Follicle-stimulating hormone, interleukin-1, and bone density in adult women

Abstract

Recent studies have indicated that follicle-stimulating hormone (FSH) promotes bone loss. The present study tested the hypothesis that FSH enhances the activity of bone-resorbing cytokines [interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and IL-6], either by inducing their secretion or by altering their receptor expression. Thirty-six women between the ages of 20 and 50 were assessed for bone mineral density (BMD), reproductive hormone, cytokine ligand and soluble receptor concentrations, and surface expression of cytokine receptors on monocytes. In addition, isolated mononuclear cells were incubated in vitro with exogenous FSH. Univariate regression analyses indicated that BMD was inversely related to serum FSH (r = -0.29 to -0.51, P = 0.03-0.001, depending upon the skeletal site). Physical activity and body composition were also identified as significant factors by multiple regressions. Exogenous FSH induced isolated cells to secrete IL-1beta, TNF-alpha, and IL-6 in proportion to the surface expression of FSH receptors on the monocytes. Endogenous (serum) FSH concentrations correlated with the circulating concentrations of these cytokines. None of these individual cytokines was related to BMD, but the IL-1beta to IL-1 receptor antagonist (IL-1Ra) ratio was inversely related to BMD (r = -0.53, P = 0.002) in all but the most physically active women, who had significantly lower expression of IL-1 type I receptors relative to type II (decoy receptors, P = 0.01). Physical activity also correlated positively with secretion of inhibitory soluble IL-1 receptors (r = 0.53, P = 0.003). Moreover, IL-1Ra correlated strongly with percent body fat (r = 0.66, P < 0.0001). These results indicate that BMD is related to FSH concentration, physical activity, and body composition. Although each of these factors likely has direct effects on bone, the present study suggests that each may also influence BMD by modulating the activity of the osteoresorptive cytokine IL-1beta.

Fig. 1.

A: serum concentrations of follicle-stimulating hormone (FSH; ●) and luteinizing hormone (LH; ○) plotted by age. The line indicates the regression of FSH vs. age for women ≤45 yr old. B: serum concentrations of estradiol (●) and progesterone (○) plotted by age. The line indicates the regression of estradiol vs. age for women ≤45 yr old. All women were tested within the first 8 days of the follicular phase except two: these perimenopausal women with irregular cycles are indicated by triangles.

Fig. 2.

Bone mineral density (BMD) vs. serum FSH concentration. Solid line, regression for all subjects; broken line, regression for subjects ≤45 years of age. A: total BMD, all subjects: r = −0.38, P = 0.023, ≤45 yr: r = −0.44, P = 0.02. B: femoral neck BMD, all subjects: r = −0.41, P = 0.01, ≤45 yr: r = −0.42, P = 0.03. C: total hip BMD, all subjects: r = −0.36, P = 0.03, ≤45 yr: r = −0.37, P = 0.05. D: lumbar spine BMD, all subjects: r = −0.52, P = 0.001, ≤45 yr: r = −0.31, P = 0.10. Women with regular cycles tested within the first 8 days of the follicular phase are indicated by circles; perimenopausal women with irregular cycles are indicated by triangles.

Fig. 3.

Representative examples of FSH-induced secretion of interleukin (IL)-1β (A) and tumor necrosis factor (TNF)-α (B) by isolated mononuclear cells.

Fig. 4.

Expression of FSH receptors on monocytes. A: scatterplot of CD14⁺ cells (FL4) stained with isotype control. B: scatterplot of CD14⁺ cells stained with anti-FSH receptor (FL2); C: histograms of the isotype control data and the anti-FSH receptor data (shaded area).

Fig. 5.

FSH-induced cytokine secretion plotted as a function of FSH receptor expression on monocytes. A: IL-1β (r = 0.44, P = 0.048); B: TNF-α (r = 0.45, P = 0.042); C: IL-6 (r = 0.40, P = 0.075). Secretion is expressed as the log of the area under the dose-response curves (AUC), as shown in Fig. 3.

Fig. 6.

Relation between circulating IL-1β and FSH concentrations (r = 0.40, P = 0.02).

Fig. 7.

Total BMD plotted as a function of the serum IL-1β/IL-1 receptor antagonist (IL-1Ra) ratio. The solid line indicates the regression for the physically less-active women (●, r = −0.67, P = 0.0007). ○ (broken line), women in the top tertile of leisure time physical activity (≥180 min/wk, P not significant).

Fig. 8.

The ratio of signaling [IL-1 receptor type I (IL-1RI)] to decoy [IL-1 receptor type II (IL-1RII)] receptor expression on monocytes isolated from the upper tertile of physical activity (high, ≥180 min/wk) compared with the middle and lower tertiles (low). *P = 0.01.

Fig. 9.

Association of leisure time physical activity with secretion of soluble IL-1RI (A) (r = 0.525, P = 0.005) and soluble IL-1RII (B) (r = 0.534, P = 0.003).

Fig. 10.

Association between plasma leptin and IL-1Ra (r = 0.70, P < 0.0001).