Therapeutic Potential for the Selective Progesterone Receptor Modulator Asoprisnil in the Treatment of Leiomyomata

Asoprisnil is a novel selective progesterone receptor modulator that exhibits partial agonist and antagonist activities in animals and humans. It demonstrates a high degree of progesterone receptor specificity and tissue selectivity. Although asoprisnil at high doses exhibited some antiglucocorticoid activity in animal models, no antiglucocorticoid effects were observed at therapeutic doses in humans. In male rats, asoprisnil showed mixed androgenic and antiandrogenic properties. Unlike antiprogestins, asoprisnil at high doses exhibited only marginal labor-inducing activity in guinea pigs during midpregnancy and was completely ineffective in inducing preterm parturition. In nonhuman primates, asoprisnil completely eliminated menstrual cyclicity and induced endometrial atrophy. Early clinical studies of asoprisnil in healthy volunteers demonstrated a dose-dependent suppression of menstruation, irrespective of the effects on ovulation, with no change in basal estrogen concentrations and no breakthrough bleeding. Phase 2 studies in subjects with uterine fibroids demonstrated that asoprisnil induced amenorrhea and reduced the volume of the dominant leiomyoma in a dose-dependent manner without altered basal estrogen and with virtually no clinical symptoms of estrogen deprivation. Asoprisnil seems to exhibit a direct inhibitory effect on both the endometrium and leiomyoma. In all studies to date, asoprisnil has maintained a favorable safety and tolerability profile. Thus, asoprisnil has the potential to target the major clinical symptoms of leiomyomata related to both menorrhagia and the size of the tumors and may, therefore, reduce or eliminate the need for surgery.

KEYWORDS

Asoprisnil - selective progesterone receptor modulator - leiomyomata - uterine fibroids - uterus

REFERENCES

• 1 Cramer D W. Epidemiology of myomas.  Semin Reprod Endocrinol. 1992;  10 320-324
• 2 Buttram V C, Reiter R C. Uterine leiomyomata: etiology, symptomatology and management.  Fertil Steril. 1981;  36 433-445
• 3 Stewart E A, Novak R A. Leiomyoma-related bleeding: a classic hypothesis updated for the molecular era.  Hum Reprod Update. 1996;  2 295-306
• 5 Lepine L A, Hillis S D, Marchbanks P A et al.. Hysterectomy surveillance-United States, 1980-1993.  MMWR CDC Surveill Summ. 1997;  46 1-15
• 4 Wilcox L S, Koonin L M, Pokras R et al.. Hysterectomy in the United States 1988-1990.  Obstet Gynecol. 1994;  83 549-555
• 6 Nationwide Inpatient Sample (NIS) .(electronic database, release 6) Available at: http://ntis.gov/fcpc/cpn8834.htm Rockville, MD; Agency for Healthcare Research and Quality 1997
• 7 Broder M S, Kanopuse D E, Mittman B S, Bernstein S J. The appropriateness of recommendations for hysterectomy.  Obstet Gynecol. 2000;  95 199-205
• 8 Stovall T G, Muneyyirici-Delale O, Summitt R L, Scialli A R. GnRH agonist and iron versus placebo and iron in the anemic patient before surgery for leiomyomas: a randomized controlled trial. Leuprolide Acetate Study Group.  Obstet Gynecol. 1995;  86 65-71
• 9 Myers E R, Barber M D, Gustilo-Ashby T, Couchman G, Matchar D B, McCrory D C. Management of uterine leiomyomata: what do we really know?.  Obstet Gynecol. 2002;  100 8-17
• 10 Stewart E A. Uterine fibroids.  Lancet. 2001;  357 293-298
• 11 Williams A J, Powell W L, Collins T, Morton C C. HMGI(Y) expression in human uterine leiomyomata. Involvement of another high-mobility group architectural factor in a benign neoplasm.  Am J Pathol. 1997;  150 911-918
• 12 Brandon D D, Bethea C L, Strawn E Y et al.. Progesterone receptor messenger ribonucleic acid and protein are overexpressed in human uterine leiomyomas.  Am J Obstet Gynecol. 1993;  169 78-85
• 13 Englund K, Blanck A, Gustavsson I et al.. Sex steroid receptors in human myometrium and fibroids: changes during the menstrual cycle and gonadotropin-releasing hormone treatment.  J Clin Endocrinol Metab. 1998;  83 4092-4096
• 14 Nisolle M, Gillerot S, Casanas-Roux F, Squifflet J, Berliere M, Donnez J. Immunohistochemical study of the proliferation index, oestrogen receptors and progesterone receptors A and B in leiomyomata and normal myometrium during the menstrual cycle and under gonadotrophin-releasing hormone agonist therapy.  Hum Reprod. 1999;  14 2844-2850
• 15 Andersen J, Grine E, Eng C L et al.. Expression of connexin-43 in human myometrium and leiomyoma.  Am J Obstet Gynecol. 1993;  169 1266-1276
• 16 Weir E C, Goad D L, Daifoitis A G, Burtis W J, Dreyer B E, Nowak R A. Relative overexpression of the parathyroid hormone-related protein gene in human leiomyomas.  J Clin Endocrinol Metab. 1994;  78 784-789
• 17 Giudice L C, Irwin J C, Dsupin B A et al.. Insulin-like growth (IGF), IGF binding protein (IGFBP), and IGF receptor gene expression and IGF synthesis in human uterine leiomyomata.  Hum Reprod. 1993;  8 1796-1806
• 18 Hsueh A JW, Peck Jr E J, Clark J H. Progesterone antagonism of the oestrogen receptor and oestrogen-induced uterine growth.  Nature. 1975;  254 337-339
• 19 Rein M S, Barbieri R L, Friedman A J. Progesterone: a critical role in the pathogenesis of uterine myomas.  Am J Obstet Gynecol. 1995;  172 14-18
• 20 Rein M S. Advances in uterine leiomyoma research: the progesterone hypothesis.  Environ Health Perspect. 2000;  108(suppl 5) 791-793
• 21 Kawaguchi K, Fujii S, Konishi I, Nanbu Y, Nonogaki H, Mori T. Mitotic activity in uterine leiomyomas during the menstrual cycle.  Am J Obstet Gynecol. 1989;  160 637-641
• 22 Tiltman A J. The effects of progestins on the mitotic activity of uterine fibromyomas.  Int J Gynecol Pathol. 1985;  4 89-96
• 23 Harrison-Woolrych M I, Charnock-Jones D S, Smith S K. Quantification of messenger ribonucleic acid for epidermal growth factor in human myometrium and leiomyomata using reverse transcriptase polymerase chain reaction.  J Clin Endocrinol Metab. 1994;  78 1179-1184
• 24 Matsuo H, Maruo T, Samoto T. Increased expression of Bcl-2 protein in human uterine leiomyoma and its up-regulation by progesterone.  J Clin Endocrinol Metab. 1997;  82 1293-1300
• 25 Maruo T, Matsuo H, Samoto T et al.. Effects of progesterone on uterine leiomyoma growth and apoptosis.  Steroids. 2000;  65 585-592
• 26 Mixson W T, Hammond D D. Response of fibromyomas to a progestin.  Am J Obstet Gynecol. 1961;  82 754-760
• 27 Carr B R, Mrashburn P T, Whetherall P T et al.. An evaluation of the effect of gonadotropin-releasing hormone analogs and medroxyprogesterone acetate on uterine leiomyomata volume by magnetic resonance imaging: a prospective, randomized, double blind, placebo-controlled crossover trial.  J Clin Endocrinol Metab. 1993;  76 1217-1223
• 28 Friedman A J, Daly M, Juneau-Norcross M et al.. A prospective, randomized trial of gonadotropin-releasing hormone agonist plus estrogen-progestin or progestin “add-back” regimens for women with leiomyomata uteri.  J Clin Endocrinol Metab. 1993;  76 1439-1445
• 29 Murphy A A, Kettel L M, Morales A J, Roberts V J, Yen S SC. Regression of uterine leiomyomata in response to the antiprogesterone RU486.  J Clin Endocrinol Metab. 1993;  76 513-517
• 30 Murphy A A, Morales A J, Kettel L M, Yen S SC. Regression of uterine leiomyomata to the antiprogesterone RU486: dose-response effect.  Fertil Steril. 1995;  64 187-190
• 31 Eisinger S H, Meldrum S, Fiscella K, le Roux H D, Guzick D S. Low-dose mifepristone for uterine leiomyomata.  Obstet Gynecol. 2003;  101 243-250
• 32 Reinsch R C, Murphy A, Morales A J, Yen S SC. The effects of RU486 and leuprolide acetate on uterine artery blood flow in the fibroid uterus: a prospective, randomized study.  Am J Obstet Gynecol. 1994;  170 1623-1628
• 33 Elger W, Bartley J, Schneider B, Kaufmann G, Schubert G, Chwalisz K. Endocrine-pharmacological characterization of progesterone antagonists and progesterone receptor modulators (PRMs) with respect to PR-agonistic and antagonistic activity.  Steroids. 2000;  65 713-723
• 34 DeManno D, Elger W, Garg R et al.. Asoprisnil (J867): a selective progesterone receptor modulator for gynecological therapy.  Steroids. 2003;  68 1019-1032
• 35 Chwalisz K, Brenner R M, Fuhrmann U, Hess-Stumpp H, Elger W. Antiproliferative effects of progesterone antagonists and progesterone receptor modulators on the endometrium.  Steroids. 2000;  65 741-751
• 36 Chwalisz K, Garg R, Brenner R M, Schubert G, Elger W. Selective progesterone receptor modulators (SPRMs): a novel therapeutic concept in endometriosis.  Ann N Y Acad Sci. 2002;  955 373-387
• 37 Kelly R W, King A E, Critchley H OD. Inflammatory mediators and endometrial function-focus on the perivascular cell.  J Reprod Immunol. 2002;  57 81-93
• 38 Chwalisz K, Elger W, McCrary K, Beckman P, Larsen L. Reversible suppression of menstruation in normal women irrespective of the effect on ovulation with the novel selective progesterone receptor modulator (SPRM)J867.  J Soc Gynecol Investig. 2002;  9(suppl):Abstract 49
• 39 Chwalisz K, Parker L, Williamson S. Treatment of uterine leiomyomas with the novel selective progesterone receptor modulator (SPRM).  J Soc Gynecol Investig. 2003;  10:Abstract 301A