Treatment Strategies for Uterine Leiomyoma: The Role of Hormonal Modulation

 

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Uterine leiomyomas are the most common gynecological tumors and are a significant health concern for many women. Although the exact etiology of these tumors is unknown, epidemiological and experimental animal studies have established a role for ovarian hormones in the pathogenesis of this disease. Current treatment regimens for symptomatic tumors primarily require surgical intervention. However, a major emphasis of leiomyoma research involves understanding how hormones regulate tumor growth to target the hormonal dependence of these tumors with new therapeutic strategies. Gonadotropin-releasing hormone agonists that block hormone production and induce a hypoestrogenic milieu can be utilized as adjuvant therapy; however, these drugs do little to reduce tumor cellularity, and their negative impact on bone mineral density limits their use. Selective estrogen receptor modulators (SERMs) are nonsteroidal therapeutic agents that bind to the estrogen receptor and elicit tissue-specific estrogen agonist or antagonist effects. SERMs are effective in the treatment and prevention of breast cancer, and preclinical and clinical data suggest that these hormonal modulators may also be beneficial for the treatment of uterine leiomyomas. Continued efforts to understand the role of hormones in the development of this disease will allow the development of newer, less invasive treatment strategies, which will help minimize the negative impact of these tumors on women's health.

REFERENCES

• 1 Buttram V, Reiter R. Uterine leiomyomata: etiology, symptomatology, and management.  Fertil Steril. 1981;  36 433-445
  PubMedGoogle Scholar
• 2 Cramer S, Patel B. The frequency of uterine leiomyomas.  Am J Clin Pathol. 1990;  94 435-438
  CrossrefPubMedGoogle Scholar
• 3 Ross R K, Pike M C, Vessey M P et al.. Risk factors for uterine fibroids: reduced risk associated with oral contraceptives.  Br Med J (Clin Res Ed). 1986;  293 359-362
  PubMedGoogle Scholar
• 4 Parazzini F, La Vecchia C, Negri E, Cecchetti G, Fedele L. Epidemiologic characteristics of women with uterine fibroids: a case-control study.  Obstet Gynecol. 1988;  72 853-857
  PubMedGoogle Scholar
• 5 Parazzini F, Negri E, La Vecchia C et al.. Oral contraceptive use and risk of uterine fibroids.  Obstet Gynecol. 1992;  79 430-433
  PubMedGoogle Scholar
• 6 Parazzini F, Negri E, La Vecchia C et al.. Uterine myomas and smoking. Results from an Italian study.  J Reprod Med. 1996;  41 316-320
  PubMedGoogle Scholar
• 7 Parazzini F, Negri E, La Vecchia C et al.. Reproductive factors and risk of uterine fibroids.  Epidemiology. 1996;  7 440-442
  PubMedGoogle Scholar
• 8 Kjerulff K H, Langenberg P, Seidman J D, Stolley P D, Guzinski G M. Uterine leiomyomas. Racial differences in severity, symptoms and age at diagnosis.  J Reprod Med. 1996;  41 483-490
  PubMedGoogle Scholar
• 9 Marshall L M, Spiegelman D, Barbieri R L et al.. Variation in the incidence of uterine leiomyoma among premenopausal women by age and race.  Obstet Gynecol. 1997;  90 967-973
  CrossrefPubMedGoogle Scholar
• 10 Marshall L M, Spiegelman D, Goldman M B et al.. A prospective study of reproductive factors and oral contraceptive use in relation to the risk of uterine leiomyomata.  Fertil Steril. 1998;  70 432-439
  CrossrefPubMedGoogle Scholar
• 11 Marshall L M, Spiegelman D, Manson J E et al.. Risk of uterine leiomyomata among premenopausal women in relation to body size and cigarette smoking.  Epidemiology. 1998;  9 511-517
  CrossrefPubMedGoogle Scholar
• 12 Chiaffarino F, Parazzini F, La Vecchia C et al.. Diet and uterine myomas.  Obstet Gynecol. 1999;  94 395-398
  CrossrefPubMedGoogle Scholar
• 13 Chiaffarino F, Parazzini F, La Vecchia C et al.. Use of oral contraceptives and uterine fibroids: results from a case- control study.  Br J Obstet Gynaecol. 1999;  106 857-860
  PubMedGoogle Scholar
• 14 Andreyko J L, Marshall L A, Dumesic D A, Jaffee R B. Therapeutic uses of gonadotropin-releasing hormone analogs.  Obstet Gynecol Surv. 1987;  42 1-21
  PubMedGoogle Scholar
• 15 Cohen D, Mazur M T, Jozefczyk M A, Badawy S ZA. Hyalinization and cellular changes in uterine leiomyomata after gonadotropin releasing hormone agonist therapy.  J Reprod Med. 1994;  39 337-380
  PubMedGoogle Scholar
• 16 Adamson G D. Treatment of uterine fibroids: current findings with gonadotropin- releasing hormone agonists.  Am J Obstet Gynecol. 1992;  166 746-751
  PubMedGoogle Scholar
• 17 Friedman A J, Lobel S M, Rein M S, Barbieri R L. Efficacy and safety considerations in women with uterine leiomyomas treated with gonadotropin-releasing hormone agonists: the estrogen threshold hypothesis.  Am J Obstet Gynecol. 1990;  163(4 Pt 1) 1114-1119
  PubMedGoogle Scholar
• 18 Dawood M Y, Lewis V, Ramos J. Cortical and trabecular bone mineral content in women with endometriosis: effect of gonadotropin-releasing hormone agonist and danazol.  Fertil Steril. 1989;  52 21-26
  PubMedGoogle Scholar
• 19 Otubu J A, Buttram V C, Besch N F, Besch P K. Unconjugated steroids in leiomyomas and tumor-bearing myometrium.  Am J Obstet Gynecol. 1982;  143 130-133
  PubMedGoogle Scholar
• 20 Yamamoto T, Takamori K, Okada H. Estrogen biosynthesis in leiomyoma and myometrium of the uterus.  Horm Metab Res. 1984;  16 678-679
  PubMedGoogle Scholar
• 21 Rein M, Nowak R. Biology of uterine myomas and myometrium in vitro.  Semin Reprod Endocrinol. 1992;  10 310-319
  PubMedGoogle Scholar
• 22 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
• 23 Brandon D D, Erickson T E, Keenan E J et al.. Estrogen receptor gene expression in human uterine leiomyomata.  J Clin Endocrinol Metab. 1995;  80 1876-1881
  CrossrefPubMedGoogle Scholar
• 24 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
• 25 Nisolle M, Gillerot S, Casanas-Roux F et al.. 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
• 26 Pollow K, Sinnecker G, Boquoi E, Pollow B. In vitro conversion of estradiol-17β into estrone in normal human myometrium and leiomyoma.  J Clin Chem Clin Biochem. 1978;  16 493-502
  PubMedGoogle Scholar
• 27 Folkerd E J, Newton C J, Davidson K, Anderson M C, James V H. Aromatase activity in uterine leiomyomata.  J Steroid Biochem. 1984;  20 1195-1200
  CrossrefPubMedGoogle Scholar
• 28 Bulun S E, Simpson E R, Word R A. Expression of the CYP19 gene and its product aromatase cytochrome P450 in human uterine leiomyoma tissues and cells in culture.  J Clin Endocrinol Metab. 1994;  78 736-743
  CrossrefPubMedGoogle Scholar
• 29 Liehr J G, Ricci M J, Jefcoate C R et al.. 4-Hydroxylation of estradiol by human uterine myometrium and myoma microsomes: implications for the mechanism of uterine tumorigenesis.  Proc Natl Acad Sci U S A. 1995;  92 9220-9224
  PubMedGoogle Scholar
• 30 Reddy V V, Hanjani P, Rajan R. Synthesis of catechol estrogens by human uterus and leiomyoma.  Steroids. 1981;  37 195-203
  CrossrefPubMedGoogle Scholar
• 31 Deligdish L, Loewenthal M. Endometrial changes associated with myomata of the uterus.  J Clin Pathol. 1970;  23 676-680
  PubMedGoogle Scholar
• 32 Farrer-Brown G, Beilby J O, Tarbit M H. The vascular patterns in myomatous uteri.  J Obstet Gynaecol Br Commonw. 1970;  77 967-975
  PubMedGoogle Scholar
• 33 Andersen J VM, DyReyes V M, Barbieri R L, Coachman D M, Miksicek R J. Leiomyoma primary cultures have elevated transcriptional response to estrogen compared with autologous myometrial cultures.  J Soc Gynecol Investig. 1995;  2 542-551
  PubMedGoogle Scholar
• 34 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(1 Pt 1) 14-18
  CrossrefPubMedGoogle Scholar
• 35 Kettel L M, Murphy A A, Morales A J, Yen S S. Clinical efficacy of the antiprogesterone RU486 in the treatment of endometriosis and uterine fibroids.  Hum Reprod. 1994;  9 116-120
  PubMedGoogle Scholar
• 36 Murphy A A, Kettel L M, Morales A J, Roberts V J, Yen S S. Regression of uterine leiomyomata in response to the antiprogesterone RU 486.  J Clin Endocrinol Metab. 1993;  76 513-517
  CrossrefPubMedGoogle Scholar
• 37 Kawaguchi K, Fuji S, Konishi I et al.. Mitotic activity in uterine leiomyomas during the menstrual cycle.  Am J Obstet Gynecol. 1989;  160 637-641
  CrossrefPubMedGoogle Scholar
• 38 Shimomura Y, Matsuo H, Samoto T, Maruo T. Up-regulation by progesterone of proliferating cell nuclear antigen and epidermal growth factor expression in human uterine leiomyoma.  J Clin Endocrinol Metab. 1998;  83 2192-2198
  CrossrefPubMedGoogle Scholar
• 39 Matsuo H, Maruo T, Samoto T. Increased expression of Bc1-2 protein in human uterine leiomyoma and its upregulation by progesterone.  J Clin Endocrinol Metab. 1997;  82 293-299
  CrossrefPubMedGoogle Scholar
• 40 Hodges L C, Houston K D, Hunter D S et al.. Transdominant suppression of estrogen receptor signaling by progesterone receptor ligands in uterine leiomyoma cells.  Mol Cell Endocrinol. 2002;  196 11-20
  CrossrefPubMedGoogle Scholar
• 41 Walker C L, Burroughs K D, Davis B et al.. Preclinical evidence for therapeutic efficacy of selective estrogen receptor modulators for uterine leiomyoma.  J Soc Gynecol Investig. 2000;  7 249-256
  PubMedGoogle Scholar
• 42 Walker C L, Cesen-Cummings K, Houle C et al.. Protective effect of pregnancy for development of uterine leiomyoma.  Carcinogenesis. 2001;  22 2049-2052
  CrossrefPubMedGoogle Scholar
• 43 Cesen-Cummings K, Houston K D, Copland J A et al.. Uterine leiomyomas express myometrial contractile-associated proteins involved in pregnancy-related hormone signaling.  J Soc Gynecol Investig. 2003;  10 11-20
  CrossrefPubMedGoogle Scholar
• 44 Cesen-Cummings K, Copland J A, Barrett J C, Walker C L, Davis B J. Pregnancy, parturition, and prostaglandins: defining uterine leiomyomas.  Environ Health Perspect. 2000;  108(suppl 5) 817-820
  PubMedGoogle Scholar
• 45 Gottardis M M, Robinson S P, Satyaswaroop P G, Jordan V C. Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse.  Cancer Res. 1988;  48 812-815
  PubMedGoogle Scholar
• 46 Satyaswaroop P G, Zaino R J, Mortel R. Estrogen-like effects of tamoxifen on human endometrial carcinoma transplanted into nude mice.  Cancer Res. 1984;  44 4006-4010
  PubMedGoogle Scholar
• 47 Love R R, Mazess R B, Barden H S et al.. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer.  N Engl J Med. 1992;  326 852-856
  CrossrefPubMedGoogle Scholar
• 48 Guetta V, Lush R M, Figg W D, Waclawiw M A, Cannon R O. Effects of the antiestrogen tamoxifen on low-density lipoprotein concentrations and oxidation in postmenopausal women.  Am J Cardiol. 1995;  76 1072-1073
  CrossrefPubMedGoogle Scholar
• 49 Ettinger B, Black D M, Mitlak B H et al.. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators.  JAMA. 1999;  282 637-645
  CrossrefPubMedGoogle Scholar
• 50 Delmas P D, Bjarnason N H, Mitlak B H et al.. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women.  N Engl J Med. 1997;  337 1641-1647
  CrossrefPubMedGoogle Scholar
• 51 Porter K B, Tsibris J C, Nicosia S V et al.. Estrogen-induced guinea pig model for uterine leiomyomas: do the ovaries protect?.  Biol Reprod. 1995;  52 824-832
  PubMedGoogle Scholar
• 52 Porter K B, Tsibris J C, Porter G W et al.. Effects of raloxifene in a guinea pig model for leiomyomas.  Am J Obstet Gynecol. 1998;  179 1283-1287
  PubMedGoogle Scholar
• 53 Yeung R S, Xiao G H, Jin F et al.. Predisposition to renal carcinoma in the Eker rat is determined by germ-line mutation of the tuberous sclerosis 2 (TSC2) gene.  Proc Natl Acad Sci U S A. 1994;  91 11413-11416
  PubMedGoogle Scholar
• 54 Kobayashi T, Hirayama Y, Kobayashi E, Kubo Y, Hino O. A germline insertion in the tuberous sclerosis (Tsc2) gene gives rise to the Eker rat model of dominantly inherited cancer.  Nat Genet. 1995;  9 70-74
  PubMedGoogle Scholar
• 55 Everitt J I, Wolf D C, Howe S R, Goldsworthy T L, Walker C L. Rodent model of reproductive tract leiomyomata. Clinical and pathological features.  Am J Pathol. 1995;  146 1556-1567
  PubMedGoogle Scholar
• 56 Howe S R, Gottardis M M, Everitt J I et al.. Rodent model of reproductive tract leiomyomata. Establishment and characterization of tumor-derived cell lines.  Am J Pathol. 1995;  146 1568-1579
  PubMedGoogle Scholar
• 57 Fuchs-Young R, Howe S, Hale L, Miles R, Walker C. Inhibition of estrogen-stimulated growth of uterine leiomyomas by selective estrogen receptor modulators.  Mol Carcinog. 1996;  17 151-159
  CrossrefPubMedGoogle Scholar
• 58 Burroughs K D, Kiguchi K, Howe S R et al.. Regulation of apoptosis in uterine leiomyomata.  Endocrinology. 1997;  138 3056-3064
  CrossrefPubMedGoogle Scholar
• 59 Howe S R, Gottardis M M, Everitt J I, Walker C. Estrogen stimulation and tamoxifen inhibition of leiomyoma cell growth in vitro and in vivo.  Endocrinology. 1995;  136 4996-5003
  CrossrefPubMedGoogle Scholar
• 60 Palomba S, Sammartino A, Di Carlo C et al.. Effects of raloxifene treatment on uterine leiomyomas in postmenopausal women.  Fertil Steril. 2001;  76 38-43
  CrossrefPubMedGoogle Scholar
• 61 Palomba S, Orio F, Morelli M et al.. Raloxifene administration in premenopausal women with uterine leiomyomas: a pilot study.  J Clin Endocrinol Metab. 2002;  87 3603-3608
  CrossrefPubMedGoogle Scholar
• 62 Palomba S, Russo T, Orio F et al.. Effectiveness of combined GnRH analogue plus raloxifene administration in the treatment of uterine leiomyomas: a prospective, randomized, single-blind, placebo-controlled clinical trial.  Hum Reprod. 2002;  17 3213-3219
  CrossrefPubMedGoogle Scholar
• 63 Palomba S, Orio F, Morelli M et al.. Raloxifene administration of women treated with gonadotropin-releasing hormone agonist for uterine leiomyomas: effects on bone metabolism.  J Clin Endocrinol Metab. 2002;  87 4476-4481
  CrossrefPubMedGoogle Scholar
• 64 Baird D D, Dunson D B. Why is parity protective for uterine fibroids?.  Epidemiology. 2003;  14 247-250
  CrossrefPubMedGoogle Scholar

Cheryl Lyn WalkerPh.D. 

Ruth and Walter Sterling Professor of Carcinogenesis, Department of Carcinogenesis, University of Texas, M.D. Anderson Cancer Center

Science Park-Research Division

P.O. Box 389, Smithville, TX 78957