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.

Lack of synergy between estrogen and progesterone on local IGF-I, IGFBP-3 and IGFBP-2 secretion by both hormone-dependent and hormone-independent breast cancer explants in vitro. Effect of tamoxifen and mifepristone (RU 486)

“…The second part of our study confirmed our earlier finding of progesterone-induced increase in IGF-I secretion in malignant and non-malignant breast PR(+) explants [5][6][7]. Additionally, we once again showed the decreased IGFBP-3 level which was paralleled by the increase in IGFBP-2 secretion by hormone-dependent breast cancer explants [6,27].…”

“…We previously reported the stimulatory effect of progesterone on the activation of local hGH/IGF-I/IGF binding protein axis in breast tissue expressing progesterone receptors [5,6]. Moreover, we showed that the differences in secretion of hGH and IGF-I from breast tissue explants depended on the type of progestagens used and the steroid receptor phenotype of both malignant and adjacent non-malignant tissue [7].…”

The anticancer effects of Levonorgestrel on human esophageal squamous carcinoma cells

“…While some researchers reported that LNG or LNG-IUS associated with a decreased risk of ovarian and endometrial cancer, without increased risk of breast cancer [7, 10, and 15]. Scientists think that the different role of LNG or LNG-IUS in cancers may be associated with pathological process [12,13], hormone levels [23], or the expression of molecules related hormone [24][25]. For example, Nikolopoulos et al and Westin et al found LNG-IUS offers an effective and safe treatment for early-stage, lowgrade endometrial cancer [12,13]; Siegelmann-Danieli et al think that LNG-IUS was associated with a slightly increased risk for invasive breast cancer in the subgroup of women in their early 40's, while not associated with an increased total risk in perimenopausal women [23].…”

Progesterone‐only and non‐hormonal contraception in the breast cancer survivor: Joint review and committee opinion of the Society of Obstetricians and Gynaecologists of Canada and the Society of Gynecologic Oncologists of Canada

“…One study demonstrated that progesterone could induce secretion of these growth factors from human breast cancer explants in-vitro [23]. GH secretion of malignant cell lines was increased in response to progesterone even when progesterone receptors were absent.…”

“…GH secretion of malignant cell lines was increased in response to progesterone even when progesterone receptors were absent. Synthetic progestins showed a variable effect on these growth factors, depending on the type of progestin used, the receptor status of the cell lines, and whether or not the cell lines were malignant [23].…”