Is there a protective role of progestogens on the proliferation of human ovarian cancer cells in the presence of growth factors?

Purpose of investigation: The role of progestogens in the genesis of ovarian cancer remains unclear although a rather protective behaviour has been suggested. Epidemiological studies indicate a possible increase in the risk for combined estrogen/progestin as compared to estrogen alone. It is ambigious whether a difference exists within the various progestogens. Apart from sex steroids, growth factors play a crucial role in the genesis of ovarian cancer, although as yet little investigated. In the present study we have explored the effect of progesterone (P), medroxyprogesterone acetate (MPA) and norethisterone (NET) on the proliferation of human ovarian cancer cells alone and in the presence of growth factors.

Methods: For the experiments human ovarian cancer cells (OVCAR-3) were used. The progestogens were tested at the concentrations of 0.01 to 10 microM. The growth factor mixture consisted of EGF, FGF and IGF-I, each at a concentration of 10 pM. The incubation time was three or seven days. Proliferation rate was measured by an ATP-assay.

Results: After three days' incubation the growth factors induced an increase in the proliferation rate of about 50%. Progesterone alone did not show any significant change as compared to the control values, whereas NET and MPA elicited a significant increase at 1 and 10 microM and at 1 microM, respectively. In the presence of growth factors none of the progestogens was able to inhibit the proliferative stimulation. After seven days' incubation the growth factors still showed an increase of about 50%. MPA alone had an inhibitory effect at 10 microM, for NET and P no effects were observed. Again in the presence of growth factors no progestogen was able to show an inhibitory effect.

Conclusion: Our results indicate that progestogens do not have a protective role on the growth of pre-existing ovarian cancer cells, at least in the presence of growth factors. Further investigations are worthwile to evaluate possible differences between the effect of the various progestogens.

Progesterone; Norethisterone; Medroxyprogesterone acetate; Growth factors; Proliferation; Human ovarian cancer cells

[1] Ho S.-M.: "Estrogen, progesterone and epithelial ovarian cancer". Reprod. Biol. Endocrinol., 2003, 1, 73.

[2] Writing Group for the Women's Health Initiative Investigators: "Risks and benefits of estrogen plus progestin in healthy postmenopausal women". JAMA, 2002, 288, 321.

[3] Auersperg, N., Wong, A .S.T., Choi K.-C., Kang S.K., Leung P.C.K.: "Ovarian surface epithelium: Biology, endocrinology and pathology". Endocrine Reviews, 2001, 22, 255.

[4] Andreotti P.E., Thornthwaite J.T., Morse I.S.: "ATP tumor chernosensitivity assay". In: Stanley P., Kricka L.J. (eds.). "Biolurninescence and Chernoluminescence: Current Status". Chichester, J. Wiley & Sons, 1991, 417.

[5] Greenlee R.T., Murray T., Bolden S., Wingo P.A.: "Cancer statistics, 2000". Cancer J. Clin., 2000, 50, 7.

[6] Rodriguez G.C., Nagarsheth N.P., Lee K.L., Bentley R.C., Walmer D.K., Cline M. et al.: "Progestin-induced apoptosis in the Macaque ovarian epithelium: differential regulation of transforming growth factor-β"- J. Natl. Cancer Inst., 2002, 94, 50.

[7] Bu S.-Z., Yin D.-L., Ren X.-H., Jiang L.-Z., Wu Z.-J., Gao Q.-R., Pei G.: "Progesterone induces apoptosis and up-regulation of p53 expression in human ovarian carcinoma cell lines". Cancer, 1997, 79, 1944.

[8] Syed V., Ho S.-M.: "Progesterone-induced apoptosis in immortalized normal and malignant human ovarian surface epithelial cells involves enhanced expression of FasL". Oncogene, 2003, 22, 6883.

[9] Rodriguez C., Patel A.V., Calle E.E., Jacob E.J., Thun M.J.: "Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women". JAMA, 2001, 285, 1460.

[10] Lacey Jr. J.V., Mink P.J., Lubin J.H., Sherman M.E., Troisi R., Hartge P. et al.: "Menopausal hormone replacement therapy and risk of ovarian cancer". JAMA, 2002, 288, 334.

[11] Anderson G.L., Judd H.L., Kaunitz A.M., Barad D.H., Beresford S.A., Pettinger M. et al.: "Effects of estrogen plus progestin on gynaecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial". JAMA, 2003, 290, 1739.

[12] Coughlin S.S., Giustozzi A., Smith S.J., Lee N.C.: "A meta-analysis of estrogen replacement therapy and risk of epithelial ovarian cancer". J. Clin. Epidemiol., 2000, 53, 367.

[13] Negri E., Tzonou A., Bera! V., Lagiou P., Trichopoulos D., Parazzini F. et al.: "Hormonal therapy for menopause and ovarian cancer in a collaborative reanalysis of European studies". Int. J. Cancer, 1999, 80, 848.

[14] Svensson L.O., Johnson S.H., Olsson S.E.: "Plasma concentrations of medroxyprogesterone acetate, estradiol and estrone following oral administration of Klimaxil", Trisequence®/Provera® and Divina". A randomised, single-blind, triple cross-over bioavailability study in menopausal women". Maturitas, 1994, 18, 229.

[15] Stanczyk F.Z., Brenner P.F., Mishell D.R., Ortiz A., Gentzschein E.K.E., Goebelsmann U.: "A radioimmunoassay for norethindrone (NET): measurement of serum net concentrations following ingestion of NET-containing oral contraceptive steroids". Contraception, 1978, 18, 615.