Transgenic mice overexpressing the LH receptor in the female reproductive system spontaneously develop endometrial tumour masses.

The receptor for the luteinizing hormone (LH-R) is aberrantly over expressed in cancers of the reproductive system. To uncover whether LH-R over expression has a causative role in cancer, we generated a transgenic (TG) mouse which overexpresses the human LH-R (hLH-R) in the female reproductive tract, under the control of the oviduct-specific glycoprotein (OGP) mouse promoter (mogp-1). The transgene was highly expressed in the uterus, ovary and liver, but only in the uterus morphological and molecular alterations (increased proliferation and trans-differentiation in the endometrial layer) were detected. A transcriptomic analysis on the uteri of young TG mice showed an up regulation of genes involved in cell cycle control and a down regulation of genes related to the immune system and the metabolism of xenobiotics. Aged TG females developed tumor masses in the uteri, which resembled an Endometrial Cancer (EC). Microarray and immunohistochemistry data indicated the deregulation of signaling pathways which are known to be altered in human ECs. The analysis of a cohort of 126 human ECs showed that LH-R overexpression is associated with early-stage tumors. Overall, our data led support to conclude that LH-R overexpression may directly contribute to trigger the neoplastic transformation of the endometrium.

Detection of PIK3CA E545A mutation in circulating tumor DNA of a patient affected by uterine carcinosarcoma.

Uterine carcinosarcomas are biphasic neoplasms consisting of mixed epithelial and mesenchymal elements, representing less than 5% of all uterine malignancies. Carcinosarcomas are rare, although the most common cause of uterine cancer-specific death. Few information is available on the pathogenesis, and molecular characterization is poorly investigated. Consequently, the treatment has not changed over the last years and is far too being tailored, consisting of surgery and traditional chemotherapy and radiotherapy. Molecular characterization of liquid biopsy by circulating tumor DNA (ctDNA)/circulating cell-free DNA (ccfDNA) evaluation in a patient with uterine carcinosarcoma. Here, we describe a case report of an 83-year-old woman with carcinosarcomas, stage T3aN0M0. Cancer cells did not express estrogen nor progesterone receptors, while p53 and p16 were positive. Molecular characterization of ccfDNA and of ctDNA was performed by quantitative PCR, amplification-refractory mutation system technology. The presence of phosphatidylInositol-4,5-bisphosphate 3-Kinase catalytic subunit alpha p.E545A mutation was detected in plasma. This approach may suggest the use of liquid biopsy and the development of specific targeted therapy for precision personalized medicine even in rare carcinosarcomas.

Mutational profile in circulating tumor DNA in a patient affected by low-risk endometrial cancer: predictable tool of relapse?

Endometrial cancer is the commonest gynecological cancer, the majority is endometrioid type, diagnosed at an early stage with 69-88% 5-year survival. Low-grade endometrial cancers have low recurrence rates and often do not receive adjuvant therapy; however, a subset of these patients will have poor outcomes and would benefit from adjuvant treatment has been challenging. We evaluate the circulating cell-free DNA (ccfDNA) in a patient with low-risk endometrial cancer in order to identify the presence of molecular markers associated with risk of recurrence. The evaluation of mutation profile was performed by next-generation sequencing (NGS) in primary tumor formalin-fixed paraffin-embedded (FFPE) tissue and in circulating tumor DNA (ctDNA). We identified a specific mutational profile in ctDNA, different from primary tumor tissue suggesting that the clone involved in the relapse may be different in comparison to the most represented in the primary tumor. These findings open new prospective and new wonderings. The molecular characterization of tissue may be useful for setting new target personalized therapy even in the treatment of endometrial cancer, moreover, endometrial cancer at low risk should be not underestimated for the incidence of relapse, and for this evaluation the molecular characterization may be useful. Moreover, these results suggest that the single analysis of primary tumors may be not sufficient for setting a specific personalized therapy targeted to avoid the relapse but may be necessary to join the molecular characterization of liquid biopsy to primary tissue.

Identification of a Gene Panel for Endometrioid Endometrial Cancer: a Possible Prognostic Value?

The incidence of endometrial cancer (EC) is increasing in developed countries. The most frequent is the endometrioid subtype with usually good prognosis; nevertheless, some cases escape this paradigm and may have recurrence. A recent study from The Cancer Genome Atlas suggested to implement the EC analysis by molecular profile for improving diagnosis, prognosis, and therapeutic treatment. The present preliminary study was performed on 15 G3 endometrioid endometrial cancers (G3 EEC) for the identification of somatic mutations in a panel of specific exons in selected genes as ARID1A, CTNNB1, KRAS, PIK3CA, POLE, PTEN, and TP53. The combined procedure, based on the Sanger sequencing and PCR-high-resolution melting analysis, allowed the identification of variations of the selected gene panel in most of patients (93%) of our cohort. The overall evaluation of mutational load exhibited that the most frequent mutated genes were PTEN (93%), followed by PIK3CA (47%) suggesting a deep involvement of PI3K pathway alteration in G3 EEC. Mutations in TP53 (27%), ARID1A (27%), POLE (13%), and at the lower level in KRAS and CTNNB1 (7%) were also observed (exclusively in FIGO III stage patients). The evaluation of the mutations of our proposed panel (ARID1A, CTNNB1, KRAS, PIK3CA, POLE, PTEN, TP53) is suitable to improve the characterization of G3 EEC and could suggest targetable pathways for development of personalized treatments.

Pilot investigation of the mutation profile of PIK3CA/PTEN genes (PI3K pathway) in grade 3 endometrial cancer.

Endometrial cancer (EC) comprises a biological and clinical heterogeneous group of tumors. Several genetic alterations are involved in the development and progression of EC, and may be used for targeted therapy, particularly in patients with advanced­stage EC. In the present study, a combined procedure was developed based on polymerase chain reaction (PCR)­high resolution melting analysis (HRMA) and Sanger sequencing for the evaluation of somatic mutations in selected phosphoinositide 3­kinase (PI3K) catalytic subunit α (PIK3CA; exons 1, 9 and 21) and phosphatase and tensin homolog (PTEN; exons 5, 6, 7 and 8) exons. This combined procedure has the specificity and sensitivity of the two techniques, and overcomes their limitations. A pilot study was performed on 18 selected homogenous EC samples, of grade 3 endometrioid subtype (G3 EEC). First, the feasibility of the combined procedure was investigated to properly identify the presence of somatic mutations on PIK3CA and PTEN, the variations identified were analyzed using Catalogue of Somatic Mutations in Cancer, PolyPhen­2 and Mutation Taster software, and the frequency of mutations/variations was determined in the selected samples. The evaluation of mutational load revealed that the majority of the G3 EEC samples exhibited PIK3CA mutations (39%) and PTEN mutations (67%), and the majority of the samples (83%) had mutations in at least one of the two genes, and 33% had mutations in the two genes. The results of the present pilot study suggested that the cost­effective combined PCR­HRMA and Sanger sequencing procedure may be suitable for identification of PTEN and PIK3CA mutations in G3 EEC and that their frequency was consistent in G3 EEC, indicating that the PI3K pathway serves a pivotal function that may have potential for defining targeted therapy for the treatment of G3 EEC.

Spontaneous Resolution of an Acquired Uterine Arteriovenous Malformation in an Elderly Primigravida.

BACKGROUND Uterine arteriovenous malformation (AVM) is an uncommon lesion characterized by an abnormal connection between arterial and venous circulation that can be congenital or acquired. Acquired uterine AVMs are generally traumatic and follow delivery, abortion, curettage, or uterine surgery. CASE REPORT A 45-year-old female who was gravida 1 para 0 presented to our hospital with severe vaginal bleeding. Two weeks before, the patient underwent therapeutic abortion. At admission, a transvaginal ultrasound showed an unclear intrauterine lesion that spread out to the myometrium. Color Doppler evaluation demonstrated an elevated color score. Beta human chorionic gonadotropin (beta-hCG) levels were measured at admission and daily repeated, with a progressive decrease of values up to a negative level. A pelvic magnetic resonance imaging described an area of tubular and tortuous structures involving the myometrium. A computed tomography angiography confirmed the presence of a lesion infiltrating the endometrium and myometrium containing arteriovenous structures with a highly enhanced effect. Despite these findings, the patient was clinically stable. A diagnosis of uterine AVM was made and, after accurate counselling with the patient, she was discharged and underwent "watch and wait" management. After 35 days, the patient had a follow-up ultrasound that showed a complete resolution of the uterine lesion. CONCLUSIONS AVM should be considered in the presence of heavy and sudden vaginal bleeding in a patient with risk factors for acquired AVM. A color Doppler ultrasound scan should be performed as the first approach and an expectant management should be taken into account especially with a patient of childbearing age and hemodynamic instability.

Luteinizing Hormone/Human Chorionic Gonadotropin Receptor Immunohistochemical Score Associated with Poor Prognosis in Endometrial Cancer Patients.

The aim of this study was to develop a scoring system of the immunohistochemical (IHC) expression of luteinizing hormone/human chorionic gonadotropin receptor (LHCG-R) in endometrial cancer (EC) patients. Nonconsecutive hysterectomy specimens containing EC collected from April 2013 to October 2015 were selected. Hematoxylin-eosin stained sections from each case were reviewed and representative sections from each tumor were selected. IHC staining was performed for the detection of LHCG-R. The percentage of stained cells and the staining intensity were assessed in order to develop an immunohistochemical score. Moreover, we examined the correlation of the score with grading and lymphovascular space invasion (LVSI). There was a statistically significant positive correlation between grading and IHC scoring (p = 0.01) and a statistically significant positive correlation between LVSI and IHC score (p < 0.01). In conclusion, we suggest that the immunohistochemical score presented here could be used as a marker of bad prognosis of EC patients. Nevertheless, further studies are needed in order to validate it. The study was registered in the Careggi Hospital public trials registry with the following number: 2013/0011391.

From pathogenesis to clinical practice: Emerging medical treatments for endometriosis.

Endometriosis is a chronic disease, and a lifelong management plan should be developed by using pharmacological treatment and surgical procedures. The pathogenesis of endometriosis is complicated and has not been definitively established. The mechanisms involved are numerous, and their understanding is constantly evolving. Currently, the first-line drugs act by blocking ovarian function, creating an hypoestrogenic environment. The blockade of estrogen secretion and receptor activity and the activation of progesteron receptors are the main target of several current drugs, as well as those under development. The oral GnRH antogonists, the aromatase inhibitors, SERMs, and SPRMs are the hormonal drugs currently studied for treating endometriosis. The increasing knowledge of the pathogenesis has allowed the development of new treatments. The most studied are the anti-inflammatory drugs, starting from the new NSAIDs to the monoclonal antibodies and the statins. Among the antiangiogenic compounds, a role is suggested for Icon, PPARs, and HDACIs. A new class of drugs is the cannabinoids. The aim of this review was to investigate the new therapeutic hormonal and non-hormonal alternatives to standard treatments.

Severe Fetal Distress and Placental Damage might be Associated with High Troponin I (cTnI) Levels in Mothers.

BACKGROUND Troponin I is the gold standard for the diagnosis of adult acute coronary syndrome. Although it is known that a hypoxic fetus may produce cTnI, fetal cTnI passage in maternal blood has never been documented. CASE REPORT We report a case where the rise of cTnI in the blood of a pregnant woman was not related to maternal heart disease. Instead, it might be suggestive of a fetal cardiac origin, as there was a severe placental insufficiency with a fetal intrauterine growth restriction. CONCLUSIONS This study suggests that the rise of cTnI in maternal blood in a cardiovascular healthy pregnant woman might have a fetal origin. After having excluded any maternal causes, cTnI elevation could be explained with the transfer of fetal cTnI through an injured placenta.

New adverse obstetrics outcomes associated with endometriosis: a retrospective cohort study.

PURPOSE: The main aim of this study was to evaluate the incidence of endometriosis and intrahepatic cholestasis (ICP) and induction of labor in pregnant women with endometriosis compared with women without endometriosis. The secondary aim was to confirm increased incidence of already known endometriosis-related pregnancy complications in these patients. METHODS: This is a retrospective cohort study performed at a tertiary hospital between January 2009 and December 2014 to compare obstetrics outcome between women with endometriosis and women without endometriosis. Pregnant patients with endometriosis were included in the study group. Patients were divided in the following subgroups: patients with deep infiltrating endometriosis (DIE subgroup) and patients without deep infiltrating endometriosis (non-DIE subgroup); patients with singleton pregnancy and spontaneous conception (subgroup A) and patients with multiple pregnancy and/or patients who underwent assisted reproductive technology (subgroup B). To form a control group, for each patient with endometriosis, two patients without endometriosis were selected as the control group by means of matched sample. RESULTS: The study population included 262 pregnant women with endometriosis and 524 controls. Patients of the study population had significantly increased risks of placenta praevia (p < 0.05), ICP (p < 0.01), induction of labor (p < 0.01) and preterm birth (p < 0.01). DIE patients had a significantly higher percentage only of preterm birth (p < 0.01), while in non-DIE group all complications had a higher incidence except for placenta praevia, which did not differ with control. Subgroup A had a statistically higher incidence of placenta praevia (p < 0.01), ICP (p < 0.01), induction of labor (p < 0.01) and preterm birth (p < 0.01) compared to its control subgroup. There was no difference in distribution of pregnancy complications between subgroup B and control subgroup. CONCLUSIONS: Our results showed for the first time that women with endometriosis are at higher risk of developing ICP and experiencing an induced labor. Further studies are warranted to clarify whether the history of endometriosis might be taken into account in the antenatal care of these patients.

Spontaneous Unscarred Uterine Rupture at 15 Weeks of Pregnancy: A Case Report.

BACKGROUND: Uterine rupture during pregnancy is a serious obstetric complication. The presence of a previous uterine scar is the most important risk factor, whereas rupture in an unscarred uterus is a rare event. CASE REPORT: A 34-year-old woman, gravida 3 para 1, presented with sudden acute hypogastric pain at 15 weeks of gestation. The patient had no history of cesarean delivery. Ultrasound scans showed an empty endometrial cavity continuing directly into the amniotic sac that developed mainly outside the uterus. Because of the ultrasound findings and the patient's progressive anemia, a laparoscopy was performed that revealed a massive hemoperitoneum caused by the rupture of the uterine fundus with exteriorization of most of the amniotic sac. Laparoscopy was converted to laparotomy, the pregnancy was removed, and the uterine disruption was repaired. CONCLUSION: Early diagnosis and prompt treatment of uterine rupture may significantly improve prognosis. This severe obstetric complication should be considered even in early gestational age pregnancies and in the absence of known risk factors.

LH/hCG-Receptor Expression May Have a Negative Prognostic Value in Low-Risk Endometrial Cancer.

INTRODUCTION: A 51 year-old woman was diagnosed with endometrial cancer (EC) and underwent surgical staging. Pathological evaluation showed a 2 cm × 1 cm G2 endometrioid EC with a 30% myometrial deep invasion (FIGO Stage 1A). The patient was classified as low risk of recurrence, and no adjuvant treatment was offered. Six months after surgery, the patient developed an early vescico-vaginal recurrence, and chemotherapy treatment was started. Few months later, a subsequent involvement of vaginal wall, ileum, and omentum was detected, and the patient underwent second surgery. BACKGROUND: LH/hCG-receptor (LH/hCG-R) expression has been previously reported to be associated with an invasive phenotype in EC cells. Moreover, in a preclinical mouse model of EC behaves as a prometastatic molecular device. DISCUSSION: We analyzed the expression level of LH/hCG-R in cancer specimens collected during surgeries. Molecular and immunohistochemical analyses showed a strong expression of both mRNA and protein for LH/hCG-R in all specimens. CONCLUSION: LH/hCG-R expression may be assessed together with other clinicopathological parameters in order to better predict the risk of recurrence in low-risk EC patients. Further clinical trials are warranted in order to validate LH/hCG-R as biomarker in EC.

Differences in psychophysical well-being and signs of depression in couples undergoing their first consultation for assisted reproduction technology (ART): an Italian pilot study.

OBJECTIVE: The data we refer to belong to a longitudinal research project starting at the first contact of individual couples with the Infertility Unity; they were then followed-up till pregnancy or failure of treatments. The study aims at investigating in depth the emotional state of patients admitted for first consultation. Specifically, we investigated the emotional state of the two members of an infertile couple, considering also their biomedical and socio-demographic characteristics. STUDY DESIGN: This is a cross-sectional study evaluating a consecutive series of 309 couples, consulting for the first time our Infertility Unit for a multidisciplinary diagnostic evaluation in relation to their infertility. The multidisciplinary equip is composed of a gynaecologist, an andrologist and a clinical psychologist. Two standardized instruments were administered by the clinical psychologist to the two members of the couple: the Edinburgh Depression Scale (EDS) and the General Health Questionnaire-form 12 (GHQ-12), for screening of non-somatic signs of depression and psychophysical well-being, respectively. Couples were eligible for the study if they had not received any prior ART treatment in our Unit and were able to read and understand Italian. In addition, they had to agree to provide informed consent for the study. RESULTS: We obtained a response in 62% of all eligible couples. There were two major unexpected findings: CONCLUSION: Psychological and counselling services dedicated to ART should consider also socio-demographic data and always specifically consider gender differences, not only a couple's psychology and its dynamics.

DNA fragmentation in brighter sperm predicts male fertility independently from age and semen parameters.

OBJECTIVE: To evaluate whether sperm DNA fragmentation (sDF), measured in brighter, dimmer, and total populations, predicts natural conception, and to evaluate the intra-individual variability of sDF. DESIGN: Prospective study. SETTING: Outpatient clinic and diagnostic laboratory. PATIENT(S): A total of 348 unselected patients and 86 proven fertile men. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): sDF was revealed with the use of terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL)/propidium iodide (PI). Receiver operating characteristic (ROC) curves were built before and after matching fertile men to patients for age (76:152) or semen parameters (68:136) or both (49:98). Intra-individual variability of sDF was assessed over 2 years. RESULT(S): Brighter (area under ROC curve [AUC] 0.718 ± 0.54), dimmer (AUC 0.655 ± 0.63), and total (AUC 0.757 ± 0.54) sDF predict male fertility in unmatched and age- or semen parameters-matched subjects. After matching for both age and semen parameters, only brighter (AUC 0.711 ± 0.83) and total (AUC 0.675 ± 0.92) sDF predict male fertility. At high values of total sDF, brighter predicts natural conception better than total sDF. Intra-individual coefficients of variation of sDF were 9.2 ± 8.6% (n = 25), 12.9 ± 12.7% (n = 53), and 14.0 ± 12.6% (n = 70) over, respectively, 100-day and 1- and 2-year periods, appearing to be the most stable of the evaluated semen parameters. CONCLUSION(S): The predictive power of total sDF partially depends on age and semen parameters, whereas brighter sDF independently predicts natural conception. Therefore, brighter sDF is a fraction of sDF that adds new information to the routine semen analysis. At high levels of sDF, distinguishing the two sperm populations improves the predictive power of sDF. Overall, our results support the idea that TUNEL/PI can be of clinical usefulness in the male fertility workup.

Hatha-yoga as a psychological adjuvant for women undergoing IVF: a pilot study.

OBJECTIVES: To evaluate the influence of Hatha-yoga (HY) practice on distress of women before starting their first in vitro fertilization (IVF) cycle. STUDY DESIGN: We offered 143 consecutive women with couple infertility the opportunity to attend a free HY course lasting 3 months as a psychological support before starting their first IVF cycle. All women were asked to complete the State-Trait Anxiety Inventory-Y1 (STAY-Y1), Edinburgh Depression Scale (EDS) and General Health Questionnaire-12 (GHQ-12) at baseline (T1) and after 3 months (T2), to evaluate symptoms of anxiety, depression and distress, respectively. RESULTS: Of the 143 women, 120 completed all three questionnaires. Of these, 45 attended the HY course and 75 did not. At T1, EDS and GHQ-12 scores were significantly higher in the HY group than in the non-HY group. There were no group differences in STAI-Y1 scores. At T2 there were no group differences. When, in each group, the score of each questionnaire at T1 was compared to the score at T2, a significant T1 to T2 reduction was observed in the HY group (p<0.0001 for STAY-Y1 and GHQ-12, p<0.001 for EDS). CONCLUSIONS: Our data suggest that women who are more distressed are more likely to accept psychological support before starting an IVF cycle and that in these women HY practice is associated with distress reduction.

Is tissue factor pathway inhibitor a marker of procoagulable status in healthy infertile women undergoing ovarian stimulation for assisted reproduction?

Increased serum estradiol levels occurred during ovarian stimulation for assisted reproduction. Tissue factor pathway inhibitor (TFPI) plays a relevant role in regulating haemostatic equilibrium, and its decrease has been documented in conditions in which blood coagulation occurs. We investigated TFPI concentrations and coagulative pathway in healthy infertile women undergoing ovarian stimulation. We investigated 27 healthy infertile women, median age 37 (25-41) years, undergoing ovarian stimulation, observed during the mid-luteal phase of cycle (T0) and on day 5 (T1), and between day 7 and 9 (T2) of ovarian stimulation. Coagulative pathway was assessed by a global test [endogenous thrombin potential, (ETP)] and TFPI concentrations. TFPI values progressively and significantly decreased throughout the ovarian stimulation procedure (P = 0.03), contemporarily estradiol levels progressively and significantly increased from baseline to T2 (P < 0.0001). A significant negative correlation between changes in estradiol and TFPI levels was observed (P = 0.03). As concerns ETP parameters a significant increase of ETP (mA) and Cmax (mA/min) throughout the ovarian stimulation cycle was found (P = 0.003 and P = 0.002, respectively). TFPI values progressively and significantly decreased throughout the ovarian stimulation, and negatively correlated with estradiol, thus suggesting that TFPI may represent one of the main 'actors' involved in the hypercoagulable status, occurring during assisted reproduction. The relationship between TFPI and estradiol levels might contribute to the knowledge of mechanisms able to modify a quite milieu into a prothrombotic status. Nevertheless, the small number of individuals investigated might influence the relevance of our results.

Over-Expression of the LH Receptor Increases Distant Metastases in an Endometrial Cancer Mouse Model.

OBJECTIVE: The aim of the present study was to define the role of luteinizing hormone receptor (LH-R) expression in endometrial cancer (EC), using preclinical mouse models, to further transfer these data to the clinical setting. MATERIALS AND METHODS: The role of LH-R over-expression was studied using EC cells (Hec1A, e.g., cells with low endogenous LH-R expression) transfected with the LH-R (Hec1A-LH-R). In vitro cell proliferation was measured through the WST-1 assay, whereas cell invasion was measured trough the matrigel assay. The effects of LH-R over-expression in vivo were analyzed in an appropriately developed preclinical mouse model of EC, which mimicked postmenopausal conditions. The model consisted in an orthotopic xenograft of Hec1A cells into immunodeficient mice treated daily with recombinant LH, to assure high levels of LH. RESULTS: In vitro data indicated that LH-R over-expression increased Hec1A invasiveness. In vivo results showed that tumors arising from Hec1A-LH-R cells injection displayed a higher local invasion and a higher number of distant metastases, mainly in the lung, compared to tumors obtained from the injection of Hec1A cells. LH withdrawal strongly inhibited local and distant metastatic spread of tumors, especially those arising from Hec1A-LH-R cells. CONCLUSION: The over-expression of the LH-R increases the ability of EC cells to undergo local invasion and metastatic spread. This occurs in the presence of high LH serum concentrations.

Fibrinolysis alterations in infertile women during controlled ovarian stimulation: influence of BMI and genetic components.

INTRODUCTION: Ovarian stimulation protocols have been described to induce prothrombotic phenotype through alterations of both coagulation and fibrinolysis pathways. We investigated fibrinolytic changes during ovarian stimulation through a global test (CLT) and PAI-1 and TAFI concentrations at different times of ovarian stimulation procedure, and the influence of polymorphisms in genes encoding for fibrinogen chains (FGA, FGB, FGG), t-PA (PLAT), TAFI (CBP2), FXIII (FXIIA1, FXIIIB), plasminogen (PLG) and PAI-1 (PAI1) on their intermediate phenotype. MATERIALS AND METHODS: We evaluated fibrinolytic and genetic parameters in 110 infertile women undergoing ovarian stimulation procedure (in vitro fertilization, IVF or intracytoplasmic sperm injection, ICSI). All women were observed during the mid-luteal phase of cycle (T(0)) and on day 5 (T(1)), 7 (T(2)) and 9 (T(3)) of the ovarian stimulation. RESULTS: Significant changes in fibrinolytic parameters from T(0) to T(3) of ovarian stimulation were found (CLT p=0.003; TAFI p=0.009 and PAI-1 p=0.003). CLT values, TAFI and PAI-1 concentrations significantly increased from baseline to T(1) (p<0.0001, p=0.01, p=0.005, respectively)(,) and decreased at T(2,) but remained higher than those at T(0). Moreover, at baseline overweight women showed longer CLT, higher TAFI and PAI-1 concentrations than normal weight women, as well as at T(1) two-fold longer CLT and higher PAI-1 concentrations were observed (p=0.001 and p=0.05, respectively). Significant differences of TAFI and PAI-1 concentrations during ovarian stimulation according to TAFI and PAI1 polymorphisms were observed. CONCLUSIONS: This study shows alterations of fibrinolysis and suggests the contribution of TAFI and PAI1 genes in modulating fibrinolysis changes during the ovarian stimulation cycle.

Unexplained infertility: association with inherited thrombophilia.

INTRODUCTION: Unexplained infertility represents one of the most common diagnoses in fertility care. Attention is being paid to the association between inherited thrombophilia and infertility causes. In this study we investigated the prevalence of inherited thrombophilia according to infertility causes. MATERIALS AND METHODS: We studied Prothrombin gene G20210A mutation, Factor V Leiden, deficiencies in protein S and C and antithrombin in 930 Caucasian infertile women referred to Fertility Center of the Department of Sciences for Woman and Child's Health, University of Florence, of whom 230 with unexplained, 195 female and 283 male infertility, and in 240 women who have conceived naturally without hormonal stimulation therapy. RESULTS: A significant relationship between inherited thrombophilia [OR 95%CI 1.97 (1.05-3.68), p = 0.03] and unexplained infertility was observed, whereas no association between thrombophilia and female and male infertility was found. Significantly higher prevalence of prothrombin gene mutation in unexplained infertile women in comparison to that observed in fertile women was observed (5.7% vs 2.1% p = 0.04); the prevalence of the other thrombophilia determinants was higher, even if not significantly, in the unexplained infertile group. CONCLUSIONS: This study demonstrates the relationship between inherited thrombophilia and unexplained infertility, thus suggesting the contribution of genetic components in modulating unexplained infertility, behind anovulation, male and tubal factor.

Effect of dalteparin sodium administration on IVF outcome in non-thrombophilic young women: a pilot study.

This study evaluated whether heparin administration could affect IVF outcome. A total of 172 women, aged <40years, without laboratory findings of thrombophilia and undergoing their first IVF cycle, were randomly allocated to treatment (n=86) and control (n=86) groups. Patients allocated to the treatment group received low-molecular-weight heparin dalteparin sodium 2500IU s.c. daily, in addition to routine luteal phase support, from oocyte retrieval up to the day of the pregnancy test or up to the ninth week of pregnancy in the cases of positive human chorionic gonadotrophin. From the day after the oocyte retrieval, all patients began standard supplementation with vaginal progesterone 200mg twice a day. At the sixth week of pregnancy, patients underwent an ultrasound scan to assess the number/viability of gestational sacs. Implantation rates were 15% and 12% in the dalteparin and control groups, respectively. The clinical pregnancy rates/embryo transfers were 26% (19/73) and 20% (16/80), in the dalteparin and control groups, respectively, with live birth rates/embryo transfer of 21% (15/73) and 16% (13/80). Despite the lack of statistical significance, the increase in pregnancies observed in the treatment group may be considered as an important clinical point in the optimization of IVF clinical outcome.