12-month change in IL-6 was negatively correlated with 12-month change in C-reactive protein (r value -0.31, P = .055). In adjusted models predicting 12-month C-reactive protein change, an interaction between change in IL-6 and treatment group was highly significant (P=.0008-P <.0001) for each of the progestin-containing groups compared with the conjugated equine estrogen-only group. In the conjugated equine estrogen-only group, the change in C-reactive protein per unit increase in IL-6 was -0.88, whereas in the progestin-containing groups it ranged from 1.46 to 2.85 (P <.0001 for each comparison with conjugated equine estrogen-only).


CONCLUSIONS
Progestins in combination with conjugated equine estrogen potentiate the IL-6 (inflammatory)-mediated stimulation of C-reactive protein. These findings support the hypothesis that progestins plus estrogen, not estrogen alone, generate C-reactive protein through an inflammatory mechanism.
Reuben
David B
DB
Multicampus Program in Geriatric Medicine and Gerontology, David Geffen School of Medicine at University of California, Los Angeles 90095-1687, USA. dreuben@mednet.ucla.edu
Palla
Shana L
SL
Hu
Peifeng
P
Reboussin
Beth A
BA
Crandall
Carolyn
C
Herrington
David M
DM
Barrett-Connor
Elizabeth
E
Greendale
Gail A
GA
D002097:C-Reactive Protein / Q000378:metabolism*; D015914:Estrogen Replacement Therapy; D004966:Estrogens, Conjugated (USP) / Q000494:pharmacology*; D004970:Estrone / Q000097:blood; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D008875:Middle Aged; D017698:Postmenopause / Q000097:blood; D011372:Progestins / Q000494:pharmacology*; D016032:Randomized Controlled Trials as Topic; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism
D004966:Estrogens, Conjugated (USP); D015850:Interleukin-6; D011372:Progestins; D012738:Sex Hormone-Binding Globulin; D004970:Estrone; D002097:C-Reactive Protein; D017258:Medroxyprogesterone Acetate