Effects of the natural and artificial menstrual cycle on the production of osteoprotegerin and the bone resorptive cytokines IL-1beta and IL-6

Calcif Tissue Int. 2003 Jan;72(1):18-23. doi: 10.1007/s00223-002-2037-y. Epub 2002 Oct 21.


Bone remodelling changes within the menstrual cycle. Though the luteal phase is accompanied by decreased bone resorption, it is also paradoxically a time of increased production of bone resorptive cytokines. The present study examined the hypothesis that changes in serum osteoprotegerin (OPG) within the menstrual cycle prevent the increase in bone remodelling, which would otherwise have been the result of the luteal increase in the capacity for producing resorptive cytokines. The study population consisted of healthy female volunteers: premenopausal women (n = 11, mean age 39.4 y +/- 6.1) without cycle irregularities. Postmenopausal women (n = 11, mean age 56.8 y +/- 3.6) receiving cyclic HRT (estradiol and noretisterone acetate). Luteal and follicular phase blood samples were diluted and cultured for 24 hours with and without lipopolysaccharide (LPS). The supernatant was assayed for IL-1 beta and IL-6 by ELISA. Serum OPG was measured by ELISA. The LPS-stimulated production of IL-1 and IL-6 was significantly higher in the luteal phase. When the analysis was restricted to the natural menstrual cycle, only the increase in IL-1 production remained statistically significant. NTX excretion was similar in the two phases of HRT, but decreased nonsignificantly (p = 0.05) in the luteal phase in the premenopausal women. OPG levels did not exhibit any menstrual cycle-dependent changes. In conclusion, bone resorption is suppressed in the luteal phase through a mechanism that does not involve increases in serum OPG. An increased cytokine secretory capacity of blood cells may be an epiphenomenon particular to the luteal phase but unrelated to bone metabolism.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Bone Resorption / blood*
  • Cells, Cultured
  • Estradiol / blood
  • Estradiol / pharmacology
  • Estrogen Replacement Therapy
  • Female
  • Follicle Stimulating Hormone / blood
  • Glycoproteins / blood*
  • Humans
  • Interleukin-1 / metabolism*
  • Interleukin-6 / metabolism*
  • Menstrual Cycle / blood*
  • Menstrual Cycle / drug effects
  • Middle Aged
  • Norethindrone / analogs & derivatives*
  • Norethindrone / pharmacology
  • Norethindrone Acetate
  • Osteoprotegerin
  • Receptors, Cytoplasmic and Nuclear / blood*
  • Receptors, Tumor Necrosis Factor


  • Glycoproteins
  • Interleukin-1
  • Interleukin-6
  • Osteoprotegerin
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Tumor Necrosis Factor
  • TNFRSF11B protein, human
  • Estradiol
  • Follicle Stimulating Hormone
  • Norethindrone Acetate
  • Norethindrone