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DOI: 10.1055/s-2005-864035
Progesterone Receptor Antagonists and the Endometrial Antiproliferative Effect
Publikationsverlauf
Publikationsdatum:
15. Februar 2005 (online)
ABSTRACT
Progesterone receptors (PR) mediate multiple aspects of female reproduction and are important targets for reagents that can modulate progesterone-dependent events. Many such reagents have been developed, and they range from full PR antagonists (PAs) to compounds with mixed agonist/antagonist actions, currently known as selective progesterone receptor modulators (SPRMs). In women and nonhuman primates, many PR antagonists suppress estrogen-dependent mitotic activity in the endometrial glands as well as block progestational development of the endometrium. These latter effects are tissue- and species-specific, are most dramatic in women and nonhuman primates, and are referred to as endometrial antiproliferative effects. Recent evidence suggests that the endometrial androgen receptor plays an important role in these effects. For example, endometrial androgen receptors are increased by treatment with PAs, and combination treatment with estrogen, a PA, and an antiandrogen (flutamide) prevents the endometrial antiproliferative effect. Various PR modulators have great promise as gynecological therapeutics, but additional research is needed to improve our understanding of their endometrial effects.
KEYWORDS
Progesterone receptor - antagonist - agonist - endometrium - androgen receptor - endometrial antiproliferative effect
REFERENCES
- 1 Spitz I M, Robbins A. Mechanism of action and clinical effects of antiprogestins on the non- pregnant uterus. Hum Reprod Update. 1998; 4 584-593
- 2 Leonhardt S A, Edwards D P. Mechanism of action of progesterone antagonists. Exp Biol Med (Maywood). 2002; 227 969-980
- 3 Cadepond F, Ulmann A, Baulieu E E. RU486 (mifepristone): mechanisms of action and clinical uses. Annu Rev Med. 1997; 48 129-156
- 4 Bennink H. The Jerusalem declaration on progesterone receptor modulators. Steroids. 2000; 65 839
- 5 Philibert D. RU 38486: an original multifaceted antihormone in vivo. In: Agarwal MK Adrenal Steroid Antagonism Berlin, Germany; Gruyter 1984: 77-101
- 6 Slayden O D, Chwalisz K, Brenner M R. Reversible suppression of menstruation with progesterone antagonists in rhesus macaques. Hum Reprod. 2001; 16 1562-1574
- 7 Gainer E, Ulmann A. Pharmacologic properties of CDB (VA)-2914. Steroids. 2003; 68 1005-1011
- 8 Elger W, Bartley J, Schneider B et al.. Endocrine pharmacological characterization of progesterone antagonists and progesterone receptor modulators with respect to PR-agonistic and antagonistic activity. Steroids. 2000; 65 713-723
- 9 Chwalisz K, Brenner R M, Fuhrmann U, Hess-Stumpp H, Elger W. Antiproliferative effects of progesterone antagonists and progesterone receptor modulators (PRMs) on the endometrium. Steroids. 2000; 65 741-751
- 10 Wolf J P, Hsiu J G, Anderson T L et al.. Noncompetitive antiestrogenic effect of RU 486 in blocking the estrogen- stimulated luteinizing hormone surge and the proliferative action of estradiol on endometrium in castrate monkeys. Fertil Steril. 1989; 52 1055-1060
- 11 Slayden O D, Zelinski-Wooten M B, Chwalisz K, Stouffer R L, Brenner M R. Chronic treatment of cycling rhesus monkeys with low doses of the antiprogestin ZK 137 316: morphometric assessment of the uterus and oviduct. Hum Reprod. 1998; 13 269-277
- 12 Grow D R, Williams R F, Hsiu J G, Hodgen D G. Antiprogestin and/or gonadotropin-releasing hormone agonist for endometriosis treatment and bone maintenance: a 1-year primate study. J Clin Endocrinol Metab. 1996; 81 1933-1939
- 13 Grow D R, Reece M T, Hsiu J G et al.. Chronic antiprogestin therapy produces a stable atrophic endometrium with decreased fibroblast growth factor: a 1-year primate study on contraception and amenorrhea. Fertil Steril. 1998; 69 936-943
- 14 Cameron S T, Critchley H OD, Thong K J et al.. Effects of daily low dose mifepristone on endometrial maturation and proliferation. Hum Reprod. 1996; 11 2518-2526
- 15 Brown A, Cheng L, Lin S, Baird T D. Daily low-dose mifepristone has contraceptive potential by suppressing ovulation and menstruation: a double-blind randomized control trial of 2 and 5 mg per day for 120 days. J Clin Endocrinol Metab. 2002; 87 63-70
- 16 Zelinski-Wooten M B, Chwalisz K, Iliff S A et al.. A chronic, low dose regimen of the antiprogestin ZK 137 316 prevents pregnancy in rhesus monkeys. Hum Reprod. 1998; 13 2132-2138
- 17 Borman S M, Schwinof K M, Niemeyer C et al.. Low-dose antiprogestin treatment prevents pregnancy in rhesus monkeys and is reversible after 1 year of treatment. Hum Reprod. 2003; 18 69-76
- 18 Demanno B, Elger W, Garg R et al.. Asoprisnil (J867): a selective progesterone receptor modulator for gynecological therapy. Steroids. 2003; 68 1019-1032
- 19 Chwalisz K, Larsen L, McCrary K, Edmonds A. Effects of the novel selective progesterone receptor modulator (SPRM) asoprisnil on bleeding patterns in subjects with leiomyomata. J Soc Gynecol Investig. 2004; 11(suppl 2) 320-321
- 20 Bardon S, Vignon F, Montcourrier P, Rochefort H. Steroid receptor-mediated cytotoxicity of an antiestrogen and an antiprogestin in breast cancer cells. Cancer Res. 1987; 47 1441-1448
- 21 Murphy A A, Zhou M H, Malkapuram S et al.. RU486-induced growth inhibition of human endometrial cells. Fertil Steril. 2000; 74 1014-1019
- 22 Parthasarathy S, Morales A J, Murphy A A. Antioxidant: a new role for RU-486 and related compounds. J Clin Invest. 1994; 94 1990-1995
- 23 Han S, Sidell N. RU486-Induced growth inhibition of human endometrial cells involves the nuclear factor-kappaB signaling pathway. J Clin Endocrinol Metab. 2003; 88 713-719
- 24 Chwalisz K, Stöckemann K, Fritzemeier K-H. Fuhrmann U. Modulation of oestrogenic effects by progesterone antagonists in the rat uterus. Hum Reprod Update. 1998; 4 570-583
- 25 Grody M H, Lampe E H, Masters H W. Estrogen-androgen substitution therapy in the aged female. Obstet Gynecol. 1953; 2 36-45
- 26 Okon M A, Laird S M, Tuckerman E M, Li T-C. Serum androgen levels in women who have recurrent miscarriages and their correlation with markers of endometrial function. Fertil Steril. 1998; 69 682-690
- 27 Rose G L, Dowsett M, Mudge J E, White J O, Jeffcoate L S. The inhibitory effects of danazol, danazol metabolites, gestrinone, and testosterone on the growth of human endometrial cells in vitro. Fertil Steril. 1988; 49 224-228
- 28 Tuckerman E M, Okon M A, Li T-C, Laird M S. Do androgens have a direct effect on endometrial function? An in vitro study. Fertil Steril. 2000; 74 771-779
- 29 Critchley H, Wang H, Jones R et al.. Morphological and functional changes in human endometrium following intrauterine levonorgestrel delivery. Hum Reprod. 1998; 13 1218-1224
- 30 Critchley H OD, Brenner R M, Henderson T A et al.. Estrogen receptor beta, but not estrogen receptor alpha, is present in the vascular endothelium of the human and nonhuman primate endometrium. J Clin Endocrinol Metab. 2001; 86 1370-1378
- 31 Cameron S T, Critchley H OD, Buckley C H, Kelly R W, Baird T D. Effect of two antiprogestins (mifpristone and onapristone) on endometrial factors of potential importance for implantation. Fertil Steril. 1997; 67 1046-1053
- 32 Slayden O D, Nayak N R, Burton K A et al.. Progesterone antagonists increase androgen receptor expression in the rhesus macaque and human endometrium. J Clin Endocrinol Metab. 2001; 86 2668-2679
- 33 Narvekar N, Cameron S, Critchley H et al.. Low-dose mifepristone inhibits endometrial proliferation and up-regulates androgen receptor. J Clin Endocrinol Metab. 2004; 89 2491-2497
- 34 Slayden O D, Brenner M R. Flutamide counteracts the antiproliferative effects of antiprogestins in the primate endometrium. J Clin Endocrinol Metab. 2003; 88 946-949
- 35 Cooke P S, Buchanan D L, Young P et al.. Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium. Proc Natl Acad Sci USA. 1997; 94 6535-6540
- 36 McClellan M C, Rankin S, West N B, Brenner M R. Estrogen receptors, progestin receptors and DNA synthesis in the macaque endometrium during the luteal-follicular transition. J Steroid Biochem Mol Biol. 1990; 37 631-641
- 37 Ikonen T, Palvimo J J, Kallio P J, Reinikainen P, Janne A O. Stimulation of androgen-regulated transaction by modulators of protein phosphorylation. Endocrinology. 1994; 135 1359-1366
- 38 Apparao K B, Lovely L P, Gui Y, Lininger R A, Lessey A B. Elevated endometrial androgen receptor expression in women with polycystic ovarian syndrome. Biol Reprod. 2002; 66 297-304
- 39 Ajossa S, Guerriero S, Paoletti A M, Orru M, Melis B G. The antiandrogenic effect of flutamide improves uterine perfusion in women with polycystic ovary syndrome. Fertil Steril. 2002; 77 1136-1140
- 40 de Ziegler D, Bessis R, Frydman R. Vascular resistance of uterine arteries: physiological effects of estradiol and progesterone. Fertil Steril. 1991; 55 775-779
- 41 Reinsch R C, Murphy A A, Morales A J, Yen S SC. The effects of RU 486 and leuprolide acetate on uterine artery blood flow in the fibroid uterus: a prospective, randomized study. Am J Obstet Gynecol. 1994; 170 1623-1628
- 42 Charmandari E, Calis K A, Keil M F et al.. Flutamide decreases cortisol clearance in patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2002; 87 3197-3200
- 43 Baird D T, Brown A, Critchley H O et al.. Effect of long-term treatment with low-dose mifepristone on the endometrium. Hum Reprod. 2003; 18 61-68
- 44 Eisinger S, Meldrum S, Fiscella K, le Roux H, Guzick D. Low-dose mifepristone for uterine leiomyomata. Obstet Gynecol. 2003; 101 243-250
- 45 Croxatto H B, Kovács L, Massai R et al.. Effects of long-term low-dose mifepristone on reproductive function in women. Hum Reprod. 1998; 13 793-798
- 46 Murphy A, Kettel L, Morales A et al.. Endometrial effects of long-term low-dose administration of RU486. Fertil Steril. 1995; 63 761-766
- 47 Newfield R, Spitz I, Isacson C, New M. Long-term mifepristone (RU486) therapy resulting in massive benign endometrial hyperplasia. Clin Endocrinol (Oxf). 2001; 54 399-404
- 48 Bamberger A M, Milde-Langosch K, Loning T, Bamberger M C. The glucocorticoid receptor is specifically expressed in the stromal compartment of the human endometrium. J Clin Endocrinol Metab. 2001; 86 5071-5074
- 49 Henderson T A, Saunders P T, Moffett-King A, Groome N P, Critchley O H. Steroid receptor expression in uterine natural killer cells. J Clin Endocrinol Metab. 2003; 88 440-449
- 50 Brenner R M, Slayden O D, Rodgers W H et al.. Immunocytochemical assessment of mitotic activity with an antibody to phosphorylated histone H3 in the macaque and human endometrium. Hum Reprod. 2003; 18 1185-1193
Robert M BrennerPh.D.
Division of Reproductive Sciences, Oregon National Primate Research Center, Oregon Health & Sciences University
505 NW 185th Ave, Beaverton, OR 97006
eMail: brennerr@ohsu.edu