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Background: Endometriosis is most commonly found in the peritoneum of the lesser pelvis and in the genital tract (in the ovaries). Its malignant transformation is quite rare, which usually appears in patients who previously underwent surgical procedures aimed at treating endometriosis. Years of hormone substitution (unopposed estrogen therapy) is also considered to have a role. According to the present authors' current knowledge, these are mostly well-differentiated tumors with low malignancy, which are primarily treated surgically. Case: In the present case the authors present a 73-year-old female patient who underwent a laparotomy due to abdominal pain and a mass in the lesser pelvis. The authors performed hysterectomy along with bilateral adnexectomy and omental resection. The histological examination of the specimens verified an endometrial adenocarcinoma formed on the ground of adenomyosis and the endometrial adenocarcinoma of the left ovary. Conclusion: The malignant transformation of endometriosis is rare, and the mechanisms how it develops on the grounds of adenomyosis is currently unclear. [ABSTRACT FROM AUTHOR]

The ionic environment within the nucleoplasm might diverge from the conditions found in the cytoplasm, potentially playing a role in the cellular stress response. As a result, it is conceivable that interactions of nuclear actin and actin-binding proteins (ABPs) with apoptosis factors may differ in the nucleoplasm and cytoplasm. The primary intracellular stress response is Ca 2+ influx. The junctional mediating and regulating Y protein (JMY) is an actin-binding protein and has the capability to interact with the apoptosis factor p53 in a Ca 2+ -dependent manner, forming complexes that play a regulatory role in cytoskeletal remodelling and motility. JMY's presence is observed in both the cytoplasm and nucleoplasm. Here, we show that ex vivo ectocervical squamous cells subjected to electroporation with JMY protein exhibited varying morphological alterations. Specifically, the highly differentiated superficial and intermediate cells displayed reduced nuclear size. In inflamed samples, nuclear enlargement and simultaneous cytoplasmic reduction were observable and showed signs of apoptotic processes. In contrast, the less differentiated parabasal and metaplastic cells showed increased cytoplasmic activity and the formation of membrane protrusions. Surprisingly, in severe inflammation, vaginosis or ASC-US (Atypical Squamous Cells of Undetermined Significance), JMY appears to influence only the nuclear and perinuclear irregularities of differentiated cells, and cytoplasmic abnormalities still existed after the electroporation. Our observations can provide an appropriate basis for the exploration of the relationship between cytopathologically relevant morphological changes of epithelial cells and the function of ABPs. This is particularly important since ABPs are considered potential diagnostic and therapeutic biomarkers for both cancers and chronic inflammation.

Összefoglaló. Bevezetés és célkitűzés: A női kismedencei funkciózavarok változatos tünetekkel jelentkezhetnek, és jelentősen befolyásolják az érintettek életminőségét. Vizsgálatunk célja volt felmérni a medencefenék-diszfunkciós tüneteket és azok hatását az egyén életminőségére. Módszer: Vizsgálatunkba 203 nőt vontunk be. Az adatgyűjtést két kérdőív, egy általunk összeállított és az Australian Pelvic Floor Questionnaire segítségével végeztük. Az adatok statisztikai elemzéséhez SPSS 20.0 rendszert használtunk. Spearman-korrelációt, khi-négyzet-próbát, Mann-Whitney-féle U-tesztet, Kruskal-Wallis-próbát és többváltozós lineáris regressziót alkalmaztunk. A szignifikanciaszintet p≤0,05 határnál állapítottuk meg. Eredmények: A hólyagdiszfunkciók gyakorisága (56,2%) szignifikáns kapcsolatot mutatott az életkor növekedésével (p<0,001), az obesitassal (p<0,001), a szülésszámmal és -móddal (p<0,001; p<0,001), az episiotomiával (p<0,001) és a prolapsusműtétekkel (p = 0,010). A süllyedéses kismedencei kórképek gyakorisága (27,1%) szignifikáns kapcsolatot mutatott az életkor növekedésével (p = 0,002), a szülésszámmal és -móddal (p<0,001; p<0,001) és a korábbi episiotomiával (p<0,001). Az analis incontinentia gyakorisága (58,9%) a magasabb testtömegindexszel (p = 0,029) volt szignifikáns kapcsolatban. Szexuális diszfunkciót (53,2%) allergia és tüdőbetegségek (p = 0,048) jelenlétével kapcsolatban találtunk. A többes diszfunkció előfordulási gyakorisága az életkor növekedésével (p<0,001), az obesitassal (p = 0,043), a korábbi hysterectomiával (p = 0,046) és prolapsusműtétekkel (p<0,001) mutatott szignifikáns kapcsolatot. Minden diszfunkció esetén kimutatható volt az életminőség-romlás (hólyagfunkciók: p<0,001; bél- és székletürítési funkciók: p<0,001, hüvelyfali süllyedés: p<0,001, szexuális funkciók: p<0,001). Következtetés: Az általunk vizsgált női populációban nagy arányban találtunk kismedencei funkciózavarokat, melyek kedvezőtlen hatással voltak az érintettek életminőségére. Orv Hetil. 2021; 162(43): 1724-1731., Introduction and Objective: Pelvic floor dysfunction (PFD) can cause several complaints in women and has an adverse effect on the quality of life (Qol). The aim of our study was to evaluate the prevalence of pelvic floor dysfunction and its effect on Qol., Method: 203 women were included. We used two questionnaires, a self-constructed and the Australian Pelvic Floor Questionnaire. Statistical analysis was performed by SPSS 20.0. Spearman's correlation, chi-square, Mann-Whitney U, Kruskal-Wallis tests and multivariate linear regression were used. Statistical significance was set at p≤0.05., Results: There was a significant association between the prevalence of urinary incontinence (56.2%) and age (p<0.001), obesity (p<0.001), number and mode of deliveries (p<0.001; p<0.001), episiotomy (p<0.001) and pelvic organ prolapse (POP) surgery (p = 0.010); between the occurrence of POP (27.1%) and age (p = 0.002), the number and mode of deliveries (p<0.001; p<0.001) and episiotomy (p<0.001); between the prevalence of anal incontinence (58.9%) and obesity (p = 0.029); between sexual dysfunction (SD) (53.2%) and respiratory disease and allergy (p = 0.048). Multiple PFD was significantly associated with age (p<0.001), obesity (p = 0.043), hysterectomy (p = 0.046) and POP surgery (p = 0.010). There was a significant difference between women having more severe PFD than milder complaints regarding Qol (bladder p<0.001; bowel p<0.001; SD p<0.001 and POP p<0.001)., Conclusion: Pelvic floor dysfunction was common in our study population and had a great adverse effect on Qol. Orv Hetil. 2021; 162(43): 1724-1731.

Background: National, regional and global trends in prevalence of infertility indicate its public health importance, however it effects various life dimensions of individuals and couples as well. Lifestyle habits may counteract with these factors. The aim of the study was the multicausal analysis of psychosocial and lifestyle factors undergoing assisted reproductive therapy (ART) with special regard to pre-treatment habitual physical activity (PA)., Methods: In a cross-sectional, observational cohort study on ART patients (N = 60, age 34.6 ± 5.2 years, BMI 24.2 ± 4.9 kg/m 2 ) with follow up on outcome measures a detailed description was given on PA patterns (ActriGraph GT3X, GPAQ-H) and on general and infertility related distress (BDI-13, FPI)., Results: Respondents reported normal mood state (BDI-13) but moderately high infertility-related distress (FPI) in Social- and very high distress in Sexual Concern. It was revealed that time spent with recreational PA (RPA) could counteract with infertility-related distress (Social Concern R = -0.378, p = 0.013; Relationship Concern R = -0.365, p = 0.019). In the presence of clinical pregnancy GPAQ-H RPA MET was significantly higher (p = 0.048), in the non-pregnant group cumulative values and work-related PA were higher. Correlations could be found between RPA time and the number of oocytes (R = 0.315, p = 0.045), matured oocytes (R = 0.339, p = 0.030) and embryos (R = 0.294, p = 0.062) by women who reached at least 150 min RPA (GPAQ-H). Multivariate linear regression revealed that the number of oocytes was positively influenced by the GPAQ-H recreation MET (R 2  = 0.367; F = 10.994, p = 0.004; B = 0.005, p = 0.004, B Constant = 4.604). Regarding the number of embryos (R 2  = 0.757, F = 17.692, p < 0.001, B Constant = 1.342) positive relationship was found with GPAQ-H RPA MET (B = 0.004, p < 0.001) and negative with BMI (B = -0.167, p = 0.038). It was disclosed (R 2  = 0.958, F = 408.479, p < 0.001) that higher Very Vigorous Activity (ActiGraph) was accompanied with higher hCG (B = 63.703, p ≤ 0.001). However, time spent with moderate PA (GPAQ-H) (B = 0.002, SE = 0.001, Wald = 3.944, p = 0.047, OR = 1.002) was significantly associated with live births., Conclusions: Amount of PA alone did not have a positive effect on outcome of ART. Type and intensity seemed to be more significant. Existing differences in response to infertility due to recreational PA suggest the importance of the development of a specific intervention. The robust overestimation of PA in self-reports highlights the need to improve physical literacy of women undergoing ART.

Összefoglaló. A szerzők ismertetik vizsgálataik eredményeit, melyeket a közelmúltban az in vitro fertilizációs kezelésben részesülő betegeikben a tüszőfolyadék biomarkereinek analízisével értek el. A vizsgálatok célja annak feltárása volt, hogy az in vitro fertilizációs eljárás során a petesejtek aspirációjakor nyert tüszőfolyadék-biomarkerek lokális/ovarialis vagy szisztémás eredetűek, és milyen összefüggést mutatnak az in vitro fertilizáció eredményességét jelző paraméterekkel. Megerősítettük, hogy az autokrin/parakrin szerotoninrendszer már a fejlődés legkorábbi időszakában is működőképes, és mind az anyai szérum, mind a tüszőfolyadék szerotoninszintje szignifikáns pozitív összefüggést mutatott az érett petesejtek számával és a klinikai terhességgel (β = 0,447, p = 0,015, illetve β = 0,443, p = 0,016). Az agyi eredetű neurotrofikus faktor (BDNF) esetében ilyen kapcsolat nem volt igazolható, de a tüszőfolyadék BDNF- és szerotoninszintjei közötti pozitív korreláció (r = 0,377, p = 0,040) azt mutatja, hogy a két neurohormon 'feed-forward' (előrecsatoló ) szabályozása ovarialis szinten is működik. A hypothalamicus kisspeptin esetében csupán a posztstimulációs anyai szérumhormonszint befolyásolta az érett petesejtek számát (β = 0,398, p = 0,029). A triptofán-kinurenin-szerotonin rendszer elemzése azt mutatta, hogy kedvezőbb in vitro fertilizációs kimenetel várható, ha a szerotonin-kinurenin egyensúly a szerotonin javára tolódik el. Az oxidatívstressz-markerek közül vizsgálták a DNS-károsodás biomarkerét, a 8-hidroxi-2'-deoxiguanozin és a totális antioxidáns-kapacitás szérum- és tüszőfolyadékszintjeit, és megállapították, hogy mindkét marker kedvezőtlenül befolyásolja az életképes embriók számát (r = 0,302, p = 0,027 és r = 0,268, p = 0,039). A protektív hatású szirtuinok - nikotinamid-adenin-dinukleotid-függő hiszton-deacetiláz fehérjék - közül a vizsgált szirtuin-1 és szirtuin-6 a szérumszintektől függetlenül kimutatható a tüszőfolyadékban. Szignifikáns pozitív korreláció van a tüszőfolyadék-szirtuin-6 és az érettpetesejt-szám (F = 6,609, p = 0,016), valamint a szérum-szirtuin-1 (F = 10,008, p = 0,005) és a szérum-szirtuin-6 (F = 5,268, p = 0,031) és a klinikai terhesség gyakorisága között. Eredményeink alapján megállapítható, hogy a tüszőfolyadék biomarkereinek vizsgálata javíthatja az in vitro fertilizáció kimenetelének megítélését. Orv Hetil. 2021; 162(14): 523-529. Summary. This article outlines the result of recent studies on several follicular fluid biomarkers in patients undergoing in vitro fertilization. The aim of these studies was to investigate whether 1) the follicular fluid biomarkers in question are produced locally by the ovaries or they originate from the circulating plasma, 2) and to establish their association with parameters of in vitro fertilization outcome. It was confirmed that the autocrine/paracrine serotonin system is functional already at the earliest stage of development and both maternal serum and follicular fluid serotonin levels were positively related to the number of mature oocytes (β = 0.447, p = 0.015 and β = 0.443, p = 0.016, respectively) and clinical pregnancy (β = 1.028, p = 0.047). Such associations for brain-derived neurotrophic factor (BDNF) could not be found, but BDNF and serotonin in the follicular fluid were closely related (r = 0.377, p<0.040) suggesting that the feed-forward regulation of these neurohormones is activated at ovarian level. The hypothalamic kisspeptin in the post-stimulation maternal serum also increased the number of mature oocytes (β = 0.398, p = 0.029). Analysis of the tryptophan-kynurenine-serotonin system showed a more favourable in vitro fertilization outcome when the serotonin-kynurenine balance was shifted and serotonin predominated over kynurenine. The oxidative stress markers, 8-hydroxy-2'-deoxyguanosine, an indicator of DNA damage and the total antioxidant capacity in follicular fluid and maternal serum had negative impact on the number of viable embryos (r = 0.302, p = 0.027 and r = 0.268, p = 0.039), respectively. The protective sirtuins - the nicotinamide adenine dinucleotide-dependent histone deacetylase proteins - could be detected in follicular fluid irrespective of their maternal serum levels. Significant positive relationship was demonstrated between follicular fluid sirtuin 6 and mature oocytes (F = 6.609, p = 0.016) as well as between serum sirtuin 1 (F = 10.008, p = 0.005) and serum sirtuin 6 (F = 5.268, p = 0.031) and the rate of clinical pregnancy, respectively. On the basis of these results, it can be concluded that measuring several follicular fluid biomarkers may improve the prediction of the outcome of in vitro fertilization. Orv Hetil. 2021; 162(14): 523-529.

Objective: This study aimed to examine the effect of interactions between serotonin (5-HT), brain-derived neurotrophic factor (BDNF), and kisspeptin on the reproductive potential in women receiving in vitro fertilization (IVF)., Methods: Paired serum and follicular fluid (FF) samples were obtained from 30 consecutive patients receiving IVF. Primary and secondary outcome measures were the rate of chemical/clinical pregnancy and the number of mature oocytes and embryos, respectively. Serum and FF 5-HT, BDNF, kisspeptin, and platelet-activating factor (PAF) levels were measured by enzyme-linked immunosorbent assay., Results: In response to ovarian hyperstimulation, serum 5-HT and kisspeptin levels significantly increased, whereas serum BDNF and PAF levels remained unchanged. These factors were detected in FF, but they were unrelated to serum levels. FF 5-HT and BDNF levels were positively correlated. Serum kisspeptin levels were negatively correlated with FF BDNF and serum and FF PAF levels. Women who were pregnant had significantly lower FF BDNF levels compared with women who were not pregnant (21.96±12.75 vs 47.63±52.90 µg/mL). Multivariate stepwise linear regression and logistic regression analyses showed that only 5-HT and kisspeptin improved IVF outcome., Conclusions: This study indicates a role of serotoninergic mechanisms in success of IVF, but the contribution of interacting neuropeptides requires additional investigation.

Introduction: Endometrial cancer is the most common invasive gynecologic malignancy in developed countries. The best survival rates are expected after surgical removal, thus the aim of a complex treatment is to achieve resecability in locally and locoregionally advanced disease. Aim: The primary purpose of this study was to evaluate if the neoadjuvant systemic treatment leads to better overall survival compared to irradiation solely. Method: From January 2015 to December 2018, we enrolled 28 patients diagnosed with irresecable, locally and locoregionally advanced high-risk endometrial carcinoma. Patients were treated by neoadjuvant paclitaxel-carboplatin, then radical hysterectomy, bilateral oophorectomy and lymphadenectomy were performed. Results: After administration of 6 cycles of carboplatin-paclitaxel, the control MR test showed tumor shrinkage in all patients. Complete resection was achieved in the case of every patient. Tumor residuum in lymph nodes was verified in 4 cases by pathological evaluation. The 2-year survival and the 2-year progression-free survival rates were 65,1% and 66,1%, respectively. The median overall survival was 16,5 months. Conclusion: Neoadjuvant treatment can be an effective approach in providing the conditions for complete tumor resection, which may result in survival advantage. Despite multimodal treatment, prognosis is poor. Orv Hetil. 2020; 161(11): 425-433.

Aim: This study examined the fertility performance of women after combined hysterolaparoscopic surgical management of endometriosis. Design: This study is a hospital-based retrospective review., Materials and Methods: Data collected from the records of all patients presented with endometriosis-related infertility using a checklist designed for the purpose. Result: A total of 81.3% (370/455) of women who have had the desire to have children became pregnant during the study period after the surgery. Of those who became pregnant, all three-hundred-forty-seven patients were followed to the end of their pregnancies. A successful live birth occurred in 94.2% (327/347) of individuals, and pregnancy loss occurred in 5.8% (20/347). The mean patient age was 34.1 ± 4.1 years, and the average duration of infertility was 3.4 ± 3.3 years. Pregnancy occurred spontaneously in 39.5% (146/370) of patients, after artificial insemination (AIH) in 3.8% (14/370) of women, and after in vitro fertilization-embryo transfer (IVF-ET) in 56.8% (210/370) of cases. Patients aged ≤ 35 years had a higher chance of conception post-surgery-84% versus 77%, respectively ( p = 0.039). Based on the modes of pregnancy, the timely introduction of an assisted reproductive technique (ART) demonstrated a significant effect on fertility performance postsurgery. Comparatively, this effect was 91.3% vs. 74.1% among the ≤35- and >35-year-old age groups, respectively. There was no significant difference in reproductive performance based on stages of endometriosis, nor in the other parameters evaluated. Conclusion: Our data are consistent with previous clinical studies regarding the management options of endometriosis-related infertility. Overall, the combined hysterolaparoscopy treatment is a very effective and reliable procedure, and is even more effective when combined with ART. It enhances women's wellbeing and quality of life, and significantly improves reproductive performance.

Purpose: Earlier findings revealed the damaging effect of visible light on zygotes and gametes. The aim of our study is to eliminate or significantly reduce the potentially harmful effects of light exposure during in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) and to investigate the effect of light protection on embryo development and implantation., Materials and Methods: To protect sperm cells, oocytes, and embryos from the potential harmful effects of light exposure during laboratory procedures, we created a dark environment for the cells and applied red filters on laboratory lamps and UV or infrared filters in the microscopes in order to eliminate white light exposure of the cells throughout all work stages., Results: The fertilization rate was significantly (p = 0.011) higher in light-protected ICSI cycles. Blastocyst development rates (blastocyst/embryo) were significantly (p < 0.001) higher in light-protected embryos than in those manipulated in conventional light conditions both in IVF (20.9% difference) and ICSI (38.6% difference). Numbers of clinical pregnancies/transfers of ICSI fertilized day 5 blastocysts were also significantly (p = 0.040) higher in light-protected conditions., Conclusions: These data show that light protection has a positive effect on fertilization rate and increases the blastocyst development as well as the number of clinical pregnancies/transfers. Implementation of this light protection method in IVF centers may improve the success rate while maintaining maximal embryo safety., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Transient Receptor Potential Vanilloid 1 (TRPV1) and Transient Receptor Potential Ankyrin 1 (TRPA1) expressed mainly by primary sensory neurons function as major nociceptive integrators. They are also present on the rat endometrium in an oestrogen-regulated manner. TRPV1 is upregulated in peritoneal and ovarian endometriosis patients, but there is no information about TRPA1 and their pathophysiological significances. In this study, patients undergoing laparoscopic surgery were investigated: severe dysmenorrhoea due to rectosigmoid deep infiltrating endometriosis ( n = 15), uterine fibroid-induced moderate dysmenorrhoea ( n = 7) and tubal infertility with no pain ( n = 6). TRPA1 and TRPV1 mRNA and protein expressions were determined by quantitative polymerase chain reaction and semi-quantitative immunohistochemistry from the endometrium samples taken by curettage. Results were correlated with the clinical characteristics including pain intensity. TRPA1 and TRPV1 receptors were expressed in the healthy human endometrium at mRNA and protein levels. Sparse, scattered cytoplasmic TRPA1 and TRPV1 immunopositivities were found in the stroma and epithelial layers. We detected upregulated mRNA levels in deep infiltrating endometriosis lesions, and TRPV1 gene expression was also elevated in autocontrol endometrium of deep infiltrating endometriosis patients. Histological scoring revealed significant TRPA1 and TRPV1 difference between deep infiltrating endometriosis stroma and epithelium, and in deep infiltrating endometriosis epithelium compared to control samples. Besides, we measured elevated stromal TRPV1 immunopositivity in deep infiltrating endometriosis. Stromal TRPA1 and TRPV1 immunoreactivities strongly correlated with dysmenorrhoea severity, as well TRPV1 expression on ectopic epithelial cells and macrophages with dyspareunia. Epithelial TRPA1 and stromal TRPV1 immunopositivity also positively correlated with dyschezia severity. We provide the first evidence for the presence of non-neuronal TRPA1 receptor in the healthy human endometrium and confirm the expression of TRPV1 channels. Their upregulations in rectosigmoid deep infiltrating endometriosis lesions and correlations with pain intensity suggest potential roles in pathophysiological mechanisms of the disease.

The aim of our prospective study was to assess the concordance between postvoid residual volumes (PVR) of the urinary bladder obtained by two different three-dimensional (3-D) ultrasound (US) volumetric methods (VOCAL and XI VOCAL) and with measurement by the catheter in postoperative patients who have undergone radical hysterectomy. The 3-D sonographic volume-determination of PVR with both methods correlated significantly with the actual amount of PVR by the catheter. The accuracy of both 3-D US volumetric methods was significantly higher under 300 mL of PVR. Bland-Altman plots were generated to examine limits of agreement. Both noninvasive 3-D sonographic methods are appropriate for the correct volume-determination of PVR following radical hysterectomy. Thus, we may avoid routine, albeit often unnecessary, catheterization to measure postoperative residual bladder volumes and subsequently the incidence of lower urinary tract infection may be reduced and better postoperative comfort for patients may be permitted., (Copyright © 2011 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the effect of low-dose aspirin therapy on ovarian hyperstimulation syndrome (OHSS) in an unselected group of patients undergoing in vitro fertilization (IVF)., Design: Randomized clinical trial., Setting: Division of Reproductive Medicine at the Department of Obstetrics and Gynecology, University of Pécs, Faculty of Medicine, Pécs, Hungary., Patient(s): Patients who underwent IVF between 2000 and 2006., Intervention(s): Initiation of 3154 IVF cycles, for which gonadotropin-releasing hormone agonist was used in 2425 cycles; 1503 cycles randomly selected for low-dose aspirin treatment starting from the first day of controlled ovarian hyperstimulation compared with no treatment in the remaining 922 cycles., Main Outcome Measure(s): The incidence of severe or critical OHSS and the rate of clinical pregnancy., Result(s): During this time period, 45 cases of severe OHSS were detected. Only two of the OHSS patients had received aspirin previously., Conclusion(s): Based on our preliminary results, introduction of low-dose aspirin therapy during ovulation induction for the prevention of OHSS in high-risk patients should be considered., (Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to determine whether a weekly or seasonal variation could be observed in the onset of acute myocardial infarction (AMI)., Methods: A retrospective analysis of patients diagnosed with AMI between 2000 and 2004 in Hungary (n=81,215 patients) was carried out. Data were collected by the National Health Insurance Fund Administration (OEP). We calculated the number of AMI cases (incidence) per year, month, and per day in the course of a week with 95% confidence interval. Statistical analysis using one-way analysis of variance (ANOVA) was performed., Results: A peak period of the occurrence of AMI was found during spring, while minimum number of events were recorded during summer. Significant difference was observed between the number of events each season (F=34.741; p<0.001). Between 2000 and 2004 the monthly occurrence of AMI was highest in March, May and October (F=11.658; p<0.001). The weekly peak period of AMI morbidity was found on the first day of the week, showing a gradually decreasing tendency all week-through, reaching its minimum incidence on Sunday (F=4.162; p<0.001)., Conclusions: Results of our study reveal that the incidence of AMI shows a characteristic rhythm with respect to seasons and the days of the week, which should be considered in the development of preventive concepts.

Background: Seasonal variations of reproductive functions in wild mammals are well known. Similar but blunted seasonal trends have also been described for humans., Methods: We performed a questionnaire-based study of 149 patients that was designed to search for environmental influence on symptom presentation among patients attending an open menopause service., Results: The evaluated data show a conspicuous seasonality in cessation of menstrual bleeding, with a higher peak after the vernal (spring) equinox and a lower one after the autumn equinox., Conclusions: Of the several environmental factors considered in this study, the sequence of seasons seems to affect most obviously the process leading to the loss of menstrual cycling. The triggering factor(s) eliciting the onset of the menopausal process and the mediators involved, however, need further analysis.

Numerous investigations have recently proved the importance of sentinel lymph node detection in various malignant tumours. It is widely accepted that this procedure is to be recommended only in patients with early stage tumours. The lymph node status and prognosis are closely related. Appropriate staging is essential in the management of malignant tumours and should be individualised. In many cases, the nodal status does not correlate with the clinical stage of the disease. In this survey, we consider some of the most common gynaecological malignancies and the type of staging most appropriate to them. Differences between these staging systems, and controversies concerning them, are related to the concept of sentinel lymph node investigation. The authors believe that sentinel node sampling is in fact a beneficial method in both early and advanced stage disease for determination of the tumour status and individualisation of surgical interventions.

Background: Receptors for luteinizing hormone-releasing hormone (LH-RH) found in prostate cancers might be used for targeting of chemotherapeutic agents. Doxorubicin derivative 2-pyrrolinodoxorubicin (AN-201) can be linked to carrier analog [D-Lys6]LH-RH to form the targeted cytotoxic analog of LH-RH, AN-207., Methods: We evaluated the effects of AN-207 and its components on the growth of LH-RH receptor-positive human prostate cancer PC-82 xenografted into nude mice. Analog AN-207, radical AN-201, carrier [D-Lys6]LH-RH, or a mixture of [D-Lys6]LH-RH and AN-201 were injected intravenously once at doses of 200 nmol/kg. Tumor growth, body weight, total WBC counts, and serum prostate-specific antigen (PSA) were determined. Receptors for LH-RH on PC-82 tumors were evaluated, and the expression of mRNA for LH-RH receptors was assessed by RT-PCR., Results: Eight weeks after administration of cytotoxic analog AN-207, there was a 67.8% reduction in tumor volume (P < 0.01), 70.7% decrease in tumor burden (P < 0.01), and 36.5% decrease in serum PSA levels (P < 0.01) as compared with controls. Only one of 8 animals treated with AN-207 died. Cytotoxic radical AN-201 caused a 34.2% (not significant, NS) reduction in tumor volume with no change in serum PSA, and killed 3 of 8 mice due to toxicity. Carrier [D-Lys6]LH-RH and the unconjugated mixture of [D-Lys6]LH-RH and AN-201 had no effect on tumor growth. LH-RH receptors as well as the expression of their mRNA were found in PC-82 tumors.

In previous studies, we showed that LH-RH antagonist Cetrorelix inhibits the growth of DU-145 and PC-3 human androgen-independent prostate cancers in nude mice. To investigate the mechanisms involved, we treated male nude mice bearing xenografts of DU-145 human androgen-independent prostate cancer with Cetrorelix at a dose of 100 microg/animal subcutaneously (s.c.) once a day. Tumor growth, serum and tumor levels of IGF-I and -II as well as the mRNA expression of IGF-I and -II in tumors were evaluated. After 8 weeks of treatment, final volume and weight of DU-145 tumors in mice treated with Cetrorelix were significantly decreased compared with controls and serum IGF-1 showed a significant reduction. Therapy with Cetrorelix also reduced by 84% the levels of IGF-II in DU-145 tumor tissue compared with controls, but did not affect the concentration of IGF-I. RT-PCR analyses revealed a high expression of mRNA for IGF-II, but not for IGF-I in DU-145 tumors. Treatment with Cetrorelix decreased the expression of IGF-II mRNA by 78% (p < 0.01) as compared with controls. Our study indicates that LH-RH antagonist Cetrorelix may inhibit the growth of DU- 145 human androgen-independent prostate cancers by decreasing the production and mRNA expression of IGF-II by the tumor tissue. This also suggests that LH-RH antagonist Cetrorelix could interfere with the signal transduction pathways involving IGF-II, leading to tumor growth inhibition.

Insulin-like growth factors I and II (IGF-I and -II) are potent mitogens for various cancers, including carcinoma of the prostate. In several experimental cancers, treatment with antagonists of growth hormone-releasing hormone (GH-RH) produces a reduction in IGF-I and -II, concomitant to inhibition of tumor growth. To investigate the mechanisms involved, we treated male nude mice bearing xenografts of DU-145 human androgen-independent prostate cancer for 8 weeks with potent GH-RH antagonist MZ-5-156 at a dose of 20 microg/animal s.c. twice a day. Tumor growth, serum and tumor levels of IGF-I and -II, and the mRNA expression of IGF-I and -II in tumors were evaluated. After 8 weeks of therapy, final volume and weight of DU-145 tumors in mice treated with MZ-5-156 were significantly (P < 0.01) decreased compared with controls, and serum IGF-I showed a significant reduction. Treatment of nude mice bearing DU-145 xenografts with MZ-5-156 also significantly (P < 0.01) diminished by 77% the levels of IGF-II in tumor tissue compared with controls, but did not affect the concentration of IGF-I. Reverse transcription-PCR analyses revealed a high expression of IGF-II mRNA in DU-145 tumors. Treatment with GH-RH antagonist MZ-5-156 decreased the expression of IGF-II mRNA by 58% (P < 0.01) as compared with controls. Our work suggests that GH-RH antagonist MZ-5-156 may inhibit the growth of DU-145 human androgen-independent prostate cancers through a reduction in the production and mRNA expression of IGF-II by the tumor tissue. These findings extend our observations on the mechanism of action of GH-RH antagonists and may explain how GH-RH antagonists inhibit tumor growth.

Experimental data suggest that a follicle stimulating hormone-releasing factor (FSH-RF) distinct from luteinizing hormone-releasing hormone (LHRH) exists. In the present study, we investigated, in short-term ovariectomized (OVX) rats, whether FSH-RF(s) can be released from nerve terminals by electrochemical stimulation (ECS) of the median eminence. To prevent the effect of LHRH liberated by ECS, 100 microg of a potent LHRH antagonist (MI-1544) was administered to one group of OVX rats 60 min before ECS. Two groups of OVX rats were used as controls. One group was treated with the solvent of the LHRH antagonist 60 min before the ECS; the other group received sham-ECS only. In-vitro experiments using a hypothalamus-pituitary coperifusion system were also performed to investigate the direct effect of ECS of the median eminence on LH and FSH release from pituitary cells. ECS in vivo induced 4.6-fold (P<0.01) and 10.2-fold (P<0.01) elevation of serum LH concentration, measured by RIA at 10 min and 60 min after ECS, respectively. Serum FSH concentrations increased 1.35-fold at 10 min (P<0.01) and 1.50-fold at 60 min (P<0.01) after ECS, compared with sham-stimulated controls. Administration of LHRH antagonist attenuated the ECS-induced release of LH by 44% at 10 min and prevented it entirely at 60 min after ECS. However, the ECS-induced release of FSH was not modified by the antagonist at 10 min and was diminished by only 17% at 60 min after ECS, compared with solvent-treated and stimulated controls. Immunohistological examination of the hypothalami showed that LHRH-immunoreactivity was depleted in the region of ECS. In the study in vitro, substances released from the fragments of mediobasal hypothalami bearing ECS in the median eminence induced significant release of both LH and FSH, and the induced release of LH, but not FSH, was prevented by the LHRH antagonist. The present study suggests that FSH-releasing factor(s) different from LHRH can be released from the median eminence and that a significant portion of FSH secretion is independent of the control of LHRH.

To create cytotoxic hybrid analogs of somatostatin (SST), octapeptides RC-160 (D-Phe-Cys-Tyr-D-Trp- Lys-Val-Cys-Trp-NH2) and RC-121 (D-Phe-Cys-Tyr-D-Trp- Lys-Val-Cys-Thr-NH2) were linked to doxorubicin (DOX) or its superactive derivative, 2-pyrrolino-DOX (AN-201). The conjugation was performed by coupling N-9-fluorenylmethoxycarbonyl (N-Fmoc)-DOX-14-O-hemiglutarate or 2-pyrrolino-DOX-14-O-hemiglutarate to the amino terminus of [Lys(Fmoc)5]RC-160 yielding AN-163 and AN-258, respectively, after deprotection. The respective cytotoxic conjugates of RC-121 (AN-162 and AN-238) were prepared similarly. In vitro tests on human cancer cell lines-MKN-45 gastric cancer, MDA-MB-231 breast cancer, PC-3 prostate cancer, and MIA PaCa-2 pancreatic cancer-demonstrated that the antiproliferative activity of the cytotoxic radicals in these conjugates was virtually retained. In H-345 human small cell lung carcinoma cell line, conjugates of RC-121 preserved the cytotoxic activity of their radicals, but the hybrids with RC-160 showed approximately 10 times lower activity. The ability of the carriers and the hybrids to inhibit the binding of 125I-labeled RC-160 to receptors for SST on rat pituitary membrane preparation was also determined. The cytotoxic conjugates inhibited 50% of the specific binding of the radioligand in the nanomolar concentration range (IC50 < 80 nM). When SST-like activities of AN-238 and its carrier, RC-121, were compared in the rat pituitary superfusion system, both compounds were found to suppress a stimulated growth hormone release at nanomolar concentrations. Preliminary studies in animal models of breast and prostate cancers showed that AN-238 is less toxic than AN-201 and more potent in inhibiting tumor growth. These highly active cytotoxic analogs of SST have been designed as targeted antitumor agents for the treatment of various cancers expressing receptors for SST octapeptides.