Uterine treatment

Uracil is used more effectively, in nucleic acid synthesis within a rat hepatoma than in normal liver. This observation appears to have stimulated the synthesis of 5-fluorouracil (1027) as an antimetabolite mainly because the introduction of a fluorine atom involves a minimal increase in size. In the event, 5-fluorouracil did prove to have antineoplastic activity and it is now a valuable drug for treatment of tumors of the breast, colon or rectum, and to a lesser extent, gastric, hepatic, pancreatic, uterine, ovarian and bladder carcinomas. As with other drugs which interfere with DNA synthesis, the therapeutic index is quite low and great care is required during treatment (69MI21301). 

Adrenergic receptor agonists are also used to treat premature labour by causing uterine relaxation. Fenoterol and ritodrine are frequently used. The effectiveness of long-term tocolysis is controversial, since both desensitization of the receptors and the symptomatic nature of this treatment may limit their effects to 1-2 days according to one large study. 

The first SPRM to reach the advanced stage of clinical development for treatment of endometriosis and uterine fibroids, asoprisnil, is expected to receive FDA approval this year. The therapeutic effect of asoprisnil stems from its PR antagonist/ antiproliferative activity in the endometrium and breast. Unlike classical PR antagonists however, this compound does not induce labor in animal models of pregnancy and parturition. Recent structural studies... 

The progestins are used in the treatment of amenorrhea, endometriosis, and functional uterine bleeding. Progestins are also used as oral contraceptives, either alone or in combination with an estrogen (see the Summary Drug Table Female Hormones and Table 52-1). 

Nearly all the clinical data comes from the use of atosiban (see Peptide Antagonists), a peptide oxytocin antagonist that is licensed in Europe for acute (48 h) treatment of preterm labour. Early clinical studies demonstrated the ability of atosiban to inhibit uterine contractions associated with labour [14]. Following these successful phase II trials, full phase III trials were... 

EM-800 (SCH-57050) and its active metabolite EM-652 (acolbifene, SCH-57068), are highly potent antiestrogens in human breast and uterine cancer cells in vitro as well as in vivo in nude mice and are currently undergoing clinical trials in the treatment of hormone-dependent breast cancer and endometrial cancer (Labrie et al 1999). Acolbifene shows a higher capacity of binding to... 

The overall uterine effects obtained in animals treated with the different compounds make it possible to assume that pure antiestrogens could be used in the treatment of endometrial disorders and endometrial carcinoma (Gradishar and Jordan 1997). 

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). 

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). 

Fig. 12.1. Variation (%) from baseline in uterine and leiomyoma sizes and in A size after 3, 6, 9, and 12 cycles of treatment. Values are reported as mean SD.a p < 0.05 vs. baseline. A = group A = group B (Palomba et al. 2001). Permission to publish from Elsevier...

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