title: Cyproterone, norethindrone, medroxyprogesterone and levonorgestrel are less potent local human growth hormone and insulin-like growth factor I secretion stimulators than progesterone in human breast cancer explants expressing the estrogen receptor.
abstract: The aim of the present study was to compare the ability of natural progesterone and synthetic progestins to stimulate local growth hormone (GH) and insulin-like growth factor I (IGF-I) secretion by breast cancer explants. Explants obtained during surgery were divided according to their estrogen/progesterone receptor phenotype - ER(+)PR(-); ER(+)PR(+); ER(-)PR(+) - as determined by immunocytochemistry. Natural progesterone (10(-5) mol/l) and synthetic progestins (cyproterone acetate (5 x 10(-7) mol/l), norethindrone (10(-5) mol/l), medroxyprogesterone acetate (10(-7) mol/l), and levonorgestrel (10(-7) mol/l) were tested in vitro for their ability to induce secretion of proliferation-promoting agents such as human GH (hGH) and IGF-I. All hormone-dependent breast cancer cell types responded to progesterone stimulation with increased local hGH secretion, while in the non-malignant tissue this effect was observed only in PR(+) cells. Moreover, progesterone in only PR(+) cells in vitro stimulated local IGF-I secretion by both malignant and non-malignant tissue. Medroxyprogesterone and levonorgestrel increased GH secretion by both malignant and non-malignant ER(-)PR(+) breast cancer explants, while cyproterone stimulated it only in non-malignant tissue. None of the synthetic progestins tested in this experiment exerted an effect on GH secretion by both malignant and non-malignant tissue of ER(+) breast cancer explants. The present data additionally showed that, apart from cyproterone, which increased IGF-I secretion in the same manner as progesterone by both malignant and non-malignant ER(-)PR(+) breast explants, other progestins tested had either no effect on IGF-I local secretion or decreased it. Medroxyprogesterone and levonorgestrel induced a decrease in IGF-I secretion noted in ER(+) explants of non-malignant tissue and in malignant ER(-)PR(+) breast tissue. All progestins tested decreased IGF-I secretion by malignant ER(+)PR(+) explants. Taken together, the tested synthetic progestins widely used as oral contraceptives and in hormone replacement therapy were less potent than progesterone in inducing secretion of proliferation-promoting agents such as hGH and IGF-I in ER-containing breast tissue. Despite the lack of confirmation of the link between the use of progestins and breast cancer risk, patients should be informed that the use of certain estrogen/progestin preparations is of no influence on breast cancer risk while others may increase it.
authors.affiliation: Department of Endocrinology and Fertility, Collegium Medicum, Jagiellonian University, Krakow, Poland.
authors.forename: T
authors.initials: T
authors.lastname: Milewicz
authors.forename: J
authors.initials: J
authors.lastname: Kolodziejczyk
authors.forename: J
authors.initials: J
authors.lastname: Krzysiek
authors.forename: A
authors.initials: A
authors.lastname: Basta
authors.forename: K
authors.initials: K
authors.lastname: Sztefko
authors.forename: S
authors.initials: S
authors.lastname: Kurek
authors.forename: J
authors.initials: J
authors.lastname: Stachura
authors.forename: E L
authors.initials: EL
authors.lastname: Gregoraszczuk
mesh_terms: D001940:Breast / Q000187:drug effects / Q000378:metabolism; D001943:Breast Neoplasms / Q000737:chemistry / Q000378:metabolism*; D003534:Cyproterone / Q000494:pharmacology; D005260:Female; D019382:Human Growth Hormone / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D016912:Levonorgestrel / Q000494:pharmacology; D008525:Medroxyprogesterone / Q000494:pharmacology; D009640:Norethindrone / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology*; D045167:Progesterone Congeners / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000032:analysis*
chemical_list: D045167:Progesterone Congeners; D011960:Receptors, Estrogen; D019382:Human Growth Hormone; D011374:Progesterone; D016912:Levonorgestrel; D007334:Insulin-Like Growth Factor I; D003534:Cyproterone; D008525:Medroxyprogesterone; D009640:Norethindrone