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Proc Natl Acad Sci U S A. Jun 15, 1991; 88(12): 5134–5138.

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


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 alpha (TNF-alpha) 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-alpha 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.

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  • Richelson LS, Wahner HW, Melton LJ, 3rd, Riggs BL. Relative contributions of aging and estrogen deficiency to postmenopausal bone loss. N Engl J Med. 1984 Nov 15;311(20):1273–1275. [PubMed]
  • Nilas L, Christiansen C. Bone mass and its relationship to age and the menopause. J Clin Endocrinol Metab. 1987 Oct;65(4):697–702. [PubMed]
  • Riggs BL, Melton LJ., 3rd Evidence for two distinct syndromes of involutional osteoporosis. Am J Med. 1983 Dec;75(6):899–901. [PubMed]
  • Nilas L, Gotfredsen A, Hadberg A, Christiansen C. Age-related bone loss in women evaluated by the single and dual photon technique. Bone Miner. 1988 Apr;4(1):95–103. [PubMed]
  • Genant HK, Cann CE, Ettinger B, Gordan GS. Quantitative computed tomography of vertebral spongiosa: a sensitive method for detecting early bone loss after oophorectomy. Ann Intern Med. 1982 Nov;97(5):699–705. [PubMed]
  • Ettinger B, Genant HK, Cann CE. Long-term estrogen replacement therapy prevents bone loss and fractures. Ann Intern Med. 1985 Mar;102(3):319–324. [PubMed]
  • Lindsay R, Hart DM, Forrest C, Baird C. Prevention of spinal osteoporosis in oophorectomised women. Lancet. 1980 Nov 29;2(8205):1151–1154. [PubMed]
  • Selby PL, Peacock M, Barkworth SA, Brown WB, Taylor GA. Early effects of ethinyloestradiol and norethisterone treatment in post-menopausal women on bone resorption and calcium regulating hormones. Clin Sci (Lond) 1985 Sep;69(3):265–271. [PubMed]
  • Morel G, Boivin G, David L, Dubois PM, Meunier PJ. Immunocytochemical evidence for endogenous calcitonin and parathyroid hormone in osteoblasts from the calvaria of neonatal mice. Absence of endogenous estradiol and estradiol receptors. Cell Tissue Res. 1985;240(1):89–93. [PubMed]
  • Eriksen EF, Colvard DS, Berg NJ, Graham ML, Mann KG, Spelsberg TC, Riggs BL. Evidence of estrogen receptors in normal human osteoblast-like cells. Science. 1988 Jul 1;241(4861):84–86. [PubMed]
  • Komm BS, Terpening CM, Benz DJ, Graeme KA, Gallegos A, Korc M, Greene GL, O'Malley BW, Haussler MR. Estrogen binding, receptor mRNA, and biologic response in osteoblast-like osteosarcoma cells. Science. 1988 Jul 1;241(4861):81–84. [PubMed]
  • Raisz LG. Local and systemic factors in the pathogenesis of osteoporosis. N Engl J Med. 1988 Mar 31;318(13):818–828. [PubMed]
  • Beutler B, Greenwald D, Hulmes JD, Chang M, Pan YC, Mathison J, Ulevitch R, Cerami A. Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature. 1985 Aug 8;316(6028):552–554. [PubMed]
  • Old LJ. Tumor necrosis factor (TNF). Science. 1985 Nov 8;230(4726):630–632. [PubMed]
  • Dinarello CA. Biology of interleukin 1. FASEB J. 1988 Feb;2(2):108–115. [PubMed]
  • Metcalf D. The molecular biology and functions of the granulocyte-macrophage colony-stimulating factors. Blood. 1986 Feb;67(2):257–267. [PubMed]
  • Smith KA, Lachman LB, Oppenheim JJ, Favata MF. The functional relationship of the interleukins. J Exp Med. 1980 Jun 1;151(6):1551–1556. [PMC free article] [PubMed]
  • Beutler B, Cerami A. Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature. 1986 Apr 17;320(6063):584–588. [PubMed]
  • Sieff CA. Hematopoietic growth factors. J Clin Invest. 1987 Jun;79(6):1549–1557. [PMC free article] [PubMed]
  • Thomson BM, Saklatvala J, Chambers TJ. Osteoblasts mediate interleukin 1 stimulation of bone resorption by rat osteoclasts. J Exp Med. 1986 Jul 1;164(1):104–112. [PMC free article] [PubMed]
  • Thomson BM, Mundy GR, Chambers TJ. Tumor necrosis factors alpha and beta induce osteoblastic cells to stimulate osteoclastic bone resorption. J Immunol. 1987 Feb 1;138(3):775–779. [PubMed]
  • Gowen M, Wood DD, Russell RG. Stimulation of the proliferation of human bone cells in vitro by human monocyte products with interleukin-1 activity. J Clin Invest. 1985 Apr;75(4):1223–1229. [PMC free article] [PubMed]
  • Canalis E. Interleukin-1 has independent effects on deoxyribonucleic acid and collagen synthesis in cultures of rat calvariae. Endocrinology. 1986 Jan;118(1):74–81. [PubMed]
  • Tashjian AH, Jr, Voelkel EF, Lazzaro M, Goad D, Bosma T, Levine L. Tumor necrosis factor-alpha (cachectin) stimulates bone resorption in mouse calvaria via a prostaglandin-mediated mechanism. Endocrinology. 1987 May;120(5):2029–2036. [PubMed]
  • Boyce BF, Aufdemorte TB, Garrett IR, Yates AJ, Mundy GR. Effects of interleukin-1 on bone turnover in normal mice. Endocrinology. 1989 Sep;125(3):1142–1150. [PubMed]
  • MacDonald BR, Mundy GR, Clark S, Wang EA, Kuehl TJ, Stanley ER, Roodman GD. Effects of human recombinant CSF-GM and highly purified CSF-1 on the formation of multinucleated cells with osteoclast characteristics in long-term bone marrow cultures. J Bone Miner Res. 1986 Apr;1(2):227–233. [PubMed]
  • Pfeilschifter J, Chenu C, Bird A, Mundy GR, Roodman GD. Interleukin-1 and tumor necrosis factor stimulate the formation of human osteoclastlike cells in vitro. J Bone Miner Res. 1989 Feb;4(1):113–118. [PubMed]
  • Pacifici R, Rifas L, Teitelbaum S, Slatopolsky E, McCracken R, Bergfeld M, Lee W, Avioli LV, Peck WA. Spontaneous release of interleukin 1 from human blood monocytes reflects bone formation in idiopathic osteoporosis. Proc Natl Acad Sci U S A. 1987 Jul;84(13):4616–4620. [PMC free article] [PubMed]
  • Pacifici R, Rifas L, McCracken R, Vered I, McMurtry C, Avioli LV, Peck WA. Ovarian steroid treatment blocks a postmenopausal increase in blood monocyte interleukin 1 release. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2398–2402. [PMC free article] [PubMed]
  • Pacifici R, Rupich R, Vered I, Fischer KC, Griffin M, Susman N, Avioli LV. Dual energy radiography (DER): a preliminary comparative study. Calcif Tissue Int. 1988 Sep;43(3):189–191. [PubMed]
  • Pacifici R, Rupich R, Griffin M, Chines A, Susman N, Avioli LV. Dual energy radiography versus quantitative computer tomography for the diagnosis of osteoporosis. J Clin Endocrinol Metab. 1990 Mar;70(3):705–710. [PubMed]
  • Brown CB, Hart CE, Curtis DM, Bailey MC, Kaushansky K. Two neutralizing monoclonal antibodies against human granulocyte-macrophage colony-stimulating factor recognize the receptor binding domain of the molecule. J Immunol. 1990 Mar 15;144(6):2184–2189. [PubMed]
  • Cuturi MC, Murphy M, Costa-Giomi MP, Weinmann R, Perussia B, Trinchieri G. Independent regulation of tumor necrosis factor and lymphotoxin production by human peripheral blood lymphocytes. J Exp Med. 1987 Jun 1;165(6):1581–1594. [PMC free article] [PubMed]
  • Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983 Dec 16;65(1-2):55–63. [PubMed]
  • Garman RD, Jacobs KA, Clark SC, Raulet DH. B-cell-stimulatory factor 2 (beta 2 interferon) functions as a second signal for interleukin 2 production by mature murine T cells. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7629–7633. [PMC free article] [PubMed]
  • Wood DD, Cameron PM. The relationship between bacterial endotoxin and human B cell-activating factor. J Immunol. 1978 Jul;121(1):53–60. [PubMed]
  • PROCKOP DJ, UDENFRIEND S. A specific method for the analysis of hydroxyproline in tissues and urine. Anal Biochem. 1960 Nov;1:228–239. [PubMed]
  • Price PA, Nishimoto SK. Radioimmunoassay for the vitamin K-dependent protein of bone and its discovery in plasma. Proc Natl Acad Sci U S A. 1980 Apr;77(4):2234–2238. [PMC free article] [PubMed]
  • Brown JP, Delmas PD, Malaval L, Edouard C, Chapuy MC, Meunier PJ. Serum bone Gla-protein: a specific marker for bone formation in postmenopausal osteoporosis. Lancet. 1984 May 19;1(8386):1091–1093. [PubMed]
  • Dinarello CA, Mier JW. Lymphokines. N Engl J Med. 1987 Oct 8;317(15):940–945. [PubMed]
  • Sullivan R, Gans PJ, McCarroll LA. The synthesis and secretion of granulocyte-monocyte colony-stimulating activity (CSA) by isolated human monocytes: kinetics of the response to bacterial endotoxin. J Immunol. 1983 Feb;130(2):800–807. [PubMed]
  • Hesketh PJ, Sullivan R, Valeri CR, McCarroll LA. The production of granulocyte-monocyte colony-stimulating activity by isolated human T lymphocyte subpopulations. Blood. 1984 May;63(5):1141–1146. [PubMed]
  • Pacifici R, Rothstein M, Rifas L, Lau KH, Baylink DJ, Avioli LV, Hruska K. Increased monocyte interleukin-1 activity and decreased vertebral bone density in patients with fasting idiopathic hypercalciuria. J Clin Endocrinol Metab. 1990 Jul;71(1):138–145. [PubMed]
  • Fakih H, Baggett B, Holtz G, Tsang KY, Lee JC, Williamson HO. Interleukin-1: a possible role in the infertility associated with endometriosis. Fertil Steril. 1987 Feb;47(2):213–217. [PubMed]
  • Sambrook PN, Reeve J. Bone disease in rheumatoid arthritis. Clin Sci (Lond) 1988 Mar;74(3):225–230. [PubMed]
  • Horowitz MC, Coleman DL, Flood PM, Kupper TS, Jilka RL. Parathyroid hormone and lipopolysaccharide induce murine osteoblast-like cells to secrete a cytokine indistinguishable from granulocyte-macrophage colony-stimulating factor. J Clin Invest. 1989 Jan;83(1):149–157. [PMC free article] [PubMed]
  • Sisson SD, Dinarello CA. Production of interleukin-1 alpha, interleukin-1 beta and tumor necrosis factor by human mononuclear cells stimulated with granulocyte-macrophage colony-stimulating factor. Blood. 1988 Oct;72(4):1368–1374. [PubMed]
  • Gulshan S, McCruden AB, Stimson WH. Oestrogen receptors in macrophages. Scand J Immunol. 1990 Jun;31(6):691–697. [PubMed]
  • Polan ML, Daniele A, Kuo A. Gonadal steroids modulate human monocyte interleukin-1 (IL-1) activity. Fertil Steril. 1988 Jun;49(6):964–968. [PubMed]
  • Polan ML, Loukides J, Nelson P, Carding S, Diamond M, Walsh A, Bottomly K. Progesterone and estradiol modulate interleukin-1 beta messenger ribonucleic acid levels in cultured human peripheral monocytes. J Clin Endocrinol Metab. 1989 Dec;69(6):1200–1206. [PubMed]
  • Ralston SH, Russell RG, Gowen M. Estrogen inhibits release of tumor necrosis factor from peripheral blood mononuclear cells in postmenopausal women. J Bone Miner Res. 1990 Sep;5(9):983–988. [PubMed]
  • Pacifici R, Carano A, Santoro SA, Rifas L, Jeffrey JJ, Malone JD, McCracken R, Avioli LV. Bone matrix constituents stimulate interleukin-1 release from human blood mononuclear cells. J Clin Invest. 1991 Jan;87(1):221–228. [PMC free article] [PubMed]
  • Dinarello CA, Ikejima T, Warner SJ, Orencole SF, Lonnemann G, Cannon JG, Libby P. Interleukin 1 induces interleukin 1. I. Induction of circulating interleukin 1 in rabbits in vivo and in human mononuclear cells in vitro. J Immunol. 1987 Sep 15;139(6):1902–1910. [PubMed]
  • Beksaç MS, Kişnişci HA, Cakar AN, Beksaç M. The endocrinological evaluation of bilateral and unilateral oophorectomy in premenopausal women. Int J Fertil. 1983;28(4):219–224. [PubMed]

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