Endocrinology: Two cases of ovarian tumours in women who had undergone multiple ovarian stimulation attempts

Concerns have been raised recently about the possible associationbetween superovulation and ovarian cancer. In order to contributeto the limited literature on this important issue, two casesof ovarian tumours in women who had undergone multiple ovulationinductions are presented. In the first case, the patient hadsecondary anovulatory infertility. She was treated with humanmenopausal gonadotrophin (HMG) alone and in combination withclomiphene citrate or buserelin for six cycles. She then underwentovarian stimulation with buserelin/HMG in the long protocolfor in-vitro fertilization (IVF) and embryo transfer. In preparationfor a new IVF/embryo transfer attempt, 8 months later, the screeningultrasound revealed a cystic formation of the left ovary andan enlargement of the right. During laparotomy, both ovarieswere found to bear large tumours (approximately 6x5x4 cm) whichwere removed. Histological examination showed that they wereepithelial tumours (serous-papillary cystadenomas) of borderlinemalignancy. The patient conceived spontaneously 1.5 years afterthe operation. In the second case, the patient presented withsecondary anovulatory infertility. She underwent ovulation inductionwith clomiphene/HMG and with buserelin/HMG in the long protocol,and intra-uterine insemination with husband's spermatozoa andconceived (singleton pregnancy). She was delivered by Caesareansection, during which a cystic tumour of the left ovary wasremoved. Histological examination revealed a benign mucous cystadenomaof the ovary. In conclusion, the clinical information from thesetwo cases does not support a causal association between ovarianstimulation and ovarian tumours but does potntially supporta facilitating one.     

Regression of endometrial hyperplasia after treatment with the gonadotrophin-releasing hormone analogue triptorelin: a prospective study

Endometrial hyperplasia is thought to be caused by the prolonged, unopposed oestrogenic stimulation of the endometrium. The regression of hyperplastic back to normal endometrium is the main purpose of any conservative treatment in order to prevent development of adenocarcinoma. The aim of this study was to evaluate the regression of hyperplastic to normal endometrium in patients with various forms of endometrial hyperplasia after treatment with the gonadotrophin-releasing hormone analogue (GnRHa) triptorelin for 6 months. Fifty-six patients with endometrial hyperplasia were enrolled in this trial; 39 patients (group I) presented simple hyperplasia, 14 (group II) complex hyperplasia and three (group III) atypical complex hyperplasia. All patients were treated with triptorelin for 6 months. Bleeding control during treatment was excellent. A post-treatment curettage for estimation of endometrial histology was performed on 54 out of 56 patients 100.1 +/- 44.7 days after the last triptorelin dose, following the restoration of pituitary function. Regression of hyperplastic to normal endometrium was observed in 32 (86.5%) out of 37 patients in group I and in 12 (85.7%) out of 14 in group II. Persistence of simple hyperplasia was found in five (14.5%) out of 37 patients in group I. Persistence of complex hyperplasia was found in 1 (7.1%) out of 14 patients and progression to atypical complex hyperplasia in another one (7.1%) woman in group II. In some of these cases, the presence of risk factors such as obesity, diabetes mellitus and ovulatory disturbances may contribute to the disease persistence despite therapy. On the other hand, in group III, none of the three patients had normal post-treatment endometrial histology. It seems, therefore, that in cases of endometrial hyperplasia without atypia, the administration of the GnRHa triptorelin is associated with high regression rates to normal endometrium. Conversely, the presence of atypia seems to be a poor prognostic factor. Treatment tolerance and bleeding control during therapy is excellent.     

Expression of genes that regulate follicle development and maturation during ovarian stimulation in poor responders

Research questionSex hormone-binding globulin (SHBG), androgen receptor (AR), LH beta polypeptide (LHB), progesterone receptor membrane component 1 (PGRMC1) and progesterone receptor membrane component 2 (PGRMC2) regulate follicle development and maturation. Their mRNA expression was assessed in peripheral blood mononuclear cells (PBMC) of normal and poor responders, during ovarian stimulation.DesignFifty-two normal responders and 15 poor responders according to the Bologna criteria were enrolled for IVF and intracytoplasmic sperm injection and stimulated with 200 IU of follitrophin alpha and gonadotrophin-releasing hormone antagonist. HCG was administered for final oocyte maturation. On days 1, 6 and 10 of stimulation, blood samples were obtained, serum hormone levels were measured, RNA was extracted from PBMC and real-time polymerase chain reaction was carried out to identify the mRNA levels. Relative mRNA expression of each gene was calculated by the comparative 2^?DDCt method.ResultsDifferences between mRNA levels of each gene on the same time point between the two groups were not significant. PGRMC1 and PGRMC2 mRNA levels were downregulated, adjusted for ovarian response and age. Positive correlations between PGRMC1 and AR (standardized beta = 0.890, P < 0.001) from day 1 to 6 and PGRMC1 and LHB (standardized beta = 0.806, P < 0.001) from day 1 to 10 were found in poor responders. PGRMC1 and PGRMC2 were positively correlated on days 6 and 10 in normal responders.ConclusionsPGRMC1 and PGRMC2 mRNA are significantly decreased during ovarian stimulation, with some potential differences between normal and poor responders.     

Pregnancy and child outcome after assisted reproduction techniques

The introduction and widespread application of assisted reproduction techniques have raised major concern about the outcome of resulting pregnancies, as well as about the offspring's health. It seems that pregnancies achieved after standard in-vitro fertilization (IVF) bear an increased risk for prematurity and low birth weight. On the other hand, pregnancy outcome of singletons achieved after intracytoplasmic sperm injection (ICSI) and after the transfer of frozen-thawed embryos is similar to that of spontaneously conceived singletons, and pregnancy complications are related only to gestation multiplicity. The incidence of congenital and chromosomal anomalies after standard IVF seems to be similar to that expected in the general population. The prevalence of congenital malformations does not seem to be higher after ICSI. On the other hand, there is a slightly increased risk for transmission of chromosomal aberrations of paternal origin and a higher risk of de novo, mainly sex-chromosomal aberrations. Postnatal growth and development of children born after standard IVF and cryopreservation seem to be within the normal ranges. Growth of ICSI children is also normal while their mental development needs further investigation. Family functioning in assisted reproduction families is better.     

Abstracts of the 25<Superscript>th</Superscript> Annual Congress of the European Society for Gynaecological Endoscopy (ESGE), 2<Superscript>nd</Superscript>-5<Superscript>th</Superscript> October 2016, Square – Brussels – Belgium

What is the recommended diagnostic work-up of female genital anomalies according to the European Society of Human Reproduction and Embryology (ESHRE)/European Society for Gynaecological Endoscopy (ESGE) system? The ESHRE/ESGE consensus for the diagnosis of female genital anomalies is presented. Accurate diagnosis of congenital anomalies still remains a clinical challenge due to the drawbacks of the previous classification systems and the non-systematic use of diagnostic methods with varying accuracy, with some of them quite inaccurate. Currently, a wide range of non-invasive diagnostic procedures are available, enriching the opportunity to accurately detect the anatomical status of the female genital tract, as well as a new objective and comprehensive classification system with well-described classes and sub-classes. The ESHRE/ESGE Congenital Uterine Anomalies (CONUTA) Working Group established an initiative with the goal of developing a consensus for the diagnosis of female genital anomalies. The CONUTA working group and imaging experts in the field have been appointed to run the project. The consensus is developed based on (1) evaluation of the currently available diagnostic methods and, more specifically, of their characteristics with the use of the experts panel consensus method and of their diagnostic accuracy performing a systematic review of evidence and (2) consensus for (a) the definition of where and how to measure uterine wall thickness and (b) the recommendations for the diagnostic work-up of female genital anomalies, based on the results of the previous evaluation procedure, with the use of the experts panel consensus method. Uterine wall thickness is defined as the distance between interostial line and external uterine profile at the midcoronal plane of the uterus; alternatively, if a coronal plane is not available, the mean anterior and posterior uterine wall thickness at the longitudinal plane could be used. Gynaecological examination and two-dimensional ultrasound (2D US) are recommended for the evaluation of asymptomatic women. Three-dimensional ultrasound (3D US) is recommended for the diagnosis of female genital anomalies in “symptomatic” patients belonging to high-risk groups for the presence of a female genital anomaly and in any asymptomatic woman suspected to have an anomaly from routine avaluation. Magnetic resonance imaging (MRI) and endoscopic evaluation are recommended for the sub-group of patients with suspected complex anomalies or in diagnostic dilemmas. Adolescents with symptoms suggestive for the presence of a female genital anomaly should be thoroughly evaluated with 2D US, 3D US, MRI and endoscopy. The various diagnostic methods should be used in a proper way and evaluated by experts to avoid mis-, over- and underdiagnosis. The role of a combined ultrasound examination and outpatient hysteroscopy should be prospectively evaluated. It is a challenge for further research, based on diagnosis, to objectively evaluate the clinical consequences related to various degrees of uterine deformity.     

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.