Proliferative Lesions of Ovarian Granulosa Cells and Reversible Hormonal Changes Induced in Rats by a Selective Estrogen Receptor Modulator

Abstract

This study assessed the effects of raloxifene, a selective estrogen receptor modulator (SERM), on ovarian morpholog y and circulating hormone levels in rats. Female Fischer-344 rats (65/group) were given dietary raloxifene for 6 months at average daily doses of 0, 15, 75, and 365 mg/kg. Morphologic evaluation of ovaries was conducted on 25 rats/group at the end of the treatment period and from 20 rats per group after 1 and 3 months withdrawal from treatment. Plasma hormone analyses were conducted on 10 rats per group at the end of the treatment period and after each withdrawal period.Treatment with raloxifene for 6 months resulted in disruption of the hypothalamic-pituitary-ovaria n axis, manifested by increased plasma concentrations of luteinizing hormone (LH) and estradiol-17b (E2), and failure of ovulation, manifested by ovarian follicular prominence (retained anovulatory follicles), lack of corpora lutea (CL), and depressed plasma progesterone (P4). Many (56% to 80%) rats in all raloxifene treated groups had focal, minimal to slight hyperplasia of granulosa cells within individual retained follicles. A few treated rats in the mid-and high-dose groups (2 of 25 and 3 of 25, respectively) had more extensive focal proliferation of granulosa cells. These foci were approximately 3 to 6 mm in overall size and were characterized by moderate papillary proliferation of large granulosa cells associated with cystic spaces, often with hemorrhage. In 4 of the 5 rats with this focal cystic granulosa cell hyperplasia, the remainder of the involved ovary and the contralateral ovary were atrophic.After 1 or 3 months of drug withdrawal, most previously treated rats examined had morphologic evidence of ovarian cyclic changes, including developing follicles, various stages of CL, and normal plasma levels of LH, E2, and P4. Continued lack of cyclic changes was limited to 4 of 20 rats from the low-dose group after 1 month of recovery and to 1 low dose rat after 3 months. Intrafollicular granulosa cell hyperplasia was not seen in rats in the reversibility phase. Areas of prior focal cystic granulosa cell hyperplasi a were represented by focal sclerosis that included hemorrhage and/or hemosiderin. The foci of sclerosis were associated with cystic spaces after 1 month and were solid after 3 months.A granulosa cell tumor, approximatel y 12-13 mm diameter, was present in a high-dose rat in the 3-month reversibility group. This tumor effaced 1 ovary and was characterized by proliferative granulosa cells, usually in papillary formations and cords within cystic spaces. This rat had atrophy of the uninvolve d ovary, excessive plasma levels of E2 and prolactin, and high P4 levels considering the absence of CL.The results of this study indicate that ovarian granulosa cells in rats are susceptible to proliferative changes when stimulated chronically with excessive trophic hormones. Most of these proliferative changes were reversible upon cessation of the hormonal stimulation. However, the proliferative lesion in one treated rat progre...

Effects of long-lasting raloxifene treatment on serum prolactin and gonadotropin levels in postmenopausal women

“…Recently, Pinilla et al (7) showed that raloxifene inhibited the pulsatile secretion of LH and increased PRL levels in ovariectomized rats which had not undergone estrogen replacement therapy. On the contrary, other authors (16) showed that in normally estrogenized rats, 6 months of raloxifene treatment increased serum LH and E2 concentrations, and blocked ovulation. Data about the action of raloxifene on human pituitary secretion are, at present, few.…”

The role of reproductive hormones in epithelial ovarian carcinogenesis

“…In more recent years, rodents treated with raloxifene, a selective ER modulator, demonstrated persistent elevations of serum LH levels in the absence of the preovulatory LH surge (Cohen et al 2000, Long et al 2001. In a study assessing the effects of raloxifene on ovarian morphology, rats were noted to develop granulosa cell hyperplasia following treatment, in a dose dependent manner, while one rat developed a granulosa cell tumor (Long et al 2001), supporting the idea that hormonal imbalances can result in malignant transformation.…”

“…In a study assessing the effects of raloxifene on ovarian morphology, rats were noted to develop granulosa cell hyperplasia following treatment, in a dose dependent manner, while one rat developed a granulosa cell tumor (Long et al 2001), supporting the idea that hormonal imbalances can result in malignant transformation. Similar results were observed in ERA knockout mice in which the hypothalamic-pituitary-gonadal feedback mechanism was disturbed (Korach 1994).…”

Androgen Dependent Mammary Gland Virilism in Rats Given the Selective Estrogen Receptor Modulator LY2066948 Hydrochloride

“…In contrast to the lack of LH effects at pharmacologic doses (Geiser et al, 2005), female rats given LY2066948 at the dose used in the present studies have elevated levels of LH resulting in hyperstimulation of the ovary. The effects on the HPO axis were expected and occur because of ER antagonism in the hypothalamus and loss of estrogen negative feedback on LH secretion (Long et al, 2001;Crouse et al, 2003). In the rat, estrogen and androgen synthesis occur in the ovary from a common intermediate, the androgen androstenedione (Stryer, 1999).…”

“…There were no mammary gland changes in these preliminary studies and findings were limited to changes in the female reproductive tract that represent expected pharmacology (uterine atrophy) and class effects of SERMs described elsewhere (Long et al, 2001;Geiser et al, 2005).…”