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.

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.

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.

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.

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.

Effect of a hormone-releasing intrauterine system (Mirena(®)) on aromatase and Cox-2 expression in patients with adenomyosis submitted or not, to endometrial resection.

OBJECTIVE: To investigate the effect of a levonorgestrel-releasing intrauterine system (Mirena(®)) on aromatase and cyclooxygenase-2 (Cox-2) expression in the endometrium of patients with adenomyosis who were submitted to endometrial resection at the time of insertion, compared to a group not submitted to endometrial resection and a group of controls with adenomyosis not submitted to any previous hormonal treatment. PATIENTS AND METHODS: Patients with adenomyosis (n = 89) were included in this study. Twenty- two patients had been using Mirena(®) for 5 years but had not been submitted to endometrial resection prior to insertion of the device. Twenty-four patients were submitted to endometrial resection at the time of Mirena(®) insertion. The remaining 43 patients with adenomyosis had undergone no previous hormonal treatment and served as a control group. Cox-2 and aromatase expression were determined in the endometrium by immunohistochemistry. RESULTS: Use of Mirena(®) for 5 years reduced aromatase expression in the endometrium; however, this reduction was significantly greater in the uteri previously submitted to endometrial resection. The reduction in Cox-2 expression was significant only in the uteri submitted to endometrial resection followed by the insertion of Mirena(®). CONCLUSION: Endometrial resection followed by the insertion of Mirena(®) was associated with greater rates of amenorrhea in patients with adenomyosis, which in turn were associated with a more effective inhibition of aromatase and Cox-2 expression in the endometrium.

Effects of subdermal implants of estradiol and testosterone on the endometrium of postmenopausal women.

A retrospective review of the medical records of 258 postmenopausal patients using estradiol and testosterone implants as combined hormone therapy was carried out to evaluate the effects of testosterone on the endometrium after two years of continuous use. Endometrial thickness was measured by ultrasonography. Histology was performed on samples of thickened endometria obtained during hysteroscopy with biopsy. In the 44 patients in whom endometrial thickening was >5 mm at the end of the second year of implant use, the most frequent finding at hysteroscopy was polypoid lesion in 61.3% of cases, followed by normal uterine cavity in 31.8% of cases and submucous myoma in 6.8%. Histology of the endometrial samples confirmed endometrial polyp in 38.6% of cases, a histologically normal endometrium in 31.8% of cases, simple endometrial hyperplasia in 20.4% of cases, and myoma and atrophic endometrium in 4.5%. It is possible that testosterone may exert its antiproliferative effects on the endometrium but not on polyps in an action similar to that exerted by combined estrogen/progestin therapies. A greater incidence of simple, low-grade endometrial hyperplasia was found in our study compared with studies using continuous estrogen/progestin regimens. The use of progestins as the ideal endometrial protection should therefore be reconsidered.

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.

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.

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.

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.

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.

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