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Semin Reprod Med 2004; 22(2): 113-119
DOI: 10.1055/s-2004-828617
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

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

Kristof Chwalisz1 , Deborah DeManno1 , Ramesh Garg1 , Lois Larsen1 , Cynthia Mattia-Goldberg1 , Therese Stickler1
  • 1Research and Development, TAP Pharmaceutical Products, Inc., Lake Forest, Illinois
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Publication History

Publication Date:
26 May 2004 (online)

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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
    PubMedGoogle Scholar
  • 2 Buttram V C, Reiter R C. Uterine leiomyomata: etiology, symptomatology and management.  Fertil Steril. 1981;  36 433-445
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 4 Wilcox L S, Koonin L M, Pokras R et al.. Hysterectomy in the United States 1988-1990.  Obstet Gynecol. 1994;  83 549-555
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 10 Stewart E A. Uterine fibroids.  Lancet. 2001;  357 293-298
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 20 Rein M S. Advances in uterine leiomyoma research: the progesterone hypothesis.  Environ Health Perspect. 2000;  108(suppl 5) 791-793
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 22 Tiltman A J. The effects of progestins on the mitotic activity of uterine fibromyomas.  Int J Gynecol Pathol. 1985;  4 89-96
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 25 Maruo T, Matsuo H, Samoto T et al.. Effects of progesterone on uterine leiomyoma growth and apoptosis.  Steroids. 2000;  65 585-592
    CrossrefPubMedGoogle Scholar
  • 26 Mixson W T, Hammond D D. Response of fibromyomas to a progestin.  Am J Obstet Gynecol. 1961;  82 754-760
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 34 DeManno D, Elger W, Garg R et al.. Asoprisnil (J867): a selective progesterone receptor modulator for gynecological therapy.  Steroids. 2003;  68 1019-1032
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar

Kristof ChwaliszM.D. Ph.D. 

TAP Pharmaceutical Products, Inc., 675 N. Field Drive

Lake Forest, IL 60045

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