Effect of surgical menopause and estrogen replacement on cytokine release from human blood mononuclear cells.

Abstract

To determine whether mononuclear cell secretory products contribute to the changes in bone turnover that characterize the development of postmenopausal osteoporosis, we evaluated the effects of oophorectomy and subsequent estrogen replacement on the spontaneous secretion of interleukin 1 (IL-1) and tumor necrosis factor a (TNF-a) and on the phytohemagglutinin A-induced secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) from peripheral blood mononuclear cells. In 15 healthy premenopausal women who underwent oophorectomy, increases in GM-CSF activity were observed as early as 1 week after surgery, whereas elevations in IL-1 and TNF-a and in hydroxyproline/creatinine and calcium/creatinine ratios, two urinary indices of bone resorption, were detectable 2 weeks after the surgical procedure. Six of the oophorectomized women received no estrogen therapy after surgery and in these subjects hydroxyproline/creatinine and calcium/creatinine ratios plateaued 6 weeks postoperatively, and all three cytokines reached the highest levels 8 weeks after oophorectomy, when the study ended. In the remaining 9 women, who were started on estrogen replacement therapy 4 weeks after oophorectomy, decreases in the indices of bone resorption paralleled decreases in the secretion of the cytokines, with lower levels detected after 2 weeks of therapy. In the women who did not receive estrogen therapy, circulating osteocalcin, a marker of bone formation, increased beyond preoperative levels 8 weeks after oophorectomy, whereas in the estrogen-treated subjects osteocalcin remained unchanged in the entire study period. In 9 female controls who underwent simple hysterectomy, cytokine release and biochemical indices of bone turnover did not change after surgery. These data indicate that changes in estrogen status in vivo are associated with the secretion of mononuclear cell immune factors in vitro and suggest that alterations in the local production of bone-acting cytokines may underlie changes in bone turnover caused by surgically induced menopause and estrogen replacement.Postmenopausal osteoporosis, a common disorder characterized by a decreased bone mass and increased fracture risk (1), stems from an accelerated loss of bone that begins after natural or surgically induced menopause and progresses rapidly for 5 or 10 years thereafter (2, 3). That estrogen deficiency plays a major role in this condition is well supported by the higher prevalence of osteoporosis in women than in men (4), by the increase in the rate of bone mineral loss detectable by bone densitometry after artificial or natural menopause (5, 6), and by the protective effect of estrogen replacement with respect to both bone mass loss and fracture incidence (7,8). Although the bone-sparing effect of estrogen appears to be related to an inhibitory effect on bone resorption (9), the mechanism of the estrogen response remains unknown.The discovery of estrogen receptors in osteoblasts (10-12) and osteoclasts (13) suggests that a direct mechanism(s) may be in...

A distinctive role of the leukotriene B 4 receptor BLT1 in osteoclastic activity during bone loss

“…Estrogen withdrawal after ovariectomy or natural menopause is associated with increased production of TNF-␣ and IL-1 (37,38), both of which increase LTB 4 production in neutrophils (44) and macrophages (45). LPS was also reported to increase LTB 4 production in both cell types (46,47).…”

Circulating miR-21, miR-146a and Fas ligand respond to postmenopausal estrogen-based hormone replacement therapy – A study with monozygotic twin pairs

“…Several ex vivo studies have shown that estrogen deficiency causes spontaneous increase in pro-inflammatory cytokine levels, such as interleukin 1 (IL-1), interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α) in circulating monocytes (Pacifici, et al 1989, Pacifici, et al 1991, bone marrow macrophages (Jilka, et al 1992, Bismar, et al 1995 and osteoblasts (Passeri, et al 1993). In contrast, in vivo studies in tissue samples or circulation have not been able to clearly demonstrate the effects of estrogen deficiency on pro-inflammatory cytokines.…”

Interleukin-1.BETA. Stimulates Transendothelial Mobilization of Human Peripheral Blood Mononuclear Cells with a Potential to Differentiate into Osteoclasts in the Presence of Osteoblasts.

“…Several studies suggested that increased IL-1 production by human peripheral blood mononuclear cells (PBMCs) is responsible for development of osteoporosis [12,13]. It has been also reported that increased osteoclastogenesis and bone resorption in ovariectomized mice was inhibited by IL-1 receptor antagonists, suggesting that endogenous IL-1 plays an important role in osteoclastic bone resorption in vivo [14].…”

“…Monocyte infiltration is thought to be triggered by various chemoattractants and cytokines including IL-1 [18,19]. Increased secretion levels of IL-1 activity by PBMCs have been reported in postmenopausal women [13]. Concentration levels of IL-1 secreted by PBMCs from patients with periodontal disease [22] and those in tissues from sites of periodontal disease [1] are 0.45-13.00 ng/ml/ 106 cells/24 h and approximately 11 ng/ml, respectively.…”