Regulation of endometrial cancer cell growth by luteinizing hormone (LH) and follicle stimulating hormone (FSH)

Abstract

Endometrial cancer occurs most commonly in postmenopausal women and is therefore coincidentally associated with elevated plasma LH and FSH levels (Nagamani et al, 1993). LH and FSH secretion is partly controlled by hypothalamic gonadotrophin releasing hormone (GnRH) and it is notable that recurrent endometrial cancer can be treated with GnRH analogues (Gallagher et al, 1991). However, the exact mechanism by which these analogues exert their clinical effect on endometrial cancer cell growth is not fully understood. The in vivo physiological response to GnRH administration is an initial rise followed by suppression of LH and FSH secretion (Dowsett et al, 1988). Emons et al (1993) found two types of GnRH binding sites in the HEC-1A and Ishikawa endometrial cancer cell lines; specific high affinity GnRH receptors were also found in the DU-145 prostate tumours (Lamharzi et al, 1998). However, we found no functional GnRH receptor in normal or malignant endometrium and no direct growth modulating effect in vitro on endometrial cancer cells (Chatzaki et al, 1996).In this study we explore the hypothesis that the antitumour activity of GnRH is an indirect consequence of reducing circulating LH and FSH levels. We describe the growth response of endometrial cancer cells to administration of LH and FSH; the second messenger response and the expression of LH and FSH receptors by these cells. MATERIALS AND METHODS Cell linesThe human endometrial adenocarcinoma cell line Ishikawa (Nishida et al, 1985) was a gift from Dr J White (Department of Reproductive Physiology, Hammersmith Hospital, London, UK) and the human endometrial papillary adenocarcinoma cell line HEC-1A was obtained from the American Type Culture Collection (Bethesda, MD). The human embryonic kidney cell lines 293L and 293F derived from 293 cells after stable transfection with LH and FSH receptor cDNA respectively were donated by Dr D Segaloff (University of Iowa College of Medicine, Iowa, USA). LH and FSHPituitary-derived LH and FSH were obtained from Sigma (Dorset, UK) and recombinant human LH and FSH were obtained from Dr M Page (Serono). Growth experiments293, 293L and 293F cells were grown in phenol-red free DMEM media (Sigma-Aldrich Company Ltd, Dorset, UK) supplemented with 5% heat-inactivated newborn calf serum (NCS), gentamycin, 10 mM HEPES, 2 mM glutamine plus antibiotic/antimycotic solution (Sigma, Dorset, UK). Ishikawa cells were grown in phenolred free DMEM nutrient mixture F-12 Ham media (Sigma, Dorset, Summary Gonadotrophin releasing hormone analogues (GnRHa) have been used to treat recurrent endometrial cancer. However, the mode of action is uncertain. Our previous studies showed no direct effect of GnRHa on endometrial cancer cell growth in vitro. We have now examined the effect of luteinizing hormone (LH) and follicle stimulating hormone (FSH) on endometrial cancer cell growth. The aim was to determine whether suppression of pituitary LH and FSH by GnRHa could explain the tumour regression seen in up to 44% of patients treated with this drug. We ...

The levels of the sex hormones are not different between type 1 and type 2 endometrial cancer

“…It is well known that FSH and LH promote ovulation and stimulate secretion of estrogen and progesterone from the ovaries before the menopause. A number of studies have also suggested that FSH, LH and testosterone are involved in the pathogenesis of endometrial cancer via their ability to regulate endometrial cancer cell growth242527. In this study, our data show that the numbers of premenopausal patients with excess levels of FSH or LH were higher in both type 1 and type 2 endometrial cancer, suggesting that excess FSH or LH contributes to higher levels of estrogen in endometrial cancer.…”

Quantitative PCR marker genes for endometrial adenocarcinoma

“…LHCGR is also associated with tumor staging (36). It is also important for cell proliferation (37,38) and may be correlated with grading of endometrial carcinomas (39). Table II) and were cultured in Dulbecco's modified Eagle's medium (DMEM; Biochrom, Ltd., Berlin, Germany), supplemented with 10% fetal calf serum (FCS; Biochrom, Ltd.) and 1% penicillin/streptomycin (P/S) (Biochrom, Ltd.), except KLE, as they required DMEM-F12 (Biochrom, Ltd.), 10% FCS and 1% P/S as culture medium.…”

Expression of hCG and GnRHs and Their Receptors in Endometrial Carcinoma and Hyperplasia

“…10,12,13,33 In tumors expressing hCG and LH/hCGR, the hormone can regulate growth of cancer cells via autocrine/ paracrine signaling. 34,35 It has already been demonstrated that high expression of membrane-associated hCGA correlates with primary malignant growth and metastatic phenotype of cancer. 13 Recent studies indicate that normal gonadotropins can also act as tissue-specific angiogenic factors, providing an optimal vascular supply in the female reproductive tract and in pathological conditions (eg, ovarian hyperstimulation or endometriosis).…”