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Objective Uterine fibroids affect 2–10 % of pregnant women. Although usually asymptomatic, they may be associated with pregnancy complications. Myomectomy is preferably avoided antenatally, however, it has been reported in symptomatic cases that did not respond to conservative management. The aim of this study was to summarize the published literature and present the reported outcomes and associated risks of this procedure. Study Design A systematic research of the literature was conducted in PubMed/MEDLINE, Scopus and the Cochrane Library, including case reports and case series. An effort was made to numerically analyse all parameters included in the case reports. Results Overall, 54 relevant articles were identified, including 97 patients. The median gestational age at diagnosis was 13 (range 6–26) weeks, while the median age at myomectomy was 16 (range 6–26) weeks. Abdominal pain, not responding to medical treatment was the most common indication for surgery. The median number of fibroids removed per patient was one (range 1–5). Most of them were subserous pedunculated or subserous and fundal. Laparotomy (78.4 %) was the principal surgical approach, however, laparoscopic and vaginal operations were also reported. The median duration of surgery was 53 (range 20–150) min. The histopathology revealed necrosis and degeneration as the main findings of removed fibroids. The pregnancy outcome was favourable in most of the cases, with few complications reported. Conclusion Based on the limited published data, myomectomy during pregnancy appears as a safe procedure in cases of symptomatic uterine fibroids not responding to conservative management and therefore it may be considered, following appropriate counselling regarding the associated risks.

The aim of the present study was to test whether inhibition of ovarian primordial follicles and subsequent activation can be achieved by transient mTOR inhibition. In this preclinical investigation, forty-five female immature Wistar rats were randomized in 5 groups. The control group received subcutaneous saline injections. The other groups received Everolimus, Everolimus plus Verapamil, Everolimus plus Fisetin, and Fisetin alone. Primary and secondary outcomes were measured in the left ovary after a treatment period of 8 weeks. Ten days later, animals received 35 IU FSH for 4 days and 35 IU of hCG on the 5th day. The same parameters were examined in the right ovary. AMH, estradiol, and progesterone levels were assessed at the end of both interventions. Significantly, more primordial and less atretic follicles were observed in the Everolimus plus Verapamil group. AMH and progesterone levels were substantially lower in the Everolimus group. Interestingly, after ovarian stimulation higher levels of AMH and progesterone were observed in the Everolimus plus Verapamil group. Immunoblot analysis of ovarian extracts revealed that the administration of Everolimus led to a significant reduction in the mTORC1-mediated phosphorylation of the 70-kDa ribosomal protein S6 kinase 1. This decrease was reversed in the presence of FSH after stopping drug administration. The expression of the anti-apoptotic molecule Bcl2 as well as of LC3-II and ATG12 was increased after removal of the Everolimus plus Verapamil combination, indicating reduced apoptosis and increased autophagy, whereas the levels of the proliferation marker PCNA in the granulosa cells were elevated, consistent with initiation of follicular growth.Thus, the combination of Everolimus plus Verapamil is capable of increasing the number of competent primordial follicles while reducing atresia.

In recent years, the development of Assisted Reproductive Technique, the egg and embryo donation changed substantially the role of the uterus in recent years. It provided a higher chance for a pregnancy even in women over 45 years or post-menopause. In fact, the number of aged patients and in peri/post-menopause in pregnancy is nowadays increasing, but it increases obstetrical and neonatal related problems. The human uterus is richly innervated and modified especially during pregnancy and labor, and it is endowed with different sensory, parasympathetic, sympathetic and peptidergic neurofibers. They are differently distributed in uterine fundus, body and cervix, and they are mainly observed in the stroma and around arterial vessel walls in the myometrial and endometrial layers. Many neurotransmitters playing important roles in reproductive physiology are released after stimulation by adrenergic or cholinergic nerve fibers (the so called sympathetic/parasympathetic co-transmission). Immunohistochemical study demonstrated the localization and quantitative distribution of neurofibers in the fundus, the body and cervix of young women of childbearing age. Adrenergic and cholinergic effects of the autonomous nervous system are the most implicated in the uterine functionality. In such aged women, the Adrenergic and AChE neurofibers distribution in the fundus, body and cervix is progressively reduced by increasing age. Adrenergic and AChE neurotransmitters were closely associated with the uterine arteries and myometrial smooth muscles, and they reduced markedly by ageing. The Adrenergic and AChE neurofibers decreasing has a dramatical and negative impact on uterine physiology, as the reduction of pregnancy chance and uterine growth, and the increase of abortion risk and prematurity.

Objective To describe the characteristics and peripartum outcomes of patients diagnosed with uterine rupture (UR) by an observational cohort retrospective study on 270 patients. Methods Demographic information, surgical history, symptoms, and postoperative outcome of maternal and neonates after UR were collected in a large database. The statistical analysis searched for correlation between UR, previous uterine interventions, fibroids, and the successive perinatal outcomes in patients with previous UR. Results UR was significantly associated with previous uterine surgery, occurring, on average, at 36,81 weeks of gestation in patients also without previous uterine surgery. UR did not rise exponentially with an increasing number of uterine operations. Fibroids were related to URs. The earliest UR occurred at 159 days after hysteroscopic myomectomy, followed by laparoscopic myomectomy (251 days) and laparotomic myomectomy (253 days). Fertility preservation was feasible in several patients. Gestational age and birth weight seemed not to be affected in the subsequent pregnancy. Conclusion data analysis showed that previous laparoscopic and abdominal myomectomy were associated with UR in pregnancy, and hysteroscopic myomectomy was associated at earlier gestational ages. UR did not increase exponentially with an increasing number of previous scars. UR should not be considered a contra-indication to future pregnancies.

Importance Several predictive models and scoring systems have been developed to differentiate between benign and malignant ovarian masses, in order to guide effective management. These models use combinations of patient characteristics, ultrasound markers, and biochemical markers. Objective The aim of this study was to describe, compare, and prioritize, according to their strengths and qualities, all the adnexal prediction models. Evidence acquisition This was a state-of-the-art review, synthesizing the findings of the current published literature on the available prediction models of adnexal masses. Results The existing models include subjective assessment by expert sonographers, the International Ovarian Tumor Analysis models (logistic regression models 1 and 2, Simple Rules, 3-step strategy, and ADNEX [Assessment of Different NEoplasias in the adneXa] model), the Risk of Malignancy Index, the Risk of Malignancy Ovarian Algorithm, the Gynecologic Imaging Reporting and Data System, and the Ovarian-Adnexal Reporting and Data System. Overall, subjective assessment appears to be superior to all prediction models. However, the International Ovarian Tumor Analysis models are probably the best available methods for nonexpert examiners. The Ovarian-Adnexal Reporting and Data System is an international approach that incorporates both the common European and North American approaches, but still needs to be validated. Conclusions Many prediction models exist for the assessment of adnexal masses. The adoption of a particular model is based on local guidelines, as well as sonographer's experience. The safety of expectant management of adnexal masses with benign ultrasound morphology is still under investigation.

Authors evaluated the impact of laparoscopic intracapsular myomectomy (LIM) in women 40 years of age and over with desire of future fertility compared with medical management of symptomatic fibroids, by a prospective cohort study in University affiliated Hospitals. This study includes a cohort of women 40 years of age and older with symptomatic intramural fibroids with desire of future fertility. Women with symptomatic fibroid uterus were offered to undergo LIM or medical management. They were encouraged to attempt conception either spontaneously or by assisted reproductive technology (ART) according to their individual preference. All women were followed for 2 years. Fibroid characteristics, pre- and post-surgical variables, including surgical complications, days of hospitalization, pregnancy rate, and obstetrical outcomes were collected. A total of 100 patient were included in the analysis. Fifty patients were assigned to the LIM group and 50 to the medical treatment group (MT). Groups were similar regarding age (43.5 ± 2.4 and 43.5 ± 2.4, p = 0.99), body mass index (23.8 ± 3.1 and 24.2 ± 3.1, p = 0.54), parity (0.46 ± 0.09 and 0.58 ± 0.09, p = 0.37), fibroid number (1.38 ± 0.6 and 1.46 ± 0.6, p = 0.53), and fibroid size (5.92 ± 1.62 cm vs. 5.94 ± 1.49 cm, p = 0.949). Of the patients who underwent LIM, 62% conceived within the study period compared with 56% in the control group (p = 0.54). Pregnancy was achieved by ART in 44% of the patients of the LIM group and 30% in control group. There was no significant difference in pregnancy rates among the two groups regarding spontaneous pregnancy rate (p = 0.332), nor in pregnancies obtained by ART with own eggs (p = 0.146) and oocyte or embryo donation (p = 0.821). The take home baby rate was 65% (20/31) in the LIM group and 61% (17/28) in the control group (p = 0.7851). Both groups had similar rate of miscarriage (p = 0.748).Patients 40 years old and over with symptomatic fibroid uterus who undergo LIM have similar subsequent fertility and obstetrical outcomes than women treated with medical management. LIM has no detrimental impact on future fertility in women 40 years old and over.

Premature ovarian failure (POF), which may be undetectable for a long time, is associated with impaired fertility. The mechanisms involved in the pathogenesis of POF as well as the concomitant treatments are still unclear. Although many data exist, mainly produced by the study of transgenic animals under various experimental conditions, they remain fragmented. A systematic review of the pathways involved in premature ovarian failure was conducted. Data extraction was performed from experimental studies until 2019. The molecular processes and their correlation with the follicular developmental stage have been described. Furthermore, the effects in other cells, such as oocytes, granulosa and theca cells have been reported. An overall estimation was conducted.

Uterine Fibroids (UFs), or leiomyomas, represent the most frequent pelvic tumor in reproductive-aged women. Although of benign origin, UFs decrease fertility and cause significant reproductive dysfunctions. Compared to normal myometrium, UFs are characterized by a clinical and molecular heterogeneity as demonstrated by the presence of multiple genetic alterations and altered signaling pathways. Recently, selective progesteronereceptor modulators (SPRM), as ulipristal acetate (UPA), have demonstrated their clinical benefits by reducing tumor growth and extracellular matrix deposition. For these reasons, UPA is used in the clinical practice as an intermittent treatment for women symptomatic for UFs or, sometimes, before a myomectomy. However, drug effects on signaling pathways frequently upregulated in UFs remain largely unknown. In fact, the mechanisms of action of the UPA on UFs and on the surrounding areas are not yet understood. To learn more about UPA molecular mechanisms, UF samples were treated ex vivo with UPA and profiled for drug effects on selected markers. During this preliminary ex vivo UPA administration, significant changes were observed in the expression levels of proteins related to cell cycle regulation, cytoskeleton remodeling, and drug resistance. The UPA administration reduced cofilin, Erk and Src phosphorylation, p27 and ezrin protein levels, but not Akt phosphorylation and cyclin D1 and β-catenin levels. This preliminary ex vivo biological analysis provided new insights into the mechanism of action of UPA in the treatment of UFs, which could better explain the biological functioning of the drug on UFs.

Endometriosis is a gynecological disease characterized by the presence of endometrial glandular and stromal cells existing in the extra-uterine environment. Estimates show that endometriosis affects 10–15% of all women of reproductive age. Approximately, 25–50% of infertile women may be affected by endometriosis and 30–50% patients with endometriosis may suffer from infertility. Several mechanisms have been proposed for the association of endometriosis and infertility, including distorted pelvic anatomy, impaired ovary function, altered microenvironment, affected endometrial receptivity, and reduced oocyte/embryo quality. Patients with endometriosis have inflammatory processes within the increased amount of peritoneal fluid noted. These inflammatory processes and hormonal changes have shown to alter folliculogenesis, sperm motility, tubal transport, and embryo implantation.

The most important step for the in vitro fertilization (IVF) process is oocyte retrieval. Under ultrasound guidance, a needle is inserted through the vagina and directed to the ovary and the follicles. Subsequently, the follicular fluid together with the oocyte is aspirated. Although it is a very precise technique, complications may occur. Although these complications are rare, they could be serious and life threatening. In this chapter, we present the complications after oocyte retrieval for IVF as they are reported in case reports and studies with small series of cycles. All studies conclude that these events are associated with pelvic inflammatory disease or endometriosis that may coexist with infertility.

Laparoscopic cholecystectomy (LC) in female individuals has been challenged recently by transvaginal natural orifice transluminal endoscopic surgery cholecystectomy (TVC). TVC has not been widely accepted as a standard procedure, even though it is reported to be a safe and painless alternative to LC. This prospective comparative study aims to not only prove equality of TVC and LC but to underline the advantages of TVC over LC with regard to postoperative pain.This study presents an analysis of a single-center and single-surgeon study with 226 unselected consecutive cholecystectomies performed as either TVC or LC.A total of 226 female patients underwent surgery with either LC (136 cases) or TVC (90 cases). There were no postoperative adverse events. Twenty-two patients (24.2%) in the TVC group indicated 0 (no pain) on a visual analog scale postoperatively, whereas only 5 patients (3.7%) did so in the LC group (P = .0001). Overall consumption of non-steroidal anti-inflammatory drugs was significantly less (P .0001; t test) in the TVC group (mean, 1.2 ± 0.11 g) compared with the LC group (mean, 2.1 ± 0.1 g). Twenty-three patients (25.5%) in the TVC group needed no postoperative analgesics at all.TVC is a safe and painless procedure for patients with symptomatic cholelithiasis who are from various ethnic and cultural origins. This benefit, along with an equal safety profile compared with LC, should pave the way for wider application of TVC in women.

We are fascinated these days to read Poidevin’s prediction which has been realized in full. He wrote in 1961: “A prediction of the acceptable rate in 10 years’ time would neither be prudent nor, in itself, of any real importance. Some individual obstetricians have already arrived at the stage when cesarean section delivery is resorted to all women deviating at all from the bounds of accepted normality. This policy quickly brings the rate up to 20 per cent or more. There are, furthermore, those enthusiasts who go almost the whole way in order to protect the pelvic floor and lower genitals from natural childbirth! For those who fear the cesarean section rate will “get out of hand,” let me predict that this tendency will automatically be corrected by one factor—uterine morbidity. Uterine morbidity should no longer be crudely judged by the incidence of uterine rupture subsequent to cesarean section the thinking of the next decade should be more delicate. The next decade should see a more critical attitude toward the uterine wound, particularly, as this group in the general population will continue to grow. A reassessment of operative techniques is indicated and modifications will undoubtedly be attempted” [1].

The usefulness of various pathways inhibitors, Everolimus, an inhibitor of mammalian target of rapamycin (mTOR), Infliximab, a monoclonal antibody which blocks the tumor necrosis factor-a (TNF-a), Erlotinib, a tyrosine protein kinase inhibitor of the epidermal growth factor receptor (EGFR), Metformin, an activator of AMP-activated protein kinase enzyme (AMPK) and vascular permeability reducers were explored in an ovarian hyperstimulation syndrome (OHSS) rat model. Sixty-three female Wistar rats were randomly divided in seven groups. The control group received saline, while the OHSS group received recombinant -- follicle-stimulating hormone (rec-FSH) for four consecutive days. The other five groups received rec-FSH for 4 d and Everolimus daily, Infliximab once, Erlotinib daily, Metformin daily and Vitamin C daily, respectively. All groups received human chorionic gonadotropin (hCG) at the fifth day. The efficacy of Everolimus administration for various intervals was also explored. Significantly reduced ovarian weight was observed in the Everolimus group (rec-FSH + hCG + mTOR inhibitor) compared to the OHSS group (p < 0.001). The Everolimus group also showed the lowest progesterone (PRG) concentration (p = 0.007). The Erlotinib group (rec-FSH + hCG + EGFR inhibitor) presented with the lowest graafian follicle number, while the Everolimus group was characterized by the lowest corpus luteum number. The vascular permeability and the estradiol levels did not differ between groups. Finally, the Everolimus intra-comparison showed no difference in all measured outcomes. Studying the different pathways linked to vascular endothelial growth factor (VEGF) pathway, we conclude that targeting mTOR pathways is beneficial for reducing ovarian weight and PRG levels in an OHSS animal model.

The aim is to study the association of estrogen receptor α (ERα) and estrogen receptor β (ERβ) gene polymorphisms and diplotypes with ovarian response to follicle-stimulating hormone (FSH) stimulation and the hormone levels [FSH, luteinizing hormone (LH), E2] at the third day of the menstrual cycle. Three hundred women undergoing medically assisted reproduction and 300 women with at least one spontaneous pregnancy participated in the study. ERα PvuII and XbaI polymorphisms as well as ERβ AluI polymorphism were genotyped. The FSH, LH, and E2 levels were determined at the third day of the menstrual cycle, while the follicular size, the follicle, and oocyte numbers were recorded during oocyte retrieval. PvuII CC, XbaI GG, and AluI GG women were characterized by increased amounts of large follicles compared to PvuII TT, XbaI AA, and AluI AA women (p = 0.045, 0.01, and 0.033, respectively). The PvuII CC/XbaI GG diplotype was also significantly associated with higher large follicle numbers compared to the PvuII TT/XbaI AA diplotype (p = 0.024). However, no associations were observed between ER gene polymorphisms and the hormonal profile, the follicle/oocyte numbers, and the pregnancy rates. ERα and ERβ genetic variants were associated with ovarian response to standard gonadotropin stimulation of women undergoing in-vitro fertilization affecting mainly the follicular growth.

This article describes a Protocol for a study to determine a scope of Human Papillomavirus (HPV) infection and evaluate cervical cancer prevention measures in the western Kazakhstan. Introduction — ICO (Institut Catala d’Oncologia) working group in 2015 informed that cervical cancer in Kazakhstan ranked as the 1st most frequent cancer among 15-44 aged women. Aim — comprehensive analysis of the HPV infection across the female population to predict further trends in the cervical cancer morbidity and outline the circle of urgent preventive measures. The most important tasks are the following: to analyze a set of clinical, laboratory and socio-demographic data for identification the region-specific risk factors of the disease; to present a comparative analysis of diagnostic screening tools practiced in the region for the development corrective recommendations for existing screening strategy. Methods — This study constitutes a mix of three different types: interview+cross-sectional study for general female population and interview+case-control study for women with the first time diagnosed cervical cancer, where women of the general sample of the same age with detected HPV infection but not affected by the disease serve as a control for those with the disease. Anticipated Results — A high feasibility and pithiness of this study is expected. Obtaining a wide body of information relatively HPV scope and a quality of the screening process during a patient’s single visit is the main strength of the research. Conclusion — Successful implementation of challenges announced in the research can lead to changing a general vector or/and constituent parts of the existing screening program.

Authors evaluated the outcome of intracapsular cesarean myomectomy by a prospective case-control study on 68 patients who underwent intracapsular cesarean myomectomy, compared with a control group of 72 patients with myomatosic pregnant uterus who underwent cesarean section (CS) without myomectomy. Mostly of removed myomas were subserous or intramural, fundal in 37 women (54.4%), corporal in 22 (32.3%) and peri-low uterine segment in 9 women (18.7%). The average myoma' size was 8 cm (1.5-20), in 40 women, with 8 myomas measuring 4-6 cm, 14 myomas between 10 and 12 cm and13 cm in 6 patients. Difference in blood tests and surgical outcome in intracapsular cesarean myomectomy was non significant (p 0.05). The average duration of hospitalization of intracapsular cesarean myomectomies was 5 days. There was no correlation between complications or duration of hospital stay and patient age, gravidity, parity or indication for CS. The intracapsular cesarean myomectomy could be a reliable, feasible and safe obstetric procedure. Meticulous attention to gentle hemostasis, sharp pseudocapsule dissection, adequate approximation of the myometrium edges and all dead spaces to prevent hematoma formation, can further increase the safety of the procedure, without significant complications by experienced obstetricians.

The efficacy of pathways inhibition and the combined effect of Everolimus (mTOR inhibitor) and Verapamil (CYP3A inhibitor) in ovarian hyperstimulation syndrome (OHSS) need to be tested. Therefore, the impact of a leucotriene receptor antagonist, an anticoagulant, a GnRH antagonist as well as Everolimus plus Verapamil (at various doses and days of administration) on an OHSS rat model was tested. Sixty three female Wistar rats were randomly divided into seven groups. The control group received saline, while the OHSS group received rec-FSH for four consecutive days. The other five groups received rec-FSH for four days and Montelukast daily, Heparin daily, GnRH antagonist daily, Everolimus plus Verapamil in the last two days (half days group) and Everolimus plus Verapamil (half dose group) daily, respectively. All groups received also hCG at the fifth day. Significantly reduced ovarian weight was observed in the Everolimus plus Verapamil groups (half days and half-dose groups) and the Montelukast group compared to the OHSS group (p = 0.001 and p = 0.001, respectively). The vascular permeability was significantly reduced in the Everolimus plus Verapamil group (half dose group) and the GnRH antagonist group compared to the OHSS group (p

The aim of the current study was to explore whether anti-Mullerian hormone receptor II (AMHRII) genetic variants influence the hormonal profile and the ovarian response to standard gonadotropin stimulation of women undergoing medically assisted reproduction. Three hundred in vitro fertilization or intracytoplasmic sperm injection patients constituted the study population, while 300 women with at least one spontaneous pregnancy participated as controls. The follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2) and AMH levels were determined at the third day of the menstrual cycle. AMHRII 10A > G (rs11170555), 1749C > T (rs2071558) and -482A > G (rs2002555) polymorphisms were genotyped. The follicle and oocyte numbers, the follicle size and the clinical pregnancies were recorded. Regarding the AMHRII 1749C > T polymorphism, 1749CT women presented with higher total follicle and small follicle numbers compared to 1749CC women (p = 0.04 and p = 0.01, respectively). Whereas, as concerns the -482A > G polymorphism, -482AG women were characterized by higher total follicle and small follicle numbers comparing with -482AA women (p = 0.07 and p = 0.004, respectively). Finally, -482AG women presented with increased FSH levels compared to -482AA women (p T and -482A > G genetic variants were associated with the ovarian response to standard gonadotropin stimulation, affecting mainly the follicular growth.

In vitro fertilization is considered one of the safest medical specialties. A large number of patients undergo this technique, while the number of complications remains minimal. Till now, only case reports exist, while data from large studies contradicts these results. Complications before starting IVF, during downregulation and ovarian stimulation, will be presented. Incidents after oocyte retrieval will be examined. Pregnancy complications will be analyzed, as long as they present with minimal percentage. A brief presentation of the late consequences of IVF to the pregnancy and embryo will be examined while pathophysiologic explanation, where available, will be mentioned.

The association of cytochrome P450 aromatase gene CYP19(TTTA) ( n ) polymorphism with ovarian response to FSH stimulation was explored.Three hundred women undergoing medically assisted reproduction and 300 women with at least one spontaneous pregnancy participated in the study. CYP19(TTTA) ( n ) polymorphism was genotyped, while serum hormones were determined. During oocyte retrieval, the follicular size, the follicle and oocyte numbers were recorded.Six CYP19(TTTA) ( n ) alleles with 7 to 12 repeats were revealed. Women homozygous for long CYP19(TTTA) ( n ) alleles presented with lower serum FSH levels at the third day of the menstrual cycle (p 0.001) and higher large follicle numbers (p 0.01), compared to women homozygous for short CYP19(TTTA) ( n ) alleles. The CYP19(TTTA) ( 7 ) allele was associated with higher serum FSH levels (p 0.003), with lower total follicle (p 0.02) and large follicle numbers (p 0.03), while CYP19(TTTA) ( 7 ) allele-carriers presented more frequently with small follicles than CYP19(TTTA) ( 7 ) allele-non carriers (p 0.01).CYP19 genetic variants were associated with ovarian reserve and response to standard gonadotrophin stimulation of women undergoing in vitro fertilization.

• Elective single embryo transfer has been implemented in Belgium and Scandinavian countries to decrease the incidence of twin pregnancy and the associated complications. • The extra cost associated with achieving an equal number of pregnancies through elective single embryo transfer needs to be considered in the context of any additional neonatal care expenses associated with double embryo transfer. • Acceptable ongoing pregnancy and delivery rates have been obtained when comparing single with double embryo transfer. • Maternal age, previous attempts, day of embryo transfer and cost should be taken into account. Learning objectives: • To understand the issues raised when helping a couple choose single or double embryo transfer. Ethical issues: • Where does patient autonomy over treatment end and national regulation begin? • The management of obstetric complications and the long-term sequelae of premature birth should be factored in when considering treatment costs. Please cite this article as: Kosmas I, Van der Elst J, Devroey P, Tournaye H. Elective single embryo transfer. The Obstetrician & Gynaecologist 2008;10:163–169.

Dear editor The long-term survival rate of patients with breast cancer was improved by the application of systemic adjuvant chemotherapy,1 although the primary breast cancer treatment strategy consists of mastectomy with lymphadenectomy and radiotherapy followed by breast reconstruction.2–5 Unfortunately, most adjuvant chemotherapeutic agents trigger major side effects.1,6 Therefore, we have read with great interest an article in the International Journal of Nanomedicine on the design of docetaxel-loaded solid lipid nanoparticles (DSNs) aimed at reducing the systemic toxicity of standardized docetaxel treatment.7 Our congratulation to the authors7 for their clear demonstration of the reduced cytotoxicity of DSNs and significantly decreased myelosuppressive toxicity by recovering the proliferation and differentiation of bone marrow progenitor cells, while triggering more apoptosis in MCF-7 cells at a low dose compared with the commercial formula of docetaxel by an arrested cell cycle progression in the G2/M stage. The acute necessity for such state-of-the-art studies is linked to a high worldwide incidence of breast cancer; in the World Health Organization Fact sheet, its increased metastatic potency is listed as one of the most common causes of cancer death.8 The incidence of breast cancer is high in Western European countries, ie, about 89.7 per 100,000 women.8 The same high incidence applies to other developed countries. For our part, we have analyzed the statistical data concerning breast cancer in the Russian Federation.9 According to the statistical report by the Federal Research Institute for Health Organization and Informatics of the Ministry of Health of the Russian Federation between 2003 and 2012 (Table 1), the 10-year breast cancer incidence rates average 68.99 per 100,000 women (an average of 52,647 women annually), of which 95.1% cases were histologically verified. The average 5-year survival rate was 56.2% among women with breast cancer followed up in state and municipal cancer institutions. The average annual mortality of patients with verified breast cancer was 10.0% among individuals who were followed up in cancer institutes. Subsequently, between 2003 and 2012, about 25,697 women per year died of breast cancer in the Russian Federation. Table 1 Modified data from a statistical report for 2012 by the Federal Research Institute for Health Organization and Informatics of the Ministry of Health of the Russian Federation Our investigation, as proved by time series analysis (JMP7 software), revealed that the incidence of breast cancer had been rising continually, with increasing trends from 2003 to 2012 while at the same time the number of cancer deaths has been steadily decreasing (Table 1). Overall, the same trends exist for all cancer patients, in the same time. This phenomenon can be explained first by improvements in the Russian health care system. Government programs were set up applying new diagnostic technologies for early breast cancer screening, and preventive medical strategies were encouraged. Second, the rise in incidence of breast cancer might also be associated with gradual lifestyle changes. Many mothers in Russia decline breastfeeding and, in addition, worldwide environmental changes are reflected in an increased incidence of breast cancer, including in countries with a low prevalence of the disease. This brief analysis demonstrates that our modern community calls for new therapeutic approaches in the treatment of breast cancer. We believe that further studies could show the application of DSNs to be a basic compound for a targeted and dose-sparing personalized breast cancer treatment strategy.

All women who attended an outpatient hysteroscopy clinic over a 12-month period were asked to participate in a prospective, randomized, controlled trial comparing pain levels associated with the "no-touch" technique or the traditional technique of performing hysteroscopy. One hundred twenty patients met the eligibility requirements and agreed to participate. They were randomized to undergo hysteroscopy with either the traditional or the no-touch technique (60 each). In addition, each group was further randomized to either a 2.9-mm or a 4.00-mm hysteroscope (30 each). In the no-touch group, 10 women required local anesthesia and/or cervical dilatation-2 in the 2.9-mm hysteroscope subgroup and 8 in the 4-mm subgroup. These women were converted to the traditional technique and hysteroscopy was successfully completed. Data were then analyzed on an intent-to-treat classification. The traditional technique followed the standard pattern of speculum insertion, use of Littlewood's tenaculum to hold the cervix, dilation of the cervix if needed, and hysteroscopy. A Pipelle de Cornier sampler was used to perform endometrial biopsy if required. In the no-touch technique, the hysteroscope was placed in the vagina with no speculum and then, with saline irrigant flowing, carefully inserted into the uterus through the cervical os without grasping. When an endometrial biopsy was necessary, Littlewood's tenaculum was used to hold the cervix. If cervical dilatation or intracervical local anesthesia was required, the procedure was converted to a traditional technique. Patient assessment of each technique was made immediately after hysteroscopy and included pain scores for several phases of the procedure. Patients were also asked if they would recommend the technique to a friend, if they would ask for general anesthesia for a future procedure, and if they found the procedure acceptable. Only one hysteroscopy, in which bleeding prevented hysteroscopic assessment, was considered not to be successful. More time was required to perform the traditional technique than the no-touch technique (7.8 minutes vs 5.9 minutes). Cervical dilatation was needed in 15 patients in the traditional group and 10 in the no-touch group. Local anesthesia was required in 13 and 11 patients in each group, respectively. One of the patients in the no-touch group received local anesthesia for the biopsy only and was not converted. Biopsies were taken in 42 patients in the traditional group and 40 patients in the no-touch group. The only statistically significant difference in pain scores was a greater perception of pain with biopsy in the no-touch group than in the traditional group. Otherwise, there were no differences in pain scores associated with insertion of the hysteroscope, hysteroscope inspection, placement of the speculum, local anesthetic, end of procedure, or 30 minutes after the end of hysteroscopy. The highest scores were reported by women who were converted from the no-touch to the traditional technique for the pain from injections for local anesthesia. Overall, 92% of women found the outpatient hysteroscopy experience very or fairly acceptable. Ninety-three percent would recommend it to a friend. Fifteen percent of women whose hysteroscope was 2.9 mm said they would ask for general anesthesia for any future hysteroscopies compared with 27% of women who were randomized to the 4.0-mm hysteroscope.

BACKGROUND: Evaluation of the association between estradiol (E 2 ) levels on the day of hCG administration and pregnancy achievement in IVF has so far yielded conflicting results. The purpose of the present study was to systematically review the above association in cycles down-regulated with GnRH analogues. METHODS: Literature search was performed using Medline, Embase (1978-2004) and the Cochrane Library. Additionally, references of retrieved articles were hand-searched. Only full articles published in peer-reviewed medical journals were considered for analysis. RESULTS: All the eligible studies (n = 9) involved the use of GnRH agonists and were retrospective. Two studies (including 191 patients) suggested that the higher the E 2 levels on the day of hCG administration, the higher the probability of pregnancy. However, five studies (including 1875 patients), did not support an association between E 2 levels on the day of hCG administration and pregnancy rates. Moreover, two of the studies including (1286 patients) suggested that high E 2 levels on the day of hCG administration are associated with a decreased probability of pregnancy. If we consider only studies in which criteria used for administering hCG include follicular development but not E 2 levels (including 2687 patients), there is no study suggesting a positive association between E 2 levels on the day of hCG administration and pregnancy achievement. CONCLUSIONS: Currently there is no high-quality evidence to support or deny the value of E 2 determination on the day of hCG administration for pregnancy achievement in IVF cycles, where pituitary down-regulation is performed with GnRH agonists. Existing retrospective studies suggest that there is no positive association. However, in order to arrive at recommendations for clinical practice, there is a need to perform well-designed prospective studies in both agonist and antagonist cycles.

To evaluate whether the C677T polymorphism of the methylenetetrahydofolate reductase (MTHFR) gene is consistently associated with hypertension in pregnancy.Meta-analysis of studies comparing women with and without hypertension in pregnancy for the C677T MTHFR polymorphism.Studies were identified with MEDLINE and EMBASE searches complemented with perusal of bibliographies of retrieved articles and communication with investigators. Between-study heterogeneity was estimated and data were combined with random effects models. Sensitivity analyses examined the effect of population and disease characteristics. Bias diagnostics evaluated the evolution of the postulated genetic effect over time and the potential for publication bias.Across 23 comparisons (3169 hypertensive women, 3044 controls), having the T allele (TT or CT) increased the odds of hypertensive disease of pregnancy by 1.21-fold (95% confidence interval, 1.01-1.44), but there was large between-study heterogeneity (P = 0.003). The results were similar and heterogeneity persisted when sensitivity analyses were limited to studies of Caucasian populations, or those of patients with significant proteinuria. While patients with diastolic hypertensionor = 110 mmHg showed an odds ratio of 1.41 (95% confidence interval, 1.03-1.73), no association was seen in patients with less severe diastolic hypertension (odds ratio, 1.00; 95% confidence interval, 0.61-1.65). Early published studies tended to show stronger associations than the subsequent studies.While bias cannot be excluded, the meta-analysis suggests that the T allele may increase the risk of severe diastolic hypertension during pregnancy.

Authors investigated 75 patients with uterine myomas, appraising whether fibroid pseudocapsule (FP) thickness varies depending on fibroid location, by a prospective cohort trial (level of evidence II-2) settled in University-affiliated Hospitals. Uteri were scanned via bidimensional and power Doppler ultrasound (US) to map the fibroids and record the FP thickness, prior to hysterectomy for symptomatic uterine fibroids. After hysterectomy, FP specimens were sampled and analyzed by pathologists. Ultrasound and histology data were matched. Pseudocapsule thickness of 108 fibroids was measured: subserosal fibroids (SSFs), intramural fibroids (IMFs), and fibroids near the endometrial cavity (FEC). The FEC's pseudocapsules were considerably thicker than those of IMF and SSF measured by US and histology (P = .001). A clear cutoff existed between FEC pseudocapsule thickness and all other pseudocapsules, with significant differences observed at 2 mm (P = .001). Similarity between histological and US measurements was observed only with IMF pseudocapsules, whereas FEC or SSF showed significant differences. The pseudocapsule of fibroids is considerably thicker near the endometrial cavity when compared to those of both IMFs and SSFs. Since fibroids closest to the endometrial cavity are the most involved in fertility and infertility and FP is considerably thicker near the endometrial cavity, it is possible to hypothesize an involvement of FP of fibroid near the endometrium since FP contains many neuropeptides and neurotransmitters that are physiologically active, even if these data may take on a broader meaning in a study on a larger number of patients.

OBJECTIVE: The efficacy of vascular endothelial growth factor (VEGF), COX-2, calcium and aromatase inhibitors in an ovarian hyperstimulation syndrome (OHSS) rat model was tested. METHODS: One hundred and eight female Wistar rats were randomly divided in nine groups. The control group received saline, while the OHSS group received rec-FSH for 4 consecutive days. The other seven groups received rec-FSH (4d) and Bevacizumab twice, Parecoxib daily, Verapamil daily, Parecoxib daily and Bevacizumab twice, Verapamil daily and Bevacizumab twice, Parecoxib and Verapamil daily, Letrozole and Meloxicam daily, respectively. All groups received also hCG at the 5th day. RESULTS: All intervention groups were characterized by reduced vascular permeability compared to the OHSS group, which in the groups of Verapamil (Calcium inhibition) and Parecoxib + Verapamil (COX-2 + Calcium inhibition) presented significant statistical difference. The Verapamil group showed the lowest corpus luteum formation, while theParecoxib (COX-2 inhibition), the Parecoxib + Verapamil (COX-2 + Calcium inhibition), the Bevacizumab + Parecoxib (VEGF + COX-2 inhibition) and the Bevacizumab + Verapamil (VEGF + Calcium inhibition) groups were also characterized by lower corpus luteum numbers compared to the OHSS group. Furthermore, lower graafian follicle formation was observed in the above groups, while the ovarian weight and the hormonal profile were not significantly affected. CONCLUSIONS: Studying the different check points of the VEGF pathway, we conclude that targeting calcium pathways could be beneficial for the vascular permeability control in an OHSS animal model.

This editorial opinion article is based on our own experience and literature review. The NESA adhesion formation study team members recommend an unique model as a hypothesis building and testing tool in a surgical experimental research.

CO2-insufflation and electrocoagulation were advanced as causative factors of postsurgical adhesions. We assumed that severe tissue reaction due to electrocoagulation might obscure CO2-insufflation impact on adhesion formation. Therefore, the purpose of this study was to evaluate the effects and interactions of surgical trauma and CO2-insufflation on adhesion formation. Prospective-randomized study with 60 rats, equally divided into 3 groups. In the control group, the sidewall adhesion model was induced by monopolar coagulation of the uterine horn and ipsilateral parietal peritoneum and by mechanical damaging – in the opposite side through open laparoscopy without CO2-insufflation. In two other groups, CO2 was insufflated for 60 min at 15 cm of water, either before or after the sidewall model-induction. Parameters of sidewall and lesion site adhesions of parietal peritoneum and uterine horns were evaluated by scoring system and analyzed by two-way ANOVA with Bonferroni posttests, one-way ANOVA Student-Newman-Keuls multiple comparisons test, as well as by two-tailed unpaired Mann-Whitney test. Monopolar coagulation significantly increased peritoneal lesion site adhesion scores, as compared with the scores for mechanical damaging (p=0.0001). Visceral peritoneal lesion sites were more predisposed to adhesion formation than parietal peritoneal lesion sites (p=0.0009), whereas CO2 did not affect parameters of either sidewall or peritoneal lesion site adhesions, regardless of the insufflation mode (p>0.05). The data suggest that both surgical trauma and peritoneal lesion sites had a substantial impact on adhesion formation, whereas CO2 did not interfere with adhesion parameters irrespective of its insufflation mode. These findings may improve our insights into adhesion formation pathophysiology and open new perspectives in developing future adhesion prevention strategies.

The association of sperm nuclear chromatin condensation and ploidy with embryo development and outcome after intracytoplasmic sperm injection (ICSI) was explored. The study population consisted of 16 couples referred to Ioannina University Medical School In vitro Fertilization Unit with male factor infertility and serious impairments in sperm nuclear chromatin condensation and ploidy, according to sperm flow cytometry. Additionally, 20 couples with male factor infertility and relatively high sperm flow cytometry parameters participated as controls. The 35 cycles of the study population were characterized by a lower fertilization rate (P

study question: Does synergism between AR(CAG)n and CYP19(TTTA)n polymorphisms influence the quality of sperm? summary answer: AR(CAG)n and CYP19(TTTA)n polymorphisms had a synergistic effect on sperm concentration and motility. what is known already: Androgens exert their action in the testicular tissue by binding to androgen receptor (AR), while their action is mediated by the aromatase P450 enzyme (CYP19). AR(CAG)n alleles are associated with sperm motility and CYP19(TTTA)n allelic variants have implications for sperm concentration and motility. study design, size, duration: Two hundred oligozoospermic and 250 normozoospermic men who presented for infertility investigation were examined during a period of 2 years. participants/materials, setting, methods: Conventional semen analysis was performed. DNA was extracted from spermatozoa and both polymorphisms were genotyped by polymerase chain reaction. Serum hormone levels were determined. main results and the role of chance: Six combined genotypes were identified between the 18 AR(CAG)n alleles with 12 –32 repeats and the 6 CYP19(TTTA)n alleles with 7–12 repeats. A gradual reduction in the sperm concentration (10 6 /ml) and motility (%) from long AR allele –non-CYP19(TTTA)7 allele carriers to long AR allele – CYP19(TTTA)7 homozygotes and from short AR allele – nonCYP19(TTTA)7 carriers to short AR allele –CYP19(TTTA)7 homozygotes was observed in normozoospermic men (means+ SD; concentration: 93+ 53.1 versus 65+ 48.6 and 85+ 60.1 versus 37+ 17.2l, P , 0.002; motility: 63+ 10.3 versus 55+ 14.5 and 52+ 19.6 versus 41+ 13.7, P , 0.001, respectively). Similar associations were observed in oligozoospermic men (concentration: 10+ 4.2 versus 9+ 5.9 and 10+ 6.3 versus 6+ 3.1, P , 0.03; motility: 47+ 17.1 versus 39+ 6.2 and 39+ 22 versus 27+ 18.3, P , 0.003, respectively). The above associations of the combined genotypes with sperm concentration and motility were confirmed in the total study population (P , 0.006 and P , 0.001, respectively). limitations, reasons for caution: Our study population was limited to Greek Caucasian adult males, residents of Northwest Greece. wider implications of the findings: The confirmation of our findings in other populations would verify the significance of AR and CYP19 genes for spermatogenesis. study funding/competing interests: This study did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. The authors declare no conflicts of interest.

Summary Follicle-stimulating hormone (FSH), interacting with its receptor (FSHR), participates in the production of spermatozoa and androgens. Androgens exert their effects on male sex determination, development and sperm production by binding to androgen receptor (AR). In the present study, we sought to explore the potential synergistic effects of FSHR and AR gene variants on sperm quality. 200 oligozoospermic and 250 normozoospermic men were examined. DNA was extracted from spermatozoa, and the FSHR 307 (T/A), FSHR 680 (N/S) and AR (CAG)n polymorphisms were genotyped. Their parallel analysis revealed six combined genotypes. A gradual reduction of sperm motility, from long AR allele-Thr307Thr/Asn680Asn carriers to long AR allele-Ala307Ala/Ser680Ser carriers and from short AR allele-Thr307Thr/Asn680Asn carriers to short AR allele-Ala307Ala/Ser680Ser carriers was revealed in normozoospermic men (P

Case of heterotopic quadruplet pregnancy with coexistence of tubal and intrauterine twins. Objective (s): To present the case heterotopic quadruplet pregnancy with coexistence of tubal and intrauterine twins and its successful surgical management with brief literature review. Design: A case report supplemented with brief literature review and discussion. Setting: City clinical university hospital. Patient (s): Heterotopic quadruplet pregnancy with tubal and intrauterine twins in a 31-year-old woman after natural conception. Intervention (s): Laparoscopy, adhesiolisys, aspiration of tubal embryos through tubotomy and cervical dilatation and vacuum aspiration of intrauterine embryos as well as vaginal and intraoperative laparoscopic ultrasound examination. Main outcome measure (s): Physical examination, laparoscopy and postsurgical hCG serum assay, as well as preintra- and postoperative vaginal ultrasound and intraoperative laparoscopic sonography. Result (s): Successful diagnosis and treatment of a case of heterotopic quadruplet pregnancy with coexistence of tubal and intrauterine twins in a 31-year-old woman with 6 artificial abortions, pelvic inflammatory diseases and periadnexal adhesions, after natural conception was described. An intraoperative laparoscopic sonography was applied to complete diagnosis of heterotopic pregnancy with coexistence of tubal and intrauterine twins after control of bleeding and stabilization of patient condition due to necessity to perform an emergency surgery. The case was supplemented with a brief review of literature and discussion. Conclusion (s): A unique case of heterotopic quadruplet pregnancy with coexistence of tubal and intrauterine twins after natural conception was presented in the first time.

Background Many factors have been put forward as a driving mechanism of surgery-triggered adhesion formation (AF). In this study, we underline the key role of specific surgical trauma related with open surgery (OS) and laparoscopic (LS) conditions in postoperative AF and we aimed to study peritoneal tissue inflammatory reaction (TIR), remodelling specific complications of open surgery (OS) versus LS and subsequently evaluating AF induced by these conditions. Methods A prospective randomized study was done in 80 anaesthetised female Wistar rats divided equally into 2 groups. Specific traumatic OS conditions were induced by midline incision line (MIL) extension and tissue drying and specific LS conditions were remodelled by intraperitoneal CO2 insufflation at the 10 cm of water. TIR was evaluated at the 24th, 72nd, 120th and 168th hour by scoring scale. Statistical analysis was performed by the non-parametric t test and two-way ANOVA using Bonferroni post-tests. Results More pronounced residual TIR was registered after OS than after LS. There were no significant TIR interactions though highly significant differences were observed between the OS and LS groups (p < 0.0001) with regard to surgical and time factors. The TIR change differences between the OS and LS groups were pronounced with postoperative time p < 0.05 at the 24th and 72nd; p < 0.01 - 120th and p < 0.001 - 168th hrs. Adhesion free wounds were observed in 20.0 and 31.0% of cases after creation of OS and LS conditions respectively; with no significant differences between these values (p > 0.05). However larger adhesion size (41.67 ± 33.63) was observed after OS in comparison with LS (20.31 ± 16.38). The upper-lower 95% confidential limits ranged from 60.29 to 23.04 and from 29.04 to 11.59 respectively after OS and LS groups with significant differences (p = 0.03). Analogous changes were observed in adhesion severity values. Subsequently, severe TIR parameters were followed by larger sizes of severe postoperative adhesions in the OS group than those observed in the LS group. Conclusions MIL extension and tissue drying seem to be the key factors in the pathogenesis of adhesion formation, triggering severe inflammatory reactions of the peritoneal tissue surrounding the MIL resulting in local and systemic consequences. CO2 insufflation however, led to moderate inflammation and less adhesion formation.

Ectopic pregnancy represents a rare pregnancy complication. In the last 20 years, with the use of IVF, heterotopic pregnancies have become more frequent, while this percentage differs between IVF programs. Many factors contribute to this, like the active management of hydrosalpinx or treatment of Chlamydia infection before starting a cycle. Although, in vitro fertilization is an expensive treatment, ectopic complication adds to this cost. Not a lot of studies exist for ectopic pregnancy after IVF. Most of them are case reports. Not a standard way exists, for dealing with heterotopic pregnancies, even in the era of modern laparoscopy. Not a lot of research has been performed on molecules that involved. Studies have tried to associate certain techniques during IVF, with this entity, but with controversial results. There is no standard form for diagnosing, dealing and presenting heterotopic pregnancies. Most of them are diagnosed when ruptured. Because it is rare event, costeffectiveness studies could not be performed and this complication is added to the overall IVF. Knowledge, on this field, is taken from the management of ectopic pregnancies in the general population, even if these present at a lower percentage. The purpose of the study is to systematically evaluate studies on molecular aspects of ectopic pregnancy, the ART techniques that are associated with ectopic pregnancy, the diagnosis of this entity and finally present case reports of heterotopic pregnancies and their management. At the end, cost-effectiveness models from the general population will be presented in parallel with systematic examination of these studies. Finally, new research targets will be pointed.

Microarray technology is a promising method for investigating gynaecological benign pathology. This systematic review examined various parameters of the design of these studies, the methods used and the gene outcome in these diseases. Electronic searches were performed in Medline (up to April 2009). An overall representation of important genes for each disease detected was performed. The results showed genes were up-regulated or down-regulated. However, studies suffer from several flaws in their design, the sample size employed and the reporting method. In conclusion, a significant amount of work has been performed on benign gynaecological diseases using microarray technology. New trial designs need to be employed that incorporate microarray reporting standards. New research directions should evolve based on these results.

Human chorionic gonadotrophin (HCG) may substitute FSH to complete follicular growth in IVF cycles. This may be useful in the prevention of ovarian hyperstimulation syndrome. Relevant studies were identified on Medline. To evaluate outcomes, a meta-analysis of low-dose HCG-supplemented IVF cycles versus non-supplemented ones was performed with data from 435 patients undergoing IVF who were administered low-dose HCG in various agonist and antagonist protocols and from 597 conservatively treated patients who served, as control subjects. Using these published data, a decision analysis evaluated four different management strategies. Effectiveness and economic outcomes were assessed by FSH consumption, clinical pregnancy and incremental cost-effectiveness ratios. Clinical pregnancy and ovarian hyperstimulation were the main outcome measures. Nine trials published in 2002-2007 were included. From the prospective studies, in the gonadotrophin-releasing hormone antagonist group, a trend for significance in clinical pregnancy rate was evident (odds ratio [OR], 1.54; 95% confidence interval [CI], 0.98-2.42). Ovarian hyperstimulation was less significant in the antagonist low-dose HCG protocol compared with the non-supplemented agonist protocol (OR 0.30; 95% CI 0.09-0.96). Less FSH was consumed in the low-dose HCG group but this difference was not statistically significant. Low-dose HCG supplementation may improve pregnancy rates in antagonist protocols. Overall, low-dose HCG-supplemented protocols are a cost-effective strategy. Reprod Biomed Online

Objective To describe a case of cesarean scar pregnancy treated successfully by endoscopic technique and medical therapy. Design Case report. Setting State general hospital in a major city. Patient(s) A 32-year-old woman with two cesarean sections and a recent curettage presented with ectopic cesarean scar pregnancy. Intervention(s) Transvaginal ultrasound and hysteroscopy were used for diagnosis, and conservative therapy with methotrexate and hysteroscopy to treat the patient. Main Outcome Measure(s) Modified hysteroscopic technique and outcome. Result(s) Sonography and hysteroscopy revealed the presence of a gestational sac in the lower segment of the uterus in a patient with a cesarean section scar. She was successfully treated with systemic methotrexate and aspiration of the sac and local methotrexate injection under endoscopic control. Conclusion(s) Endoscopic intervention combined with medical treatment can result in a good therapeutic outcome with preservation of fertility in early ectopic cesarean scar pregnancy.