A review of current research on the effects of progesterone.

245 International Journal of Pharmaceutical Compounding Vol. 6 No. 4 July/August 2002 Effects of Progesterone on Bone Current studies2 examining the role of progesterone on bone homeostasis indicate that the effects of progesterone are mediated by its nuclear receptors. In the 1970s, O’Malley et al2 showed that those receptors are composed of two receptor proteins, PRa and PRb, each of which binds progesterone.2 Research by MacNamara and Loughrey3 in 1998 indicated that PRa and PRb messenger r ibonucle ic ac id (mRNA) transcripts are expressed in human osteoblasts and that progesterone receptor promoter activity is estrogen responsive. This provides evidence that boneforming cells are physiologically influenced by progesterone. A study4 by Luo and Liao supports the role of progesterone in regulating the function of metalloproteinase (specifically matrix metalloproteinase [MMP]) in osteoblast cells involved in bone remodel ing and resorption. MMP initiates bone resorption by degrading the bone matrix. This requires the activation of MMP-2 via a complex consisting of a membrane-type matrix metalloproteinase-1 (MT1-MMP) and a tissue inhibitor of metalloproteinase (TIMP-2) on the cell surface. In that study, progesterone was shown to increase the levels of MT1-MMP and mRNA in osteoblasts. Progesterone acted only on the MT1-MMP protein; that action may contribute to bone formation. Progesterone binding to glucocorticoid receptors is another pathway that may modulate bone remodeling. Glucocorticoids cause bone loss by blocking osteocalcin synthesis and preventing the attachment of osteoblasts to matrix proteins such as osteonectin. Some studies5,6 indicate that progesterone exerts an antiglucocorticoid effect by acting as a ligand for glucocorticoid receptors. A study7,8 of progesterone replacement in very premature infants yielded exciting results with respect to the role of progesterone in bone development. During pregnancy, the plasma concentrations of estradiol and progesterone in the fetus increase by a factor of 100. A prematurely delivered infant is deprived of those hormones at an early developmental stage. Seventy years ago, estradiol supplementation was used on premature infants to promote body-weight gain, but the success of that treatment was minimal and the practice was abandoned.7,8 However, because of the positive benefits of postmenopausal hormone replacement, the effect of estradiol supplementation on the prevention of the osteopenia of prematurity was again examined. When intrauterine levels of estradiol and progesterone were supplemented for 6 weeks postnatally in premature infants, an improvement in bone mineral accretion was demonstrated.7,8