[First-line management of infertile couple. Guidelines for clinical practice of the French College of Obstetricians and Gynecologists 2022]. / Prise en charge de première intention du couple infertile : mise à jour des RPC 2010 du CNGOF.

OBJECTIVE: To update the 2010 CNGOF clinical practice guidelines for the first-line management of infertile couples. MATERIALS AND METHODS: Five major themes (first-line assessment of the infertile woman, first-line assessment of the infertile man, prevention of exposure to environmental factors, initial management using ovulation induction regimens, first-line reproductive surgery) were identified, enabling 28 questions to be formulated using the Patients, Intervention, Comparison, Outcome (PICO) format. Each question was addressed by a working group that had carried out a systematic review of the literature since 2010, and followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE®) methodology to assess the quality of the scientific data on which the recommendations were based. These recommendations were then validated during a national review by 40 national experts. RESULTS: The fertility work-up is recommended to be prescribed according to the woman's age: after one year of infertility before the age of 35 and after 6months after the age of 35. A couple's initial infertility work-up includes a single 3D ultrasound scan with antral follicle count, assessment of tubal permeability by hysterography or HyFOSy, anti-Mullerian hormone assay prior to assisted reproduction, and vaginal swabbing for vaginosis. If the 3D ultrasound is normal, hysterosonography and diagnostic hysteroscopy are not recommended as first-line procedures. Chlamydia trachomatis serology does not have the necessary performance to predict tubal patency. Post-coital testing is no longer recommended. In men, spermogram, spermocytogram and spermoculture are recommended as first-line tests. If the spermogram is normal, it is not recommended to check the spermogram. If the spermogram is abnormal, an examination by an andrologist, an ultrasound scan of the testicles and hormonal test are recommended. Based on the data in the literature, we are unable to recommend a BMI threshold for women that would contraindicate medical management of infertility. A well-balanced Mediterranean-style diet, physical activity and the cessation of smoking and cannabis are recommended for infertile couples. For fertility concern, it is recommended to limit alcohol consumption to less than 5 glasses a week. If the infertility work-up reveals no abnormalities, ovulation induction is not recommended for normo-ovulatory women. If intrauterine insemination is indicated based on an abnormal infertility work-up, gonadotropin stimulation and ovulation monitoring are recommended to avoid multiple pregnancies. If the infertility work-up reveals no abnormality, laparoscopy is probably recommended before the age of 30 to increase natural pregnancy rates. In the case of hydrosalpinx, surgical management is recommended prior to ART, with either salpingotomy or salpingectomy depending on the tubal score. It is recommended to operate on polyps>10mm, myomas 0, 1, 2 and synechiae prior to ART. The data in the literature do not allow us to systematically recommend asymptomatic uterine septa and isthmoceles as first-line surgery. CONCLUSION: Based on strong agreement between experts, we have been able to formulate updated recommendations in 28 areas concerning the initial management of infertile couples.

Pain assessment in women with or without endometriosis during the IVF process: a prospective study.

RESEARCH QUESTION: How does the typology and effect of pain vary between infertile patients with or without endometriosis during the different stages of the IVF process? DESIGN: A prospective, monocentric, observational cohort study was conducted at Lille University Hospital between November 2019 and June 2021. The study was proposed to all patients starting an IVF cycle. Pain assessment questionnaires using validated scales (about type of pain, without specific location), were completed by patients at key points during IVF: before starting treatment, at the end of stimulation and on the day of oocyte retrieval. RESULTS: A total of 278 patients were analysed: 73 patients with endometriosis and 205 without. At the start of the IVF process, patients with endometriosis had higher pain scores than disease-free women (mean numerical scale score 3.47 versus 1.12 [P < 0.0001]) and 17.81% of patients with endometriosis had neuropathic pain. For mental disorders before starting treatment, 22% of patients with endometriosis had suspected or confirmed depression, and 33% had anxiety compared with 8% and 20% in patients without endometriosis, respectively. During IVF, for patients without endometriosis, pain increased significantly between the baseline, the end of stimulation and on the day of retrieval (P ≤ 0.05). In patients with endometriosis, however, pain did not significantly vary during these times. CONCLUSION: Endometriosis is associated with higher pain scores, but no increase in pain was observed during IVF for these patients. It seems essential to screen and characterize pain phenotypes in all patients before starting treatment and during stimulation to improve pain management.

Evaluating the Performance of High-Dimensional Propensity Scores Compared with Standard Propensity Scores for Comparing Antihypertensive Therapies in the CPRD GOLD Database.

INTRODUCTION: Propensity score (PS) matching is widely used in medical record studies to create balanced treatment groups, but relies on prior knowledge of confounding factors. High-dimensional PS (hdPS) is a semi-automated algorithm that selects variables with the highest potential for confounding from medical databases. The objective of this study was to evaluate performance of hdPS and PS when used to compare antihypertensive therapies in the UK clinical practice research datalink (CPRD) GOLD database. METHODS: Patients initiating antihypertensive treatment with either monotherapy or bitherapy were extracted from the CPRD GOLD database. Simulated datasets were generated using plasmode simulations with a marginal hazard ratio (HRm) of 1.29 for bitherapy versus monotherapy for reaching blood pressure control at 3 months. Either 16 or 36 known covariates were forced into the PS and hdPS models, and 200 additional variables were automatically selected for hdPS. Sensitivity analyses were conducted to assess the impact of removing known confounders from the database on hdPS performance. RESULTS: With 36 known covariates, the estimated HRm (RMSE) was 1.31 (0.05) for hdPS and 1.30 (0.04) for PS matching; the crude HR was 0.68 (0.61). Using 16 known covariates, the estimated HRm (RMSE) was 1.23 (0.10) and 1.09 (0.20) for hdPS and PS, respectively. Performance of hdPS was not compromised when known confounders were removed from the database. RESULTS ON REAL DATA: With 49 investigator-selected covariates, the HR was 1.18 (95% CI 1.10; 1.26) for PS and 1.33 (95% CI 1.22; 1.46) for hdPS. Both methods yielded the same conclusion, suggesting superiority of bitherapy over monotherapy for time to blood pressure control. CONCLUSION: HdPS can identify proxies for missing confounders, thereby having an advantage over PS in case of unobserved covariates. Both PS and hdPS showed superiority of bitherapy over monotherapy for reaching blood pressure control.

Hypothalamic neuroglial plasticity is regulated by anti-Müllerian hormone and disrupted in polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common reproductive-endocrine disorder affecting between 5 and 18% of women worldwide. An elevated frequency of pulsatile luteinizing hormone (LH) secretion and higher serum levels of anti-Müllerian hormone (AMH) are frequently observed in women with PCOS. The origin of these abnormalities is, however, not well understood. METHODS: We studied brain structure and function in women with and without PCOS using proton magnetic resonance spectroscopy (MRS) and diffusion tensor imaging combined with fiber tractography. Then, using a mouse model of PCOS, we investigated by electron microscopy whether AMH played a role on the regulation of hypothalamic structural plasticity. FINDINGS: Increased AMH serum levels are associated with increased hypothalamic activity/axonal-glial signalling in PCOS patients. Furthermore, we demonstrate that AMH promotes profound micro-structural changes in the murine hypothalamic median eminence (ME), creating a permissive environment for GnRH secretion. These include the retraction of the processes of specialized AMH-sensitive ependymo-glial cells called tanycytes, allowing more GnRH neuron terminals to approach ME blood capillaries both during the run-up to ovulation and in a mouse model of PCOS. INTERPRETATION: We uncovered a central function for AMH in the regulation of fertility by remodeling GnRH terminals and their tanycytic sheaths, and provided insights into the pivotal role of the brain in the establishment and maintenance of neuroendocrine dysfunction in PCOS. FUNDING: INSERM (U1172), European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement n° 725149), CHU de Lille, France (Bonus H).

Comparison of two endometrial preparation methods for frozen-thawed embryo transfer in anovulatory PCOS patients: Impact on miscarriage rate.

OBJECTIVE: Some studies have suggested that patients with polycystic ovary syndrome (PCOS) are at high risk of miscarriage. However, this still remains controversial. Several potential factors might explain this association: obesity, hyperinsulinemia and hyperandrogenism. Artificial and stimulated cycles appear to be comparable for endometrial preparation in frozen-thawed embryo transfer (FET) in PCOS patients. Only a few studies have assessed miscarriage rates specifically in PCOS. We have evaluated the impact of endometrial preparation on FET outcomes in anovulatory PCOS patients. METHODS: A retrospective cohort study was conducted at the Lille University Hospital, including 255 FET cycles in 134 PCOS patients between January 2011 and December 2017. PCOS was defined by the presence of at least two of the three Rotterdam's criteria. Patients were under 35 years old. Two endometrial preparation protocol were studied: stimulated cycle (gonadotropins on the second day of the cycle and luteal phase support including natural progesterone 600 mg/day) and artificial cycle (6 mg oral estradiol valerate and 800 mg micronized vaginal progesterone daily). RESULTS: 137 FET were performed under stimulated cycle and 118 FET under artificial cycle. Early pregnancy rates (30% versus 37.3%, p = NS), miscarriage rates (22% versus 25%, p = NS) and live birth rates (23.4% versus 26.3%, p = NS) were similar. CONCLUSIONS: In anovulatory PCOS women, the type of endometrial preparation does not influence FET outcomes, specifically regarding the miscarriage rate.

Systematic use of long-acting intramuscular progesterone in addition to oral dydrogesterone as luteal phase support for single fresh blastocyst transfer: A pilot study.

Objective: The need of luteal support after FET is no longer to be proven. Different routes of progesterone administration are available with interindividual differences in metabolization and serum progesterone levels, the latter being highly correlated with pregnancy and delivery rates. The administration of 2 different routes of progestogen significantly improves success rates in FET. The aim of the current study was to investigate the added value to combine intramuscular administration of progesterone to dydrogesterone in fresh embryo transfer. Methods: This is a retrospective study from prospectively collected data. Patient, aged between 18 and 43 years old, had received a fresh blastocyst transfer between January 2021 and June 2021. In the first group, all patients received only oral dydrogesterone 10mg, three times a day, beginning the evening of oocyte retrieval. In the second group, patients received, in addition to dydrogesterone, a weekly intramuscular injection of progesterone started the day of embryo transfer. Primary endpoint was ongoing pregnancy rate. Results: 171 fresh single blastocyst transfers have been performed during this period. 82 patients were included in "dydrogesterone only" and 89 patients in "dydrogesterone + IM". Our two groups were comparable except for body mass index. After adjustment on BMI, our two groups were comparable regarding implantation rate, early pregnancy rate (46.1 versus 54.9, OR 1.44 [0.78; 2.67], p=0.25) miscarriage rate, ongoing pregnancy rate (30.3 versus 43.9, OR 1.85 [0.97; 3.53] p= 0.06). Conclusion: Using systematically long acting intramuscular progesterone injection in addition to oral dydrogesterone as luteal phase support seems to have no significant impact on IVF outcomes when a single fresh blastocyst transfer is performed.

Polycystic ovary syndrome is transmitted via a transgenerational epigenetic process.

Polycystic ovary syndrome (PCOS) is the most common reproductive and metabolic disorder affecting women of reproductive age. PCOS has a strong heritable component, but its pathogenesis has been unclear. Here, we performed RNA sequencing and genome-wide DNA methylation profiling of ovarian tissue from control and third-generation PCOS-like mice. We found that DNA hypomethylation regulates key genes associated with PCOS and that several of the differentially methylated genes are also altered in blood samples from women with PCOS compared with healthy controls. Based on this insight, we treated the PCOS mouse model with the methyl group donor S-adenosylmethionine and found that it corrected their transcriptomic, neuroendocrine, and metabolic defects. These findings show that the transmission of PCOS traits to future generations occurs via an altered landscape of DNA methylation and propose methylome markers as a possible diagnostic landmark for the condition, while also identifying potential candidates for epigenetic-based therapy.

Transformation of paracetamol into 1,4-benzoquinone by a manganese oxide bed filter.

This study investigates the transformation of paracetamol (PRC) by a granular manganeseoxide in a column bed reactor. Paracetamol was quantitatively transformed into p-benzoquinone(BZQ) for empty bed residence times (EBRT) <5 min at pH 6.0. For 5mM MOPS (3-morpholinopropane-1-sulfonic acid) and pH 7.0, the mean removal yield of PRC was 77% for initial PRC concentrations ranging from 0.1 to 50 µM. Conversion of PRC and formation of BZQ decreased when pH increased from 6 to 8. Dimer of PRC was observed at pH 7.0, which could explain the lower conversion into BZQ when pH increased. The presence of organic buffer MOPS and natural organic matter (NOM) reduced the oxidation of PRC because of competition reactions for active sites. The formation of the toxic BZQ metabolite was reduced in presence of NOM because of cross-coupling reactions between phenoxyl radicals and NOM. Results suggest that manganese oxide bed filter can be used to remove pharmaceutical compounds including phenolic moiety in their structure.

One pot synthesis of new hybrid versatile nanocarrier exhibiting efficient stability in biological environment for use in photodynamic therapy.

A new versatile hybrid nanocarrier has been designed using a "soft chemistry" synthesis, to efficiently encapsulate a photosensitizer - the protoporphyrin IX (Pp IX) - while preserving its activity intact in biological environment for advantageous use in photodynamic therapy (PDT). The synthesized Pp IX silica-based nanocarriers show to be spherical in shape and highly monodisperse with size extending from 10 nm up to 200 nm according to the synthesis procedure. Upon laser irradiation, the entrapped Pp IX shows to efficiently deliver reactive oxygen species (ROS) which are responsible for damaging tumor tissues. The ability of Pp IX silica-based nanocarriers to induce tumor cell death has been tested successfully in vitro. The stability of the Pp IX silica-based nanocarriers has been followed by UV-vis absorption and fluorescence emission in aqueous media and in 100% mouse serum media. The flexibility of the nanocarrier silica core has been examined as the key parameter to tune the Pp IX stability in biological environment. Indeed, an additional biocompatible inorganic surface coating performed on the Pp IX silica-based nanocarriers to produce an optimized bilayer coating demonstrates to significantly enhance the Pp IX stabilization in biological environments. Such versatile hybrid nanocarriers open new perspectives for PDT.

Pp IX silica nanoparticles demonstrate differential interactions with in vitro tumor cell lines and in vivo mouse models of human cancers.

Protoporphyrin IX (Pp IX) silica nanoparticles, developed for effective use in photodynamic therapy (PDT), were explored in in vitro and in vivo models with the ambition to improve knowledge on the role of biological factors in the photodamage. Pp IX silica nanoparticles are found efficient at temperature with extreme metabolic downregulation, which suggest a high proportion of passive internalization. For the first time, clearance of silica nanoparticles on tumor cells is established. Cell viability assessment in six tumor cell lines is reported. In all tumor types, Pp IX silica nanoparticles are more efficient than free Pp IX. A strong fluorescence signal of reactive oxygen species generation colocalized with Pp IX silica nanoparticles, correlates with 100% of cell death. In vivo studies performed in HCT 116, A549 and glioblastoma multiforme tumors-bearing mice show tumor uptake of Pp IX silica nanoparticles with better tumor accumulation than the control alone, highlighting a high selectivity for tumor tissues. As observed in in vitro tests, tumor cell type is likely a major determinant but tumor microenvironment could more influence this differential time accumulation dynamic. The present results strongly suggest that Pp IX silica nanoparticles may be involved in new alternative local applications of PDT.

[Clinical and molecular consequences of microsatellite instability in human cancers]. / Conséquences cliniques et moléculaires de l'instabilité des microsatellites dans les cancers humains.

During each cell division, DNA polymerase makes mistakes while copying DNA. These errors, more frequent at the level of repeated sequences called microsatellites are normally repaired by a system called MMR (mismatch repair). Tumors defective in their MMR system accumulate mutations (deletions and insertions of some nucleotides) at the level of microsatellites and are called MSI (microsatellite instability). Microsatellites are numerous and scattered throughout the genome, in coding and non-coding regions. The instability of non-coding microsatellites is not known to have a major role in the process of cell transformation, but is a good indicator of the MSI status. On the other hand, instability by deletion or insertion in a coding region leads to a frameshift within the gene containing the repeat. The consequence is, the more often, the inactivation of this gene that potentially plays a role in initiation and/or MSI tumor progression. The MSI phenotype was first described in about 15 % of colorectal cancers that maybe of sporadic or hereditary (Lynch syndrome, or HNPCC for hereditary non-polyposis colorectal cancer) origin. It is also associated with about 15 % of gastric and endometrial tumors, and to a lesser extent with other human tumors. Besides a fundamental interest because of its original transformation mechanism, the analysis of MSI tumors is also important for clinical reasons. It was indeed shown that MSI tumors were associated with a better prognosis than non-MSI (also called MSS for microsatellite stable) tumors, and responded differently to conventional chemotherapeutic drugs used for the management of colorectal cancers. All these points will be discussed in details in the present review.

Fabry disease: a review.

Fabry disease is an inherited deficiency of the lysosomal hydrolase alpha-galactosidase A (alpha GalA) due to mutations in the Gal gene at Xq22. The result is intralysosomal accumulation of glycosphingolipids. In males who carry the mutation (1/40,000), severe multisystem disease develops in childhood or adolescence. Attacks of acute pain lasting a few minutes to a few days occur in the hands and feet, joints, muscles, and abdomen, sometimes with a fever. Highly suggestive skin lesions called angiokeratomas develop, as well as cornea verticillata characterized by corneal deposits without visual impairment. Stroke, seizures, heart disorders (conduction disturbances, valve disease, and left heart failure) and kidney disorders (proteinuria and chronic renal failure) develop in the third or fourth decade of life. Women who are heterozygous for the Gal gene can transmit the disease to their sons but are usually free of symptoms, although many have cornea verticillata. However, they may have moderate or severe disease related to uneven chromosome X inactivation. Late-onset variants with predominant neurological, cardiac, or renal manifestations have been described. The diagnosis is difficult when the family history is negative for Fabry disease. Tests on plasma and leukocytes show very low levels of alpha GalA activity in affected men, confirming the diagnosis. The Gal gene mutation should be looked for to detect heterozygous women. Symptomatic treatments include analgesics, antihypertensives, antiplatelet agents or anticoagulants to treat ischemic events, and hemodialysis or kidney transplantation to treat chronic renal failure. The recent introduction of enzyme replacement therapy with recombinant agalsidase alpha or beta has been a major breakthrough in the treatment of Fabry disease. Enzyme replacement therapy relieves the pain and decreases the risk of complications. The safety profile is good. Given the high cost of agalsidase therapy (about 160,000 euro/year/patient) and the low incidence of Fabry disease, patients should be referred to highly specialized centers (see addresses on the France Orphanet web site).

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS): definition, semiology, prognosis, pathogenesis, treatment, and place relative to other periodic joint diseases.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant inherited condition of periodic fever and pain. Most patients are of northern European descent. The attacks manifest as fever and pain in the joints, abdomen, muscles, skin, or eyes, with variations across patients. An acute-phase response occurs during the attacks. Patients with TRAPS are at risk for AA amyloidosis, the most common targets being the kidneys and liver. Soluble TNFRSF1A is usually low between the attacks and may be normal during the attacks, when TNF levels are high. TNFRSF1A is found in abnormally high numbers on leukocyte cell membranes. TRAPS is the first condition for which naturally occurring mutations in a TNF receptor were found; the mutations affect the soluble TNFRSF1A gene in the 12p13 region. In some patients, the pathogenesis involves defective TNFRSF1A shedding from cell membranes in response to a given stimulus. Thus, TRAPS is a model for a novel pathogenic concept characterized by failure to shed a cytokine receptor. This review compares TRAPS to other inherited periodic febrile conditions, namely, familial Mediterranean fever, Muckle-Wells syndrome, cold urticaria, and hyper-IgD syndrome. The place of TRAPS relative to other intermittent systemic joint diseases is discussed. Colchicine neither relieves nor prevents the attacks, whereas oral glucocorticoid therapy is effective when used in dosages greater than 20 mg/day. The pathogenic hypothesis involving defective TNFRSF1A shedding suggests that medications targeting TNF may be effective in TRAPS.