Uterine Leiomyomas

Young, L.A., N.P. Lung, R. Isaza, and D. Heard. 1994. Anemia in a chimpanzee (Pan troglodytes) associated with lead toxicity and uterine leiomyoma. Proc. Amer. Assoc. Zoo Veterin. 1994 287. 

The most common benign gynecological diseases, for prevalence and related economic costs, are probably uterine leiomyomas and endometriosis (Stewart 2001 Missmer et al. 2003). Notwithstanding the fact that both conditions are characterized by a sex-hormone-related development and by the possibility of a medical treatment consisting of hormonal manipulation, at present the main approach to these conditions is surgical excision (Palomba et al. 2006a Olive etal. 2001). 

First we shall describe the effects of tamoxifen, a first-generation SERM used as adjuvant treatment in women with breast cancer, on uterine leiomyomas and endometriosis. Considerable space will be devoted to raloxifene, a second-generation SERM administered for the prevention and treatment of postmenopausal women recently tested for the treatment of these two sex-hormone-related diseases. Unfortunately, at present no or very little data are available on the new third-generation SERMs such as lasofoxifene, idroxifene, droloxifene, ospemifene, azomifene, fulvestrant, and MDL 103.323. 

Uterine leiomyomas are the most frequent benign disease of the female reproductive apparatus. At least 20-25% of women of fertile age and 50% of women studied in postmortem have uterine leiomyomas (Stewart 2001 Palomba et al. 2005a). In between 20 and 50% of cases, the uterine leiomyomas cause a clinically relevant symptomatology (such as menorrhagia, infertility, recurrent abortion, pelvic pain, and so on) and treatment is required (Stewart 2001 Palomba et al. 2006a). Thus, this disease is one of the main causes of health expense in the field of gynecology (Stewart 2001 Palomba et al. 2006a). In fact,... 

To date, the standard treatment for uterine leiomyomas is their laparo-tomic/laparoscopic excision in women who want to preserve their fertility, whereas the use of a more extensive surgery, such as the hysterectomy, is reserved for disseminating uterine leiomyomatosis, generally in the peri-menopausal period (Stewart 2001 Palomba et al. 2006a). 

Table 12.1. Medical therapies for uterine leiomyomas (Palomba et al. 2000a)...

The first data on the effects of tamoxifen on uterine leiomyomas were obtained in a rat model. They showed that tamoxifen increased tumor latency and decreased tumor size (Howe et al. 1995). These findings were confirmed more recently by Walker et al. (2000). In the same period, moreover, several case reports were published showing an increase in uterine leiomyoma dimensions following tamoxifen administration (Dilts et al. 1992 Leo et al. 1994 Ugwumadu et al. 1994). 

The scientific data on the effects of tamoxifen on uterine leiomyomas are generally extrapolated from safety data on the use of tamoxifen in women with breast cancer, and for this reason the studies available are essentially clinical studies on human models. 

The effects of tamoxifen on uterine leiomyomas have been studied also in postmenopausal patients with breast cancer (Schwartz et al. 1998). After an average treatment of about 1 year, uterine and leiomyoma volumes increased significantly, confirming an agonistic effect of tamoxifen on the uterus. No significant difference in agonist effect on the uterus has been detected between tamoxifen and toremifene (Tomas et al. 1995). 

The discrepancy between these two studies (Walker et al. 2000 Palomba et al. 2005c) are probably due to the different models used. This suggestion is supported by the absence of a correspondence between beneficial effects of tamoxifen on uterine leiomyomas in the rat (Walker et al. 2000) and findings obtained in clinical studies in humans (Leo et al. 1994 Ugwumadu et al. 1994 Lumsden et al. 1989a,b Schwartz et al. 1998 Tomas et al. 1995 Sadan et al. 

Like the medical treatment of uterine leiomyomas, danazol, gestrinone, mifepristone, and GnRH-a, with or without add-back therapy, have been proposed for the treatment of endometriosis as well (Olive et al. 2001 Stones et al. 2004), but unlike leiomyomas, oral contraceptive pills, in cyclic or continuous administration, and medroxyprogesterone acetate also seem to be effective (Olive et al. 2001 Stones et al. 2004). A significant benefit in terms of pelvic pain relief also is obtained with the use of nonsteroidal anti-inflammatory drugs (Olive et al. 2001 Stones et al. 2004). 

At present, the only SERMs routinely used in clinical practice are tamoxifen and raloxifene. Tamoxifen is used essentially as adjuvant treatment in women with breast cancer. Its use is related to estrogenic effects on the uterus. Specifically, tamoxifen can be associated with an increase not only in endometrial hyperplasia and cancer risk but also in uterine leiomyoma dimensions and in a risk of developing active endometriotic lesions. 

Raloxifene is actually used for the treatment and prevention of postmenopausal osteoporosis. Also, if raloxifene has been shown to have any effect on uterine leiomyomas in vitro and in animal models, to date no concrete efficacy has been demonstrated in normally cycled premenopausal women. Moreover, the addition of raloxifene to GnRH-a administration can be useful for limiting GnRH-a-related side effects and increasing the rate of reduction in tumor size. 

Regarding the use of SERMs in women with endometriosis, the efficacy of raloxifene or other compounds is only potential. Experimental studies to determine if SERMs have a greater potency against uterine leiomyomas and endometriosis are currently in progress. 

Barbieri RL (1997) Reduction in the size of a uterine leiomyoma following discontinuation of an estrogen-progestin contraceptive. Gynecol Obstet Invest 43 276-277... 

Bulun SE, Simpson ER, Word RA (1994) Expression of the CYP19 gene and its product aromatase cytochrome P450 in human uterine leiomyoma tissue and cells in culture. J Clin Endocrinol Metab 78 736-743... 

Fuchs-Young R, Howe S, Hale L, Miles R, Walker C (1996) Inhibition of estrogen stimulated growth of uterine leiomyomas by selective estrogen receptor modulators. Mol Carcinog 17 151-159... 

Gao Z, Matsuo H, Wang Y, Nakago S, Maruo T (2001) Up-regulation by IGF-I of proliferating cell nuclear antigen and Bcl-2 protein expression in human uterine leiomyoma cells. J Clin Endocrinol Metab 86 5593-5599... 

Higashijima T, Kataoka A, Nishida T, YakushijiM (1996) Gonadotropin-releasing hormone agonist therapy induces apoptosis in uterine leiomyoma. Eur J Obstet Gynecol Reprod Biol 68 169-173... 

Jirecek S, Lee A, Pavo I, Crans G, Eppel W, Wenzl R (2004) Raloxifene prevents the growth of uterine leiomyomas in premenopausal women. Fertil Steril 81 132-136... 

Kawaguchi K, Fujii S, Konishi I, Nanbu Y, Nonogaki H, Mori T (1989) Mitotic activity in uterine leiomyomas during the menstrual cycle. Am J Obstet Gynecol 160 637-641... 

Minakuchi K, Kawamura N, Tsujimura A (1999) Remarkable and persistent shrinkage of uterine leiomyoma associated with interferon alfa treatment for hepatitis. Lancet 353 2127-2128... 

Palomba S, Affinito P, Di Carlo C, Bifulco G, Nappi C (1999) Longterm administration of tibolone plus gonadotropin-releasing hormone agonist for treatment of uterine leiomyomas effectiveness and effects on vasomotor symptoms, bone mass, and lipid profile. Fertil Steril 72 889-895... 

Palomba S, Sammartino A, Di Carlo C, Affinito P, Zullo F, Nappi C (2001) Effects of raloxifene treatment on uterine leiomyomas in postmenopausal women. Fertil Steril 76 38-43... 

Palomba S, Orio F Jr, Morelli M, Russo T, Pellicano M, Zupi E, Lombardi G, Nappi C, Benedetti Panici PG, Zullo F (2002a) Raloxifene administration in premenopausal women with uterine leiomyomas a pilot study. J Clin Endocrinol Metab 87 3303-3308... 

Palomba S, Orio F Jr, Russo T, Falbo A, Cascella T, Doldo P, Nappi C, Lombardi G, Mastrantonio P, Zullo F (2004c) Long-term effectiveness and safety of GnRH agonist plus raloxifene administration in women with uterine leiomyomas. Hum Reprod 19 1308-1314... 

Palomba S, Falbo A, Russo T, Zullo F (2005a) Emerging drugs in uterine leiomyomas. Exp Opin Emerg Drugs (in press)... 

Rein MS (2000) Advanced in uterine leiomyoma research the progesterone hypothesis. Environ Health Perspect 108 791-793... 

Schwartz LB, Rutkowski N, Horan C, Nachtigall LE, Snyder J, Goldstein SR (1998) Use of transvaginal ultrasonography to monitor the effects of tamoxifen on uterine leiomyoma size and ovarian cyst formation. J Ultrasound Med 17 699-703... 

Shozu M, Murakami K, Segawa T, Kasai T, Inoue M (2003) Successful treatment of a symptomatic uterine leiomyoma in a perimenopausal woman with a nonsteroidal aromatase inhibitor. Fertil Steril 79 628-631... 

Walker CL, Burroughs KD, Davis B, Sowell K, Everitt JI, Fuchs-Young R (2000) Pre-dinical evidence for therapeutic efficacy of selective estrogen receptor modulators for uterine leiomyoma. J Soc Gynecol Invest 7 249-256... 

---