Increased 2-hydroxylation of estrogen in women with a family history of osteoporosis

J Clin Endocrinol Metab. 2005 Apr;90(4):2035-41. doi: 10.1210/jc.2004-1425. Epub 2005 Jan 5.


Recent studies indicate that women with predominant estrogen metabolism through the 2-hydroxyl (inactive) pathway have lower bone mineral density (BMD) compared with those with predominant 16alpha-hydroxylation (active). Although many factors have been identified to affect estrogen metabolism, the role of a family history of osteoporosis remains unknown. The objective of this study was to investigate the influence of family history of osteoporosis and other clinical factors on estrogen hydroxylation. This was a cross-sectional study conducted in a university-based research center from May 2002 to February 2004. The participants included 175 otherwise healthy postmenopausal women at least 1 yr from the last menstrual period. Main outcome measures were urinary estrogen metabolites and BMD of the spine and femur. Women with a family history of osteoporosis had significantly higher log-transformed ratios of 2-hydroxyestrone/16alpha-hydroxyestrone (0.303 +/- 0.03 vs. 0.226 +/- 0.03; P = 0.04) and 2-methoxyestrone/16alpha-hydroxyestrone (0.024 +/- 0.02 vs. -0.036 +/- 0.02; P = 0.03) compared with women without family history. As expected, these women also had significantly lower BMD at the total femur, trochanter, and intertrochanter. Surprisingly, calcium intake positively correlated with metabolite levels, and women in the highest quartile of calcium intake had the highest levels of urinary metabolites. In conclusion, women with a positive family history of osteoporosis have predominant estrogen metabolism through the inactive 2-hydroxyl pathway; thus, the increased risk of osteoporosis in those with family history may in part be related to inherited differences in estrogen metabolism. The finding that calcium intake modulates estrogen hydroxylation has never been reported and thus deserves additional investigation.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Bone Density
  • Calcium / administration & dosage
  • Cross-Sectional Studies
  • Estrogens / metabolism*
  • Female
  • Humans
  • Hydroxylation
  • Middle Aged
  • Osteoporosis / etiology*
  • Osteoporosis / genetics
  • Osteoporosis / metabolism


  • Estrogens
  • Calcium