The comprehensiveness of the ESHRE/ESGE classification of female genital tract congenital anomalies: a systematic review of cases not classified by the AFS system.

STUDY QUESTION How comprehensive is the recently published European Society of Human Reproduction and Embryology (ESHRE)/European Society for Gynaecological Endoscopy (ESGE) classification system of female genital anomalies? SUMMARY ANSWER The ESHRE/ESGE classification provides a comprehensive description and categorization of almost all of the currently known anomalies that could not be classified properly with the American Fertility Society (AFS) system. WHAT IS KNOWN ALREADY Until now, the more accepted classification system, namely that of the AFS, is associated with serious limitations in effective categorization of female genital anomalies. Many cases published in the literature could not be properly classified using the AFS system, yet a clear and accurate classification is a prerequisite for treatment. STUDY DESIGN, SIZE AND DURATION The CONUTA (CONgenital UTerine Anomalies) ESHRE/ESGE group conducted a systematic review of the literature to examine if those types of anomalies that could not be properly classified with the AFS system could be effectively classified with the use of the new ESHRE/ESGE system. An electronic literature search through Medline, Embase and Cochrane library was carried out from January 1988 to January 2014. Three participants independently screened, selected articles of potential interest and finally extracted data from all the included studies. Any disagreement was discussed and resolved after consultation with a fourth reviewer and the results were assessed independently and approved by all members of the CONUTA group. PARTICIPANTS/MATERIALS, SETTING, METHODS Among the 143 articles assessed in detail, 120 were finally selected reporting 140 cases that could not properly fit into a specific class of the AFS system. Those 140 cases were clustered in 39 different types of anomalies. MAIN RESULTS AND THE ROLE OF CHANCE The congenital anomaly involved a single organ in 12 (30.8%) out of the 39 types of anomalies, while multiple organs and/or segments of Müllerian ducts (complex anomaly) were involved in 27 (69.2%) types. Uterus was the organ most frequently involved (30/39: 76.9%), followed by cervix (26/39: 66.7%) and vagina (23/39: 59%). In all 39 types, the ESHRE/ESGE classification system provided a comprehensive description of each single or complex anomaly. A precise categorization was reached in 38 out of 39 types studied. Only one case of a bizarre uterine anomaly, with no clear embryological defect, could not be categorized and thus was placed in Class 6 (un-classified) of the ESHRE/ESGE system. LIMITATIONS, REASONS FOR CAUTION The review of the literature was thorough but we cannot rule out the possibility that other defects exist which will also require testing in the new ESHRE/ESGE system. These anomalies, however, must be rare. WIDER IMPLICATIONS OF THE FINDINGS The comprehensiveness of the ESHRE/ESGE classification adds objective scientific validity to its use. This may, therefore, promote its further dissemination and acceptance, which will have a positive outcome in clinical care and research. STUDY FUNDING/COMPETING INTERESTS None.

Kinase signalling pathways in endometriosis: potential targets for non-hormonal therapeutics.

BACKGROUND Endometriosis, the growth of endometrial tissue outside the uterine cavity, is associated with chronic pelvic pain, subfertility and an increased risk of ovarian cancer. Current treatments include the surgical removal of the lesions or the induction of a hypoestrogenic state. However, a reappearance of the lesion after surgery is common and a hypoestrogenic state is less than optimal for women of reproductive age. Additional approaches are required. Endometriosis lesions exist in a unique microenvironment characterized by increased concentrations of hormones, inflammation, oxidative stress and iron. This environment influences cell survival through the binding of membrane receptors and a subsequent cascading activation of intracellular kinases that stimulate a cellular response. Many of these kinase signalling pathways are constitutively activated in endometriosis. These pathways are being investigated as therapeutic targets in other diseases and thus may also represent a target for endometriosis treatment. METHODS To identify relevant English language studies published up to 2015 on kinase signalling pathways in endometriosis, we searched the Pubmed database using the following search terms in various combinations; 'endometriosis', 'inflammation', 'oxidative stress', 'iron', 'kinase', 'NF kappa', 'mTOR', 'MAPK' 'p38', 'JNK', 'ERK' 'estrogen' and progesterone'. Further citing references were identified using the Scopus database and finally current clinical trials were searched on the clinicaltrials.gov trial registry. RESULTS The current literature on intracellular kinases activated by the endometriotic environment can be summarized into three main pathways that could be targeted for treatments: the canonical IKKβ/NFκB pathway, the MAPK pathways (ERK1/2, p38 and JNK) and the PI3K/AKT/mTOR pathway. A number of pharmaceutical compounds that target these pathways have been successfully trialled in in vitro and animal models of endometriosis, although they have not yet proceeded to clinical trials. The current generation of kinase inhibitors carry a potential for adverse side effects. CONCLUSIONS Kinase signalling pathways represent viable targets for endometriosis treatment. At present, however, further improvements in clinical efficacy and the profile of adverse effects are required before these compounds can be useful for long-term endometriosis treatment. A better understanding of the molecular activity of these kinases, including the specific extracellular compounds that lead to their activation in endometriotic cells specifically should facilitate their improvement and could potentially lead to new, non-hormonal treatments of endometriosis.

Surplus embryos in Switzerland in 2003: legislation and availability of human embryos for research

Legislation influences the availability of embryos for research. The law in Switzerland, and in some other European countries, is restrictive concerning medically assisted reproduction and stem cell research. Swiss law prohibits the creation of embryos for research purposes. It permits the derivation of human embryonic stem cells for research from surplus embryos but prohibits research with intact surplus embryos and embryo donation to other couples. Swiss law defines all embryos generated during a reproductive cycle and not used for reproduction as surplus embryos. The aim of this study was to evaluate the surplus embryos generated in Switzerland in 2003. A detailed questionnaire was sent to all registered IVF units in Switzerland (n = 22). 11727 embryos were generated during 2003. Of these, 93.5% were transferred into the uterus and 0.4% were cryopreserved. The remaining 6.1% (n = 711) became surplus. Of these, 2.7% were transferred intravaginally and the rest discarded due to poor quality (1.6%), development arrest (1.5%), renunciation by the couple (0.2%) or for other reasons (0.1%). The number of surplus embryos in Switzerland in 2003 was evaluated. Most surplus embryos became so during a therapeutic cycle. The restrictive legal regulation decreases the availability of human embryos for research.

Human MAMLD1 Gene Variations Seem Not Sufficient to Explain a 46,XY DSD Phenotype

MAMLD1 is thought to cause disordered sex development in 46,XY patients. But its role is controversial because some MAMLD1 variants are also detected in normal individuals, several MAMLD1 mutations have wild-type activity in functional tests, and the male Mamld1-knockout mouse has normal genitalia and reproduction. Our aim was to search for MAMLD1 variations in 108 46,XY patients with disordered sex development, and to test them functionally. We detected MAMDL1 variations and compared SNP frequencies in controls and patients. We tested MAMLD1 transcriptional activity on promoters involved in sex development and assessed the effect of MAMLD1 on androgen production. MAMLD1 expression in normal steroid-producing tissues and mutant MAMLD1 protein expression were also assessed. Nine MAMLD1 mutations (7 novel) were characterized. In vitro, most MAMLD1 variants acted similarly to wild type. Only the L210X mutation showed loss of function in all tests. We detected no effect of wild-type or MAMLD1 variants on CYP17A1 enzyme activity in our cell experiments, and Western blots revealed no significant differences for MAMLD1 protein expression. MAMLD1 was expressed in human adult testes and adrenals. In conclusion, our data support the notion that MAMLD1 sequence variations may not suffice to explain the phenotype in carriers and that MAMLD1 may also have a role in adult life.

Retinoic acid receptor beta and angiopoietin-like protein 1 are involved in the regulation of human androgen biosynthesis

Androgens are essential for sexual development and reproduction. However, androgen regulation in health and disease is poorly understood. We showed that human adrenocortical H295R cells grown under starvation conditions acquire a hyperandrogenic steroid profile with changes in steroid metabolizing enzymes HSD3B2 and CYP17A1 essential for androgen production. Here we studied the regulatory mechanisms underlying androgen production in starved H295R cells. Microarray expression profiling of normal versus starved H295R cells revealed fourteen differentially expressed genes; HSD3B2, HSD3B1, CYP21A2, RARB, ASS1, CFI, ASCL1 and ENC1 play a role in steroid and energy metabolism and ANGPTL1, PLK2, DUSP6, DUSP10 and FREM2 are involved in signal transduction. We discovered two new gene networks around RARB and ANGPTL1, and show how they regulate androgen biosynthesis. Transcription factor RARB stimulated the promoters of genes involved in androgen production (StAR, CYP17A1 and HSD3B2) and enhanced androstenedione production. For HSD3B2 regulation RARB worked in cooperation with Nur77. Secretory protein ANGPTL1 modulated CYP17A1 and DUSP6 expression by inducing ERK1/2 phosphorylation. By contrast, our studies revealed no evidence for hormones or cell cycle involvement in regulating androgen biosynthesis. In summary, these studies establish a firm role for RARB and ANGPTL1 in the regulation of androgen production in H295R cells.