RSS-Feed abonnieren
DOI: 10.1055/s-2004-828616
Treatment Strategies for Uterine Leiomyoma: The Role of Hormonal Modulation
Publikationsverlauf
Publikationsdatum:
26. Mai 2004 (online)
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.
KEYWORDS
Uterine leiomyoma - hormone - selective estrogen receptor modulators - therapy - antagonists
REFERENCES
- 1 Buttram V, Reiter R. Uterine leiomyomata: etiology, symptomatology, and management. Fertil Steril. 1981; 36 433-445
- 2 Cramer S, Patel B. The frequency of uterine leiomyomas. Am J Clin Pathol. 1990; 94 435-438
- 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
- 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
- 5 Parazzini F, Negri E, La Vecchia C et al.. Oral contraceptive use and risk of uterine fibroids. Obstet Gynecol. 1992; 79 430-433
- 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
- 7 Parazzini F, Negri E, La Vecchia C et al.. Reproductive factors and risk of uterine fibroids. Epidemiology. 1996; 7 440-442
- 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
- 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
- 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
- 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
- 12 Chiaffarino F, Parazzini F, La Vecchia C et al.. Diet and uterine myomas. Obstet Gynecol. 1999; 94 395-398
- 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
- 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
- 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
- 16 Adamson G D. Treatment of uterine fibroids: current findings with gonadotropin- releasing hormone agonists. Am J Obstet Gynecol. 1992; 166 746-751
- 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
- 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
- 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
- 20 Yamamoto T, Takamori K, Okada H. Estrogen biosynthesis in leiomyoma and myometrium of the uterus. Horm Metab Res. 1984; 16 678-679
- 21 Rein M, Nowak R. Biology of uterine myomas and myometrium in vitro. Semin Reprod Endocrinol. 1992; 10 310-319
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 30 Reddy V V, Hanjani P, Rajan R. Synthesis of catechol estrogens by human uterus and leiomyoma. Steroids. 1981; 37 195-203
- 31 Deligdish L, Loewenthal M. Endometrial changes associated with myomata of the uterus. J Clin Pathol. 1970; 23 676-680
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 58 Burroughs K D, Kiguchi K, Howe S R et al.. Regulation of apoptosis in uterine leiomyomata. Endocrinology. 1997; 138 3056-3064
- 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
- 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
- 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
- 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
- 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
- 64 Baird D D, Dunson D B. Why is parity protective for uterine fibroids?. Epidemiology. 2003; 14 247-250
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