HHV-6A Infection of Endometrial Epithelial Cells Induces Increased Endometrial NK Cell-Mediated Cytotoxicity.

Background: We have recently reported the presence of Human herpesvirus-6A (HHV-6A) DNA in the 43% of endometrial epithelial cells from primary idiopathic infertile women, with no positivity in fertile women. To investigate the possible effect of HHV-6A infection in endometrial (e)NK cells functions, we examined activating/inhibitory receptors expressed by eNK cells and the corresponding ligands on endometrial cells during HHV-6A infection. Methods: Endometrial biopsies and uterine flushing samples during the secretory phase were obtained from 20 idiopathic infertile women and twenty fertile women. HHV-6A infection of endometrial epithelial cells was analyzed by Real-Time PCR, immunofluorescence and flow cytometry. eNKs receptors and endometrial ligands expression were evaluated by immunofluorescence and flow cytometry. Results: We observed the presence of HHV-6A infection (DNA, protein) of endometrial epithelial cells in the 40% of idiopathic infertile women. The eNK from all the subgroups expressed high levels of NKG2D and NKG2A receptors. Functional studies showed that NKG2D activating receptor and FasL are involved in the acquired cytotoxic function of eNK cells during HHV-6A infection of endometrial epithelial cells. In the presence of HHV-6A infection, eNK cells increased expression of CCR2, CXCR3 and CX3CR1 chemokine receptors (p = 0.01) and endometrial epithelial cells up-modulated the corresponding ligands: MCP1 (Monocyte chemotactic protein 1, CCL2), IP-10 (Interferon gamma-induced protein 10, CXCL10) and Eotaxin-3 (CCL26). Conclusion: Our results, for the first time, showed the implication of eNK cells in controlling HHV-6A endometrial infection and clarify the mechanisms that might be implicated in female idiopathic infertility.

Presence of HHV-6A in Endometrial Epithelial Cells from Women with Primary Unexplained Infertility.

To elucidate the roles of human herpesvirus (HHV)-6 primary unexplained infertile women, a prospective randomized study was conducted on a cohort of primary unexplained infertile women and a cohort of control women, with at least one successful pregnancy. HHV-6 DNA was analyzed and the percentage and immune-phenotype of resident endometrial Natural Killer (NK) cells, as the first line of defense towards viral infections, was evaluated in endometrial biopsies. Cytokine levels in uterine flushing samples were analyzed. HHV-6A DNA was found in 43% of endometrial biopsies from primary unexplained infertile women, but not in control women. On the contrary, HHV-6B DNA was absent in endometrial biopsies, but present in PBMCs of both cohorts. Endometrial NK cells presented a different distribution in infertile women with HHV6-A infection compared with infertile women without HHV6-A infection. Notably, we observed a lower percentage of endometrial specific CD56brightCD16- NK cells. We observed an enhanced HHV-6A-specific endometrial NK cell response in HHV-6A positive infertile women, with a marked increase in the number of endometrial NK cells activating towards HHV-6A infected cells. The analysis of uterine flushing samples showed an increase in IL-10 levels and a decrease of IFN-gamma concentrations in infertile women with HHV6-A infection. Our study indicates, for the first time, that HHV-6A infection might be an important factor in female unexplained infertility development, with a possible role in modifying endometrial NK cells immune profile and ability to sustain a successful pregnancy.

Impact of soluble HLA-G levels and endometrial NK cells in uterine flushing samples from primary and secondary unexplained infertile women.

The aim of this research was to determine the levels of human leukocyte antigen G (HLA-G) and endometrial Natural Killer ((e)NK) cell percentages in uterine flushing samples from primary and secondary infertile women. sHLA-G levels were lower in the uterine flushing samples from primary infertile women in comparison with women with secondary infertility. Lower CD56+KIR2DL4+ (e)NK cell percentages were detected in primary infertile women compared with secondary infertile women. This is the first study demonstrating that primary and secondary unexplained infertilities are characterized by different basal sHLA-G levels and CD56+KIR2DL4+ (e)NK cell percentages.

Hysterosalpingo contrast sonography (HyCoSy): let's make the point!

INTRODUCTION: The accurate evaluation of tubal patency as well of the morphologic characteristics of the uterine cavity is a fundamental step in the diagnostic work-up for infertility. Hysteroscopy and laparoscopy and dye have long been regarded as the reference methods to assess uterine morphology and tubal patency, respectively. However, their technical and clinical limitations have supported the introduction of an emerging technique: hysterosalpingo contrast sonography (HyCoSy), which has recently been improved with the use of modern contrast agents and three-dimensional resolution. METHODS: A systematic literature search was performed in electronic databases (PubMed and Scopus). Key search terms included Hysterosalpingo contrast sonography (HyCoSy), Tubal patency, Infertility, Uterine cavity, Ultrasounds. RESULTS: HyCoSy has proved to be as reliable as laparoscopic techniques in the assessment of tubal patency and uterine morphology, and also it overcomes such major drawbacks as hospitalization, radiation exposure, anesthesia and use of iodinated contrast media. All in all, HyCoSy is considered as a safe and well tolerated outpatient procedure, which apparently favors the onset of spontaneous pregnancies. CONCLUSION: This paper provides a comprehensive overview of the literature dealing with HyCoSy to support its use as a first-line technique in standard infertility work-up.

Laparoscopic supracervical hysterectomy with transcervical morcellation: our experience.

STUDY OBJECTIVE: To present our experience with laparoscopic supracervical hysterectomy with transcervical morcellation (LSH-TM). DESIGN: A retrospective observational study (Canadian Task Force Classification III). SETTING: Gynecologic Department at Brunico Hospital, Brunico, Italy. PATIENTS: Three hundred sixty-five patients affected by gynecologic benign diseases who underwent LSH-TM. INTERVENTIONS: A minimally invasive surgical technique for supracervical hysterectomy that involves extraction of the morcellated uterus through the cervical canal. MEASUREMENTS AND MAIN RESULTS: We performed LSH-TM successfully in 365 patients; the mean (standard deviation) operating time was 72.24 (23.21) minutes. We registered no intraoperative complications. The main postoperative complications resulted in 2 cases of second-look laparoscopy because of internal bleeding, 5 cases of asymptomatic hematoma around the cervical stump, and 7 cases of pelvic pain. CONCLUSION: Our experience shows that LSH-TM is a safe and easy to perform technique and that it ensures minimal blood loss.

Women taking the "blue pill" (sildenafil citrate): such a big deal?

For years, phosphodiesterase type 5 inhibitors have been used for the treatment of erectile dysfunctions. Due to the similarities between male and female sexual response, several studies have assessed the effects of sildenafil citrate (Viagra(®)) in women affected by female sexual arousal disorder. The results are still conflicting and the drug is not devoid of adverse effects. Furthermore, female sexual arousal disorder is a heterogeneous condition whose underlying causes are difficult to diagnose and appropriate treatment requires a thorough sexual, psychological, and medical history along with specialist consultations. The clinician should pursue a global approach to the patient with sexual difficulties, while non-hormonal treatment such as phosphodiesterase type 5 inhibitors (ie, sildenafil citrate) should be kept as the last option.

Role of imaging in endometriosis.

Endometriosis--the presence of endometrial tissue outside the uterine cavity--is first suspected on the basis of its signs and symptoms. The diagnosis is confirmed by imaging and surgery. Imaging, particularly transvaginal ultrasonography and magnetic resonance imaging, is essential to confirm the diagnosis and guide surgical treatment.

A literature review on the relationship between infertility and sexual dysfunction: does fun end with baby making?

OBJECTIVE: To analyse the relationship between infertility and sexuality, and the effect of assisted reproductive technology (ART) on a couple's sexual relationship. METHOD: The literature review is a result of a search that was undertaken with the keywords 'infertility' and 'sexuality' in PubMed from 2000 until 2013. RESULTS: Even though abstinence or inadequate sexual activity are often reported in infertile couples, sexual disorders rarely cause infertility. They usually arise, instead, as a result of involuntary childlessness and assisted reproduction. Qualitative studies provide a detailed description of the impact of infertility and its treatment on the couples' sexual relationship, along with its specific gender effects, yet it is difficult to set standardised parameters to quantify sexual strain and the reliability of the studies available is limited by major drawbacks. CONCLUSIONS: Appropriate measures should be designed to identify sexual disorders in infertile couples, and the medical team should be trained to deal systematically with the couple's sexuality and propose strategies to overcome sexual disturbances. This approach could preserve the quality of the couple's sexual relationship and maximise pregnancy chances in ART.

Ulipristal acetate: a novel pharmacological approach for the treatment of uterine fibroids.

Uterine fibroids are the most common benign tumors of the female genital tract. The management of symptomatic fibroids has traditionally been surgical; however, alternative pharmacological approaches have been proposed to control symptoms. To date, gonadotropin-releasing hormone analogs are the only available drugs for the preoperative treatment of fibroids. However, the US Food and Drug Administration recently authorized ulipristal acetate (UPA), an oral selective progesterone-receptor modulator, for the same indication. UPA is a new, effective, and well-tolerated option for the preoperative treatment of moderate and severe symptoms of uterine fibroids in women of reproductive age. According to clinical data, UPA shows several advantages: it is faster than leuprolide in reducing the fibroid-associated bleeding, it significantly improves hemoglobin and hematocrit levels in anemic patients, and it grants a significant reduction in the size of fibroids, which lasts for at least 6 months after the end of the treatment. Furthermore, UPA displays a better tolerability profile when compared to leuprolide; in fact, it keeps estradiol levels at mid follicular phase range, thereby reducing the incidence of hot flushes and exerting no impact on bone turnover. On the grounds of this evidence, the administration of 5 mg/day ulipristal acetate for 3 months is suggested for different patient categories and allows for planning a treatment strategy tailored to meet an individual patient's needs.

Herpes Gestationis after Ovodonation: Is Placenta the only Target of the Immune Reaction?

Herpes Gestationis (HG) is an autoimmune disorder that rarely complicates pregnancy. Its pathogenesis has not been clarified yet, as it derives from a complex interplay between immunologic, genetic, and hormonal factors. We present a case of HG occurring in a surrogate mother whose pregnancy was achieved via egg donation and in vitro fertilisation (IVF). The disease appeared at 26 weeks and 6 days of gestation and subsequently worsened despite the administration of oral and topic corticosteroids. A healthy baby was delivered at 35 weeks and 2 days of gestation by elective cesarean section and the clinical manifestations resolved in the postpartum period.

Hysterosalpingocontrast sonography (HyCoSy): evaluation of the pain perception, side effects and complications.

BACKGROUND: Tubal and uterine cavity diseases commonly compromise female fertility. At the present time, hysteroscopy, laparoscopy with chromopertubation and RX-Hysterosalpingography (RX-HSG) are widely accepted screening procedures enabling the effective assessment of both tubal patency and uterine cavity. Nevertheless, consistent evidence supports the reliability of Hysterosalpingocontrast sonography (HyCoSy) in uterine cavity and tubal patency investigation, as a part of the standard infertility work-up. This prospective study was aimed at evaluating the tolerability of the technique as well as the incidence of related side effects and complications in a large series of infertile patients. METHODS: Pain perception of 632 infertile women was measured by means of an 11-point numeric rating scale. Side effects and late complications were also recorded. RESULTS: The mean numeric rating scale was 2.15 ± 2.0 SD. Most of the patients (374/632, 59.17%) rated HyCoSy as a non-painful procedure, whereas 24.36% (154/632) women reported mild pelvic pain and 9.96% (63/632) classified the discomfort as "moderate". Only 6.48% (41/632) of the patient population experienced severe pelvic pain. Fifteen (2.37%) patients required drug administration for pain relief. Twenty-six patients (4.11%) showed mild vaso-vagal reactions that resolved without atropine administration. No severe vaso-vagal reactions or late complications were observed. CONCLUSIONS: HyCoSy is a well-tolerated examination and the associated vagal effects are unusual and generally mild. Consequently, we support its introduction as a first-line procedure for tubal patency and uterine cavity investigation in infertile women.

Focus on intracytoplasmic morphologically selected sperm injection (IMSI): a mini-review.

Intracytoplasmic sperm injection (ICSI) is the recommended treatment in many cases of male-factor infertility. Several studies have demonstrated a positive correlation between optimal sperm morphology and positive ICSI outcomes. In fact, spermatozoa with severe abnormalities of the head are well documented to be associated with low fertilisation, implantation and pregnancy rates. However, a spermatozoon which is classified as 'normal' by microscopic observation at low magnification could contain ultrastructural defects that impair both the fertilisation process and embryonic development. The intracytoplasmic morphologically selected sperm injection (IMSI) procedure changed the perception of how a spermatozoon suitable for injection should appear. Sperm selection is carried out at ×6000 magnification, allowing improved assessment of the sperm nucleus. Currently, standardized clinical indications for IMSI are lacking and the candidates are selected on the grounds of their medical history or of a careful analysis of the sperm suspension. Further prospective randomized studies are needed to confirm the advantages of IMSI in specific groups of patients. In addition to providing a brief overview of the IMSI procedure, this study aims to review the literature, which explains the theoretical basis and the clinical outcomes of this technique. Several reports show that IMSI is associated with improved implantation and clinical pregnancy rates as well as lower abortion rates when compared to ICSI. Although a possible correlation between the sperm's abnormal nucleus shape, increased DNA fragmentation and negative laboratory and clinical outcomes has been long investigated, the results are conflicting.

Correlation of endocrine disrupting chemicals serum levels and white blood cells gene expression of nuclear receptors in a population of infertile women.

Significant evidence supports that many endocrine disrupting chemicals could affect female reproductive health. Aim of this study was to compare the internal exposure to bisphenol A (BPA), perfluorooctane sulphonate (PFOS), perfluorooctanoic acid (PFOA), monoethylhexyl phthalate (MEHP), and di(2-ethylhexyl) phthalate (DEHP) in serum samples of 111 infertile women and 44 fertile women. Levels of gene expression of nuclear receptors (ER α , ER ß , AR, AhR, PXR, and PPAR γ ) were also analyzed as biomarkers of effective dose. The percentage of women with BPA concentrations above the limit of detection was significantly higher in infertile women than in controls. No statistically significant difference was found with regard to PFOS, PFOA, MEHP and DEHP. Infertile patients showed gene expression levels of ER α , ER ß , AR, and PXR significantly higher than controls. In infertile women, a positive association was found between BPA and MEHP levels and ER α , ER ß , AR, AhR, and PXR expression. PFOS concentration positively correlated with AR and PXR expression. PFOA levels negatively correlated with AhR expression. No correlation was found between DEHP levels and all evaluated nuclear receptors. This study underlines the need to provide special attention to substances that are still widely present in the environment and to integrate exposure measurements with relevant indicators of biological effects.

Preserving fertility in female cancer patients: a snapshot of the options.

With the odds of surviving cancer improving, many young women facing chemotherapy or radiotherapy may first wish to take steps to ensure that they will still be able to bear children afterward. The options depend on the type of disease, the treatment required, the age of the patient, whether she has a long-term partner, and whether cancer treatment can be delayed. This paper is an overview of current and experimental strategies for preserving fertility in female cancer patients.

A response to Gadarowski's letter to the editor.

This discussion is meant to examine the issues raised by Gadarowski in a recent Letter to the Editor.This is a reply to http://www.hqlo.com/content/pdf/1477-7525-11-52.pdf.

Clinical outcome after IMSI procedure in an unselected infertile population: a pilot study.

BACKGROUND: To date the IMSI procedure represents the only real-time and unstained method available to discard spermatozoa with ultrastructural defects. Several studies demonstrated that IMSI provides positive results in couples with severe male factor infertility or repeated ICSI failures. Aim of this pilot study is to evaluate the differences between IMSI and ICSI in terms of IVF outcomes in an unselected infertile patient population. METHODS: Three hundred and thirty-two couples were analyzed: 281 couples underwent conventional ICSI procedure and 51 underwent IMSI technique. RESULTS: No statistically significant differences were found between implantation rate (ICSI: 16,83%; IMSI: 16,67%), fertilization rate (ICSI: 77,27%; IMSI: 80,00%) and pregnancy rate (ICSI: 25,30%; IMSI: 23,50%). Both groups were comparable when considering live birth rate (ICSI: 11,39%; IMSI:13,72%), ongoing pregnancy rate (ICSI: 7,47%; IMSI: 5,88%) and miscarriage rate (ICSI: 17,78; IMSI: 5,26%). The subgroup analyses did not show a statistical difference between ICSI and IMSI neither in male factor infertility subgroup nor in patients with more than one previous ICSI attempt. A trend towards better laboratory and clinical outcomes was detected in the male factor infertility subgroup when IMSI was applied. CONCLUSIONS: Our preliminary results show that the IMSI technique does not significantly improve IVF outcomes in an unselected infertile population.

The adjuvant use of N-palmitoylethanolamine and transpolydatin in the treatment of endometriotic pain.

OBJECTIVE: To test the adjuvant use of the combination of N-palmitoylethanolamine and transpolydatin in the medical treatment of endometriotic pain. STUDY DESIGN: We enrolled 47 patients admitted to the Outpatient Endometriosis Care Unit of Ferrara University from January 2011 to December 2011. They were divided into two groups according to the endometriosis site (group A: recto-vaginal septum; group B: ovary). One tablet, containing 400 mg of micronized N-palmitoylethanolamine plus 40 mg transpolydatin, was administered twice daily on a full stomach for 90 days. Each patient was requested to grade the severity of dysmenorrhea, chronic pelvic pain, dyspareunia and dyschezia using a 0-10 cm visual analogic scale prior to beginning treatment (T0), after 30 days (T1), 60 days (T2) and 90 days (T3). The continuous and categorical variables were compared, respectively, using Student's t-test and the chi-square test. Analysis of variance for repeated measures was used to verify the reduction of endometriotic pain. RESULTS: The intensity of endometriotic pain decreased significantly for both groups (p<0.0001). The efficacy of drug treatment was significant after 30 days. Pain intensity decreased equally in the two groups except for dysmenorrhea, which was reduced more rapidly in group B. CONCLUSIONS: The combination of N-palmitoylethanolamine and transpolydatin reduced pain related to endometriosis irrespective of lesion site. It had a marked effect on chronic pelvic pain determined by deep endometriosis and on dysmenorrhea correlated to ovarian endometriosis.