The case for mild stimulation for IVF: recommendations from The International Society for Mild Approaches in Assisted Reproduction.

The practice of ovarian stimulation for IVF is undergoing a fundamental re-evaluation as recent data begin to successfully challenge the traditional paradigm that ovarian stimulation should be aimed at the retrieval of as many oocytes as possible, in the belief that this will increase pregnancy rates. An opposing view is that live birth rate should not be the only end-point in evaluating the success of IVF treatment and that equal emphasis should be placed on safety and affordability. The International Society for Mild Approaches in Assisted Reproduction (ISMAAR) committee has carried out an up-to-date literature search, with the evidence being graded according to the University of Oxford's Centre for Evidence-Based Medicine. The recommendations were formulated taking into account the quality of evidence on the efficacy, risk and cost of each intervention. ISMAAR recommends adopting a mild approach to ovarian stimulation in all clinical settings as an increasing body of evidence suggests that mild stimulation is as effective as conventional stimulation, while being safer and less expensive. Mild ovarian stimulation could replace conventional stimulation, thus making IVF safer and more accessible worldwide.

Is there a link between plasma progesterone 1-2 days before frozen embryo transfers (FET) and ART outcomes in frozen blastocyst transfers?

OBJECTIVE: To study the efficacy of combined administration of subcutaneous and vaginal progesterone for priming frozen blastocysts transfers, looking at progesterone levels and ART outcome. DESIGN: Retrospective study. SETTING PATIENTS: Three hundred and twenty frozen blastocyst transfer cycles conducted in 213 women aged up to 42 years, BMI between 18 and 30 kg/m2, with anatomically normal uterus who underwent frozen embryo transfers (FETs) from February 2019 to December 2019 with a combined luteal-phase support (LPS) associating subcutaneous and vaginal progesterone. Patients with recurrent pregnancy loss (RPL) were excluded. RESULTS: When using combined vaginal and subcutaneous LPS, SPL >10.50 ng/mL in 95% of cases, with a minimum value of 7.02 ng/mL. CPR, OPR, and global miscarriage rates were 38.4%, 30.9%, and 19.5%, respectively. Analyzing results per quartiles, revealed that miscarriage rates were significantly inferior, and IR were higher in the upper two quartiles of serum progesterone (>21.95 ng/mL) on the day before FET, while there was no difference in CPR and OPR. CONCLUSIONS: We report ART outcome of frozen blastocyst transfers performed using a combination of vaginal and subcutaneous progesterone for LPS. ART results were honorable and SPL favorable 1-2 days before FET in 99% of cases.

Comparative anatomy on 3-D MRI of the urogenital sinus and the periurethral area before and during the second stage of labor during childbirth.

PURPOSE OF THE STUDY: To describe the observable MRI changes in the urogenital sinus during the second stage of labor and delivery by comparing the changes in the positions of the anatomical structures of the maternal perineum using MRI-based vector 3-D models. MATERIALS AND METHODS: Seven pregnant women underwent 3-D MRI sequences using a Philips 1 T Panorama open MRI during the pre-labor period and during the second stage of labor. A 3-D vector reconstruction platform (BABYPROGRESS, France) enabled the transformation of volumes of 2-D images into finite element meshes. The polygonal meshes labeled with the principal components of the urogenital sinus were used as part of a biomechanical study of the pressure exerted on the perineum during fetal descent. RESULTS: The expansion of the urogenital sinus was observed in all patients. Qualitative stretching was observed toward the rear and bottom of the iliococcygeus, pubococcygeus, puborectalis and obturator internus muscles. Significant length differences were measured along the iliococcygeus and pubococcygeus muscles but not along the tendinous arch of the levator ani or the puborectalis muscle. The inversion of the levator ani muscle curvature was accompanied by the transmission of pressure generated during fetal descent to the pubic muscle insertions and the descent of the tendinous arch of the levator ani. CONCLUSION: Mechanical pressures responsible for the tensioning of the constituent muscles of the urogenital sinus were qualitatively identified during the second stage of labor. MRI-based vector 3-D models allow the quantitative assessment of levator ani muscle stretching during labor, but 2-D MRI is not sufficient for describing perineal expansion. Vector 3-D models from larger scale studies have the potential to aid in the calibration of a realistic simulation based on the consideration of the reaction of each muscular element. These models offer perspectives to enhance our knowledge regarding perineal expansion during childbirth as a risk factor for postpartum perineal defects.

[Uterus transplantation: state of knowledge and ethical reflection]. / Greffe utérine : état des lieux et réflexion éthique.

Uterus transplantation: state of knowledge and ethical reflection. Nowadays is uterine transplantation the only treatment for absolute uterine infertility. This experimental surgery is spreading worldwide since the past two years. The first livebirths from uterus transplantations from living donors in Sweden gave the impetus for more research. Since several team works on the uterine transplantation from living or deceased donors. Uterus transplantation and the choice between live and deceased donor raises up technical and ethical questions.

Greffe utérine : état des lieux et réflexion éthique. La greffe utérine est à ce jour le seul traitement de la stérilité d'origine utérine. Cette chirurgie expérimentale est en expansion à travers le monde, en particulier depuis ces deux dernières années. L'élan a été donné par les premières naissances obtenues en Suède en 2014 à l'issue de greffes à partir de donneuses vivantes. Depuis, plusieurs équipes travaillent sur la greffe à partir de donneuses vivantes mais également en état de mort encéphalique. La greffe utérine en tant que telle ainsi que le choix entre les donneuses vivantes et décédées soulèvent de nombreuses questions techniques et éthiques.

Mutation dependance of the mitochondrial DNA copy number in the first stages of human embryogenesis.

Mitochondrial DNA (mtDNA) content is thought to remain stable over the preimplantation period of human embryogenesis that is, therefore, suggested to be entirely dependent on ooplasm mtDNA capital. We have explored the impact of two disease-causing mutations [m.3243A>G myopathy, encephalopathy, lactic acidosis and stroke-like syndrome (MELAS) and m.8344A>G myoclonic epilepsy associated with ragged-red fibers (MERRF)] on mtDNA amounts in human oocytes and day 4-5 preimplantation embryos. The mtDNA amount was stable in MERRF and control materials, whereas gradually increasing from the germinal vesicle of oogenesis to the blastocyst stage of embryogenesis in MELAS cells, MELAS embryos carrying ∼3-fold higher mtDNA amount than control embryos (P = 0.0003). A correlation between mtDNA copy numbers and mutant loads was observed in MELAS embryos (R(2) = 0.42, P < 0.0013), suggestive of a compensation for the respiratory chain defect resulting from high mutation levels. These results suggest that mtDNA can replicate in early embryos and emphasize the need for sufficient amount of wild-type mtDNA to sustain embryonic development in humans.

Poor correlations in the levels of pathogenic mitochondrial DNA mutations in polar bodies versus oocytes and blastomeres in humans.

Because the mtDNA amount remains stable in the early embryo until uterine implantation, early human development is completely dependent on the mtDNA pool of the mature oocyte. Both quantitative and qualitative mtDNA defects therefore may negatively impact oocyte competence or early embryonic development. However, nothing is known about segregation of mutant and wild-type mtDNA molecules during human meiosis. To investigate this point, we compared the mutant levels in 51 first polar bodies (PBs) and their counterpart (oocytes, blastomeres, or whole embryos), at risk of having (1) the "MELAS" m.3243A>G mutation in MT-TL1 (n = 30), (2) the "MERRF" m.8344A>G mutation in MT-TK (n = 15), and (3) the m.9185T>G mutation located in MT-ATP6 (n = 6). Seven out of 51 of the PBs were mutation free and had homoplasmic wild-type counterparts. In the heteroplasmic PBs, measurement of the mutant load was a rough estimate of the counterpart mutation level (R(2) = 0.52), and high mutant-load differentials between the two populations were occasionally observed (ranging from -34% to +34%). The mutant-load differentials between the PB and its counterpart were higher in highly mutated PBs, suggestive of a selection process acting against highly mutated cells during gametogenesis or early embryonic development. Finally, individual discrepancies in mutant loads between PBs and their counterparts make PB-based preconception diagnosis unreliable for the prevention of mtDNA disorder transmission. Such differences were not observed in animal models, and they emphasize the need to conduct thorough studies on mtDNA segregation in humans.

Concerns about the widespread use of rodent models for human risk assessments of endocrine disruptors.

Fetal testis is a major target of endocrine disruptors (EDs). During the last 20 years, we have developed an organotypic culture system that maintains the function of the different fetal testis cell types and have used this approach as a toxicological test to evaluate the effects of various compounds on gametogenesis and steroidogenesis in rat, mouse and human testes. We named this test rat, mouse and human fetal testis assay. With this approach, we compared the effects of six potential EDs ((mono-(2-ethylhexyl) phthalate (MEHP), cadmium, depleted uranium, diethylstilboestrol (DES), bisphenol A (BPA) and metformin) and one signalling molecule (retinoic acid (RA)) on the function of rat, mouse and human fetal testis at a comparable developmental stage. We found that the response is similar in humans and rodents for only one third of our analyses. For instance, RA and MEHP have similar negative effects on gametogenesis in the three species. For another third of our analyses, the threshold efficient concentrations that disturb gametogenesis and/or steroidogenesis differ as a function of the species. For instance, BPA and metformin have similar negative effects on steroidogenesis in human and rodents, but at different threshold doses. For the last third of our analyses, the qualitative response is species specific. For instance, MEHP and DES affect steroidogenesis in rodents, but not in human fetal testis. These species differences raise concerns about the extrapolation of data obtained in rodents to human health risk assessment and highlight the need of rigorous comparisons of the effects in human and rodent models, when assessing ED risk.

Serous adenocarcinoma of the ovary diagnosed during ultrasound evaluation for fertility preservation.

Breast cancer is the most common malignant tumor in women of reproductive age, and fertility preservation counseling is now an integral part of the initial management of these patients. This article reports the case of a 33-year-old woman diagnosed with breast cancer and referred for oncofertility counseling before her treatment. Despite a previous negative cancer workup, a transvaginal ultrasound scan, performed for antral follicle count as part of the initial ovarian reserve assessment, revealed a synchronous ovarian adenocarcinoma. A BRCA1 mutation was confirmed weeks later. This report highlights the role of transvaginal ultrasound in the initial evaluation and reviews the risks associated with fertility preservation in breast cancer patients.

Differences in transcriptomic profiles of human cumulus cells isolated from oocytes at GV, MI and MII stages after in vivo and in vitro oocyte maturation.

BACKGROUND: Oocyte maturation and competence to development depends on its close relationship with cumulus cells (CCs). However, the maturation conditions of human cumulus-oocyte complexes (COCs) might affect gene expression in both oocyte and CCs. We thus compared the transcriptome profiles of CCs isolated from in vivo and in vitro matured COCs at different nuclear maturation stages. METHODS: Three groups of CCs from patients who underwent ICSI were included: CCs of patients with polycystic ovary syndrome (PCOS) referred for in vitro maturation (IVM), CCs from patients with PCOS for in vivo maturation (used as controls) and CCs from normal responders referred for in vivo maturation. CCs were isolated from COCs at the germinal vesicle, metaphase I and metaphase II stages. Microarray technology was used to analyse the global gene expression and significance analysis of microarray to compare the expression profiles of CCs from COCs at different nuclear maturation stages following IVM or in vivo maturation. Selected genes were validated by RT-qPCR. RESULTS: In CCs isolated after IVM, genes related to cumulus expansion and oocyte maturation, such as EREG, AREG and PTX3, were down-regulated, while cell cycle-related genes were up-regulated in comparison with CCs from in vivo matured COCs from PCOS and normal responder patients. Moreover, irrespective of the stage of oocyte maturation, genes involved in DNA replication, recombination and repair were up-regulated in CCs after IVM. CONCLUSIONS: The CC transcriptomic signature varies according to both the oocyte maturation stage and the maturation conditions. Our findings suggest a delay in the acquisition of the mature CC phenotype following IVM, opening a new perspective for the improvement in IVM conditions.

Oocyte cryopreservation following failed testicular sperm extraction: a French case report with implications for the management of non-obstructive azoospermia.

The French law regulating assisted reproductive technologies forbids donor spermatozoa to be available in case of failed testicular sperm extraction (TESE) performed on the day of oocyte retrieval. This article reports the first French live birth after intracytoplasmic sperm injection of donated spermatozoa into frozen-thawed oocytes cryopreserved following failure of TESE. By reinforcing the relevance of TESE performed on the day of oocyte retrieval, oocyte cryopreservation in couples having beforehand consented to go to sperm donation will avoid cycle cancellation and potentially lead to successful live birth. Therefore, it could modify the French policy of management of patients suffering from non-obstructive azoospermia.

Circulating trophoblastic cells provide genetic diagnosis in 63 fetuses at risk for cystic fibrosis or spinal muscular atrophy.

This study sought to determine whether a reliable non-invasive prenatal diagnosis (NI-PND) of cystic fibrosis (CF) or spinal muscular atrophy (SMA) can be achieved through analysis of circulating fetal trophoblastic cells (CFTC). The kinetics of CFTC circulation were also studied. CFTC were isolated by isolation by size of epithelial tumour/trophoblastic cells at 9-11 weeks of gestation, before chorionic villus sampling (CVS), from the blood of 63 pregnant women at 25% risk for having a child affected by either CF (n=32) or SMA (n=31). Collected cells were laser-microdissected, short tandem repeat-genotyped to determine fetal origin and blindly assessed for mutation analysis. CFTC were independently analysed weekly (4-12 weeks of gestation) in 14 women who achieved pregnancy following IVF. Diagnostic results were compared with those obtained by CVS. All seven CF and seven SMA pregnancies carrying an affected fetus were correctly identified as well as non-affected pregnancies. CFTC provided 100% diagnostic sensitivity (95% CI 76.8-100%) and specificity (95% CI 92.7-100%) in these 63 consecutive pregnancies at risk for CF or SMA. CFTC were found to circulate from 5 weeks of gestation and can be used to develop an early and reliable approach for NI-PND. We sought to determine whether a reliable non-invasive prenatal diagnosis (NI-PND) of two rare genetic diseases - cystic fibrosis (CF) and spinal muscular atrophy (SMA) - can be achieved through analysis of circulating fetal trophoblastic cells (CFTC) in blood of pregnant women. We also studied the time of appearance and circulation of CFTC in maternal blood. CFTC were isolated from maternal blood by isolation by size of epithelial tumour/trophoblastic cells (ISET; an approach for cell isolation from blood) at 9-11 weeks of gestation before chorionic villus sampling (CVS) from the blood of 63 pregnant women at 25% risk for having a child affected by either CF (n=32) or SMA (n=31). Collected cells were analysed by genetic test to determine fetal origin and blindly assessed for mutation analysis. We independently analysed CFTC in maternal blood samples taken weekly (4-12 weeks of gestation) from 14 women who achieved pregnancy following IVF. Diagnostic results were compared with those obtained by CVS. All seven CF and seven SMA pregnancies carrying an affected fetus were correctly identified as well as non-affected pregnancies. CFTC provided 100% diagnostic sensitivity and specificity in these 63 consecutive pregnancies at risk for CF or SMA. CFTC were found to circulate from 5 weeks of gestation and can be used to develop an early and reliable approach for NI-PND.

Predictive score for early preterm birth in decisions about emergency cervical cerclage in singleton pregnancies.

OBJECTIVE: To develop a simple score for assessing the risk of early preterm delivery before 32 weeks in women with singleton pregnancies receiving emergency cervical cerclage. DESIGN: Retrospective study. SETTING: French tertiary care center from 1994 to 2006. POPULATION: A total of 134 pregnant women underwent emergency cervical cerclage procedure at 15-26 weeks. The analysis concerned 85 singleton pregnancies after exclusion of women with a dilated cervix without visible membranes, or presenting for revision of failed prophylactic cerclage, or who had either preterm premature rupture of membranes or clinical signs of chorioamnionitis. METHODS: Multivariate logistic regression methods with rounded coefficients were used to develop a score to predict early preterm delivery before 32 weeks. MAIN OUTCOME MEASURES: Early preterm delivery before 32 weeks. RESULTS: The score, ranging from 0 to 15 points, was based on the following four criteria independently associated with early preterm delivery: obstetric history; cervical dilatation; membranes bulging into the vagina; and infection. Each score value was associated with a predicted probability of early preterm birth. CONCLUSIONS: The score and its associated early preterm probabilities may be a valuable tool to help physicians in advising women about the need for emergency cerclage.

Accuracy of three-dimensional ultrasonography in differential diagnosis of septate and bicornuate uterus compared with office hysteroscopy and pelvic magnetic resonance imaging.

STUDY OBJECTIVE: To estimate the accuracy of 3-dimensional (3-D) ultrasonography in the differential diagnosis of septate and bicornuate uterus compared with office hysteroscopy and pelvic magnetic resonance imaging (MRI). DESIGN: Prospective cohort study (Canadian Task Force Classification II-2). SETTING: University hospital. PATIENTS: Thirty-one patients referred with a suspected diagnosis of septate (n = 20) or bicornuate (n = 11) uterus. INTERVENTIONS: All patients underwent 3-D ultrasonography displaying the rebuilt coronal view of the uterus, office hysteroscopy, and pelvic MRI. Operative hysteroscopic assessment and treatment was performed in case of sonographically diagnosed septate uterus. Bicornuate uterus was confirmed by laparoscopy. MAIN OUTCOMES MEASURES: Concordance between suspected diagnosis with 3-D ultrasonography, hysteroscopy, and pelvic MRI and final diagnosis. RESULTS: A septate uterus was diagnosed with 3-D ultrasonography in 29 patients and bicornuate uterus in 2 patients. Hysteroscopic transcervical section of the uterine septum was achieved in the 29 patients. Bicornuate uterus was laparoscopically confirmed in the 2 patients. Concordance between ultrasonography and operative hysteroscopy or laparoscopy was verified in all 31 cases. Twenty-five uterine septa and 5 bicornuate uteri were diagnosed by hysteroscopy (3 false-positive diagnoses of bicornuate uterus, 1 unfeasible hysteroscopy). Hysteroscopic diagnosis was correct in 27/30 patients. Twenty-four septate uteri and 7 bicornuate uteri were diagnosed by MRI (5 false-positive diagnoses of bicornuate uterus). Two complete septate uteri diagnosed by MRI were finally confirmed as incomplete septate uteri after 3-D ultrasonography and operative hysteroscopy. MRI diagnosis was correct in 24/31 patients. CONCLUSION: Transvaginal 3-D ultrasonography appears to be extremely accurate for the diagnosis and classification of congenital uterine anomalies, more than office hysteroscopy and MRI. It may conveniently become the only mandatory step in the assessment of the uterine cavity in patients with a suspected septate or bicornuate uterus.

Treatment of twenty-two patients with complete uterine and vaginal septum.

STUDY OBJECTIVE: To assess the fertility and obstetric outcome after surgical treatment of complete uterine and vaginal septum. DESIGN: Retrospective study (Canadian Task Force Classification II-2). SETTING: Teaching hospital in France. PATIENTS: Twenty-two women who have experienced infertility, pregnancy losses, dyspareunia, or dysmenorrhea. INTERVENTION: Hysteroscopic section of complete uterine septum and resection of longitudinal vaginal septum. MEASUREMENTS AND MAIN RESULTS: Improvement of dyspareunia or dysmenorrhea and obstetric outcome, focusing on the miscarriage rate, obstetric complications, and the gestational age at delivery were assessed. Overall, 20 women had conceived a total of 37 pregnancies, with 10 and 8 deliveries before and after metroplasty, respectively. Median gestational age at delivery was not significantly different in both groups (36.5 [33-39.5] vs 38.0 weeks' gestation [35-40], respectively). Preterm delivery occurred in 4 cases (25%) before the surgery and in 3 cases (14%) after (p = .44). The live birth rate was also not significantly different before and after surgery (62.5% and 38%, respectively) (p = .19). There was a decrease of caesarean section and significantly fewer breech deliveries after metroplasty (p = .01). A decrease in the prevalence of dyspareunia or dysmenorrhea was observed after metroplasty in the 19 patients originally displaying these symptoms. No perioperative complications were observed in this series. CONCLUSION: Resection of vaginal septum and hysteroscopic metroplasty for complete uterine septum with resection of the cervical septum is a safe procedure that may improve dyspareunia and dysmenorrhea when present. Reproductive and obstetric outcomes after this procedure do not appear to be compromised, even though a relatively high miscarriage rate remains after metroplasty, questioning its systematic practice in symptom-free women without any previous obstetric history.

Segregation of mtDNA throughout human embryofetal development: m.3243A>G as a model system.

Mitochondrial DNA (mtDNA) mutations cause a wide range of serious diseases with high transmission risk and maternal inheritance. Tissue heterogeneity of the heteroplasmy rate ("mutant load") accounts for the wide phenotypic spectrum observed in carriers. Owing to the absence of therapy, couples at risk to transmit such disorders commonly ask for prenatal (PND) or preimplantation diagnosis (PGD). The lack of data regarding heteroplasmy distribution throughout intrauterine development, however, hampers the implementation of such procedures. We tracked the segregation of the m.3243A>G mutation (MT-TL1 gene) responsible for the MELAS syndrome in the developing embryo/fetus, using tissues and cells from eight carrier females, their 38 embryos and 12 fetuses. Mutant mtDNA segregation was found to be governed by random genetic drift, during oogenesis and somatic tissue development. The size of the bottleneck operating for m.3243A>G during oogenesis was shown to be individual-dependent. Comparison with data we achieved for the m.8993T>G mutation (MT-ATP6 gene), responsible for the NARP/Leigh syndrome, indicates that these mutations differentially influence mtDNA segregation during oogenesis, while their impact is similar in developing somatic tissues. These data have major consequences for PND and PGD procedures in mtDNA inherited disorders.

Human and murine amniotic fluid c-Kit+Lin- cells display hematopoietic activity.

We have isolated c-Kit(+)Lin(-) cells from both human and murine amniotic fluid (AF) and investigated their hematopoietic potential. In vitro, the c-Kit(+)Lin(-) population in both species displayed a multilineage hematopoietic potential, as demonstrated by the generation of erythroid, myeloid, and lymphoid cells. In vivo, cells belonging to all 3 hematopoietic lineages were found after primary and secondary transplantation of murine c-Kit(+)Lin(-) cells into immunocompromised hosts, thus demonstrating the ability of these cells to self-renew. Gene expression analysis of c-Kit(+) cells isolated from murine AF confirmed these results. The presence of cells with similar characteristics in the surrounding amnion indicates the possible origin of AF c-Kit(+)Lin(-) cells. This is the first report showing that cells isolated from the AF do have hematopoietic potential; our results support the idea that AF may be a new source of stem cells for therapeutic applications.

[Extending preimplantation genetic diagnosis to HLA typing: the French exception]. / Le diagnostic pré-implantatoire couplé au typage HLA: l'expérience française.

Umut-Talha, a "sibling savior", was born on 26 January 2011 at Beclère Hospital after embryo selection at the Paris preimplantation genetic diagnosis (PGD) center. His birth revived the controversy over "double PGD". This procedure, authorized in France since 2006, allows couples who already have a child with a serious, incurable genetic disease, to opt for PGD in order to select a healthy embryo that is HLA-matched to the affected sibling and who may thus serve as an ombilical cord blood donor. The procedure is particularly complex and the baby take-home rate is still very low. Double PGD is strictly regulated in France, and candidate couples must first receive individual authorization from the Biomedicine Agency. In our experience, these couples have a strong desire to have children, as reflected by the large number of prior spontaneous pregnancies (25% of couples). Likewise, most of these couples request embryo transfer even when there is no HLA-matched embryo, which accounts for more than half of embryo transfers. The controversy surrounding this practice has flared up again in recent weeks, over the concepts of "designer babies" and "double savior siblings" (the baby is selected to be free of the hereditary disease, and may also serve as a stem cell donor for the affected sibling).

[Ten years' experience of preimplantation genetic diagnosis in Paris: remaining obstacles and potential solutions]. / Diagnostic pré-implantatoire: dix ans d'expérience en région parisienne: impasse actuelle et solutions à venir.

Preimplantation genetic diagnosis (PGD) has been authorized in France since 1999. Encouraging results have been obtained during the past 10 years in our Paris center, where 832 patients have undergone 1056 IVF-PGD procedures. With the advent of new techniques for the identification of genetic disease markers, our center can now offer PGD procedures for aneuploidy and 75 single-gene diseases. New indications for PGD have also been developed, such as mitochondrial DNA diseases, amyloid neuropathy, pulmonary arterial hypertension, and HLA typing The implantation rate is currently 29,6% and, by 31 December 2009, 151 healthy babies had been born. Unfortunately, demand for PGD procedures far outstrips available technical capacity, and the waiting period is longer than 18 months. Increased funding is urgently needed

Recurrent pregnancy losses, a lasting cause of infertility.

Recurrent pregnancy loss (RPL), defined as two to three spontaneous pregnancy terminations occurring before 12 weeks of gestation, affects approximately 1% of the general population. The causes may include congenital factors that originate with the quality of the gametes (sperm or oocyte) or the resulting embryo, or factors that originate within the uterus. Alterations of endometrial receptivity from endometriosis and/or endometritis, which are associated with impaired action of progesterone, have also been implicated in RPL. Finally, immunologic factors and thrombophilia, congenital and acquired, have also been suspected to cause RPL.

Histology of genital tract and breast tissue after long-term testosterone administration in a female-to-male transsexual population.

Growing evidence indicates that androgens play a positive role in follicle proliferation and growth. Hence, many authors have assumed that androgen supplementation in women with poor ovarian reserve might improve the number of antral follicles available for ovarian stimulation. As androgen administration may become more frequently used in reproductive medicine, this study aimed at describing the histological changes observed in the genital tract and the breast of female-to-male (FTM) transsexuals. A pathological analysis of the genital tract of 112 FTM subjects who were given androgen for at least 6 months before hystero-salpingo-oophorectomy was performed. In addition, 100 bilateral mastectomies were performed, allowing a study of the breast tissue. Mean ovarian volume was increased, with histological characteristics of polycystic ovaries (PCO), defined as >12 antral follicles per ovary, observed in 89 patients (79.5%). Endometrial atrophy was observed in 45%. Breast examination revealed marked reduction of glandular tissue and increase of fibrous connective tissue in 93%, without atypical hyperplasia or carcinoma. The present data confirms and expands the putative associations between long-term androgen administration and abnormalities in ovarian architecture with macroscopic and microscopic characteristics of PCO, increased risk of endometrial atrophy and fibrotic breast tissue with marked glandular reduction.