Is the probability of pregnancy after ovarian stimulation for IVF associated with serum estradiol levels on the day of triggering final oocyte maturation with hCG? A systematic review and meta-analysis.

PURPOSE: The objective of this systematic review and metaanalysis was to examine if the probability of pregnancy after ovarian stimulation for in vitro fertilization (IVF), using GnRH analogues and gonadotrophins is associated with serum estradiol level (Ε2) on the day of triggering final oocyte maturation with human chorionic gonadotrophin (hCG). METHODS: Twenty-one studies were eligible for this systematic review, including 19,598 IVF cycles, whereas three studies were eligible for metaanalysis, including 641 IVF cycles. The main outcome measure was achievement of ongoing pregnancy/live birth and, if not available, clinical pregnancy or biochemical pregnancy. RESULTS: Pooling of data showed no differences in the probability of clinical pregnancy between patients with high and low Ε2 levels on the day of triggering final oocyte maturation. The pooled effect sizes for the Ε2 thresholds groups constructed, regarding clinical pregnancy were 2000-3000 pg/mL-OR 0.91, 95% CI 0.55 to 1.50, (fair quality/moderate risk of bias, n = 1 study), 3000-4000 pg/mL-OR 0.89, 95% CI 0.46 to 1.70, (fair quality/moderate risk of bias, n = 1 study, good quality/no information on which to base a judgement about risk of bias n = 2 studies), 4000-5000 pg/mL-OR 0.74, 95% CI 0.37 to 1.49 fair quality/moderate risk of bias, n = 1 study), 5000-6000 pg/mL-OR 0.62, 95% CI 0.19 to 1.98, (fair quality/moderate risk of bias, n = 1 study). In addition, no difference was observed in the probability of ongoing pregnancy for the Ε2 threshold group of 3000-4000 pg/mL OR 0.85, 95% CI 0.40 to 1.81(good quality/no information on which to base a judgement about risk of bias, n = 1 study). CONCLUSION: Currently, there is insufficient evidence to support or deny the presence of an association between the probability of pregnancy and serum Ε2 levels on the day of triggering final oocyte maturation with hCG in women undergoing ovarian stimulation for IVF.

Breast self-examination in Greek midwives and midwifery students.

The aim of this study is to assess breast self-examination (BSE) practice in a representative sample of Greek midwives and midwifery students. Breast self-examination (BSE) is infrequent in healthcare professionals, including physicians and nurses. All midwives (n=245) and graduating midwifery students (n=165) who attended a congress of midwives were eligible to participate in the study, and a self-administered, anonymous questionnaire was developed to assess BSE practice. Midwives performed BSE more frequently than students (p<0.001). In addition, 27.0% of students performed BSE less frequently than every year whereas the midwives' rate is 14.0% (p<0.001). The proportion of subjects searching for specific signs of breast cancer during BSE and the BSE technique did not differ between midwives and students. In midwifery students, higher perceived knowledge of breast cancer-related issues was associated with more frequent BSE. Only a minority of Greek midwives and midwifery students practice BSE every month, and therefore implications for nursing management in BSE education should be included in midwifery school curricula to ensure increased BSE frequency, improved BSE accuracy and the promotion of BSE teaching to patients.

Transdermal testosterone pretreatment in poor responders undergoing ICSI: a randomized clinical trial.

STUDY QUESTION: Does pretreatment with transdermal testosterone increase the number of cumulus-oocyte complexes (COCs) retrieved by more than 1.5 in poor responders undergoing intracytoplasmic sperm injection (ICSI), using recombinant follicle stimulating hormone (FSH) and gonadotrophin releasing hormone agonists (GnRHa)? SUMMARY ANSWER: Testosterone pretreatment failed to increase the number of COCs by more than 1.5 as compared with no pretreatment in poor responders undergoing ICSI (difference between medians: 0.0, 95% CI: -1.0 to +1.0). WHAT IS KNOWN ALREADY: Androgens are thought to play an important role in early follicular development by enhancing ovarian sensitivity to FSH. In a recent meta-analysis, testosterone pretreatment resulted in an increase of 1.5 COCs as compared with no pretreatment. However, this effect was based on the analysis of only two randomized controlled trials (RCTs) including 163 patients. Evidently, there is a need for additional RCTs that will allow firmer conclusions to be drawn. STUDY DESIGN, SIZE, DURATION: The present RCT was designed to detect a difference of 1.5 COCs (sample size required = 48 patients). From 02/2014 until 04/2015, 50 poor responders fulfilling the Bologna criteria have been randomized (using a randomization list) to either testosterone pretreatment for 21 days ( ITALIC! n = 26) or no pretreatment ( ITALIC! n = 24). PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients underwent a long follicular GnRHa protocol. Recombinant FSH stimulation was started on Day 22 following GnRHa initiation. In the testosterone pretreatment group, a daily dose of 10 mg of testosterone gel was applied transdermally for 21 days starting from GnRHa initiation. Results are expressed as median (interquartile range). MAIN RESULTS AND THE ROLE OF CHANCE: No differences in baseline characteristics were observed between the two groups compared. Testosterone levels [median (interquartile range)] were significantly higher in the testosterone pretreatment on the day of initiation of FSH stimulation [114 (99.5) ng/dl versus 20 (20) ng/dl, respectively, ITALIC! P < 0.001]. Duration of FSH stimulation [median (interquartile range)] was similar between the groups compared [12.5 (3.0) days versus 12 (3.0) days, respectively, ITALIC! P = 0.52]. The number of COCs retrieved [median (interquartile range)] was not different between the testosterone pretreatment and the no pretreatment groups [3.5 (4.0) versus 3.0 (3.0), 95% CI for the median: 2.0-5.0 versus 2.7-4.3, respectively; difference between medians: 0.0, 95% CI: +1.0 to -1.0). Similarly no differences were observed regarding fertilization rates [median (interquartile range)] [66.7% (32.5) versus 66.7% (42.9), respectively, ITALIC! P = 0.97] and live birth rates per randomized patient (7.7% versus 8.3%, respectively, rate difference: -0.6%, 95% CI: -19.0 to +16.9). LIMITATIONS, REASONS FOR CAUTION: The study was not powered to detect differences less than 1.5 COCs, although it is doubtful whether these differences would be clinically relevant. Moreover, due to sample size restrictions, no conclusions can be drawn regarding the probability of live birth. WIDER IMPLICATIONS OF THE FINDINGS: The results of this randomized clinical trial, suggesting that pretreatment with 10 mg of transdermal testosterone for 21 days does not improve ovarian response by more than 1.5 oocytes, could be used to more accurately consult patients with poor ovarian response. However, an improvement in IVF outcome using a higher dose of testosterone or a longer pretreatment period cannot be excluded. STUDY FUNDING/COMPETING INTEREST: The study was partially funded by a Scholarship from the Academy of Athens. C.A.V. reports personal fees and non-financial support from Merck, Sharp and Dome, personal fees and non-financial support from Merck Serono, personal fees and non-financial support from IPSEN Hellas S.A., outside the submitted work. B.C.T. reports grants from Merck Serono, grants from Merck Sharp & Dohme, personal fees from Merck Serono, personal fees from Merck Sharp & Dohme, personal fees from IBSA & Ferring, outside the submitted work. TRIAL REGISTRATION NUMBER: NCT01961336. TRIAL REGISTRATION DATE: 10 October 2013. DATE OF FIRST PATIENT'S ENROLLMENT: 02/2014.

Corifollitropin alfa compared with follitropin beta in poor responders undergoing ICSI: a randomized controlled trial.

STUDY QUESTION: Does substituting 150 µg corifollitropin alfa for 450 IU follitropin beta during the first 7 days of ovarian stimulation in proven poor responders, result in retrieval of a non-inferior number (<1.5 fewer) of cumulus oocyte complexes (COCs)? SUMMARY ANSWER: A single s.c. dose of 150 µg corifollitropin alfa on the first day of ovarian stimulation, followed if necessary, from Day 8 onwards, with 450 IU of follitropin beta/day, is not inferior to daily doses of 450 IU follitropin beta. The 95% CI of the difference between medians in the number of oocytes retrieved was -1 to +1 within the safety margin of 1.5. WHAT IS KNOWN ALREADY: Recent data from retrospective studies suggest that the use of corifollitropin alfa in poor responders is promising since it could simplify ovarian stimulation without compromising its outcome. STUDY DESIGN, SIZE, DURATION: Seventy-nine women with previous poor ovarian response undergoing ICSI treatment were enrolled in this open label, non-inferiority, randomized clinical trial (RCT). PARTICIPANTS/MATERIALS, SETTING, METHODS: Inclusion criteria were: previous poor response to ovarian stimulation (≤4 COCs) after maximal stimulation, age <45 years, regular spontaneous menstrual cycle, body mass index: 18-32 kg/m(2) and basal follicle stimulating hormone ≤20 IU/l. On Day 2 of the menstrual cycle, patients were administered either a single s.c dose of 150 µg corifollitropin alfa (n = 40) or a fixed daily dose of 450 IU of follitropin beta (n = 39). In the corifollitropin alfa group, 450 IU of follitropin beta were administered from Day 8 of stimulation until the day of human chorionic gonadotrophin (hCG) administration, if necessary. To inhibit premature luteinizing hormone surge, the gonadotrophin releasing hormone antagonist ganirelix was used. Triggering of final oocyte maturation was performed using 250 µg of recombinant hCG, when at least two follicles reached 17 mm in mean diameter. MAIN RESULTS AND THE ROLE OF CHANCE: The number of COCs retrieved was not statistically different between the corifollitropin alfa and the follitropin beta groups [Median 3 versus 2, 95% CI 2-4, 2-3, respectively, P = 0.26]. The 95% CI of the difference between medians in the number of oocytes retrieved was -1 to +1. A multivariable analysis adjusting for all the potential baseline differences confirmed this finding. No significant difference was observed regarding the probability of live birth between the corifollitropin alfa and the follitropin beta group (live birth per patient reaching oocyte retrieval: 7.9 versus 2.6%, respectively, difference +5.3%, 95% CI: -6.8 to +18.3). LIMITATIONS, REASONS FOR CAUTION: The present study was not powered to test a smaller difference (e.g. 1 COC) in terms of COCs retrieved as well as to show potential differences in the probability of pregnancy. Moreover, it would be interesting to assess whether the continuation of stimulation in the long acting FSH arm, where necessary, with 200 IU instead of 450 IU of follitropin beta would have altered the direction or the magnitude of the effect of the type of FSH, observed on the number of COCs retrieved. WIDER IMPLICATIONS OF THE FINDINGS: Corifollitropin alfa simplifies IVF treatment because it is administered in a GnRH antagonist protocol and replaces seven daily FSH injections with a single one of a long acting FSH without compromising the outcome. It could greatly reduce the burden of treatment for poor responders and this deserves further investigation.

The use of androgens or androgen-modulating agents in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis.

BACKGROUND: The aim of this meta-analysis was to evaluate the role of androgens or androgen-modulating agents on the probability of pregnancy achievement in poor responders undergoing IVF. METHODS: Medline, EMBASE, CENTRAL, Scopus and Web of Science databases were searched for the identification of randomized controlled trials evaluating the administration of testosterone, dehydroepiandrosterone (DHEA), aromatase inhibitors, recombinant luteinizing hormone (rLH) and recombinant human chorionic gonadotrophin (rhCG) before or during ovarian stimulation of poor responders. RESULTS: In two trials involving 163 patients, pretreatment with transdermal testosterone was associated with an increase in clinical pregnancy [risk difference (RD): +15%, 95% confidence interval (CI): +3 to +26%] and live birth rates (RD: +11%, 95% CI: +0.3 to +22%) in poor responders undergoing ovarian stimulation for IVF. No significant differences in clinical pregnancy and live birth rates were observed between patients who received DHEA and those who did not. Similarly, (i) the use of aromatase inhibitors, (ii) addition of rLH and (iii) addition of rhCG in poor responders stimulated with rFSH for IVF were not associated with increased clinical pregnancy rates. In the only eligible study that provided data, live birth rate was increased in patients who received rLH when compared with those who did not (RD: +19%, 95% CI:+1 to +36%). CONCLUSIONS: Based on the limited available evidence, transdermal testosterone pretreatment seems to increase clinical pregnancy and live birth rates in poor responders undergoing ovarian stimulation for IVF. There is insufficient data to support a beneficial role of rLH, hCG, DHEA or letrozole administration in the probability of pregnancy in poor responders undergoing ovarian stimulation for IVF.

A prospective randomized study for evaluation of wound retractors in the prevention of incision site infections after cesarean section.

Surgical site infections (SSIs) after cesarean section appear to be more common than generally believed. We prospectively evaluated 231 consecutive pregnant women who underwent elective or emergency cesarean section, and were assigned to have either the Alexis wound retractor (study group) or a conventional Doyen retractor (control group) during the operation. There was no evidence of SSI, defined as wound dehiscence, pain or tenderness in the lower abdomen, localized swelling, redness, heat or purulent discharge from the wound in any woman in the study group. Moreover, no endometritis occurred in this patient collective. There were three SSI in the control group, but no endometritis. Our preliminary data show excellent protection of wound infections with an additive protective effect to that given by antibiotic cover. After a short learning curve, the handling of the Alexis device became easier and the median insertion time was 18 sec.

Does cessation of progesterone supplementation during early pregnancy in patients treated with recFSH/GnRH antagonist affect ongoing pregnancy rates? A randomized controlled trial.

BACKGROUND: The aim of this study was to assess whether the cessation of progesterone (P) supplementation during early pregnancy after GnRH antagonist cycles is not inferior to its continuation in terms of pregnancy rates beyond 12 weeks of gestation METHODS: There were 200 patients, with a positive ß-hCG test (followed by a doubling in ß-hCG levels 48 h later) after a fixed recombinant FSH (recFSH)/GnRH antagonist protocol for IVF/ICSI and a Day-3 fresh embryo transfer (ET), participated in this randomized controlled study. All patients received luteal support, with 200 mg vaginal P being administered three times daily for 14 days, beginning on the day of ET until the second ß-hCG test, 16 days post-ET. In the control group (n = 100) the administration of P was continued until 7 weeks of gestation. In the study group (n = 100), vaginal P was discontinued on the 16th day post-ET RESULTS: The ongoing pregnancy rate beyond 12 weeks, the primary outcome measure, did not differ between the study and control groups (82 versus 73%, P = 0.175; difference 9%, 95% CI: -2.6 to 20.3). There were also no significant differences observed between the study and control group in terms of abortion before or after 7 weeks of gestation [(9 versus 12%, P = 0.645) and (8 versus 10%, P = 0.806), respectively]. The same was true for bleeding episodes (14 versus 19%, P = 0.446). CONCLUSIONS: After recFSH/GnRH antagonist cycles, the withdrawal of P supplementation in early pregnancy, with normally increasing ß-hCG levels on the 16th day post-ET, had no significant clinical impact in terms of ongoing pregnancy rates beyond 12 weeks.

ERBB2 (HER2) protein expression in uterine sarcomas.

PURPOSE: Multiple clinical trials in recent years have shown that breast cancer patients with primary tumors overexpressing ERBB2 can be effectively treated with specific forms of modern anti-ERBB2-targeted therapy. The aim of the present study was to analyze the expression of the ERBB2 (HER2) protein in uterine sarcomas, in order to investigate the possibility of applying this treatment modality in uterine sarcomas. METHODS: The expression of ERBB2 has been analyzed immunohistochemically in formalin-fixed paraffin-embedded primary uterine sarcomas (n = 11). RESULTS: Using a semi-quantitative immunohistochemical score, we found that ERBB2 expression was very weak in the majority of tumors, with only three sarcomas showing moderate ERBB2 expression. Published studies evaluating the same issue in small numbers of uterine sarcomas reached similar findings. CONCLUSION: Overall, ERBB2 expression appears to be weak in uterine sarcomas. However, targeted treatment might still be feasible in a subgroup of patients with uterine sarcomas overexpressing ERBB2.

Virilizing ovarian hilus (Leydig) cell tumor with concurrent contralateral hilus cell hyperplasia: a rare diagnosis.

Ovarian hilus or Leydig cell tumor and ovarian hilus cell hyperplasia are rare clinical entities, causing virilization in both pre- and postmenopausal women. Differentiation between these two conditions is not always straightforward; the former is usually unilateral appearing as a single, grossly visible, circumscribed mass of hilus cells, while the latter is usually bilateral, appearing as diffuse microscopic aggregates of hilus cells. We report herein an extremely rare case of ovarian hilus or Leydig cell tumor, presenting concurrently with contralateral ovarian hilus cell hyperplasia in a postmenopausal woman with virilization. To the best of our knowledge, only four such cases have been previously reported in the literature. Ovarian hilus cell tumors and hilus hyperplasia almost always have benign biological behavior, thus making bilateral salpingo-oophorectomy an appropriate and sufficient therapeutic approach.

Awareness of human papillomavirus infection, testing and vaccination in midwives and midwifery students in Greece.

Midwives play an important role in the implementation of cervical cancer screening. We assessed the knowledge of human papillomavirus (HPV) infection and of its relationship with cervical cancer in 107 midwives and 29 graduating midwifery students. The majority of midwives (78.5%) were aware that a viral infection causes cervical cancer, whereas only 48.3% of the students knew this (p = 0.003). Only one midwife (0.9%) was not aware of HPV infection compared with 10.3% of the students (p = 0.029). Midwives were also more knowledgeable of the relationship between HPV infection and cervical cancer and of the availability of a vaccine against HPV infection (p = 0.005 and p < 0.0001, respectively). In conclusion, Greek midwives have a satisfactory level of knowledge about cervical cancer and HPV infection, in contrast to midwifery students. It is important to better educate midwifery students in order to facilitate the incorporation of HPV testing and vaccination in clinical practice.

A unique case of palatinate tonsil metastasis from endometrial cancer.

Metastases from malignancies of the female genital tract to the tonsils have never been reported. A case of a 55-year-old woman presenting with a palatinate tonsil tumour two and half years after primary diagnosis of endometrioid endometrial adenocarcinoma (FIGO Stage IB, G2) and six months after local disease recurrence is presented. The tonsillar malignancy was poorly differentiated and tumour cells were immunohistochemically positive to LMW keratin and EMA, and negative to HMW keratin and LCA, strongly suggesting a possible endometrial origin of the tumour. Metastatic disease was treated with systemic chemotherapy, but the patient soon succumbed due to rapid disease progression. In conclusion, a unique case of a palatinate tonsil tumour as the first metastatic site in an endometrial cancer patient is reported.

Human placental lactogen and color Doppler in predicting expulsion of retained adherent placenta: a new clinical observation.

PURPOSE: To present a new clinical observation made in three cases of retained adherent placenta, a rare obstetrical complication, associated with potentially life-threatening hemorrhage. METHODS: Three consecutive cases of retained adherent placenta are presented. RESULTS: Diagnosis of placenta increta in two and placenta percreta in one case was established with ultrasound and MRI. Methotrexate 50 mg i.v. (300 mg total dose) and follinic acid 0.1 mg/kg were administered on alternating days, over 12 days. On follow-up, placental perfusion on color Doppler was present up to the point when circulating hPL levels were no longer detectable; this was followed in all cases by spontaneous placental expulsion within 10 days. CONCLUSIONS: The observation that both color Doppler and human placental lactogen can be used to monitor response to therapy and predict placental expulsion should be evaluated in future cases of retained adherent placenta.

KIT protein expression in uterine sarcomas: an immunohistochemical study and review of the literature.

PURPOSE: The aim of the present study was to investigate the possibility of treating uterine sarcomas with imatinib mesylate. Imatinib mesylate, a selective tyrosine kinase inhibitor, is very efficient against mesenchymal tumors of the gastrointestinal tract, known as GISTs. Imatinib mesylate acts against a tyrosine kinase encoded by the KIT gene in GISTs, and is more effective in tumors expressing this protein. METHODS: Expression of KIT was analyzed immunohistochemically (n = 12) in formalin-fixed paraffin-embedded primary uterine sarcomas. RESULTS: Using a semi-quantitative immunohistochemical score we found that KIT expression was very weak in the majority of tumors, while none of the uterine sarcomas tested showed strong expression. Overall, published studies addressing this issue in small series of uterine sarcomas yielded similar results. CONCLUSION: Current data suggest that it is unlikely that imatinib mesylate could be used effectively as a single agent in patients with uterine sarcomas.

Vaginal wall fibroid.

Localization of leiomyomas in the vaginal wall is very rare. We report about a case of a vaginal leiomyoma in the anterior vaginal wall, preoperatively identified with sonography and CT. Surgical enucleation was performed. Surgical removal in these cases is safe and usually with minimal bleeding.

Knowledge and practice of contraception among Greek female medical students.

OBJECTIVE: In Greece, modern contraceptive methods are used on a limited scale. This study aimed to investigate the knowledge as well as the practice of contraception among female medical students in Greece. STUDY DESIGN: Knowledge and practice of contraception of 102 female graduating medical students were assessed with a self-administered, anonymous questionnaire. RESULTS: Most students were using condoms as the only contraceptive method (45.1%) and 16.7% were not applying any contraceptive method at all. Oral contraceptives were used as only contraceptive means by 4.9% of the students and in combination with condoms by another 4.9%. Condoms were thought to be the most effective contraceptive method available by 28.4% of the students, whereas 4.9% responded that they did not consider any contraceptive method to be effective. Only 55.9% of the students had ever asked their gynaecologist about contraception. CONCLUSION: Much more time should be spent in teaching contraception in the Greek medical schools to ensure the delivery of adequate family planning guidance by future practitioners.

Endometrial lesions causing uterine bleeding in postmenopausal women receiving raloxifene.

It is generally accepted, that raloxifene administration does not have adverse effects on the uterus. We report the cases of two relatively young postmenopausal patients, who presented with vaginal bleeding, due to endometrial pathology, approximately 1 year after the initiation of raloxifene administration. The women were 43 and 44 years old, and received 60 mg/day of oral raloxifene for 11.5 and 10.5 months, respectively. In both cases, raloxifene was given for osteoporosis prevention in the absence of vasomotor symptoms. The first patient underwent Pipelle-biopsy and hysteroscopy with histopathology revealing simple endometrial hyperplasia. The second patient underwent hysteroscopy with removal of an endometrial polyp, with no histopathological signs of malignancy. Continuation of raloxifene administration was decided in both cases, and follow-up did not reveal any sign of recurrence. Uterine bleeding may rarely occur in postmenopausal women under raloxifene therapy. Patients should be encouraged to report bleeding or spotting and appropriate diagnostic and therapeutic management should follow as in any other case.

Clinical management of low ovarian response to stimulation for IVF: a systematic review.

Poor response is not a rare occurrence in ovarian stimulation. Although not fully accepted, the most dominant criteria for poor ovarian response are small numbers of follicles developed or oocytes retrieved, and low estradiol (E2) levels after the use of a standard stimulation protocol. There is no ideal predictive test as the poor responder is revealed only during ovulation induction; however, increased levels of day 3 FSH and E2 as well as decreased levels of inhibin B can be used to assess ovarian reserve. Several protocols have been proposed for clinical management of low ovarian response in IVF. Although high doses of gonadotrophins have been used by the vast majority of authors, results have been controversial and prospective randomized studies have shown little or no benefit. The few available relevant studies do not indicate that recombinant FSH improves outcome. Flare-up GnRH agonist protocols (including all dosage varieties) produce better results than standard long luteal protocols. Luteal initiation GnRH agonist 'stop' protocols were shown to improve ovarian response according to prospective studies with historical controls, but this was not confirmed by well-designed prospective, randomized, controlled studies. The few available data obtained with GnRH antagonists have not shown any benefits. Adjuvant therapy with growth hormone (GH) or GH-releasing factors results in no significant improvement. The use of corticosteroids reduces the incidence of poor ovarian response in women undergoing IVF treatment. The limited data obtained with nitric oxide donors are encouraging. Pretreatment with combined oral contraceptives prior to stimulation may help ovarian response. No benefit was observed with standard use of ICSI or assisted hatching of zona pellucida. Finally, natural cycle IVF has produced results which are comparable with those obtained with stimulated cycles in true poor responders. Well-designed, large-scale, randomized, controlled trials are needed to assess the efficacy of these different management strategies.