Increased estrogen formation and estrogen to androgen ratio in the synovial fluid of patients with RA

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J Rheumatol. 2003 Dec; 30(12): 2597-605.

Increased estrogen formation and estrogen to androgen ratio in the

synovial fluid of patients with rheumatoid arthritis.

Castagnetta LA, Carruba G, Granata OM, Stefano R, Miele M, Schmidt M,

Cutolo M, Straub RH.

Department of Experimental Oncology and Clinical Application, University

of Palermo, Palermo, Italy.

OBJECTIVE: It has been proposed that physiologic levels of estrogens

stimulate immune responses whereas androgens suppress inflammatory

reactions. Thus, prevalence of synovial androgens relative to estrogens

would be favorable in rheumatoid arthritis (RA). We investigated

synovial fluid (SF) concentrations of several estrogens and androgens

and conversion products of the sex steroid precursor

dehydroepiandrosterone (DHEA) in supernatants of mixed synoviocytes.

METHODS: SF steroid concentrations were measured by high performance

liquid chromotography and mass spectrometry in 12 patients with RA and 8

subjects with traumatic knee injury (noninflammatory controls).

Conversion of DHEA to downstream hormones was measured by thin-layer

chromatography and phosphorimaging detection in 3 patients with RA and 3

patients with osteoarthritis (OA). RESULTS: Overall, SF concentration of

free estrogens tended to be higher in RA patients versus controls (p <

0.06). Molar ratio of free SF estrogens/free SF androgens was elevated

in RA compared to controls (1.17 +/- 0.32 vs 0.29 +/- 0.08, without

unit; p = 0.017). The free SF concentration of the precursor

androstenedione was significantly higher in RA patients than in controls

(104.6 +/- 32.6 vs 30.4 +/- 0.4 ng/ml; p = 0.011), and SF estrone the

aromatase conversion product of androstenedione was also elevated in RA

compared to controls (13.6 +/- 2.6 vs 6.6 +/- 0.8 ng/ml; p = 0.035). The

biologically active estrogen derivatives, 16a-hydroxyestrone and

4-hydroxyestradiol, were both higher in RA compared to controls (p =

0.085 and p = 0.044, respectively). In mixed RA synoviocytes, DHEA

conversion yielded high local levels of 17beta-estradiol (708 pmol/l =

0.193 ng/ml) compared to testosterone (88 pmol/l = 0.026 ng/ml).

CONCLUSION: SF levels of estrogens relative to androgens are

significantly elevated, while those of androgens are markedly reduced,

in patients with RA compared to controls. This imbalance is most

probably due to increased aromatase activity. Thus, an available steroid

precursor, such as DHEA, may be rapidly converted to proinflammatory

estrogens in the synovial tissue, which may in turn stimulate the

inflammatory process in patients with RA.

PMID: 14719200

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