Merih Bayram

Apoptosis-related proteins and steroid hormone receptors in normal, hyperplastic, and neoplastic endometrium.

The purpose of this study was to evaluate the distribution and frequency of apoptosis-related proteins and their correlation with estrogen, progesterone, and androgen receptors in endometrial tissues. Immunohistochemical analyses of bcl-2, bax, bcl-x, and steroid receptors were performed in 22 endometrial carcinomas, 26 endometrial hyperplasias, and 19 cases of normal cyclical endometrium. Bcl-2 was expressed in 45.4% of carcinomas and 92.3% of hyperplasias. Bax immunostaining was found in 90.9% of carcinomas and 76.9% of hyperplasias. Bcl-x positivity was similar in carcinomas (68.1%) and endometrial hyperplasias (76.9%). In normal cyclical endometria, bcl-2 staining was intense and diffuse in the proliferative phase, but decreased dramatically in the early and mid-secretory phase to reappear in the late secretory phase. Bax was expressed throughout the menstrual cycle but more strongly in the secretory phase. Bcl-x displayed a similar degree of expression in proliferative and secretory endometria. Nineteen carcinomas (86.3%), 25 hyperplasias (96.1%), and 18 normal cyclical endometria (94.7%) were positive for estrogen receptor (ER). Progesterone receptor (PR) was observed in 20 carcinomas (90.9%), all hyperplasias (100%), and 18 normal cyclical endometria (94.7%). Androgen receptor (AR) positivity was seen in 7 carcinomas (31.8%), 6 hyperplasias (23.0%), and 3 normal cyclical endometria (15.7%). There was a statistically positive correlation between bcl-x and ER and a tendency toward significant correlation between bcl-x and PR and between ER and PR in carcinomas. In hyperplasias, there was a significant positive correlation between bcl-2 and PR and between bcl-2 and bax and a negative correlation between ER and bax. There was a statistically significant difference for bcl-2 (p=0.001) and bax (p=0.001) between the hyperplasia and carcinoma groups. There was increased expression of bax, decreased expression of bcl-2, and persistence of bcl-x protein in advanced endometrial carcinomas. Our findings show that ovarian hormones have a regulatory role on bcl-2 protein and that there is a correlation between other members of the bcl-2 family (bcl-x and bax) and steroid hormone receptors. Bax/bcl-x may be the major control mechanisms of apoptosis in advanced carcinomas; other members of the bcl-2 family may also be under hormonal control.

The Effects of Hormone Replacement Therapy on Ocular Surface and Tear Function Tests in Postmenopausal Women

Purpose: To prospectively investigate the impact of various hormone replacement therapies (HRT) on ocular surface and tear function tests. Methods: A total of 70 women in the postmenopausal period were enrolled in the study. The groups consisted of 16 women who were not on HRT (group 1), 29 women who were on HRT with tibolone (group 2) and 25 women who received estradiol plus medroxyprogesterone acetate treatment (group 3). All patients underwent tear film break-up time (TFBUT), Schirmer’s test and conjunctiva cytology at the time of enrollment and at 6 months’ follow-up. Results: Patients in group 2 showed improved Schirmer’s test and TFBUT results (p < 0.001); however, no significant changes occurred in group 1 and group 3 patients (p > 0.05). Conjunctival cytology scores did not differ at the time of enrollment and at 6 months’ follow-up in all groups. Conclusions: This is the first comparative clinical study on the effects of tibolone and estradiol plus medroxyprogesterone acetate on ocular surface and tear function tests. HRT with tibolone seems to improve tear function tests in postmenopausal women.

Fas-mediated pathway and apoptosis in normal, hyperplastic, and neoplastic endometrium

OBJECTIVES Abnormalities in the control of cell proliferation and apoptosis have been suggested to contribute to the development and progression of neoplasia. There are at least two pathways that activate apoptosis. The first is a mitochondria-dependent route governed by bcl-2 family proteins. The second is a parallel mechanism which involves the activation of a group of tumor necrosis factor (TNF) receptors, such as Fas. METHODS The aim of this study was to examine the distribution and interrelation between the expression patterns of apoptosis-related proteins such as Fas, caspase-3 (CPP32), and M30, and to investigate the role of Fas-mediated apoptosis in the pathogenesis and progression of endometrial neoplasms. RESULTS Using specific antibodies for Fas, caspase-3, and M30, we examined protein expressions in 29 endometrial carcinomas, 30 endometrial hyperplasias, and 21 normal cyclic endometria. The results of immunostaining for Fas and caspase-3 were analyzed semiquantitatively by using an immunohistochemical scoring system (HSCORE) that incorporated both the intensity and the distribution of specific staining. For M30, positive staining cells and extracellular particles were analyzed semiquantitatively per 10 high-power fields.HSCOREs of Fas and caspase-3 were slightly higher in the secretory endometria than in the proliferative endometria. Similarly, M30 reactivity seemed to increase in the late secretory phase of the cycle. HSCOREs of Fas and caspase-3 and the reactivity of M30 were significantly higher in the carcinoma group than in the simple hyperplasia group (P < 0.05). Complex hyperplasias, however, expressed quite similar HSCOREs of Fas and caspase-3 as carcinomas. M30 reactivity was also significantly higher in complex hyperplasias than in simple hyperplasias, and in carcinomas positivity increased significantly (P < 0.05) as the grade progressed. CONCLUSIONS The significant increase observed in Fas, caspase-3, and M30 expression in carcinomas as compared with simple hyperplasias may suggest that the Fas-related apoptotic pathway is also involved in the regulation of apoptosis in the endometrial tissue and promotes the development and progression of endometrial neoplasia.

PLASMA LEPTIN CONCENTRATIONS IN POSTMENOPAUSAL WOMEN WITH OSTEOPOROSIS

Osteoporosis is less common in obese individuals with increased bone mineral density (BMD) and plasma leptin concentrations. The aim of this study was to determine the correlation between leptin levels and BMD in postmenopausal women. The study consisted of 90 postmenopausal women with a mean age of 53.45 ± 0.87 years who visited our outpatient clinic for the evaluation of BMD. Thirty-six postmenopausal women with osteoporosis (mean age: 54.52 ± 1.41 years and mean body mass index (BMI, kg/m2) 29.33 ± 0.66), 30 age- and BMI-matched postmenopausal women with normal BMD, and 24 postmenopausal women (mean age: 52.79 ± 1.48 years and mean BMI: 29.45 ± 0.89) with osteopenic BMD were included in the study. Plasma concentrations of leptin after an overnight fast were measured by radioimmunoassay. BMD values were measured by dual-energy X-ray absorptiometry (DEXA) at the L2-L4 lumbar spine and femoral neck. The median spine BMD value in the patient group (0.67 ± 0.08 g/cm2, mean ± SEM) was significantly lower than that in the control group (1.02 ± 0.25 g/cm2, mean ± SEM ) and osteopenic group (0.87 ± 0.05 g/cm2, mean ± SEM) (p < 0.005). The mean spine BMD value (T score −3.63 ± 0.25, mean ± SEM) and the mean femur neck BMD value (T score −2.55 ± 0.18, mean ± SEM) of the osteoporosis group were significantly lower than that in the normal BMD group (+ 0.33 ± 0.14 and + 0.27 ± 0.18, p < 0.001) and in the osteopenia group (−1.74 ± 0,1 and –1.18 ± 0.05, p < 0.005). The mean plasma leptin concentration in the osteoporotic group (17.03 ± 1.40 ng/ml) was not significantly different from that in the normal BMD group and the osteopenia group (16.55 ± 1.50 ng/ml; 16.16 ± 1.60, respectively, p < 0.150). Plasma leptin concentrations were correlated with BMI in three groups (r(s) = 0.450, p = 0.025 in normal BMD group and r(s) = 0.4254, p = 0.009 in the osteoporotic group, and r(s) = 395, p = 0.015 in the osteopenia group. There was no correlation between plasma leptin concentrations and BMD values in three groups (r(s) = −0.89 in normal BMD group, r(s) = −0.124 in osteopenia group, and r(s) = −0.195 in osteoporosis group). From this study we conclude that circulating plasma leptin does not have a significant direct influence on bone mass in postmenopausal women.

Effect of tamoxifen on serum IL-18, vascular endothelial growth factor and nitric oxide activities in breast carcinoma patients.

Vascular endothelial growth factor (VEGF) is a multi‐functional cytokine that has been suggested to be a major angiogenic factor in breast cancer. Nitric oxide (NO) is a potent biological molecule that partipicates in the multi‐step process of carcinogenesis. Interleukin (IL)‐18 has been shown to have potent anti‐tumour effects. In this study, we investigated the effect of tamoxifen therapy on serum VEGF, NO and IL‐18 activity in breast cancer patients. Serum levels of VEGF, nitrate + nitrite and IL‐18 were measured in 34 postmenopausal breast cancer patients before and 3 months after the tamoxifen therapy. Both serum VEGF and IL‐18 levels decreased after tamoxifen therapy (P = 0·051, P < 0·05, respectively). Serum VEGF levels increased in patients with endometrial thickness, while patients without endometrial thickness had a significant reduction in serum VEGF levels after therapy (P < 0·05). Serum nitrate + nitrite levels increased after the therapy, but this was not statistically significant (P > 0·05). A decrease in serum VEGF levels with tamoxifen therapy may be a reflection of reduced angiogenic activity in patients without endometrial thickness. The negative effect of tamoxifen therapy on IL‐18, which is known to have a potent antitumour activity, may be related to the decreased tumour growth by induction of NO and reduction of VEGF activity as a feedback mechanism.

Change in retrobulbar circulation during menstrual cycle assessed by doppler ultrasound

Our purpose was to study the hemodynamic changes in the ophthalmic, central retinal and posterior ciliary arteries during the normal menstrual cycle and to relate the vascular changes to menstrual cycle. A total of 23 healthy women underwent serial color Doppler ultrasonography at least six times during a normal menstrual cycle, twice each in follicular, ovulatory and luteal phases. Pulsatility and resistance index and peak systolic velocity of the each arteries were assessed with color Doppler imaging. There was no statistical difference in any of the parameters during the menstrual cycle. This was supposed to be because generalized hormonal effects on heart rate, blood pressure, blood volume, cardiac output and on the diameter of the vessel cancel each other and this effect maintains the same ocular blood flow and perfusion during the menstrual cycle.

Examination of the rescue effects of folic acid on derangement of the tubo-ovarian ultrastructural architecture caused by methotrexate

The purpose of this examination was to observe the effects of folic acid (FA) on methotrexate (MTX)-induced derangements in the fallopian tubes. Investigators in this study sought to explore whether MTX-induced dysfunction in the fallopian tubes would be lessened by the addition of FA to MTX treatment. For this study, 18 albino Wistar rats were randomly divided into 6 groups, each of which comprised 3 rats; 0.1 mg/kg FA, 1 mg/kg MTX + 0.1 mg/kg FA, 5 mg/kg MTX + 0.1 mg/kg FA, 1 mg/kg MTX, and 5 mg/kg MTX were given to groups 2, 3, 4, 5, and 6, respectively; group 1 was the control group. After MTX injection, fallopian tube samples from all groups were prepared for examination under electron microscopy. The findings observed in groups 1 and 2 were similar. The level of cellular destruction was greater with the higher doses of MTX without FA; in particular, loss of cilia in the epithelium was prominent in groups 5 and 6. However, there was less cellular destruction observed in groups 3 and 4 than in groups 5 and 6. As a result, the addition of FA should not be overlooked, even when a single-dose MTX regimen is chosen for the treatment of patients with unruptured ectopic pregnancy

The contribution of nitric oxide and endothelins to angiotensin: II. Evoked responses in the rat isolated uterus smooth muscle.

The present study was designed to determine the role of endogenous endothelin peptides and nitric oxide on angiotensin II (All) responses in the isolated nonpregnant rat uterine smooth muscle. AII (10, 20, or 50 ng/ml) increases rhythmic oscillations dose dependently (32.7 +/- 8.9, 55.96 +/- 10.3, and 62.78 +/- 17.7% increase, respectively). L-arginine methyl ester (L-NAME; 10(-5) M) did not affect the increase in rhythmic oscillations induced by All (10, 20, or 50 ng/ml) (17.5 +/- 12.1, 31.5 +/- 18.3, and 52.5 +/-11.8% increase, respectively, n = 6, p > 0.05). It reduced the contractile responses to AII (10 ng/ml: from 4.63 +/- 0.6 to 1.8 +/-0.7 cm2, p < 0.05: and 20 ng/ml: from 5.59 +/- 0.8 to 2.11 +/- 0.4 cm2, p < 0.05, n = 6). L-arginine (10 mM) decreased the contractile response obtained by AII (10 or 20 ng/ml) (1.93 +/- 1.05, p < 0.05 and 2.14 +/- 0.7 cm2, p < 0.05, respectively, n = 6). BQ 485 (50 ng/ml) decreased both the number of rhythmic oscillations and the contractility increased by AII. Bosentan (10(-5) M) induced an increase in the number of rhythmic oscillations but decreased the contractile responses to the higher concentrations of All. These data show that endogenous NO and endothelin peptides contribute to the motility changes induced by AII and may play an important role in the pathophysiological events of the uterine function.

Prevalence of gestational diabetes mellitus evaluated by universal screening with a 75-g, 2-hour oral glucose tolerance test and IADPSG criteria

To determine the prevalence of gestational diabetes mellitus (GDM) and its association with maternal age among Turkish women diagnosed by International Association of Diabetes and Pregnancy Study Group (IADPSG) criteria.

Expression of steroid receptors in intact rat uterus, mammary gland, and liver treated with selective estrogen receptor modulators and conjugated equine estrogens.

The aim of the present study was to determine the effects of conjugated equine estrogens (CEE) and selective estrogen receptor modulators (SERM) (tamoxifen [TAM] and raloxifene [RAL]) on the expression of steroid receptors—estrogen receptor (ER) and progesterone receptor (PR)—in intact rat uterus, mammary gland, and liver. A total of 24 female rats weighing 250 to 300 g were randomized into 4 groups. Groups 1, 2, 3, and 4 were respectively given conjugated equine estrogen, tamoxifen, raloxifene, and vehicle for a 28-day period. ER and PR expression was detected in tissues of the uterus, mammary gland, and liver. Uterine wet weight and serum estradiol levels were established for all groups. No statistical difference was observed between groups in the ER expression of mammary gland and liver and in the PR expression of uterus, mammary gland, and liver, but differences were noted in serum estradiol levels and uterine ER expression. Serum estradiol levels were lower in the TAM-treated group; differences between the TAM-treated group and the other groups were statistically important (P > .05). Uterine ER expression was greater in the CEE-treated group; differences between the CEE-treated group and theTAM and RAL-treated groups were statistically important (P > .05). CEE or SERM versus vehicle treatment in controls did not seem to result in statistically important differences in ER and PR expression in intact rat uterus, mammary gland, and liver. Only ER expression in the uterus was found to be greater in the CEE-treated group than in SERM-treated groups.