Developmental Programming: Gestational Exposure to Excess Testosterone Alters Expression of Ovarian Matrix Metalloproteases and Their Target Proteins

Reprod Sci. 2018 Jun;25(6):882-892. doi: 10.1177/1933719117697127. Epub 2017 Mar 16.


Prenatal testosterone (T)-treated sheep, similar to women with polycystic ovary syndrome (PCOS), manifests reproductive defects that include multifollicular ovarian phenotype. Women with PCOS manifest increased ovarian matrix metalloproteinases (MMPs) activity. We tested the hypothesis that gestational T excess in sheep would alter ovarian expression of MMPs, tissue inhibitors of MMP (TIMP) and their target proteins laminin B (LAMB), collagen, tumor necrosis factor alpha (TNF), and connexin 43 (GJA1) consistent with increased MMP activity and that these changes are developmentally regulated. The ovarian content of these proteins was quantified by immunohistochemistry in fetal day 90, 140, and adult (21 months of age) ovaries. Prenatal T excess lowered GJA1 protein content in stroma and granulosa cells of primary follicles from fetal day 90 ovaries and decreased stromal MMP9, TIMP1, and LAMB in fetal day 140 ovaries. In the adult, prenatal T-treatment (1) increased MMP9 in theca cells of large preantral follicles and stroma, TNF in granulosa cells of small and large preantral follicles and theca cells of large preantral and antral follicles, and GJA1 in stroma, theca cells of large preantral follicles, and granulosa cells of antral follicles and (2) reduced TIMP1 in stroma, theca cells of large preantral and antral follicles, LAMB in stroma and small prenatral follicles, and collagen content in stroma and around antral follicles. These findings suggest a net increase in MMP activity and its target proteins TNF and GJA1 in prenatal T-treated adult but not in fetal ovaries and their potential involvement in the development of multifollicular morphology.

Keywords: PCOS; androgen; female reproduction; matrix metalloproteinases; ovary.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Connexin 43 / metabolism
  • Female
  • Gene Expression Regulation, Developmental
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinases / metabolism*
  • Ovarian Follicle / embryology
  • Ovarian Follicle / metabolism
  • Ovary / drug effects
  • Ovary / embryology*
  • Ovary / metabolism*
  • Sheep, Domestic
  • Testosterone / administration & dosage*
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Tumor Necrosis Factor-alpha / metabolism


  • Connexin 43
  • Tissue Inhibitor of Metalloproteinase-1
  • Tumor Necrosis Factor-alpha
  • Testosterone
  • Matrix Metalloproteinases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9