Grigoris F. Grimbizis

The luteal phase of nonsupplemented cycles after ovarian superovulation with human menopausal gonadotropin and the gonadotropin-releasing hormone antagonist Cetrorelix.

OBJECTIVE To analyze the luteal phase of six patients undergoing controlled ovarian hyperstimulation (COH) with hMG and a new GnRH antagonist, Cetrorelix, without receiving luteal phase supplementation. DESIGN Phase II study involving the first six patients who did not receive luteal phase support. SETTING Tertiary referral center. PATIENT(S) Six healthy women undergoing COH for assisted reproductive techniques. INTERVENTION(S) Oocyte retrieval was performed 36 hours after hCG administration, followed by embryo transfer 2 days later. No luteal phase supplementation was given. MAIN OUTCOME MEASURE(S) Serum E2, progesterone, LH, and FSH concentrations were measured. RESULT(S) The length of the luteal phase was < or =12 days in three of the six patients. One of the patients in whom the luteal phase was >12 days had a low serum progesterone concentration (2.9 ng/mL) on day 10. Serum LH concentrations decreased after the preovulatory hCG injection in all patients. However, a progressive increase in LH was observed after day 7, reaching normal values. CONCLUSION(S) Corpus luteum function seems to be impaired in cycles that are stimulated with hMG and the GnRH antagonist Cetrorelix.

Uterus-sparing operative treatment for adenomyosis

OBJECTIVE To review systematically the literature on uterus-sparing surgical treatment options for adenomyosis. DESIGN Systematic literature review. SETTING Tertiary academic center. PATIENT(S) Women with histologically proven adenomyosis treated with uterus-sparing surgical techniques. INTERVENTION(S) Conservative uterine-sparing surgery for adenomyosis classified as (1) complete excision of adenomyosis, (2) cytoreductive surgery or incomplete removal of the lesion, or (3) nonexcisional techniques, with studies selected if women with adenomyosis were treated surgically without performing hysterectomy. MAIN OUTCOME MEASURE(S) The cure rate after interventional strategies, the rate of symptom (dysmenorrhea and menorrhagia) control, and pregnancy rate in each group of intervention. RESULT(S) A quality assessment tool was used to assess the scientific value of each study. In total, 64 studies dealing with 1,049 patients were identified. After complete excision, the dysmenorrhea reduction, menorrhagia control, and pregnancy rate were 82.0%, 68.8%, and 60.5%, respectively. After partial excision, the dysmenorrhea reduction, menorrhagia control, and pregnancy rate were 81.8%, 50.0%, and 46.9%, respectively. CONCLUSION(S) Uterine-sparing operative treatment of adenomyosis and its variants appear to be feasible and efficacious. Well-designed, comparative studies are urgently needed to answer the multiple questions arising from this intriguing intervention.

The ESHRE–ESGE consensus on the classification of female genital tract congenital anomalies

The new ESHRE/ESGE classification system of female genital anomalies is presented, aiming to provide a more suitable classification system for the accurate, clear, correlated with clinical management and simple categorization of female genital anomalies. Congenital malformations of the female genital tract are common miscellaneous deviations from normal anatomy with health and reproductive consequences. Until now, three systems have been proposed for their categorization, but all of them are associated with serious limitations. The European Society of Human Reproduction and Embryology (ESHRE) and the European Society for Gynaecological Endoscopy (ESGE) have established a common Working Group, under the name CONUTA (CONgenital UTerine Anomalies), with the goal of developing a new updated classification system. A scientific committee has been appointed to run the project, looking also for consensus within the scientists working in the field. The new system is designed and developed based on: (1) scientific research through critical review of current proposals and preparation of an initial proposal for discussion between the experts, (2) consensus measurement among the experts through the use of the DELPHI procedure and (3) consensus development by the scientific committee, taking into account the results of the DELPHI procedure and the comments of the experts. Almost 90 participants took part in the process of development of the ESHRE/ESGE classification system, contributing with their structured answers and comments. The ESHRE/ESGE classification system is based on anatomy. Anomalies are classified into the following main classes, expressing uterine anatomical deviations deriving from the same embryological origin: U0, normal uterus; U1, dysmorphic uterus; U2, septate uterus; U3, bicorporeal uterus; U4, hemi-uterus; U5, aplastic uterus; U6, for still unclassified cases. Main classes have been divided into sub-classes expressing anatomical varieties with clinical significance. Cervical and vaginal anomalies are classified independently into sub-classes having clinical significance. The ESHRE/ESGE classification of female genital anomalies seems to fulfil the expectations and the needs of the experts in the field, but its clinical value needs to be proved in everyday practice. The ESHRE/ESGE classification system of female genital anomalies could be used as a starting point for the development of guidelines for their diagnosis and treatment.

A prospective comparison of transvaginal ultrasound, saline infusion sonohysterography, and diagnostic hysteroscopy in the evaluation of endometrial pathology

OBJECTIVE To compare the diagnostic performance of saline infusion sonohysterography (SIS), transvaginal ultrasound (TVS), and diagnostic hysteroscopy (DH) in the detection of endometrial lesions in symptomatic women. DESIGN Prospective, comparative study. SETTING Obstetrics and Gynecology Department of a tertiary academic hospital. PATIENT(S) A total of 105 consecutive women presenting in an outpatient clinic with symptoms of menorrhagia, postmenopausal bleeding, and infertility. INTERVENTION(S) Each patient had TVS, SIS, and DH. MAIN OUTCOME MEASURE(S) The sensitivity, specificity, and positive and negative likelihood ratios (LR+ and LR-) for TVS, SIS, and DH were determined for the diagnosis of endometrial pathology. More specifically, the diagnostic performance of each of these three methods was compared after receiver operating characteristic analysis. RESULT(S) By comparative analysis of the area under the curve, DH was found to have a significantly better diagnostic performance compared to SIS and TVS. In addition, after comparing the receiver operating characteristic curves, DH was found to be significantly more precise in the diagnosis of intracavitary masses than TVS and SIS. However, SIS was more accurate compared to TVS. CONCLUSION(S) Saline infusion sonohysterography appears to be more valuable than TVS in the diagnosis of intracavitary masses (both polyps and myomas).

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.

The effects of sperm quality on embryo development after intracytoplasmic sperm injection

Purpose : To explore the possible relationship between sperm quality and embryo development, pregnancy and implantation rates, in patients undergoing intracytoplasmic sperm injection (ICSI). Methods : Fertilization and cleavage rates, quality of embryos, blastocyst development, pregnancy and implantation rates were analyzed in 1020 embryos from 219 couples undergoing first ICSI treatment cycle. The couples were allocated in five groups, according to semen parameters: Group 1: patients with normal semen parameters, Group 2: patients with mild oligo-astheno-teratozoospermia, Group 3: patients with severe oligo-astheno-teratozoospermia, Group 4: patients with obstructive azoospermia, Group 5: patients with non-obstructive azoospermia. Results : Fertilization and cleavage rates, quality of embryos as well as blastocyst development rates were significantly reduced, as semen quality decreased. However, no significant differences were observed in clinical pregnancy and implantation rates. Conclusion : Overall, a negative relationship was observed between semen quality and embryo development, even before activation of the embryonic genome, suggesting that sperm can affect embryogenesis from a very early stage.

Clinical approach for the classification of congenital uterine malformations

A more objective, accurate and non-invasive estimation of uterine morphology is nowadays feasible based on the use of modern imaging techniques. The validity of the current classification systems in effective categorization of the female genital malformations has been already challenged. A new clinical approach for the classification of uterine anomalies is proposed. Deviation from normal uterine anatomy is the basic characteristic used in analogy to the American Fertility Society classification. The embryological origin of the anomalies is used as a secondary parameter. Uterine anomalies are classified into the following classes: 0, normal uterus; I, dysmorphic uterus; II, septate uterus (absorption defect); III, dysfused uterus (fusion defect); IV, unilateral formed uterus (formation defect); V, aplastic or dysplastic uterus (formation defect); VI, for still unclassified cases. A subdivision of these main classes to further anatomical varieties with clinical significance is also presented. The new proposal has been designed taking into account the experience gained from the use of the currently available classification systems and intending to be as simple as possible, clear enough and accurate as well as open for further development. This proposal could be used as a starting point for a working group of experts in the field.

Value of magnetic resonance imaging in diagnosis of adenomyosis and myomas of the uterus.

STUDY OBJECTIVE To estimate the diagnostic performance of magnetic resonance imaging (MRI) in detection of myomas and adenomyosis of the uterus. DESIGN Prospective cohort observational study (Canadian Task Force classification II-2). SETTING Department of obstetrics and gynecology, tertiary academic hospital. PATIENTS One hundred fifty-three consecutive women with an enlarged uterus accompanied by gynecologic symptoms and/or with an asymptomatic pelvic mass. INTERVENTION Total abdominal hysterectomy. All patients underwent MRI before the operation. MEASUREMENTS AND MAIN RESULTS The sensitivity, specificity, positive, and negative predictive value of MRI for the diagnosis of uterine pathology was calculated using histologic findings as the standard criterion for final diagnosis. Receiver operating characteristics curves were constructed to describe the diagnostic performance of MRI. In the diagnosis of myomas, MRI demonstrated sensitivity of 94.1%, specificity of 68.7%, PPV of 95.7%, and NPV of 61.1%. In the diagnosis of adenomyosis, MRI demonstrated sensitivity of 46.1%, specificity of 99.1%, PPV of 92.3%, and NPV of 88.5%. The area under the curve (AUC) for the diagnostic performance of MRI in the detection of myomas and adenomyosis was 0.81 and 0.73, respectively. Uterine sarcoma was diagnosed in 5 patients; in these cases, MRI demonstrated sensitivity of 60.0%, specificity of 99.2%, PPV of 75.0%, and NPV of 98.4%. The AUC for MRI in the diagnosis of uterine sarcomas was 0.80. CONCLUSIONS MRI exhibits a high AUC for the diagnosis of both adenomyosis and myomas. The PPV of MRI in the diagnosis of adenomyosis and myomas of the uterus is high as well. MRI seems to be a useful technique in everyday clinical practice in the diagnostic approach of these common conditions, enabling clinicians to select the most appropriate management.

Hysteroscopy in recurrent in-vitro fertilisation failure (TROPHY): a multicentre, randomised controlled trial

BACKGROUND The success rate of in-vitro fertilisation (IVF) remains low and many women undergo multiple treatment cycles. A previous meta-analysis suggested hysteroscopy could improve outcomes in women who have had recurrent implantation failure; however, studies were of poor quality and a definitive randomised trial was needed. In the TROPHY trial we aimed to assess whether hysteroscopy improves the livebirth rate following IVF treatment in women with recurrent failure of implantation. METHODS We did a multicentre, randomised controlled trial in eight hospitals in the UK, Belgium, Italy, and the Czech Republic. We recruited women younger than 38 years who had normal ultrasound of the uterine cavity and history of two to four unsuccessful IVF cycles. We used an independent web-based trial management system to randomly assign (1:1) women to receive outpatient hysteroscopy (hysteroscopy group) or no hysteroscopy (control group) in the month before starting a treatment cycle of IVF (with or without intracytoplasmic sperm injection). A computer-based algorithm minimised for key prognostic variables: age, body-mass index, basal follicle-stimulating hormone concentration, and the number of previous failed IVF cycles. The order of group assignment was masked to the researchers at the time of recruitment and randomisation. Embryologists involved in the embryo transfer were masked to group allocation, but physicians doing the procedure knew of group assignment and had hysteroscopy findings accessible. Participants were not masked to their group assignment. The primary outcome was the livebirth rate (proportion of women who had a live baby beyond 24 weeks of gestation) in the intention-to-treat population. The trial was registered with the ISRCTN Registry, ISRCTN35859078. FINDINGS Between Jan 1, 2010, and Dec 31, 2013, we randomly assigned 350 women to the hysteroscopy group and 352 women to the control group. 102 (29%) of women in the hysteroscopy group had a livebirth after IVF compared with 102 (29%) women in the control group (risk ratio 1·0, 95% CI 0·79-1·25; p=0·96). No hysteroscopy-related adverse events were reported. INTERPRETATION Outpatient hysteroscopy before IVF in women with a normal ultrasound of the uterine cavity and a history of unsuccessful IVF treatment cycles does not improve the livebirth rate. Further research into the effectiveness of surgical correction of specific uterine cavity abnormalities before IVF is warranted. FUNDING European Society of Human Reproduction and Embryology, European Society for Gynaecological Endoscopy.

The use of hormonal contraception and its protective role against endometrial and ovarian cancer

Hormonal contraception has a protective effect over ovarian and endometrial cancer development. Relative risk of ovarian cancer decreases by approximately 20% for each 5 years of use; it is approximately 50% for 15 years of use and decreasing with further use. The protective effect gained declines as time passes from its last use, but a significant effect remains a long time after ceasing. The effect is independent from the type of formulation used. Hormonal contraceptives do not protect from mucinous types of ovarian tumours. Relative risk reduction of endometrial cancer is even higher; the estimated relative risk decrease is approximately 50% with 4 years of use, approximately 70% with 12 years of use and decreasing with further use. After ceasing oral contraception, the risk begins to rise from its reduced levels but it is still approximately 50% even after >20 years after its last use. Hormonal contraception could be used for primary protection from ovarian and endometrial cancer development.