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.

Is oocyte maturation rate associated with triptorelin dose used for triggering final oocyte maturation in patients at high risk for severe ovarian hyperstimulation syndrome?

STUDY QUESTION: Are oocyte maturation rates different among 0.1, 0.2 and 0.4 mg triptorelin used for triggering final oocyte maturation in patients at high risk for ovarian hyperstimulation syndrome (OHSS) undergoing ICSI? SUMMARY ANSWER: A dose of 0.1 mg triptorelin results in similar oocyte maturation rates compared to higher doses of 0.2 and 0.4 mg in patients at high risk for OHSS undergoing ICSI. WHAT IS KNOWN ALREADY: The GnRH agonist triptorelin is widely used instead of hCG for triggering final oocyte maturation, in order to eliminate the risk of severe OHSS in patients undergoing ovarian stimulation for IVF/ICSI. However, limited data are currently available regarding its optimal dose use for this purpose in patients at high risk for OHSS. STUDY DESIGN, SIZE, DURATION: A retrospective study was performed between November 2015 and July 2017 in 131 infertile patients at high risk for severe OHSS undergoing ovarian stimulation for ICSI. High risk for severe OHSS was defined as the presence of at least 19 follicles ≥11 mm in diameter on the day of triggering final oocyte maturation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian stimulation was performed with recombinant FSH and GnRH antagonists. Patients received 0.1 (n = 42), 0.2 (n = 46) or 0.4 mg (n = 43) triptorelin for triggering final oocyte maturation. Hormonal evaluation of FSH, LH, estradiol (E2) and progesterone (PRG) was carried out on the day of triggering final oocyte maturation, 8 and 36 hours post triggering and 3, 5, 7, and 10 days after triptorelin administration. During this period, all patients were assessed for symptoms and signs indicative of severe OHSS development. Primary outcome measure was oocyte maturation rate, defined as the number of metaphase II (MII) oocytes divided by the number of cumulus-oocyte-complexes retrieved per patient. Results are expressed as median (interquartile range). MAIN RESULTS AND THE ROLE OF CHANCE: No significant differences in patient baseline characteristics were observed among the 0.1 mg, the 0.2 mg and the 0.4 mg groups. Regarding the primary outcome measure, no differences were observed in oocyte maturation rate among the three groups compared [82.6% (17.8%) versus 83.3% (18.8%) versus 85.1% (17.2%), respectively, P = 0.686].In addition, no significant differences were present among the 0.1 mg, 0.2 mg and 0.4 mg groups, regarding the number of mature (MII) oocytes [21 (13) versus 20 (6) versus 20 (11), respectively; P = 0.582], the number of oocytes retrieved [25.5 (13) versus 24.5 (11) versus 23 (12), respectively; P = 0.452], oocyte retrieval rate [81.0% (17.7%) versus 76.5% (23.5%) versus 75.0% (22.5), respectively; P = 0.088], the number of fertilized (two pronuclei) oocytes [12.5 (9) versus 14.5 (7) versus 14.0 (8), respectively; P = 0.985], fertilization rate [71.7% (22%) versus 77.1% (19.1%) versus 76.6% (23.3%), respectively; P = 0.525] and duration of luteal phase [7 (1) versus 8 (2) versus 7 (1) days, respectively; P = 0.632]. Moreover, no significant differences were present among the three triptorelin groups regarding serum levels of LH, FSH, E2 and PRG at any of the time points assessed following triggering of final oocyte maturation. LIMITATIONS, REASONS FOR CAUTION: This is a retrospective study, and although there were no differences in the baseline characteristics of the three groups compared, the presence of bias cannot be excluded. WIDER IMPLICATIONS OF THE FINDINGS: Based on the results of the current study, it appears that triggering final oocyte maturation with a lower (0.1 mg) or a higher dose (0.4 mg) of triptorelin, as compared to the most commonly used dose of 0.2 mg, does not confer any benefit in terms of oocyte maturation rate in patients at high risk for severe OHSS. STUDY FUNDING/COMPETING INTEREST(S): No external funding was obtained for this study. There are no conflicts of interest.

Ultrasound and hematological changes during early luteal phase in women at high risk for developing ovarian hyperstimulation syndrome.

OBJECTIVE: To assess ultrasound and hematological changes during the early luteal phase following triggering of final oocyte maturation with human chorionic gonadotropin (hCG) in women at high risk for developing ovarian hyperstimulation syndrome (OHSS). METHODS: This was a retrospective cohort study of 319 women undergoing in-vitro fertilization who were at high risk for OHSS following administration of hCG for the triggering of final oocyte maturation. Patients were treated with a gonadotropin-releasing hormone agonist or antagonist protocol and were monitored for 5 days post-oocyte retrieval (early luteal phase). Severe OHSS was diagnosed in the presence of at least moderate ascites and two or more of the following: maximum ovarian diameter (MOD) > 100 mm, hematocrit (Ht) > 45%, white blood cell count (WBC) > 15 000/mm3 , hydrothorax, dyspnea and oliguria. Outcome measures included change in Ht, ascites grade, WBC and MOD, as well as the association between these changes during the early luteal phase. RESULTS: Ascites grade, Ht and WBC increased significantly (P ≤ 0.001) during the early luteal phase, both in patients who developed and in those who did not develop severe early OHSS. MOD increased significantly (P = 0.001) only in patients who developed severe early OHSS. On multivariable analysis, both time following oocyte retrieval and whether severe early OHSS developed were significantly associated with ascites grade, Ht, WBC and MOD; furthermore, there was also a significant interaction between time and development of severe early OHSS for all four variables (P ≤ 0.001). CONCLUSIONS: In women at high risk of OHSS, ascites grade, Ht and WBC significantly increased with time over the 5-day observation period, in line with the pathophysiology of the syndrome. Our data support the use of MOD in the diagnosis of severe early OHSS, and provide novel evidence for the role of change in Ht as a patient-specific hemoconcentration marker during development of OHSS. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Prevalence of occult leiomyosarcomas and atypical leiomyomas after laparoscopic morcellation of leiomyomas in reproductive-age women.

STUDY QUESTION: What is the prevalence of leiomyosarcomas and atypical leiomyomas after laparoscopic morcellation of fibroids in reproductive age women? SUMMARY ANSWER: No case of leiomyosarcomas but seven atypical leiomyomas were found in 1216 subjects. WHAT IS KNOWN ALREADY: Although uterine sarcoma is a rare entity affecting usually older peri- or post-menopausal women, the Food and Drug Administration discourages use of laparoscopic power morcellation of uterine fibroids. STUDY DESIGN, SIZE, DURATION: Retrospective review of data extracted from a single center database of 1216 consecutive women who underwent laparoscopic morcellation of 2582 unsuspicious leiomyomas between June 2003 and December 2015 and were followed-up until December 2016. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: A total of 1216 women, aged 18-45 years, underwent laparoscopic morcellation of 2582 apparently benign leiomyomas by the same surgeon and all specimen slides were examined by the same experienced pathologist. MAIN RESULTS AND THE ROLE OF CHANCE: The prevalence of leiomyosarcomas and atypical leiomyomas was 0% (95% CI: 0-0.3%) and 0.6% (95% CI: 0.23-1.18%) (six atypical-bizarre and one mitotically active leiomyoma) respectively. In addition, there were identified 34 cases of adenomyomas, 45 leiomyomas with infarcts, 81 cellular leiomyomas and 133 degenerated leiomyomas. No morcellator-associated complication was recorded and none of the patients included in this study required conversion to laparotomy. LIMITATIONS, REASONS FOR CAUTION: Retrospective and single referral center study design. WIDER IMPLICATIONS OF THE FINDINGS: Laparoscopic morcellation of unsuspicious leiomyomas after careful preoperative work up seems to be safe in women of reproductive age. STUDY FUNDING/COMPETING INTEREST(S): None.

Immunohistochemical expression pattern of metastasis suppressor KISS-1 protein in adenomyosis lesions and normal endometrium.

OBJECTIVE: Kisspeptins are multifunctional peptides; it has been shown that they act as inhibitors of tumor metastasis in a range of cancers and that they are also involved in cell invasion through regulation of matrix metalloproteinases (MMPs). The aim of this study was to investigate the expression of KISS-1 protein in adenomyosis lesions compared with matched eutopic endometrium, as well as with endometrium from patients without adenomyosis. STUDY DESIGN: In this comparative, non-interventional study, adenomyosis and corresponding eutopic endometrium samples from women with histologically proven adenomyosis after hysterectomy, and eutopic endometrium samples from women without adenomyosis were analysed. Expression of KISS-1 protein was analyzed immunohistochemically in formalin-fixed, paraffin-embedded adenomyotic tissue specimens (n=29), matched eutopic endometrium from the same patients (n=29) and normal endometrium from patients without adenomyosis (n=29). RESULTS: Using a semi-quantitative immunohistochemical score, we found that KISS-1 protein expression was higher in the adenomyotic as compared with matched eutopic glandular endometrium (p<0.05), in which in turn KISS-1 protein expression was higher than those from patients without adenomyosis (p<0.001). The inverse correlation was found in the stroma, between adenomyosis lesions and matched eutopic endometrium (p<0.01), while no statistically significant correlation was found in KISS-1 protein expression in the stroma between patients with and without adenomyosis. CONCLUSIONS: KISS-1 protein expression appears to be up-regulated in adenomyotic as compared with eutopic glandular endometrium of patients with, as well as women without adenomyosis. These findings are suggestive of the involvement of KISS-1 protein in the pathogenesis and maintenance of adenomyosis. Future studies should investigate whether KISS1 protein could be used as a marker for early and minimally invasive detection of adenomyosis, based on its differential protein expression pattern in the eutopic endometrium of patients with and without adenomyosis.

Ethico-legal issues related to ovarian tissue transplantation.

Ovarian tissue transplantation (OTT) is a promising experimental method which may soon become well-established. In cases of minor oncology, where patients' fertility is seriously threatened by treatment, it may be applied as a unique fertility preservation option. OTT has a dual nature ('organ' and 'gamete'). Many stakeholders are involved, including donor, recipient, child, health-care providers and society at large. There is considerable uncertainty about the long-term consequences of the application of OTT and OT cryopreservation (OTC). Thus, application of OTT gives rise to a number of very different ethico-legal issues and dilemmas which are hard to solve coherently through a principlism-based bioethical approach. This study focuses on such dilemmas and attempts to review them. The role of virtue ethics, which may be combined with principlism, is essential to solve such dilemmas coherently and reasonably. Dealing with conflicts of ethical principles equivalent between them, or moral dilemmas without available answers and mind-sharing in a difficult interpersonal process of decision making, requires a virtue-based ethical approach. Besides, ethico-legal issues related to OTC/OTT are complex issues requiring a multidisciplinary approach (ethical considerations, medical, psychological and social evaluations etc.). We stress the crucial role of multidisciplinary Ethics Committee which is considered indispensable for each reproductive health-care unit practicing OTC/OTT.

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.

Hypovitaminosis D in pregnancy in the Mediterranean region: a systematic review.

Despite high levels of sunshine, maternal hypovitaminosis D during pregnancy is prevalent in the Mediterranean region. The aim of this study is to systematically review trials that investigated vitamin D concentrations during pregnancy in this region, in order to determine predictors of hypovitaminosis D and explain this phenomenon. After applying inclusion/exclusion criteria, 15 studies were entered into the systematic review involving 2649 pregnant women and 820 neonates. The main outcome was maternal vitamin D status, assessed by serum 25-hydroxy-vitamin D (25(OH)D) concentrations. Possible predictors of the outcome included maternal age, body mass index (BMI), race, socioeconomic status, skin type, gestational age, sun exposure, calcium and vitamin D intake and supplementation, smoking status, parity and season of delivery. Studies differed widely in vitamin D deficiency criteria, method of measurement and outcomes. The prevalence of vitamin D insufficiency ranges from 9.3 to 41.4%, whereas that of vitamin D deficiency from 22.7 to 90.3%. A positive association with 25(OH)D concentrations exists for light skin color, white race, uncovered dressing pattern, maternal vitamin D supplementation and season of gestation (spring/summer). An inverse association exists for BMI and gestational age, whereas data for smoking and socioeconomic status are controversial. We concluded that vitamin D deficiency in pregnancy seems to be quite common, even in the Mediterranean region. Racial, social and cultural habits, as well as the absence of preventive supplementation/dietary strategies, seem to negate the benefits of sun exposure.

Novasure impedance control system versus microwave endometrial ablation for the treatment of dysfunctional uterine bleeding: a double-blind, randomized controlled trial.

PURPOSE OF INVESTIGATION: To compare the efficacy and safety of two different second-generation ablation devices, Novasure impedance control system and microwave endometrial ablation (MEA), in cases of abnormal uterine bleeding (AUB). MATERIALS AND METHODS: This is a randomized controlled trial that took place in a single Gynecological Department of a University Hospital. Sixty-six women with dysfunctional uterine bleeding (DUB), unresponsive to medical treatment, were included in the trial. The ratio of women allocated to bipolar radio-frequency ablation or MEA was 1:1. Follow-up assessments were carried out at three and 12 months post-ablation. The present main outcome measure was amenorrhea rates 12-months post-treatment. RESULTS: The rate of amenorrhea at 12-months post-ablation was significantly higher in women treated by Novasure (25/33; 75.8%) as compared to those treated by MEA (8/33; 24.2%) (rate difference: +51.5%, 95% CI: +27.8 to +67.7). CONCLUSION: In women with DUB, endometrial ablation with Novasure bipolar radiofrequency impedance-controlled system is associated with increased rates of amenorrhea at 12-months post-treatment as compared to the MEA method.

Leptin increases luteinizing hormone secretion of fasting female rats.

PURPOSE: To investigate whether leptin acts directly on the anterior hypophysis by influencing gonadotropin secretion in vivo. MATERIALS AND METHODS: Cycling female rats were catheterised for frequent blood sampling and were either fasted or allowed free access to food. Stereotactic lesion of the medial preoptic area (MPOA) of the hypothalamus was performed in order to eliminate gonadotropin releasing hormone (GnRH) production. Leptin was administered at a dose of one mg/kg i.v. and blood samples were taken just before leptin administration and then after 30, 60, 90, 120, and 180 minutes. Plasma gonadotropin levels were determined. With completion of sampling, the brains were removed and the localisation of the lesions was verified histologically. RESULTS: Leptin at one mg/kg induced an increase in luteinizing hormone (LH) secretion in fasting rats, both in those with a lesion and those with intact medial preoptic area with a peak occurring 90 minutes after infusion. The augmenting effect was more prominent when the hypothalamus was intact. There was no effect in fed animals with or without lesion. Similarly, no effect was observed on follicle stimulating hormone (FSH) levels in any of the experimental groups. CONCLUSIONS: Leptin acts directly on the hypophysis enhancing LH but not FSH secretion. Nutritional state influences leptin's effect on the hypothalamus and the hypophysis.

Serum vascular endothelial growth factor levels following luteal gonadotrophin-releasing hormone antagonist administration in women with severe early ovarian hyperstimulation syndrome.

OBJECTIVE: To investigate the kinetics of serum vascular endothelial growth factor (VEGF) following gonadotrophin-releasing hormone (GnRH) antagonist administration in the luteal phase in women with established severe early ovarian hyperstimulation syndrome (OHSS). DESIGN: Pilot observational cohort study. SETTING: Private in vitro fertilisation (IVF) Unit. POPULATION: Twelve IVF women diagnosed with established severe early OHSS 5 days post oocyte retrieval (POR). METHODS: Women undergoing IVF diagnosed with severe early OHSS 5 days POR were given 0.25 mg GnRH antagonist for 4 days, from day 5 until and including day 8 POR, combined with elective blastocyst cryopreservation. Serum VEGF was measured from the day of oocyte retrieval until day 11 POR. Ovarian volume, ascites, serum estradiol and progesterone, haematocrit and white blood cells were monitored during the same period. MAIN OUTCOME MEASURES: Kinetics of VEGF following luteal GnRH antagonist administration in women with established severe early OHSS. RESULTS: The concentration of VEGF was highest (390.9 ± 137.4 pg/ml) 5 days POR, coinciding with the day of diagnosis of severe OHSS. There was a significant decline of VEGF on day 7 (302.8 ± 104.9 pg/ml; P = 0.026), day 9 (303.3 ± 148.3 pg/ml; P = 0.007), and day 11 (252.6 ± 182.7 pg/ml; P = 0.010) compared with day 5 POR. This decline was associated with an improvement of ultrasound and laboratory parameters, indicating regression of severe OHSS. All women were managed at an outpatient level. CONCLUSIONS: GnRH antagonist administration in the luteal phase is associated with a significant decline of VEGF and with regression of established severe early OHSS.

Operative treatment of gynaecologic diseases in puberty: seven years of experience.

PURPOSE OF INVESTIGATION: The aim of this study is to present the incidence and surgical management of gynaecologic pathology in adolescence in the 1st Obstetrics and Gynecology Department of Aristotle University of Thessaloniki. METHODS: After a retrospective review of the medical records of over a seven year period (2004-2011), 32 adolescent patients with reported surgical gynaecologic procedures were identified and analysed. RESULTS: Fourteen out of the 16 adolescents with ovarian masses (eight neoplastic and eight non-neoplastic) were treated by laparoscopy. Congenital anomalies were diagnosed in seven patients and only one of them was treated by laparotomy. The rest were surgically treated for uterine leiomyoma (1), ectopic pregnancy (2), pelvic abscess (1), mesosalpingeal cysts (2), mesenterian cyst (1) and investigation of chronic pelvic pain. DISCUSSION: Although benign ovarian cysts and congenital anomalies represent the major indication for operative treatment of gynaecologic diseases in puberty, laparoscopy and/or hysteroscopy should be the gold standard procedure after careful preoperative investigation.

Progesterone elevation and probability of pregnancy after IVF: a systematic review and meta-analysis of over 60 000 cycles.

BACKGROUND The aim of this meta-analysis was to evaluate the association of progesterone elevation (PE) on the day of hCG administration with the probability of pregnancy in fresh, frozen-thawed and donor/recipient IVF cycles. METHODS A literature search in MEDLINE, SCOPUS, COCHRANE CENTRAL and ISI Web of Science was performed aiming to identify studies comparing the probability of pregnancy in patients with or without PE after ovarian stimulation with gonadotrophins and GnRH analogues. Standard meta-analytic methodology was used for the synthesis of results and meta-regression for exploration of heterogeneity. RESULTS Sixty-three eligible studies were identified evaluating 55 199 fresh IVF cycles, nine studies evaluating 7229 frozen-thawed cycles and eight studies evaluating 1330 donor/recipient cycles. In fresh IVF cycles, a decreased probability of pregnancy achievement was present in women with PE (when PE was defined using a threshold ≥ 0.8 ng/ml) when compared with those without PE. The pooled effect sizes were 0.8-1.1 ng/ml: odds ratio (OR) = 0.79; 1.2-1.4 ng/ml: OR = 0.67; 1.5-1.75 ng/ml: OR = 0.64; 1.9-3.0 ng/ml: OR: 0.68 (P < 0.05 in all cases). No adverse effect of PE on achieving pregnancy was observed in the frozen-thawed and the donor/recipient cycles. CONCLUSIONS Based on the analysis of more than 60 000 cycles, it can be supported that PE on the day of hCG administration is associated with a decreased probability of pregnancy achievement in fresh IVF cycles in women undergoing ovarian stimulation using GnRH analogues and gonadotrophins. On the other hand, an adverse effect of PE does not seem to be present in frozen-thawed and donor/recipient cycles.

Pregnancy and neonatal outcomes following luteal GnRH antagonist administration in patients with severe early OHSS.

STUDY QUESTION: Do high-risk patients who develop severe early ovarian hyperstimulation syndrome (OHSS) and receive low-dose GnRH antagonist in the luteal phase have lower live birth rates compared with high-risk patients who do not develop severe early OHSS and do not receive GnRH antagonist in the luteal phase? SUMMARY ANSWER: Low-dose luteal GnRH antagonist administration in women with severe early OHSS is associated with similar live birth rates to that of high-risk patients who do not develop severe early OHSS and do not receive GnRH antagonist in the luteal phase. WHAT IS KNOWN ALREADY: It has been reported that luteal GnRH antagonist administration in patients with established severe early OHSS appears to prevent patient hospitalization and results in quick regression of the syndrome on an outpatient basis. However, the effect of such treatment on pregnancy outcome has been investigated in only a small number of animal studies. STUDY DESIGN, SIZE, DURATION: This is a prospective cohort study of 192 IVF patients who were at high risk for OHSS and who did not wish to cancel embryo transfer and have all embryos cryopreserved. The study was conducted between January 2009 and December 2011 at Eugonia Assisted Reproduction Unit. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were <40 years of age, with polycystic ovaries, at high risk for OHSS (defined by the presence of at least 20 follicles ≥11 mm on the day of triggering of final oocyte maturation) and not willing to cancel embryo transfer and cryopreserve all embryos, if severe early OHSS was diagnosed by Day 5 of embryo culture. Patients who were diagnosed with severe early OHSS on Day 5 post-oocyte retrieval were administered 0.25 mg of ganirelix for 3 days, from Day 5 until and including Day 7 (OHSS + antag group, n = 22). High-risk patients who did not develop the severe early OHSS did not receive GnRH antagonist in the luteal phase (control group, n = 172). All patients underwent embryo transfer on Day 5. MAIN RESULTS AND THE ROLE OF CHANCE: Live birth rates (40.9 versus 43.6%), ongoing pregnancy rates (45.5 versus 48.8%), clinical pregnancy rates (50 versus 65.1%), positive hCG (72.7 versus 75%), duration of gestation (36.86 ± 0.90 weeks versus 36.88 ± 2.38 weeks) and neonatal weight (2392.73 ± 427.04 versus 2646.56 ± 655.74 g) were all similar in the OHSS + antag and control groups, respectively. The incidence of major congenital malformations was 2.9% (3/103) in children born in the control group compared with no cases (0/14) in children born following luteal GnRH antagonist administration. No stillbirths or intrauterine deaths, and no cases of pregnancy-induced late OHSS were recorded in either group. None of the 22 patients with severe early OHSS required hospitalization following luteal antagonist administration. Ovarian volume, ascites, hematocrit, white blood cell count, serum estradiol and progesterone decreased significantly (P < 0.001) by the end of the monitoring period (Day 11 post-oocyte retrieval), indicating rapid resolution of the severe OHSS. LIMITATIONS, REASONS FOR CAUTION: This is a prospective cohort investigation with a very limited number of patients receiving the intervention and a larger number of control patients. Our findings suggest that low-dose luteal GnRH antagonist administration during the peri-implantation period may be safe, although larger studies with follow-up of the children born are required. WIDER IMPLICATIONS OF THE FINDINGS: Our study suggests for the first time that low-dose luteal GnRH antagonist administration in women with severe early OHSS is associated with a favourable IVF outcome, comparable to control high-risk patients without severe OHSS and not receiving the intervention. Regarding the wider implications on the concept of an OHSS-free clinic, administration of GnRH antagonist in the luteal phase may present a tertiary management level in patients with established severe OHSS, along with the use of GnRH antagonist protocols for primary prevention and the replacement of hCG with GnRH agonist for triggering final oocyte maturation for secondary prevention. However, at present, fresh embryo transfer combined with antagonist administration should only be used with caution by experienced practitioners, after carefully deciding which patients can have a fresh transfer or embryo cryopreservation, until the current data are confirmed by larger trials.

Laparoscopic management of unexpected borderline ovarian tumors in women of reproductive age.

PURPOSE OF INVESTIGATION: The aim of this study was to review the clinical features of women with unexpected borderline ovarian tumours. METHODS: Between October 1992 and December 2010, 1332 out of 4016 laparoscopies were performed for adnexal masses in women of reproductive age and 1838 cysts were removed. When ultrasonographic findings did not meet the criteria for low risk malignancy, tumour markers, colour Doppler and MRI/CT were applied. At laparoscopy any solid component or papilla was sent for rapid frozen section. RESULTS: Borderline ovarian tumours were found in eight (0.6%) out of 1332 patients, two of which were bilateral. The mean age was 28.75 +/- 9.27 years and the mean diameter of the cysts was 5.1 +/- 1.7 cm. In two cases unexpected malignancy was discovered during the diagnostic and in six cases during the operative phase of the intervention. CONCLUSION(S): Risk of failure to diagnose cancer could be minimised with careful patient selection preoperatively. Adequate training on laparoscopic oncology is the necessary prerequisite for a safe laparoscopic approach.

GnRH-agonist versus GnRH-antagonist IVF cycles: is the reproductive outcome affected by the incidence of progesterone elevation on the day of HCG triggering? A randomized prospective study.

BACKGROUND: In view of the current debate concerning possible differences in efficacy between the two GnRH analogues used in IVF stimulated cycles, the current study aimed to explore whether progesterone control in the late follicular phase differs when GnRH antagonist is used as compared with GnRH agonist, and if so, to what extent the progesterone rise affects the probability of pregnancy. METHODS: Overall 190 patients were randomized: 94 in the GnRH-agonist group and 96 in the GnRH-antagonist group. The GnRH-agonist long protocol started on Day 21 of the preceding cycle with intranasal buserelin (600 mg per day). The GnRH-antagonist protocol started on Day 6 of the stimulation with ganirelix or cetrorelix (each 0.25 mg). All blood samples were analysed with the Elecsys analyzer. An intention-to-treat analysis was applied. RESULTS: A progesterone rise >1.5 ng/ml was noticed in 23.0% of the antagonist group, comparable with 24.1% incidence within the agonist group. Per patient randomized, delivery rates were also comparable: 28.1% in the antagonist group and 24.5% in the agonist group (odds ratio = 1.21, 95% confidence interval: 0.63-2.31, P= 0.56). However, there was a reduction in delivery rates when progesterone exceeded the threshold of 1.5 ng/ml, both in the agonist group (9.5 versus 31.8%, P= 0.03) and in the antagonist group (14.3 versus 34.3%, P= 0.07). CONCLUSIONS: Although the incidence of a progesterone rise was similar between the two analogues, our findings reconfirm previous observations that insufficient progesterone control (>1.5 ng/ml) on the day of ovulation triggering is related to poor delivery rates in both protocols. The current study has shown that the reproductive outcomes with the two GnRH analogues are comparable. Possible modes of action to circumvent late follicular progesterone rise should be explored. TRIAL REGISTRATION NUMBER: NCT01191710.

Significantly lower pregnancy rates in the presence of progesterone elevation in patients treated with GnRH antagonists and gonadotrophins: a systematic review and meta-analysis.

The current meta-analysis aimed to answer the following research question: is progesterone elevation on the day of hCG administration associated with the probability of clinical pregnancy in women undergoing ovarian stimulation for IVF using GnRH antagonists? A literature search in MEDLINE, EMBASE and CENTRAL electronic databases followed by extensive hand-searching from two independent reviewers was performed to identify relevant studies. Eventually five eligible studies (n=585 patients) were identified. No significant differences were present between patients with and those without progesterone elevation regarding female age, duration of stimulation and total dose of gonadotrophins required. However, patients with progesterone elevation were characterized by higher serum estradiol levels on the day of hCG administration (+956 pg/ml, 95% +248 to +1664, random effects model, p=0.008) and more COCs retrieved (+2.9, 95% CI +1.5 to +4.4, fixed effects model, p < 0.001). Progesterone elevation on the day of hCG administration was associated with a significantly decreased probability of clinical pregnancy per cycle (-9%, 95% CI -17 to -2, fixed model effects, p). In conclusion, in patients treated with GnRH antagonists and gonadotrophins, progesterone elevation on the day of hCG administration is significantly associated with a lower probability of clinical pregnancy.

Hormonal replacement therapy in ovarian cancer survivors: a survey among Greek gynecologists.

PURPOSE OF INVESTIGATION: In this survey we evaluated the prescription attitude of Greek gynecologists towards hormone replacement therapy (HRT) for ovarian cancer survivors. METHODS: An anonymous questionnaire was sent to 900 members of the Hellenic Society of Obstetrics and Gynecology presenting a hypothetical case of an ovarian cancer survivor with indications for HRT followed by a series of relevant questions. RESULTS: Two hundred and ninety-eight responses were analyzed with regards to age, gender and practice setting. HRT would be prescribed by 48% of Greek gynecologists; regarding type of regimen, 60% would prescribe tibolone, 19% estrogen alone and 21% estrogen plus progestagen. In contrast, 52% of Greek gynecologists would not prescribe HRT due to the fear of ovarian cancer relapse (83%), or the development of breast cancer (6%), or both cancers (9%); among them, 21% would alternatively prescribe CNS medications, 9% SERMs, phyto-estrogens or bisphosphonates, while the remaining 70% would not prescribe anything. CONCLUSIONS: One out of two Greek gynecologists would prescribe HRT in ovarian cancer survivors. An alternative therapy, mainly CNS medications, would be suggested by 21% of the opposers.

Increased live birth rates with GnRH agonist addition for luteal support in ICSI/IVF cycles: a systematic review and meta-analysis.

BACKGROUND: The aim of this systematic review and meta-analysis was to evaluate whether the addition of GnRH agonist for luteal support in ICSI/IVF cycles enhances the probability of live birth. METHODS: Systematic literature search (MEDLINE, EMBASE, CENTRAL and RCT registries) was conducted to identify relevant randomized controlled trials published as full manuscripts. Meta-analysis of data yielded pooled risk differences (RDs) and 95% confidence intervals (CIs). A random effects model was applied for pooling the studies. RESULTS: Six relevant RCTs were identified including a total of 2012 patients. The probability of live birth rate (RD: +16%, 95% CI: +10 to +22%) was significantly higher in patients who received GnRH agonist support compared with those who did not. The subgroup analysis according to the type of GnRH analogue used for LH suppression did not change the effect observed (studies in which GnRH agonist was used during ovarian stimulation, RD: +15%, 95% CI: +5 to +23%); (studies in which GnRH antagonist was used during ovarian stimulation, RD: +19%, 95% CI: +11 to +27%). CONCLUSIONS: The best available evidence suggests that GnRH agonist addition during the luteal phase significantly increases the probability of live birth rates.

Hormone therapy for postmenopausal endometrial cancer survivors: a survey among Greek obstetricians-gynaecologists.

PURPOSE OF INVESTIGATION: In this study we evaluated the prescription attitude of Greek obstetricians-gynaecologists towards hormone replacement therapy (HRT) for endometrial cancer survivors. METHODS: An anonymous questionnaire was sent to 900 members of the Hellenic Society of Obstetrics and Gynaecology, presenting a hypothetical case of an endometrial cancer survivor with indications for HRT, followed by a series of relevant questions. RESULTS: Three hundred and three valid responses were received and analysed according to age, gender and practice setting. HRT would be prescribed by 30.4% of gynaecologists; as far as type of regimen is concerned, 67.4% would prescribe tibolone, 22.8% estrogen-only and 9.8% estrogen plus progestagen. In contrast, 69.6% would not prescribe HRT due to the fear of endometrial cancer recurrence (88.2%), development of breast cancer (2.8%) or both (4.7%); among them, 28.4% would prescribe central nervous system (CNS) medications, selective estrogen receptor modulators (SERMs), phyto-oestrogens or biphosphonates, as alternates. CONCLUSIONS: One out of three Greek gynaecologists would prescribe HRT to endometrial cancer survivors. Alternative therapies, mainly CNS medications, would be suggested by the opposers.