Michael Sator

Expression of inducible nitric oxide synthase in human breast cancer depends on tumor grade.

Expression of inducible nitric oxide synthase (iNOS) by tumor cells has been suggested to abrogate metastasis in several tumor models, whereas constitutive NOS expression correlated positively with tumor grade in human breast carcinoma. Whether or not expression of one of the various NOS isoforms could predict the prognosis of breast cancer, however, has not been established. In the present report we investigated the cellular distribution of NOS isoforms in a series of benign and malignant breast tumors and in normal breast tissue. Immunohistochemistry revealed that in samples of benign disease the number of iNOS + epithelial cells or total epithelial cells was 69 ± 16% (n=50). In samples of grade II invasive ductal breast carcinomas the number of iNOS+ tumor cells or total tumor cells was 62 ± 20 (n=40), compared to 12 ± 9 (n=40) in samples of grade III carcinomas (P < 0.0001). iNOS protein was also identifiable in most of the epithelial cells of normal breast tissue (n=4). In contrast, eNOS protein was restricted to vascular endothelial cells in all of the specimens studied. Since the presence of tumor cell iNOS protein is inversely related to the tumor’s metastatic potential, we conclude that endogenous tumor cell mediated iNOS expression might have an inhibitory effect on the metastatic process in breast cancer.

Analysis of an interleukin-6 gene promoter polymorphism in women with endometriosis by pyrosequencing.

Interleukin (IL)-6 has been implicated in the etiology of endometriosis. A single nucleotide polymorphism (SNP) at position - 174 in the IL-6 gene promoter appears to influence IL-6 transcription rates in vitro and basal IL-6 levels in vivo. We determined the genotype and the allele frequencies of the -174 IL-6 promoter polymorphism and the corresponding IL-6 serum levels in women with endometriosis. The pyrosequencing technique was used to assess the IL-6 genotypes in 94 women with histologically confirmed endometriosis (study group). A series of 70 healthy women without history of uterine disease served as clinical controls (control group). Allele frequencies for the G allele among women with and without endometriosis were 59.6% and 55.0%, respectively (P =.430; odds ratio [OR] 0.83, 95% confidence interval [CI] 0.53, 1.29). Homozygotes for the protective allele C were present in 17.0% of women with endometriosis and in 18.6% of controls were homozygous for the protective allele C (P =.797; OR 0.90, 95% CI 0.40, 2.02). When patients with various disease manifestations were compared, we found an association between the -174 G allele and chocolate cysts (P =.037). Serum levels of IL-6 were significantly higher in women with endometriosis than in controls (P <.001), with highest levels in women with chocolate cysts. There was no association between serum IL-6 levels and IL-6 genotype. The IL-6 promoter polymorphism -174 G/C does not contribute significantly to overall disease susceptibility but does predispose the carrier to distinct endometriosis with chocolate cysts. A genetically determined high IL-6 response might play a pathogenic role in this disease condition.

Endometrial volume change during spontaneous menstrual cycles : volumetry by transvaginal three-dimensional ultrasound

OBJECTIVE At present, only limited data are available on endometrial volume during the menstrual cycle. Most of these studies deal with animal models and use magnetic resonance imaging for volume measuring. The application of three-dimensional ultrasound in endometrial volume estimation is the subject of this study. SETTING Patients visiting the outpatient unit of the division of endocrinology and reproductive medicine of a university hospital. PATIENT(S) Twenty patients with a history of a normal menstrual cycle were selected. INTERVENTION(S) Ultrasound examinations were performed during a single menstrual cycle in addition to routine laboratory tests. MAIN OUTCOME MEASURE(S) Uterus-endometrial volume ratio. RESULT(S) Data from 18 patients could be evaluated. In 81 examinations the endometrium volume could be determined. Mean endometrial volume measured by three-dimensional ultrasound was 1.23 cm3. Mean uterus volume was 48.93 cm3. The change of the uterus-endometrial volume ratio showed a good correlation with the day of menstrual cycle. Quadratic regression analysis of volume and cycle length was R2 = 0.432. CONCLUSION(S) Three-dimensional ultrasound allows assessment of volume data of the female internal genitalia. In this study changes of the endometrial volume in menstrual cycles were measured. Additional studies are required to give information on the clinical impact of this new technique of endometrial volume estimation.

Impact of the age at menarche on adult body composition in healthy pre- and postmenopausal women

The present study focuses on the impact of age at menarche on body composition development during adulthood. With 459 healthy middle-class women between 18 and 67 years (x = 41.5) the association between age at menarche and body composition was tested. Body composition, described by absolute and relative amount of fat mass, lean body mass, and bone mass, was estimated by means of dual energy x-ray absorptiometry. In order to exclude the influence of the menopausal transition on body composition, pre- and postmenopausal females were examined separately. The absolute amount of body fat was significantly lower within the group of women whose menarche occurred later. However, postmenopausal females exhibit less significant relations between the two trait systems than premenopausal women. This may be due to the impact of menopausal transition which affected the hormone levels and body composition development independently from the adolescent hormonal transition. While in both proband groups the quantitative amount of body fat was significantly related to menarcheal age, a significant relation between menarcheal age and adult body fat distribution could not be verified.

Melatonin in postmenopausal females

Abstract There is little information about the interaction between melatonin, sexual steroids and neuroendocrine system in postmenopausal females, even if former research showed that melatonin is clearly involved in human physiology and pathophysiology. We evaluated the overnight urinary excretion of 6-sulfatoxymelatonin (6-SMT) using a radioimmunoassay in 60 postmenopausal women. The group has been divided into patients with insomnia (10), hyperprolactinemia (7), depression (9), obesity (7) and controls (27). Compared to controls 6-SMT values were significantly higher in depressive females. Patients with hyperprolactinemia showed a trend toward a significantly elevated average nocturnal melatonin concentration. Melatonin levels were significantly lower in patients with insomnia and obese postmenopausal females than in controls. Since previus studies described lower melatonin levels in postmenopausal than in premenopausal women, the indication of melatonin-therapy, especially for sleep disorders in this collective, can be handled more generously. Melatonin should be prescribed restrictively in patients with depression and in those with hyperprolactinemia. The role of melatonin in obese females remains unclear.

Ovarian hyperstimulation syndrome is correlated with a reduction of soluble VEGF receptor protein level and a higher amount of VEGF-A

BACKGROUND Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening condition associated with increased vascular permeability. The vascular endothelial growth factor (VEGF) system and its receptors have been identified as the main angiogenic factors responsible for increased capillary permeability and are therefore discussed as crucial for the occurrence of OHSS. Recently, a number of soluble receptors for the VEGFs have been detected (sVEGF-Rs) and it has been shown that these sVEGF-Rs compete with the membrane-standing VEGF-R to bind VEGFs. METHODS We analyzed the serum levels of soluble VEGF-R1, -R2 and -R3 in 34 patients suffering from OHSS and in 34 controls without this disease. In a subgroup analysis, we correlated the severity of the OHSS with the detected amounts of VEGF-R1, -R2 and -R3. In addition, we determined the amount of total VEGF-A in the samples. RESULTS All the three soluble VEGF receptors tended to be higher in the control group compared with that in the OHSS group but this difference only reached significance for sVEGF-R2 (mean ± SEM: 15.5 ± 0.6 versus 13.8 ± 0.5 ng/ml, respectively, P< 0.05). In the subgroup analysis, sVEGF-R2 levels decreased as the severity of OHSS increased (OHSS-I: 16.8 ± 1.9 ng/ml and OHSS-III: 12.7 ± 1.0 ng/ml, P< 0.05) Moreover, the serum levels of total VEGF-A were higher in the OHSS group than those in the controls (537.7 ± 38.9 versus 351 ± 53.4 pg/ml, respectively P< 0.05). CONCLUSIONS We propose that VEGF-A plays a role in the occurrence of OHSS, that the amount of biologically available VEGF-A is modulated by sVEGF-Rs and that different combinations of VEGF-A and sVEGF-R levels might contribute to the severity of OHSS.

Postmenopausal weight status, body composition and body fat distribution in relation to parameters of menstrual and reproductive history.

OBJECTIVES In the present study the association between menstrual and reproductive history patterns and weight status, fat distribution and body composition during postmenopause was tested. METHODS In 106 healthy postmenopausal women ranging in age from 48 to 58 years (x = 53.7 year) the weight status was classified according to the recommendations of the WHO. Additionally body composition was estimated by dual energy X-ray absorptiometry and fat distribution was calculated using the fat distribution index. Weight status, body composition and fat distribution were correlated with self-reported parameters of menstrual and reproductive history (age at menarche, average cycle length, number of births, age at first and last birth, average pregnancy weight gain, age at menopause). RESULTS It was shown that number of births, age at first birth and pregnancy weight gain were related significantly to the postmenopausal weight status, body composition and fat distribution. CONCLUSION An early first birth a low number of births and a high weight gain during pregnancies can be assumed as risk factors for overweight, a higher amount of adipose tissue, android fat patterning and therefore for the development of the metabolic syndrome during postmenopause. In contrast no adverse effect of menstrual and reproductive parameters on postmenopausal bone mass was found.

The effect of hormone replacement therapy on carotid arteries: measurement with a high frequency ultrasound system

OBJECTIVE To evaluate the effect of hormone replacement therapy (HRT) on carotid arteries in postmenopausal women with a high frequency ultrasound system. METHODS In a clinical cross-sectional study carotid artery layers were measured in 82 postmenopausal women receiving a sequential regimen of HRT (oestradiol valerate 2 mg and dydrogesterone 10 mg) and in 70 postmenopausal women without HRT. Measurements of the left carotid artery layers (externa, media, intima) were taken with a single mechanically activated 22.5-MHz transducer with an effective band width of 8 MHz. RESULTS A statistically significant increase in thickness of the media layer of the carotid artery was observed in the HRT group (0.34 +/- 0.06 mm) as compared to the untreated group (0.27 +/- 0.03 mm). The media/intima ratio of the treated group was statistically significantly higher than that of the untreated group (P < 0.05). The mean strength of the carotid wall was 0.70 +/- 0.17 mm in the 70 postmenopausal women without HRT and 0.76 +/- 0.24 mm in the 82 patients undergoing HRT. CONCLUSION HRT has a morphological effect on the carotid arteries in postmenopausal women. These findings support a cardioprotective effect, especially in terms of prevention of atherosclerosis. This effect can be measured non-invasively by high frequency ultrasound.

Seminal fluid ribavirin level and functional semen parameters in patients with chronic hepatitis C on antiviral combination therapy

BACKGROUND & AIMS Due to the possible teratogenic effect of ribavirin, effective contraception is mandatory during antiviral therapy in patients with chronic hepatitis C (CHC). The aim of this study was to evaluate seminal parameters and ribavirin and HCV-RNA concentrations in seminal fluid and serum prior to and during antiviral treatment. PATIENTS AND METHODS Fifteen male patients (age: 42+/-9 (years+/-SD)) with CHC treated with pegylated interferon-alpha-2a and ribavirin were investigated. Seminal fluid (sperm concentration, motility, and morphology) was analysed morphologically. HCV-RNA and ribavirin concentration were determined by quantitative PCR and HPLC, respectively. Examinations were carried out at baseline, week 4, and week 12. RESULTS Ribavirin concentration was higher in seminal fluid than in serum (week 4: 5.2+/-2.5 vs. 2.1+/-0.3; week 12: 4.4+/-1.8 vs. 2.0+/-0.3 (microg/ml, mean+/-SD; p<0.001)). Semen abnormalities were common at baseline (asthenoteratozoospermia: n=6; asthenozoospermia: n=3; teratozoospermia: n=3). Sperm density (BL: 67+/-33x10(6)/ml; week 4: 42+/-25 (p<0.05); week 12: 49+/-33 (n.s.)), percentage of sperm with progressive motility (BL: 40+/-26%; week 4: 27+/-25; week 12: 31+/-20 (n.s.)), and percentage of sperm with normal morphology (BL: 25+/-15; week 4: 20+/-11; week 12: 16+/-9; p<0.05 for both) further decreased during antiviral therapy. HCV-RNA was detectable in the seminal fluid of only two patients prior to antiviral therapy and was undetectable in all patients during combination therapy. CONCLUSION Semen abnormalities were common in CHC patients, with further impairment during antiviral therapy. Ribavirin concentration was elevated twofold in seminal fluid compared to serum levels, which reinforces the need for contraception during antiviral combination therapy.

Pharmacokinetics and safety profile of a novel progesterone aqueous formulation administered by the s.c. route

A novel aqueous progesterone formulation was developed. Study I: Three-way cross-over, open-label study in 24 post-menopausal women. Comparison of the pharmacokinetic profiles of a single 100 mg dose of test product administered by subcutaneous (s.c.) and intramuscular (i.m.) injection and an i.m. reference oily product. Study II: Three-way cross-over open-label study of 25, 50 and 100 mg s.c. single doses of the aqueous formulation in 12 post-menopausal women. Study III: Parallel-group, observer-blinded study in 25 fertile women administered multiple s.c. 25 and 50 mg doses of the aqueous formulation once daily for 11 days. Baseline-corrected pharmacokinetic parameters were evaluated. Aqueous formulation (100 mg) was promptly absorbed, achieving progesterone peak serum levels at an earlier time than the reference (1 h vs. 7 h; p < 0.0001). Test and reference were bioequivalent in the extent of exposure: confidence intervals for AUC0-t geometric means ratios were within the pre-specified 80–125% limits. Pharmacokinetics was linear over the range of doses studied. Steady state was reached within 4 days of multiple dose treatment. All treatments were well tolerated. Considering the advantages given by the possibility of self-medication, the s.c. aqueous formulation could offer a convenient alternative for patients on assisted reproductive technology treatments.