Control of sulfatase activity by nomegestrol acetate in normal and cancerous human breast tissues.

Nomegestrol acetate (NOMAC), a 17alpha-hydroxy-nor-progesterone derivative (17alpha-acetoxy-6-methyl-19-nor-4,6-pregnadiene-3,20-dione, the active substance in Lutenyl), is a potent and useful clinical synthetic progestin for the treatment of menopausal complaints and is under current development for oral contraception. Previous studies in this laboratory demonstrated that NOMAC can block sulfatase and 17beta-hydroxysteroid dehydrogenase, the enzymes involved in the biosynthesis and transformation of estradiol (E2) in hormone-dependent MCF-7 and T-47D breast cancer cells. In the present study, the effect of NOMAC on sulfatase activity using total breast cancer tissue, compared to the effect in normal breast tissue, was explored. Slices of tumoral or normal breast tissues (45-65 mg) were incubated in buffer (20 mM Tris-HCl, pH 7.2) with physiological concentrations of [3H]-estrone sulfate (5x10(-9) M), alone or in the presence of nomegestrol acetate (5x10(-5) - 5x10(-7) - 5x10(-9) M), for 4 h at 37 degrees C. Estrone sulfate (E1S), estrone (E1) and E2 were characterized by thin layer chromatography and quantified using the corresponding standard. It was observed that [3H]- E1S was only converted to [3H]- E1 and not to [3H]- E2, in normal or cancerous breast tissues, which suggests a low or no 17beta-HSD activity under these experimental conditions. The sulfatase activity was more intense with breast cancer tissue than normal tissue, since the concentrations of E1 were 42.5 +/- 3.4 and 27.2 +/- 2.5 pg/mg tissue, respectively. NOMAC, at the concentration of 5x10(-5) M, inhibited this conversion by 49.2% and 40.8% in cancerous and normal breast tissues, respectively. The sulfatase inhibition at low concentration (5x10(-7) M) was 32.5% and 22.8%, respectively. It is concluded that sulfatase activity is almost twice as potent in cancerous breast tissues than in normal tissues. Nomegestrol acetate is a strong anti-sulfatase agent, in particular with cancerous breast tissues. The inhibition of estrone sulfatase activity by NOMAC in total normal or cancerous breast tissues can open attractive perspectives for future clinical trials.

Endometrial resection and preoperative LH-RH agonists: a prospective 5-year trial.

OBJECTIVE: To evaluate the benefits of systematic preoperative treatment with LH-RH agonists prior to endometrial resection (ER). STUDY DESIGN: The study population was made up of 98 premenopausal women who underwent resectoscopic treatment for abnormal uterine bleeding (AUB) between January 1996 and December 1997. Only patients with endometrial polyps or dysfunctional bleeding were included. The population was divided into two groups: patients who had (group B) and those who had not (group A) received LH-RH before the surgical intervention. RESULTS: ER was carried out as a single procedure in 66 (67.5%) of the patients. ER plus polypectomy was necessary in 32 (32.5%) patients. There were no differences between the two groups as far as the operating time and total volume of distension medium were concerned. No intraoperative complications were seen in either group. A higher negative balance of distension medium was achieved in group A (320 +/- 23 mL versus 187 +/- 16 mL; P < 0.001), and this difference was not modified when cases with polyps were excluded. The failure rate was similar in both groups both at 12 months [group A 6 (14.8%) versus group B 7 (14.9%) patients] and at 60 months [group A, 11 (21.6%) versus group B 10 (21.2%) patients]. Likewise, the amenorrhea and hypomenorrhea rates at 12 months and at 60 months were also shown to be the same in both groups. When two doses of LH-RH are used and the failure rate is taken into account the cost of an acceptable outcome increases from 843.37 Euro to 1373.49 Euro per patient, while the total cost of a hysterectomy is 1355.42 Euro. CONCLUSIONS: Endometrial suppression with LH-RH agonists did not guarantee better results of ER, but they are strongly recommended during the learning curve to achieve a safer procedure.

Hormone replacement therapy: evolution of body mass index, bone mineral density, and lipid profile.

One hundred and eighty-five female never-hormone users with a mean age of 50.71 (SD = 5.58) years upon initiation of treatment were studied before instauration and during treatment. The profile of patients subjected to the study included body mass index (BMI), bone mineral density (BMD), and lipid profile (LP). In our population, pretreatment values were within the normal range, which is why a hormone replacement therapy (HRT), conjugated equine estrogen plus medroxyprogesterone acetate, was administered to a healthy population of women for 9.82 ± 5.42 years and follow-up comprised 1815.84 woman-years. To study the effects of treatment on the investigated clinical subjects, we resorted to comparative analyses of pretreatment and posttreatment mean values: descriptive and comparative hypothesis, followed by a repeated measurements design to investigate the evolution on three levels according to age groups just before the initiation of the treatment and on the other three levels during the treatment with a minimum follow-up of 9 years. On the basis of the numerical results, we were able to conclude that BMD decreased significantly (p = 0.00) well above the values found on curves corresponding to these age groups. The total cholesterol decreased significantly at 2-3 years interval (p = 0.04). The rest of the LP factors remained within a safe margin. Therefore, long-term HRT may be considered initially as a beneficial alternative in the treated study population.

Effect of tibolone and its principal metabolites (3α- and 3ß-hydroxy, 3α-sulfate, and 4-ene derivatives) on estrone sulfatase activity in normal and cancerous human breast tissue.

BACKGROUND: Tibolone (Org-OD14) is the active substance of Livial®, a synthetic steroid with the structure 7α,17α-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one, possessing weak tissue-specific estrogenic, progestogenic, and androgenic properties, used to treat menopausal complaints. After oral administration, tibolone is extensively metabolized into the 3α-(Org-4904) and 3ß-(Org-30126) hydroxy derivatives with estrogenic properties, its 4-ene (Org-OM38) isomer with progestogenic/androgenic activities, and the 3α-sulfate (Org-34322) derivative, a major biologically inactive circulating form. We compared the dose response of tibolone and its metabolites on estrone sulfatase activity [conversion of estrone sulfate (E1S) to estrone (E1)] in normal and cancerous human breast tissues. MATERIALS AND METHODS: Tissue minces were incubated with physiological concentrations of [3H]-E1S (5×10-9M) alone or in the presence of tibolone and its metabolites (concentration range: 5×10-7to 5×10-5M) for 4 h. Tritiated E1, estradiol (E2), and E1S were separated and evaluated quantitatively by thin-layer chromatography. RESULTS: The sulfatase activity was significantly higher in cancerous breast but strongly inhibited by tibolone and the different metabolites, whereas 3α- and 3ß-hydroxy derivatives were the most potent inhibitors. CONCLUSION: This very significant inhibitory effect of tibolone and its principal metabolites on the enzyme involved in E2biosynthesis in the human breast provides interesting perspectives to study the biological responses of these compounds in trials with breast cancer patients.

Hormone replacement therapy: 1815.84 woman-years of follow-up main clinical events.

BACKGROUND: One hundred and eighty-five women with a mean age of 50.71 (SD=5.58) years upon initiation of treatment were studied before, and during, treatment. MATERIALS AND METHODS: Included in the profile of patients under study were family and personal histories, gynecological and breast examinations. Population age: a) <60 years old, 171 women (92.43%), and b) aged 60 years or older, 14 women (7.57%). Dosage comprised both 0.625 mg/daily orally of conjugated equine estrogens and 2.5 or 5 mg/daily of medroxy progesterone acetate. No further specific treatment was prescribed. Mean duration of treatment was 9.82 (SD=5.42) years for all women; 9.70 (SD=5.44) in the younger group. Follow-up comprised 1815.84 woman-years, for 5 years or over (76.75%) on 142 women. Fifty-two women (28.11%) dropped out. RESULTS: No deaths occurred during treatment. Four cardiovascular events (2.16%) were reported. No spontaneous bone fracture was documented. Nonetheless, there were 12 bone fractures of traumatic origin (6.48%), none of them hip fractures. Five breast cancers were observed. Likewise, one diagnosis of breast cancer for every 37 treated women from our series was evidenced. There were 117 women (63.24%) without any events. CONCLUSION: A higher risk of breast cancer or of serious cardiovascular events cannot be inferred from statistical analysis of 5 years or more of treatment.