The effect of a continuous regimen of drospirenone 3 mg/ethinylestradiol 30 microg on Cox-2 and Ki-67 expression in the endometrium.

OBJECTIVE: To study Cox-2 expression in relation to bleeding patterns in patients using an oral contraceptive containing 3 mg of drospirenone and 30 microg of ethinylestradiol (DRSP/EE). METHODS: Forty-three patients of reproductive age with symptoms of menorrhagia and dysmenorrhoea, who were submitted to endometrial resection, were enrolled. Twelve patients were in the proliferative phase and the remaining 31 were either currently using DRSP/EE or had discontinued its use four to eight days prior to hysteroscopy. Cox-2 and Ki-67 expression were determined in the endometrium using immunohistochemistry. RESULTS: Cox-2 expression was significantly inhibited in the glandular epithelium of patients who became amenorrhoeic during DRSP/EE use; however, in patients with breakthrough bleeding and in those who had stopped oral contraceptive use, a significant increase occurred in Cox-2 expression in the endometrium. Ki-67 expression decreased significantly during DRSP/EE use, but returned to proliferative phase values four to eight days after discontinuation of treatment. CONCLUSION: These results suggest that endometrial bleeding during DRSP/EE use is associated with an increase in Cox-2 expression in the endometrium. A similar increase was also seen four to eight days following discontinuation of the oral contraceptive.

Activation of NF-kappaB and COX-2 expression is associated with breakthrough bleeding in patients using oral contraceptives in extended regimens.

The objective of the present study was to determine whether there is an increase in endometrial inflammation associated with the occurrence of breakthrough bleeding in patients using an oral contraceptive in extended regimens. The presence of nuclear factor NF-kappaB and Cox-2 expression was determined by immunohistochemistry in endometrial samples removed by hysteroscopy from patients with breakthrough bleeding during continuous use of an oral contraceptive containing gestodene. All patients had a history of menorrhagia associated or not with the presence of uterine pathology. The percentage of endometria showing a positive staining reaction for NF-kappaB in cell nuclei was significantly higher in patients with breakthrough bleeding than in those with amenorrhea. Cox-2 expression in the endometrium was also significantly more frequent in patients with breakthrough bleeding. The occurrence of breakthrough bleeding in patients with uterine pathology using combined oral contraceptives is associated with the activation of endometrial inflammation through the NF-kappaB pathway.

Effect of oral contraceptives on vascular endothelial growth factor, Cox-2 and aromatase expression in the endometrium of uteri affected by myomas and associated pathologies.

BACKGROUND: The study was conducted to evaluate vascular endothelial growth factor (VEGF), Cox-2 and aromatase expression in the endometrium of uteri with myomas and other associated pathologies. STUDY DESIGN: Hysteroscopy was performed in 118 women of reproductive age with myomas and menorrhagia, 40 of whom were using a pill containing 75 mcg gestodene+30 mcg ethinylestradiol. Aromatase p450, VEGF and Cox-2 expression was detected using immunohistochemistry. Fisher's Exact Test and the Mann-Whitney test were used in the statistical analysis, with significance established at p<.05. RESULTS: In patients with myomas and menorrhagia, associated pathologies such as adenomyosis, endometrial polyps and endometriosis were found in 32%, 12% and 17% of cases, respectively. Aromatase, Cox-2 and VEGF expression was greater during the proliferative phase compared to the luteal phase of the cycle or following oral contraceptive use. CONCLUSION: Endogenous progesterone or combined oral contraceptives are potent inhibitors of VEGF, aromatase and Cox-2 expression in the endometrium of patients with myomas and menorrhagia.

The effect of oral contraceptives on aromatase expression in the eutopic endometrium of patients with endometriosis.

OBJECTIVE: To determine the effect of oral contraceptives containing gestodene on aromatase expression in the endometrium of patients diagnosed with endometriosis. PATIENTS AND METHODS: Endometrial biopsies were taken at the time of laparoscopy in 40 patients with endometriosis, 16 of whom were using an oral contraceptive containing gestodene at the time of laparoscopy. The remaining 24 patients were receiving no form of treatment for endometriosis. Endometrial biopsies taken from 23 patients with normal echographic signs and no symptoms were used as controls. Aromatase expression was evaluated in endometrial samples using immunohistochemistry. RESULTS: In the untreated, symptomatic endometriosis patients, aromatase expression was detected during the proliferative phase in 92% of cases, while in the symptom-free control patients aromatase was expressed in only 9% of cases. In patients with endometriosis who were using oral contraceptives, there were significantly fewer cases of positive endometria compared with the untreated patients with endometriosis (6%). CONCLUSION: Oral contraceptives containing gestodene are effective in decreasing aromatase expression in the eutopic endometrium of patients with endometriosis.

Aromatase expression in the eutopic endometrium of myomatous uteri: the influence of the menstrual cycle and oral contraceptive use.

AIMS: To detect aromatase expression in the endometrium of myomatous uteri and to correlate it with the location of the myoma, phase of the menstrual cycle, the presence of menorrhagia and oral contraceptive use. METHOD: Aromatase p450 expression was measured using immunohistochemical methods in the endometrium of 116 patients. Sixty-one patients had menorrhagia associated with intramural/submucous myomas and nine had subserous myomas and no excessive bleeding. Forty-six patients had no uterine pathology and served as controls. Nineteen out of 61 patients with menorrhagia were oral contraceptive users at the time of the examination. Endometrial samples were obtained by hysteroscopy in all cases. RESULTS: Aromatase p450 expression was detected more frequently in the eutopic endometrium of patients with submucous or intramural myomas than in those in the subserous group, and was significantly greater during the proliferative phase than during the luteal phase or following the use of oral contraceptives. In normal uteri, aromatase expression was detected in the endometrium in less than 10% of users. CONCLUSIONS: Aromatase expression in the endometrium was affected by the location of the myoma, the presence of symptoms, and the phase of the menstrual cycle. Oral contraceptives, on the other hand, inhibited aromatase expression in the eutopic endometrium of patients with submucous/intramural myomas.

Tibone in the perimenopause for the treatment of androgen deficiency

A tibolona pode ser usada para tratar a deficiência androgênica na mulher na perimenopausa. O mecanismo de ação mais importante da tibolona é a redução dos níveis de SHBG e o aumento da testosterona livre. A tibolona também ativa a COX-2 no endométrio aumentando o risco de formação de pólipos endometriais. O aumento da testosterona livre com o uso da tibolona leva a um aumento de produção tecidual de estrogênios nos tecidos que expressam aromatase

Effect of the menstrual cycle and oral contraceptives on aromatase and cyclooxygenase-2 expression in adenomyosis.

OBJECTIVES: To determine whether aromatase expression in the eutopic endometrium and adenomyotic foci is affected by previous use of oral contraceptives containing gestodene, and to determine whether changes in cyclooxygenase-2 (COX-2) expression occur in adenomyosis during the menstrual cycle. PATIENT AND METHODS: This was a retrospective cohort study carried out in paraffin-embedded endometrial tissue obtained from patients with a histological diagnosis of adenomyosis obtained during the proliferative (n = 25) and luteal (n = 10) phases of the menstrual cycle and following the use of continuous oral contraception with gestodene/ethinyl estradiol (n = 7). COX-2 and aromatase expression were measured in both eutopic endometrium and adenomyotic foci using immunohistochemical methods. RESULTS: Aromatase expression was detected in 80% of the endometrial slices by immunohistochemistry. In positive cases, aromatase was mainly detected in the stromal cells of the eutopic endometrium, whereas in the adenomyotic foci this expression was negative in the majority of the cases. Oral contraceptives containing gestodene, on the other hand, were effective in suppressing aromatase expression in both eutopic and ectopic endometrium. COX-2 expression was detected by immunohistochemistry in the glandular epithelium of both eutopic endometrium and adenomyotic foci and there were no significant changes in its intensity throughout the menstrual cycle. CONCLUSION: Aromatase expression in the eutopic endometrium and adenomyotic foci is suppressed by oral contraceptives containing gestodene. Increased aromatase activity may be responsible for the persistent COX-2 expression during the luteal phase.

Aromatase and cyclooxygenase-2 expression in endometrial polyps during the menstrual cycle.

OBJECTIVES: To study the changes in aromatase, Ki-67 and cyclooxygenase-2 (COX-2) expression during the menstrual cycle in both endometrial polyps and normal endometria. PATIENTS AND METHODS: Paraffin-embedded tissue samples from 118 premenopausal patients were submitted to immunohistochemistry for measurement of aromatase, COX-2 and Ki-67 expression. Fifty cases of endometrial polyps and 68 cases of disease-free endometrium were included. RESULTS: The presence of aromatase expression was significantly higher in endometrial polyps than in disease-free endometria. On the other hand, changes in COX-2 and Ki-67 expression followed a similar pattern during the menstrual cycle in both groups, expression peaking during the proliferative phase and falling during the late luteal phase. CONCLUSION: A significantly higher proportion of endometrial polyps express aromatase compared with disease-free endometrium; however, no correlation was found between aromatase expression and changes in either Ki-67 or COX-2 expression during the menstrual cycle.

Cyclooxygenase-2 expression in the endometrium and its relationship to bleeding in users of continuous oral contraceptives.

OBJECTIVE: The objective of the present study was to investigate whether or not the presence of irregular bleeding during use of oral contraceptives (OC) is associated with increased cyclooxygenase-2 (COX-2) expression. PATIENTS AND METHODS: An observational study was carried out in 26 patients who were using gestodene 75 microg/ethinylestradiol 30 microg prior to endometrial resection. The patients were divided into two groups: those with amenorrhea (n = 14) and those who had irregular bleeding (n = 12). The resected endometrium was immunostained for COX-2, Bcl-2 and Ki-67 expression. Routine pathology was carried out using standard hematoxylin-eosin staining. RESULTS: Irregular bleeding during OC use was associated with strong COX-2 expression in both glandular and superficial epithelium. There were also more patients in this group with irregular endometrial maturation and higher Ki-67 values. Bcl-2 expression, on the other hand, was not affected by the presence of uterine bleeding. CONCLUSION: The presence of irregular bleeding during OC use is associated with strong COX-2 expression in the endometrium, thereby suggesting a pivotal role of prostaglandins in this process.

Comparison of two regimens of a monthly injectable contraceptive containing dihydroxyprogesterone acetophenide and estradiol enanthate.

INTRODUCTION: This study compared two regimens of a monthly injectable contraceptive containing dihydroxyprogesterone acetophenide 150 mg and estradiol enanthate 10 mg (Perlutan) over 12 cycles of use. METHODS: Three hundred sixty-five adolescents were randomized into two groups. The patients in Group 1 received an initial injection of Perlutan on the 1st-5th day of their menstrual cycle and subsequent injections every 30 +/- 3 days, whereas those in Group 2 followed the traditional schedule of administration in which the first injection is administered between Days 7 and 10 of their menstrual cycle and subsequent injections 7-10 days after Day 1 of withdrawal bleeding. This schedule may result in an irregularity in the timing of injections. RESULTS: No significant difference was found between the two groups regarding tolerability or pregnancy (two in Group 1 and three in Group 2). CONCLUSION: Monthly administration limits the annual number of injections to a maximum of 12, thus frequently reducing the total annual dose while maintaining efficacy and tolerability similar to those obtained with the traditional regimen.

Effect of the menstrual cycle and oral contraceptives on cyclooxygenase-2 expression in the endometrium.

OBJECTIVE: To compare the expression of cyclooxygenase-2 (COX-2) and proliferation markers (Ki-67) in the endometrium of patients with ovulatory cycles with those in the endometrium of patients using oral contraceptives. PATIENTS AND METHODS: Endometrial biopsies from 104 premenopausal patients with regular ovulatory cycles (n=90) or using an oral contraceptive (n=14) were selected for this study. Using immunohistochemical methods, both COX-2 (Novocastra clone 4H12) and Ki-67 (Dako clone MIB-1) expression were determined in the endometrium during the various phases of the menstrual cycle or following the use of oral contraceptives. RESULTS: COX-2 expression in the glandular epithelium was maximal during menstruation, the late proliferative phase and the early luteal phase, and minimal during the late luteal phase. However, in the surface epithelium, COX-2 expression remained strongly positive throughout the luteal phase. Ki-67 positivity increased during the proliferative phase and diminished during the luteal phase in the glands. In contraceptive users, both Ki-67 and COX-2 expression in the endometrium was low. CONCLUSION: The increased expression of COX-2 during menstruation and at mid-cycle is eliminated by the continuous use of oral contraceptives. This may be the rationale for their therapeutic action in the treatment of dysmenorrhea and bleeding.

Effect of menstrual cycle and hormonal treatment on ki-67 and bcl-2 expression and adenomyosis.

OBJECTIVE: To study the expression of proliferation markers (ki-67) and anti-apoptotic protein (bcl-2) in adenomyotic lesions during the menstrual cycle or following the use of steroid hormones. PATIENTS AND METHODS: Ninety patients of reproductive age were included, who were submitted to endometrial resection for treatment of adenomyosis-related menorrhagia. Seven patients were using oral contraceptives and another seven had a levonorgestrel intrauterine device (IUD) (Mirena) in the uterine cavity at the time of the hysteroscopic procedure. Untreated patients were divided into four groups: menstruation/early proliferative phase (n = 24), late proliferative (n = 19), early luteal phase (n = 7) and late luteal phase (n?=?26). Bcl-2 and ki-67 expression was determined in paraffin-embedded tissue blocks using immunohistochemical methods. RESULTS: Proliferation rates in adenomyotic lesions increased during the proliferative phase, reaching a peak during ovulation to decrease to values close to zero in the late luteal phase. Bcl-2 expression showed a similar curve with peak values during the later proliferative phase followed by a significant decrease in the number of cases showing strong positive expression in the late luteal phase. Both Mirena and oral contraceptives decreased ki-67 expression on adenomyosis but only Mirena was affective in diminishing bcl-2 expression. CONCLUSION: During the luteal phase, both ki-67 and bcl-2 expression is reduced in adenomyotic lesions in a similar way to that occurring in patients using Mirena. Oral contraceptives, on the other hand, do not affect bcl-2 expression in adenomyosis.

Cyclooxygenase-2 expression in endometrial polyps during menopause.

OBJECTIVE: To determine whether cyclooxygenase-2 (COX-2) is expressed in endometrial polyps during menopause and how previous hormone use may affect this expression. PATIENTS AND METHODS: Fifty-two postmenopausal patients with endometrial polyps were enrolled for this study. Eighteen patients had no history of previous hormone use, while the remaining patients had used vaginal conjugated estrogens for short periods of time (n = 25) or were long-term users of tibolone (n = 5) or tamoxifen (n = 4). The endometrial polyps were removed by hysteroscopy, and COX-2 and Ki-67 expression were measured in tissue samples by immunohistochemistry. RESULTS: Endometrial polyps expressed COX-2 in the glandular epithelium and this expression was not significantly greater in patients who had previously used tibolone, tamoxifen or vaginal estrogens. However, Ki-67 expression was greater in the group using vaginal estrogens compared with the group of non-users; while in the other two treatment groups Ki-67 expression was less than in hormone never-users. CONCLUSION: COX-2 expression is present in endometrial polyps during menopause and may play a role in their growth regulation.

Ki-67, Bcl-2 and p53 expression in endometrial polyps and in the normal endometrium during the menstrual cycle.

OBJECTIVE: To determine the presence of proteins related to proliferation (Ki-67) and apoptosis (Bcl-2, p53) in endometrial polyps and normal endometrium during the menstrual cycle. DESIGN: Retrospective study using paraffin embedded tissue. SETTING: Hospital affiliated to the university. POPULATION: Premenopausal patients with endometrial polyps. METHODS: Seventy-eight premenopausal patients in different phases of the menstrual cycle were submitted to polypectomy using the Bettocchi hysteroscope. Immunohistochemistry was used to detect the expression of these proteins in endometrial polyps. One hundred and eighteen normal endometrial biopsies were used as controls. MAIN OUTCOME MEASURES: Detection of Bcl-2 and Ki-67 expression by immunohistochemistry. RESULTS: In endometrial polyps, Ki-67, p53 and Bcl-2 expression was detected with more frequency during the proliferative than during the luteal phase of the cycle. Similar findings were observed in the normal endometrium. CONCLUSION: Endometrial polyps undergo cyclic changes in the expression of their proteins related to proliferation and apoptosis during the menstrual cycle, similar to those of the cycling endometrium.

Detection of endometrial intraepithelial neoplasia (EIN) in postmenopausal endometrium.

OBJECTIVES: To detect the presence of endometrial intraepithelial neoplasia (EIN) in the endometrium of postmenopausal patients. PATIENTS AND METHODS: Sixty-three postmenopausal patients with endometrial polyps (n=48), hyperplasia (n=12) and endometrioid carcinoma (n=3) were enrolled for this study. The diagnosis of EIN was made by using morphological criteria and immunohistochemical methods for detection of PTEN and bcl-2. RESULTS: EIN lesions were found in cases of endometrial polyp (n=1), atrophic endometrium (n=1) and in hyperplasia (n=1). The glands were packed, showed cytological atypia and were negative for both PTEN and bcl-2. Three patients with endometrial hyperplasia had isolated PTEN-negative glands but they were still bcl-2 positive. CONCLUSIONS: The use of immunohistochemical methods helps detect the presence of EIN in the postmenopausal endometrium but does not substitute the morphological criteria for this diagnosis.

P53 expression in spontaneous and estradiol-induced endometrial hyperplasia during menopause.

OBJECTIVE: To determine the percentage of endometrial hyperplasia positive for p53 expression in both spontaneously occurring cases or following the use of unopposed estradiol. METHODS: Fifty-four postmenopausal patients with endometrial hyperplasia diagnosed by endometrial biopsy and hysteroscopy were recruited to this study. Thirty-three patients had used unopposed estradiol for periods of time from 1 to 3 years. P53 expression was detected in paraffin-embedded endometrial specimens by immunohistochemical methods. RESULTS: The percentage of endometrial hyperplasia positive for p53 expression was significantly greater in spontaneously occurring hyperplasia than in cases induced by the unopposed use of estradiol. CONCLUSION: Endometrial hyperplasia caused by the unopposed use of estradiol during menopause probably harbors fewer genomic errors than those cases occurring spontaneously.

Insertion of mirena after endometrial resection in patients with adenomyosis.

STUDY OBJECTIVE: To evaluate the efficacy of Mirena, a levonorgestrel-releasing intrauterine device, after endometrial resection for treatment of menorrhagia caused by adenomyosis. DESIGN: Open, randomized, observational study (Canadian Task Force classification II-2). SETTING: Private hospital. PATIENTS: Ninety-five women. INTERVENTION: Endometrial resection, after which control patients received no further treatment and study patients had Mirena inserted immediately after the procedure. MEASUREMENTS AND MAIN RESULTS: The rate of amenorrhea after 1 year was significantly higher in the Mirena group. Nineteen percent of women in the control group had a second procedure to control bleeding compared with none in the Mirena group. CONCLUSION: Insertion of Mirena after endometrial resection is effective treatment for menorrhagia caused by adenomyosis and has very few adverse effects.

c-erbB2 over-expression in endometrial hyperplasia induced by estrogens.

OBJECTIVE: To determine whether the presence of c-erbB2 expression in both spontaneous and estrogen-induced hyperplasia can affect the number of Ki-67-positive cells. PATIENTS AND METHODS: Thirty-two postmenopausal women with endometrial hyperplasia occurring spontaneously or after using unopposed estrogens were studied. The number of cells undergoing mitosis was estimated by immunohistochemical detection of the Ki-67 antigen and compared with the presence or absence of c-erbB2 over-expression. RESULTS: The percentage of cell nuclei showing positivity for Ki-67 was significantly higher in cases of endometrial hyperplasia that displayed c-erbB2 over-expression when compared to negative cases. CONCLUSION: The presence of c-erbB2 over-expression in endometrial hyperplasia is associated with a higher number of cells being positive for the Ki-67 proliferation marker.

Efeitos do implante subdérmico de acetato de nomegestrol sobre o metabolismo de carboidatos, lipoproteínas séricas e funçäo hepática / The effects of nomegestrol acetate subdermal implant on carboydrate metabolism. serum lipoproteins and on hepatic function

Objetivos: avaliar variações de peso corporal, pressao arterial, glicemia em jejum, HbA1C, insulina, coleterol total, HDL-C, LDL-C, triglicérides, TGO, TGP, GGT e bilirrubina em mulheres usuárias de um implate único, subdérmico, de Silástico, contendo 55 mg (+10 por cento) de acetato de nomegestrol, durante dois anos. Métodos: dezoito voluntárias saudáveis e em idade reprodutiva, que desejavam fazer uso de anticoncepcionais e nao apresentavam contra-indicaçoes para o uso de contracepçao hormonal, participaram deste estudo. Todas as mulheres foram avaliadas antes do início do tratamento e a seguir, acompanhadas por um período de dois anos. Ao final do primeiro ano, as cápsulas foram retiradas e novas cápsulas foram inseridas. Resultados: o peso corporal aumentou de 54,9 + 1,5 kg na admissao para 55,3 + 2,0 Kg no 12º mês de uso (p<0,05), e para 56,0 + 2,7 Kg no 24º mês de uso. Registrou-se discreto aumento da pressao arterial, tanto sistólica quanto diastólica, no mês 12 (p<0,01). No mês 24, a pressao arterial nao era significativamente diferente dos valores de admissao. Todos os valores estiveram dentro dos limites da normalidade. Insulina, HbA1C, LDL-C e GGT permaneceram inalterados durante os vinte e quatro meses de uso do implante. Diminuiçao significativa do colesterol total (p<0,05) foi observada no 3º mês e de HDL-C (p<0,01) no 6º mês. Observou-se aumento significativo de triglicérides (p<0,05) apenas no 12º mês. Todas as alteraçoes de lipoproteínas foram inconsistentes, e os valores estiveram dentro dos limites da normalidade. Aumentos significativos dos níveis de glicemia em jejum (p<0,05 e p<0,01) foram observados respectivamente no 3º e no 6º mês. Diminuiçoes significativas da TGO (p<0,05, p<0,01 e p<0,05) foram observadas respectivamente no 6º, 18º e 24º mês e da TGP (p<0,05) no 18º mês. Somente se observou aumento significativo de bilirrubina (p<0,05) no 3º mês de uso do implante. Todas estas variaçoes permaneceram dentro dos limites da normalidade. Conclusoes: esses resultados demonstraram que, dentro dos limites da normalidade, as variaçoes de glicemia em jejum nao se correlacionaram às alteraçoes dos níveis de insulina. As alteraçoes discretas em lipoproteínas séricas, TGO, TGP e bilirrubina foram transitórias. Nao foram observados efeitos clínicos em lipoproteínas, metabolismo de carboidratos, níveis de insulina e funçao hepática entre as usuárias por dois anos.