Effect of estrogen versus testosterone on circulating osteoprotegerin and other cytokine levels in normal elderly men.
Recent studies have shown that estrogen (E) likely plays a dominant role in inhibiting bone resorption in normal elderly men. Because both E and T inhibit osteoclast development and activity, stimulate osteoclast apoptosis, and inhibit osteoblast production of IL-6, it is unclear why T is less potent than E in inhibiting bone resorption in vivo. Osteoprotegerin (OPG) binds to and inactivates RANKL, the final mediator of osteoclastogenesis. In vitro, OPG production is stimulated by E, and preliminary data suggest that T has the opposite effect. Thus, we analyzed serum for OPG levels from a study in which 59 elderly men (mean age, 68 yr) were made acutely hypogonadal using a GnRH agonist and were also placed on an aromatase inhibitor to block conversion of androgens to estrogens. They were studied first under conditions of physiologic E and T replacement, and then randomized to no replacement, replacement with E alone, T alone, or both E and T. E alone resulted in an 18.6 +/- 7.9% (mean +/- SEM) increase in serum OPG levels (P < 0.05), whereas T alone tended to decrease OPG levels (by 10.0 +/- 8.5%; P < 0.05 compared with E alone). Using a two-factor ANOVA model, there was a highly significant T effect (P = 0.006) on decreasing serum OPG levels. Serum TNF-alpha, IL-6, and IL-6 soluble receptor levels increased significantly in the men who had both E and T withdrawn, and the increases in TNF-alpha and IL-6sR were absent in the men treated with either E or T. However, due to the variability in these cytokine measurements, the ANOVA models were not significant for E or T effects. Taken together, these data suggest that in vivo, T decreases OPG levels, whereas E tends to have the opposite effect. These differential effects of E vs. T on OPG production may explain, at least in part, why T has weaker effects than E on inhibiting bone resorption in vivo in humans.
Khosla
Sundeep
S
Endocrine Research Unit, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, MN 55905, USA. khosla.sundeep@mayo.edu
Atkinson
Elizabeth J
EJ
Dunstan
Colin R
CR
O'Fallon
W M
WM
D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D001862:Bone Resorption / Q000378:metabolism; D016207:Cytokines / Q000097:blood*; D004967:Estrogens / Q000494:pharmacology*; D006023:Glycoproteins / Q000097:blood*; D012739:Gonadal Steroid Hormones / Q000494:pharmacology*; D006801:Humans; D008297:Male; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear / Q000097:blood*; D018124:Receptors, Tumor Necrosis Factor; D012016:Reference Values; D013739:Testosterone / Q000494:pharmacology*
D015415:Biomarkers; D016207:Cytokines; D004967:Estrogens; D006023:Glycoproteins; D012739:Gonadal Steroid Hormones; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506030:TNFRSF11B protein, human; D013739:Testosterone