Design of a Mestranol 2-N-Piperazino-Substituted Derivative Showing Potent and Selective in†vitro and in†vivo Activities in MCF-7 Breast Cancer Models.

Anticancer structure-activity relationship studies on aminosteroid (5α-androstane) derivatives have emerged with a promising lead candidate: RM-133 (2ß-[1-(quinoline-2-carbonyl)pyrrolidine-2-carbonyl]-N-piperazine-5α-androstane-3α,17ß-diol), which possesses high in vitro and in vivo activities against several cancer cells, and selectivity over normal cells. However, the relatively weak metabolic stability of RM-133 has been a drawback to its progression toward clinical trials. We investigated the replacement of the androstane backbone by a more stable mestranol moiety. The resulting compound, called RM-581 ({4-[17α-ethynyl-17ß-hydroxy-3-methoxyestra-1,3,5(10)-trien-2-yl]piperazin-1-yl}[(2S)-1-(quinolin-2-ylcarbonyl)pyrrolidin-2-yl]methanone), was synthesized efficiently in only five steps from commercially available estrone. In comparison with RM-133, RM-581 was found to be twice as metabolically stable, retains potent cytotoxic activity in breast cancer MCF-7 cell culture, and fully blocks tumor growth in a mouse xenograft model of breast cancer. Advantageously, the selectivity over normal cells has been increased with this estrane version of RM-133. In fact, RM-581 showed a better selectivity index (15.3 vs. 3.0) for breast cancer MCF-7 cells over normal breast MCF-10A cells, and was found to be nontoxic toward primary human kidney proximal tubule cells at doses reaching 50 µm.

Judicious usage of estrogen/progesterone for angiodysplasia.

We recently experienced a case of a female hemodialysis patient with multiple intestinal angiodysplasias. In 2001, she complained of melena, and angiographic embolization halted bleeding from ileum angiodysplasia. In 2002, she again complained of black stool. Abdominal angiography found jejunum angiodysplasia, and pharmacological therapy with estrogen/progesterone was required to stop the bleeding. Ethical demands to develop new hemodialyzers that do not release estrogen-like substances are discussed.

A longitudinal study of disturbances of the hypothalamic-pituitary-adrenal axis in women with progestin-negative functional hypothalamic amenorrhea.

OBJECTIVE: To longitudinally evaluate disturbances of the hypothalamic-pituitary-adrenal (HPA) axis in women with secondary progestin-negative hypothalamic amenorrhea. DESIGN: Retrospective cohort study. SETTING: Yokohama City University, Yokohama, Japan. PATIENT(S): Twenty-four women with progestin-negative hypothalamic amenorrhea. INTERVENTION(S): Administration of human corticotropin-releasing hormone (hCRH) and treatment with a combination of estrogen and progesterone. MAIN OUTCOME MEASURE(S): Plasma cortisol and ACTH concentrations and period required for recovery from amenorrhea. RESULT(S): Plasma ACTH concentrations 30 and 60 minutes after injection of hCRH and the percent maximum increment (%Cmax) of ACTH were significantly lower in the amenorrheic patients compared with the control group patients. The basal cortisol was significantly higher, and the %Cmax of cortisol was significantly lower. In the 16 patients who recovered from amenorrhea, there was a significant positive correlation (Y = 1.93X-10.8, r = 0.629) between the basal cortisol concentrations (X) and the period for recovery (Y). The serum E2 gradually increased before recovery, and this E2 increase was preceded by changes in the plasma cortisol concentration and the %Cmax values of cortisol and ACTH. CONCLUSION(S): The CRH test might be useful for evaluating the roles of stress and for estimating the period required for recovery in hypothalamic amenorrhea.

Diagnostic and therapeutic options in obscure gastrointestinal blood loss.

Obscure gastrointestinal bleeding is defined as an intermittent or chronic loss of blood manifested by iron deficiency anemia or overt bleeding the source of which has not been identified in upper endoscopy, colonoscopy, and barium studies. The diagnostic work-up includes repeat upper endoscopy and colonoscopy, push enteroscopy, radionuclide bleeding scan, angiography, and exploratory laparotomy with intra-operative enteroscopy. Recent publications regarding these and new diagnostic modalities, as well as advances in therapy, including combination hormonal therapy, are reviewed.

Tenoxicam versus lynestrenol-ethinyl estradiol treatment of dysfunctional uterine bleeding cases during adolescence.

BACKGROUND: The purpose of this study was to compare the effectiveness of tenoxicam versus lynestrenol-ethinyl estradiol (L-EE) in the treatment of severe cases of dysfunctional uterine bleeding (DUB) during adolescence. METHODS: Forty-eight patients with objective DUB completed a randomized comparative trial of treatment with tenoxicam (20 mg daily, n = 23) or L-EE (1 tablet containing 0.05 mg + 2.5 mg, respectively, 3 times daily, n = 25). Treatment was given during menorrhagia until bleeding ceased. Mean age of the patients was 13.74 +/- 2.1 years (range, 11-18 years). RESULTS: A significantly higher level of hematocrit (35.9% v 32.6%, t = 2.1, P = 0.0217) and hemoglobin (11.5 v 10.4 g%, t = 1.7, P = 0.0495), and significantly less hospitalization (5.75 v 8.33 days, t = 2.45, P = 0.0106) was seen in the tenoxicam group in comparison to L-EE group after completion of the treatment. Three patients were submitted to curettage and seven to transfusion in the group receiving L-EE, but no patients in the tenoxicam group required these procedures. CONCLUSIONS: Tenoxicam is considered an effective medication for the management of DUB during adolescence.

Inverted skin changes induced by estrogen and estrogen/glucocorticoid on aging dermis.

To evaluate hormone replacement therapy effects at the peripheral level, the present trial explored the oral effects of mestranol (80 micrograms/day for 10 days) and mestranol plus paramethasone (80 micrograms + 6 mg/day for 10 days) on the skin of postmenopausal women. This double-blind study included 13 patients. Skin biopsies were obtained from the thigh area by a single punch, 5 mm in diameter, before and after treatment, and the sections, six per sample, were micrometrically evaluated. Various features of the epidermis and dermis layers were stained using the hematoxylin and eosin, Masson, Verhoeff's and Gomori techniques. Statistically significant changes were found in the papillar dermis thickness; mestranol reduced it and mestranol plus paramethasone increased it. The current results encourage widening these observations of the possible advantage of this estrogen/glucocorticoid combination, in order to alleviate the cellular degenerative process.

[Estrogen and progestagen treatment in digestive hemorrhage caused by vascular malformations]. / Tratamiento con estrógenos y progestágenos en la hemorragia digestiva por malformaciones vasculares.

The efficacy of an association of estrogens and progestagens in the treatment of gastrointestinal bleeding by angiodysplasia was analyzed. Thirty-three patients with gastrointestinal bleeding due to vascular malformations were admitted from January 1986 to December 1993. Fifteen of the 33 patients were submitted to surgical or endoscopic treatment. The remaining 18 patients underwent daily oral treatment with a combination of estrogens-progestagens containing 2.5 mg of lynestrenol and 0.075 mg of mestranol. One patient presented a venous thrombosis leading to suppression of treatment at one month of initiation. The 17 remaining patients were treated for a mean of 22 +/- 4 months (range: 3-60). During treatment 13 of the 17 patients (76%) did not present evidence of hemorrhage. Likewise, the number of hemorrhagic episodes per year decreased from 4.4 +/- 1.2 prior to treatment to 0.7 +/- 0.5 during treatment (p < 0.05) with transfusional requirements decreasing from 7.9 +/- 2.8 erythrocyte concentrates per year prior to treatment to 1.2 +/- 1.0 during treatment (p < 0.05). In conclusion, the combined treatment with estrogens and progestagens prevents recurrence of gastrointestinal bleeding by angiodysplasia.

[Estrogens. Replacement therapy. Mestranol 80 ug (1962) versus mestranol 20 ug (1994) in postmenopausal women. Clinical, local, and metabolic effects]. / Estrógenos. Terapia sustitutiva. Mestranol 80 ug (1962) vs. mestranol 20 ug (1994) en mujeres postmenopáusicas. Efectos clínicos, locales y metabólicos.

A group of 37 postmenopausal women ingested mestranol (MEE) 20 ug daily per 90 days. Cervical mucus, vaginal citology, endometrial biopsy, 17 beta estradiol (E-2) low density lipoprotein-cholesterol (LDL-C) and high density lipoprotein-cholesterol (HDL-C), were determined in all of them before (phase I) and after such treatment (phase II). Besides, the relieve of vasomotor symptoms, fernlike cristallization and pyknotic nuclei cells, increase and 3/4 of the endometrial samples showed proliferation, in phase II. Endogenous circulating E-2 was not disturbed regardless MEE treatment and inverse relationship was attained on circulating lipoproteins, while LDL-C decrease (p = 0.01), HDL-C increase (p = 0.001), after comparing phase I vs. phase II. Chlormadinone acetate (2 mg/day/3 days) was administered at the end of the MEE treatment to avoid endometrial estrogenic persistence. Current studies should be enlarged to support the usage of new dose and regimen of mestranol replacement therapy.

Estrógenos; terapia sustitutiva, mestranol 80 ug (1962) vs mestranol 20 ug (1994) en mujeres postmenopáusicas: efectos clínicos, locales y metabólicos / Estrogens-substitutive therapy. Mestranol 80 ug (1962) vs. mestranol 20 ug (1994) in postmenopausal women: clinical effects, local and metabolic

Un grupo de 37 mujeres postmenopáusia recibieron mestranol (MEE) 20 ug/d/90 d. En cada una se tomaron muestras de moco cervical citología vaginal, biopsia de endometrio y sangre para medir 17 beta estradiol (E-2), fracciones de baja (LDL-C) y alta HDL-C densidad lipoproteica del colesterol antes (fase I) y después de ese tratamiento (fase II). Además de suprimir la sintomatología vasomotora, el moco endocervical y las células vaginales cariopicnóticas aumentaron y 3/4 de las biopsias presentaron proliferación en la fase II. No se produjo cambio en la concentración de estrógenos natural. La fracción LDL-C disminuyó (p=0.01) y la HLD-C aumentó (p=0.001) al comparar las fases I y II. Acetato de clormadinona fue administrado 2 mg/d/3 d para descamar el endometrio hacia el final del tratamiento con MEE. Para fundamentar esta dosis estrogénica y el nuevo régimen es necesario aumentar la casuística

Effect of hormone replacement therapy on spinal bone mineral density and T lymphocyte subsets in premature ovarian failure and Turner's syndrome.

OBJECTIVE: Our purpose was to evaluate the effect of hormone replacement therapy (HRT) on bone metabolism and the immunological change in premature ovarian failure (POF) and Turner's syndrome. METHOD: The study was conducted on 17 POF patients, 10 Turner's syndrome patients and 35 control subjects aged 20-40 years. Bone mineral density (BMD) of lumbar vertebra by dual energy X-ray absorptiometry, serum bone metabolic parameters and T lymphocyte subsets in the peripheral blood were investigated. RESULT: The untreated and treated patients of POF (0.829 +/- 0.077, 0.918 +/- 0.094 g/cm2) and the untreated and treated patients of Turner's syndrome (0.647 +/- 0.037, 0.885 +/- 0.148 g/cm2) showed spinal osteopenia compared with the control group (1.039 +/- 0.107 g/cm2). They showed a significantly lower percentage of CD4 and a ratio of CD4/CD8 in T lymphocytes as compared with the control group before HRT. CONCLUSION: POF and Turner's syndrome patients showed marked spinal osteopenia and abnormal T lymphocytes subsets. HRT slightly improved their BMD and immunological status.

Does hormonal therapy have any benefit for bleeding angiodysplasia?

Sixty-four patients took part in a cohort study measuring the efficacy of daily hormonal therapy in diminishing intestinal bleeding from small bowel angiodysplasia. Thirty patients received 5-10 mg norethynodrel either with mestranol, 0.075-0.15 mg (24 patients) or with conjugated estrogens, 0.625 mg (six patients). The cohort group consisted of 34 patients who either refused hormonal therapy (six patients) or were diagnosed early in our experience, before the resurgence of hormonal therapy (28 patients). Mean follow-up was 15.6 months (range 2-31 months) for the treated group and 13.4 months (range 1-23 months) for the untreated group. In addition, the change in monthly transfusion requirement with therapy was analyzed ("within group" analysis). Fifty percent (15 of 30) of the treated group required no further transfusion during therapy, while 44% (15 of 34) of the untreated group required no further therapy (not significant). During therapy, the mean monthly transfusion requirement of packed red blood cells in the treated group was not significantly different from that found before therapy (1.5 vs. 2.2 units, NS) or from that of the control group (1.5 vs. 1.6 units, NS). The findings do not support the use of hormonal therapy for bleeding from small intestinal angiodysplasia.

The influence of different combined oral contraceptives on the prevalence and severity of dysmenorrhea.

The influence of different oral contraceptives (OC) on the prevalence and severity of dysmenorrhea was investigated longitudinally (from age 19 to 24 years) in a representative sample of young women from an urban Swedish population. The women were grouped according to the type of OC used at the time of assessment: monophasic OC with low gestagen activity; progestogen-dominated monophasic OC; triphasic OC; neither OC nor an intrauterine device (IUD). At the age of 19 years, the severity of dysmenorrhea was lower in users of monophasic OCs with low gestagen activity (p less than 0.05) and users of progestogen-dominated monophasic OCs (p less than 0.001) compared to women who used neither OC nor an IUD. At 24 years of age, the severity of dysmenorrhea was lower in users of monophasic OCs with low gestagen activity (p less than 0.001), users of progestogen-dominated monophasic OCs (p less than 0.001) and users of triphasic OCs (p less than 0.001), compared to women who used neither OC nor an IUD. The severity of dysmenorrhea in women who did not use an OC or IUD when 19 years old was reduced in the same women who used OCs when 24 years old, compared (p less than 0.001) to women who still used neither an OC nor an IUD. There were no significant differences in the prevalence and severity of dysmenorrhea between the users of monophasic OCs, irrespective of progestagen activity, and users of triphasic preparations.

Conception in the resistant ovary syndrome occurring during hormone replacement therapy: a report of 2 cases.

Two patients with resistant ovary syndrome are described. Both patients conceived while on hormone replacement therapy. Both women were taking the phasic preparation containing mestranol and norethisterone known as 'Menophase' (Syntex Pharmaceuticals Ltd). The possible mechanism of action of this type of hormone preparation in the induction of ovulation in patients with resistant ovary syndrome is discussed.

Detection and management of pathological, non-palpable, cystic adnexal masses.

Ten patients with normal bimanual pelvic examinations were found to have small, non-palpable adnexal cysts by transvaginal ultrasound examination. After failing to respond to a course of observation and suppressive therapy with combination oral contraceptives, surgical evaluation was performed. In each case, histological examination returned a pathological diagnosis (endometrioma, serous cystadenoma, mature cystic teratoma, inflammatory cyst). This series suggests that transvaginal ultrasonography may be used to detect adnexal pathology before it is clinically apparent. A scheme for management of this clinical entity is proposed.

PIP: 10 women being evaluated for infertility by intravaginal ultrasonography had small, non-palpable cystic adnexal masses, which after conservative management proved pathological. The women ranged from 22-35 years old, with infertility of 1-4 years' duration. The ultrasound exams were performed with the ADR 4000 or Ultramark IV with 3.5 mHz vaginal probe. Women were re-examined with ultrasound after 1 month's observation, then after each of 3 cycles of treatment with either Ortho-Novum 1/35 (norethindrone 1 mg, ethinyl estradiol 35 mcg) or Ovral (norgestrel 0.5 mg, ethinyl estradiol 50 mcg) combined oral contraceptives. After this period of suppression, 6 of the masses had grown, 3 were unchanged, and 1 was slightly smaller. After diagnostic laparoscopy and laparotomy, there were no functional cysts, but 6 endometriomas, 2 serous cystadenomas, 1 inflammatory cyst, and 1 mature cystic teratoma. This preliminary series suggests that small cysts seen on vaginal ultrasound be followed with observation, then with suppression for at least 2 cycles of combines, not triphasic, oral contraceptives. The prevalence of non-palpable pathologic cysts needs to be determined.

A comparative study of three oral contraceptives in Ibadan: Norinyl 1/35, Lo-Ovral and Noriday 1/50.

A study of three combined oral contraceptives, Norinyl 1/35, Lo-Ovral and Noriday 1/50, was conducted at the University of Ibadan Teaching Hospital, Ibadan, Nigeria, to determine if there were differences in continuation rates and reasons for discontinuation. This report includes analysis of 150 women, all of whom were interval patients, randomly allocated to one of the above oral contraceptives between May 1984 and February 1985. Follow-up visits were scheduled at 1, 4 and 8 months after admission. Significantly more women in the Norinyl 1/35 group (P less than 0.05) reported intermenstrual bleeding, as well as an increase in the occurrence of intermenstrual bleeding compared to women in the Lo-Ovral group. There were no other differences between the groups for side-effects. The continuation rates at 8 months were 90.8% for the Norinyl 1/35 group, 94.4% for the Lo-Ovral group and 87.1% for the Noriday 1/50 group. The corresponding rates for those lost to follow-up were 26.0, 40.8 and 17.7. The rate for total discontinuations (all discontinuations including women lost to follow-up) was 34.0% for the Norinyl 1/35 group, 44.9% for the Lo-Ovral group and 29.4% for the Noriday 1/50 group. There was a significant difference in lost to follow-up rates between the Lo-Ovral group and the Noriday 1/50 group (P less than 0.05). There were no other significant differences between the groups for life table rates (P greater than 0.05). There were no pregnancies reported during the study period.