Proliferative lesions of ovarian granulosa cells and reversible hormonal changes induced in rats by a selective estrogen receptor modulator

被引:14
|
作者
Long, GG [1 ]
Cohen, IR
Gries, CL
Young, JK
Francis, PC
Capen, CC
机构
[1] Eli Lilly & Co, Lilly Res Labs, Toxicol & Drug Disposit, Greenfield, IN 46140 USA
[2] Ohio State Univ, Dept Vet Biosci, Columbus, OH 43210 USA
关键词
estrogen receptor; granulosa cells; granulosa cell tumor; selective estrogen receptor modulator;
D O I
10.1080/01926230152500004
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
This study assessed the effects of raloxifene, a selective estrogen receptor modulator (SERM), on ovarian morphology 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-17beta(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 hyperplasia 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, approximately 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 uninvolved 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 progressed to apparent autonomous (neoplastic) growth.
引用
收藏
页码:403 / 410
页数:8
相关论文
共 50 条
  • [31] THE EFFECTS OF A POTENT AND SELECTIVE PARTIAL ESTROGEN RECEPTOR MODULATOR (PERD) ON BONE IN INTACT FEMALE RATS
    Rissanen, J. P.
    Schmitz, A.
    Morko, J.
    Peng, Z.
    Fagerlund, K. M.
    Konkol, Y.
    Suominen, M. I.
    Bernoulli, J.
    Halleen, J. M.
    Wagenfeld, A.
    OSTEOPOROSIS INTERNATIONAL, 2016, 27 : S499 - S499
  • [32] Evidences for antiosteoporotic and selective estrogen receptor modulator activity of silymarin compared with ethinylestradiol in ovariectomized rats
    El-Shitany, Nagla A.
    Hegazy, Sahar
    El-desoky, Karema
    PHYTOMEDICINE, 2010, 17 (02) : 116 - 125
  • [33] Metabolism, distribution, and excretion of a next generation selective estrogen receptor modulator, lasofoxifene, in rats and monkeys
    Prakash, Chandra
    Johnson, Kim A.
    Schroeder, Clinton M.
    Potchoiba, Michael J.
    DRUG METABOLISM AND DISPOSITION, 2008, 36 (09) : 1753 - 1769
  • [34] Embryo/fetal toxicity assessment of lasofoxifene, a selective estrogen receptor modulator (SERM), in rats and rabbits
    Ozolins, TRS
    Gupta, U
    BIRTH DEFECTS RESEARCH PART B-DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY, 2004, 71 (03) : 161 - 170
  • [35] The selective estrogen receptor modulator, raloxifene: Reproductive assessments following premating exposure in female rats
    Hoyt, JA
    Fisher, LF
    Buelke-Sam, JL
    Francis, PC
    REPRODUCTIVE TOXICOLOGY, 1998, 12 (03) : 233 - 245
  • [36] Preventive effects of raloxifene, a selective estrogen receptor modulator, on monocrotaline-induced pulmonary hypertension in intact and ovariectomized female rats
    Nishida, Masahiro
    Hasegawa, Youichi
    Tanida, Izumi
    Nakagawa, Erika
    Inaji, Haruka
    Ohkita, Mamoru
    Matsumura, Yasuo
    EUROPEAN JOURNAL OF PHARMACOLOGY, 2009, 614 (1-3) : 70 - 76
  • [37] A new selective estrogen receptor modulator HMR-3339 fully corrects bone alterations induced by ovariectomy in adult rats
    Ammann, P
    Bourrin, S
    Brunner, F
    Meyer, JM
    Clément-Lacroix, P
    Baron, R
    Gaillard, M
    Rizzoli, R
    BONE, 2004, 35 (01) : 153 - 161
  • [38] The decrease in bone strength induced by ovariectomy in adult rats is corrected by the new selective estrogen receptor modulator PSK3471.
    Ammann, P
    Clément-Lacroix, P
    Bruynick, N
    Baron, R
    Rizzoli, R
    JOURNAL OF BONE AND MINERAL RESEARCH, 2004, 19 : S175 - S175
  • [39] ANDROGEN-INDUCED CHANGES IN RAT OVARIAN GRANULOSA-CELLS INVITRO
    ANDERSON, E
    LITTLE, B
    LEE, GS
    TISSUE & CELL, 1987, 19 (02): : 217 - 234
  • [40] Gene expression profiles with activation of the estrogen receptor α-selective estrogen receptor modulator complex in breast cancer cells expressing wild-type estrogen receptor
    Levenson, AS
    Svoboda, KM
    Pease, KM
    Kaiser, SA
    Chen, B
    Simons, LA
    Jovanovic, BD
    Dyck, PA
    Jordan, VC
    CANCER RESEARCH, 2002, 62 (15) : 4419 - 4426