Effects of estradiol, progestogens, and of tibolone on breast proliferation and apoptosis.

AIM: To study the effects of estrogen therapy, alone or combined with progestogens, and of tibolone on the expression of proliferation and apoptosis markers in normal breast tissue. METHODS: Thirty 250-day-old Wistar rats were castrated and 3 weeks later received one of the following treatments by gavage for 5 weeks: (1) estradiol benzoate; (2) estradiol benzoate + medroxyprogesterone acetate; (3) estradiol benzoate + norethisterone acetate; (4) estradiol benzoate + dydrogesterone; (5) tibolone; (6) placebo. Following treatment, the expression of proliferating cell nuclear antigen (PCNA) and caspase-3 was analyzed by quantitative immunohistochemistry in the breast tissue, and proliferation and apoptosis were analyzed semiquantitatively by microscopic imaging. RESULTS: There was a statistically significant difference among the groups for PCNA, caspase-3 and the caspase-3 : PCNA ratio. Tibolone was associated with the lowest proliferative activity, followed by estradiol benzoate + dydrogesterone; however, estradiol benzoate + dydrogesterone showed the greatest rate of apoptosis. CONCLUSIONS: The various progestogens can have more or less proliferative and pro-apoptotic effects than estradiol alone. Among the treatment schemes analyzed, the estradiol + dydrogesterone combination resulted in a higher apoptosis rate in relation to the proliferation rate and tibolone was associated with the lowest proliferation.

Is expression of rat breast matrix components influenced by estrogen, progestins and tibolone?

AIM: To study the effects of estrogen therapy, alone or combined with progestogens, and of tibolone on the expression of heparanase (HSPE), extracellular matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), perlecan and proliferating cell nuclear antigen (PCNA) in normal breast tissue. METHODS: Thirty 250-day-old Wistar rats were castrated and 3 weeks later received one of the following treatments by gavage for 5 weeks: (1) estradiol benzoate; (2) estradiol benzoate + medroxyprogesterone acetate; (3) estradiol benzoate + norethisterone acetate; (4) estradiol benzoate + dydrogesterone; (5) tibolone; (6) placebo. Following treatment, the expressions of mRNA for HSPE, MMP-2 and MMP-9 were analyzed by real-time PCR and the protein expressions of HSPE, MMP-2, MMP-9, perlecan and PCNA were quantified by immunohistochemistry. RESULTS: There was a statistically significant difference among the groups for the expression of HSPE mRNA due to high levels in the tibolone group. The groups differed in terms of PCNA, with lower levels found in the tibolone group followed by the estradiol benzoate + dydrogesterone group. A statistically significant positive correlation was observed for PCNA versus perlecan and MMP-9. CONCLUSIONS: There was no difference in the effects of combinations of estradiol and different progestogens on extracellular matrix components, and breast cell proliferation was associated with increases in perlecan and MMP-9.

Effect of abrupt discontinuation versus gradual dose reduction of postmenopausal hormone therapy on hot flushes.

OBJECTIVE: To compare the effects of the abrupt discontinuation of postmenopausal hormone therapy (HT) and reduction of the daily dosage of the hormone on climacteric symptoms. METHODS: The study included Brazilian postmenopausal women who were using estrogen-progestogen hormone therapy in full doses previously prescribed for vasomotor symptoms. The patients were randomized to receive one of three treatments: placebo for 6 months; estradiol (E2) 1 mg/day + norethisterone acetate (NETA) 0.5 mg/day for 2 months, followed by placebo for 4 months; or E2 1 mg/day + NETA 0.5 mg/day for 4 months, followed by placebo for 2 months. The climacteric symptoms were assessed by the Blatt-Kupperman Menopausal Index at baseline and at 2, 4 and 6 months. Statistical evaluation was performed using the chi(2) or Fisher's test for categorical data, the Kruskal-Wallis test for numerical data, and ANOVA for time and group relationship with the Blatt-Kupperman Menopausal Index. RESULTS: We randomized 60 women (20 in each group), and 54 completed the study. It was observed that both the full Blatt-Kupperman Menopausal Index and the hot flush score did not change significantly in the HT group during low-dose therapy compared with baseline; however, the evaluation performed at 2 months after low-dose-HT cessation showed that the full Blatt-Kupperman Menopausal Index and the hot flush score were similar to those of the group who stopped HT abruptly and significantly higher than at baseline (hot flush scores: p < 0.001 for all three groups at months 2, 4 and 6, respectively, vs. baseline). CONCLUSION: Discontinuation of HT by reducing the daily dose of estrogen for a period of 2 or 4 months did not differ in its effect from that of abrupt cessation with regard to vasomotor symptoms.

Modulation of the production of reactive oxygen species (ROS) by cAMP-elevating agents in granulocytes from diabetic patients: an Akt/PKB-dependent phenomenon.

BACKGROUND: Granulocytes from healthy subjects and from patients suffering from diabetes mellitus present differences in reactivity to stimulation with cyclic nucleotide-elevating agents. The production of reactive oxygen species (ROS) is inhibited in cells from non-diabetic subjects following such stimulation, but activated through a PKA-independent signaling pathway in granulocytes from type 1 and type 2 diabetic patients. The aim of the present study was to understand better the changes in signaling mechanisms induced by the disease. METHODS: ROS production in granulocytes from healthy subjects and from type 1 and type 2 diabetic patients was measured using a luminol-dependent chemiluminescence assay. Granulocytes were stimulated by the addition of the cAMP-elevating agent dibutyryl cAMP. In some experiments, granulocytes were pre-treated with an inhibitor of PKA or Akt/PKB prior to cAMP stimulation. RESULTS: Intracellular elevation of cAMP induced a PKA-dependent and Akt/PKB-independent inhibition of ROS production in granulocytes from healthy subjects, but a significant activation in cells from both type 1 and type 2 diabetic patients. Most significantly, activation of ROS generation in cells from diabetic patients was shown to be Akt/PKB-dependent and PKA-independent. CONCLUSIONS: These results suggest that chronic hyperglycaemia could induce metabolic adaptation in cAMP-related signaling mechanisms. Epac (exchange protein directly activated by cAMP) is a novel cAMP receptor besides PKA involved in different signaling pathways. The cAMP-stimulated inverse ROS response in granulocytes from type 1 and type 2 diabetic patients may be due to a change in signaling pathways from cAMP/PKA to cAMP/Epac/Akt/PKB. These preliminary results require further studies in order to evaluate their consequences on innate immunity and pathogenesis of diabetes mellitus.

Fistula utero-cutanea apos operacao cesariana. / Cutaneous uterine fistula after cesarean section

Os autores apresentam um caso de fistula utero-cutanea observado apos operacao cesariana, e tratada na Clinica Ginecologica do Hospital Barao de Lucena _ Recife. Justificam a apresentacao pela raridade deste tipo de fistula e fazem comentarios a respeito da etiologia, do diagnostico e do tratamento, enfatizando que o tratamento clinico conservador levou a cura completa e ao retorno de ciclos menstruais normais da paciente