, Volume 3, Issue 2, pp 107–112 | Cite as

Preantral follicles stimulate luteinizing hormone independent differentiation of ovarian theca-interstitial cells by an intrafollicular paracrine mechanism

  • Denis A. Magoffin
  • Paul C. Magarelli


Ovarian thecal cells are thought to differentiate from fibroblast-like precursor cells in the stroma adjacent to developing follicles. Since the precursor cells do not contain LH receptors, a regulator other than LH must initiate thecal differentiation. These studies were designed to test the hypothesis that preantral follicles secrete substances that can stimulate thecal differentiation. Preantral follicles devoid of theca were obtained by limited enzymatic dispersal of 26-day old rat ovaries. Follicles were cultured (5 follicles/well) in 96-well plates containing serum-free medium to generate follicle-conditioned medium (FCM). Isolated theca-interstitial cells (TIC) were cultured (2 days) in 50% FCM, to bioassay for androgen-stimulating activity. Androsterone production was measured by RIA. FCM from follicles of increasing size with 1, 2, 3, 4 or 5 layers of granulosa cells (GC) stimulated increasing amounts of androsterone suggesting that secretion of androgen-stimulating activity is developmentally regulated in preantral follicles. The androgen-stimulating activity of 7.5-fold concentrated FCM was markedly increased above control levels or the levels stimulated by insulin-like growth factor-I (100 ng/ ml), transforming growth factor-α (100 ng/ml), transforming growth-factor-β1 (10 ng/ml), inhibin A (300 ng/ml), activin A (100 ng/ml), or Müllerian inhibiting substance (MIS; 300 ng/ml) suggesting that the bioactive substances were distinct from these intrafollicular growth factors. rFSH stimulated a > 10-fold increase in androgenstimulating activity demonstrating that the bioactivity is hormonally regulated. The bioactivity was sensitive to trypsin digestion but was not inhibited by indomethacin (10 μm) suggesting that it is peptide not prostaglandin in nature. Gel filtration chromatography indicated that the M of the bioactive peptides in FCM ranged from 19 500 to 23 600. Taken together our results demonstrate that preantral follicles secrete thecal differentiating factors (TDFs) that are developmentally and hormonally regulated by FSH. The properties of the TDFs are markedly different from known intrafollicular growth factors and may represent a new paracrine regulator in the ovary that can stimulate LH-independent thecal differentiation.


theca-interstitial cells follicle development androgen production 


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  1. Adashi, E.Y., Resnick, C.E., Tedeschi, C. & Rosenfeld, R.G. (1993).Endocrinology,132, 1463–1468.PubMedCrossRefGoogle Scholar
  2. Erickson, G.F., Li, D., Sadrkhanloo, R., Liu, X., Shimasaki, S. & Ling, N. (1994a).Endocrinology,134, 1365–1372.PubMedCrossRefGoogle Scholar
  3. Erickson, G.F., Magoffin, D.A., Dyer, C.A. & Hofeditz, C. (1985).Endocr. Rev.,6, 371–399.PubMedGoogle Scholar
  4. Erickson, G.F., Mitchell, C., Nakatani, A., Ling, N. & Shimasaki, S. (1994b).Endocrine. 2, 447–456.Google Scholar
  5. Erickson, G.F., Nakatani, A., Ling, N. & Shimasaki, S. (1992a).Endocrinology,130, 1867–1878.PubMedCrossRefGoogle Scholar
  6. Erickson, G.F., Nakatani, A., Ling, N. & Shimasaki, S. (1992b).Endocrinology,130, 625–636.PubMedCrossRefGoogle Scholar
  7. Erickson, G.F., Nakatani, A., Liu, X., Shimasaki, S. & Ling, N. (1994c).Molecular Biology of the Female Reproductive System. Findlay, J.K. (ed), Academic Press: Orlando, pp. 101–127.Google Scholar
  8. Erickson, G.F., Nakatani, A., Ling, N. & Shimasaki, S. (1993).Endocrinology,133, 1147–1157.PubMedCrossRefGoogle Scholar
  9. Hirshfield, A.N. (1991).Biol. Reprod.,44, 1157–1162.PubMedCrossRefGoogle Scholar
  10. Ingram, D.L. (1959).J. Endocrinol.,19, 117–122.PubMedGoogle Scholar
  11. Khan, S.A., Keck, C., Gudermann, T. & Nieschlag, E. (1990).Endocrinology,126, 3043–3052.PubMedGoogle Scholar
  12. Lischinsky, A. & Armstrong, D.T. (1982).Can. J. Physiol. Pharmacol.,61, 472–477.Google Scholar
  13. Liu, X., Malkowski, M., Guo, Y., Erickson, G.F., Shimasaki, S. & Ling, N. (1993).Endocrinology,132, 1176–1183.PubMedCrossRefGoogle Scholar
  14. Magoffin, D.A. (1989).Endocrinology,125, 1464–1473.PubMedGoogle Scholar
  15. Magoffin, D.A. & Erickson, G.F. (1982).J. Biol. Chem.,257, 4507–4513.PubMedGoogle Scholar
  16. Magoffin, D.A. & Erickson, G.F. (1988).Endocrinology,122, 2345–2347.PubMedGoogle Scholar
  17. Magoffin, D.A. & Erickson, G.F. (1994).Molecular Biology of the Female Reproductive System. Findlay, J.K. (ed.), Academic Press: Orlando, pp. 39–65.Google Scholar
  18. Magoffin, D.A., Gelety, T.J. & Magarelli, P.C. (1994).Ovulation Induction: Basic Science and Clinical Advances. Filicori, M. & Flamigni, C. (eds), Elsevier Science Publishers: Amsterdam, pp. 25–36.Google Scholar
  19. Magoffin, D.A., Kurtz, K.M. & Erickson, G.F. (1990).Molec. Endocrinol.,4, 489–496.Google Scholar
  20. Magoffin, D.A. & Weitsman, S.R. (1993a).Endocrinology,132, 1945–1951.PubMedCrossRefGoogle Scholar
  21. Magoffin, D.A. & Weitsman, S.R. (1993b).Biol. Reprod.,48, 1166–1173.PubMedCrossRefGoogle Scholar
  22. Magoffin, D.A. & Weitsman, S.R. (1993c).Molec. Cell. Endocrinol.,96, 45–51.PubMedCrossRefGoogle Scholar
  23. Nakatani, A., Shimasaki, S., Erickson, G.F. & Ling, N. (1991).Endocrinology,129, 1521–1529.PubMedGoogle Scholar
  24. Oliver, J.E., Aitman, T.J., Powell, J.F., Wilson, C.A. & Clayton, R.N. (1989).Endocrinology,124, 2671–2679.PubMedGoogle Scholar
  25. Roy, S.K. & Greenwald, G.S. (1985).Biol. Reprod.,32, 203–215.PubMedCrossRefGoogle Scholar
  26. Sadrkhanloo, R., Hofeditz, C. & Erickson, G.F. (1987).Endocrinology,120, 146–155.PubMedCrossRefGoogle Scholar
  27. Zamecnik, J., Barbe, G., Moger, W.H. & Armstrong, D.T. (1977).Steroids,30, 679–689.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 1995

Authors and Affiliations

  • Denis A. Magoffin
    • 2
  • Paul C. Magarelli
    • 1
  1. 1.Department of Obstetrics, Gynecology and Reproductive Biology, B316 Clinical CenterMichigan State UniversityFast Lansing
  2. 2.Department of Obstetrics and CynecologyCedars-Sinai Research Institute, Cedars-Sinai Medical Center/UCLA School of MedicineLos AngelesUSA

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