Downregulation of Serotonergic System Components in an Experimentally Induced Cryptorchidism in Rabbits.

Cryptorchidism (CO) or undescended testes is defined as the failure of one or both testes to be positioned inside the scrotum. Typically, cryptorchidism is detected at birth or shortly thereafter, and in humans, it is considered to be part of the testicular dysgenesis syndrome (TDS), a complex pathology regarding the male reproductive system that apparently involves the interaction of both genetic and environmental harmful factors, mainly during embryonic development. Serotonin (5-HT) is an ancient molecule that participates in a broad range of body functions, and in recent years, its importance in reproduction has started to be elucidated. In male pathologies such as infertility, varicocele, erectile dysfunction, and primary carcinoid tumors, an increase in 5-HT concentration or its metabolites in the blood, semen, and urine has been directly related; nevertheless, the role of 5-HT in CO remains unknown. In the present work, our goal was to answer two important questions: (1) whether some serotonergic system components are present in adult male Oryctolagus cuniculus (chinchilla rabbit) and (2) if there are changes in their expression in an experimental model of CO. Using histological, molecular, and biochemical approaches, we found the presence of some serotonergic system components in the adult chinchilla rabbit, and we demonstrated that its expression is downregulated after CO was pharmacologically induced. Although we did not test the role of 5-HT in the etiology of CO, our results suggest that this indoleamine could be important for the regulation of steroidogenesis and spermatogenesis processes in the chinchilla rabbit during adulthood. Finally, in parallel experimental series, we found downregulation of kynurenine concentration in COI rabbits when compared to control ones, suggesting that CO could be affecting the kynurenine pathway and probably testicular immune privilege which in turn could lead to infertility/sterility conditions in this disorder.

The association between uterine scar defect (niche) and the presence of symptoms.

RESEARCH QUESTION: Is there association between the presence of a uterine niche and the presence of symptoms? DESIGN: This cross-sectional study was conducted at a single tertiary medical centre. All women who underwent Caesarean section from January 2017 to June 2020 were invited to the gynaecological clinics, and requested to complete a questionnaire regarding symptoms related to the presence of a niche (heavy menstrual bleeding, intermenstrual spotting, pelvic pain, infertility). Transvaginal two-dimensional ultrasonography was performed to assess the uterus and uterine scar characteristics. The primary outcome was defined as the presence of a uterine niche, evaluated by length, depth, residual myometrial thickness (RMT) and ratio between the residual myometrial thickness (RMT) and adjacent myometrial thickness (AMT). RESULTS: Of 524 women who were eligible and scheduled for evaluation, 282 (54%) completed the follow-up; 173 (61.3%) were symptomatic and 109 (38.6%) asymptomatic. Niche measurements, including RMT/AMT ratio, were comparable between the groups. In a sub-analysis of each symptom, heavy menstrual bleeding and intermenstrual spotting were associated with reduced RMT (P = 0.02 and P = 0.04, respectively) compared with women with normal menstrual bleeding. An RMT less than 2.5 mm was significantly more prevalent in women reporting heavy menstrual bleeding (11 [25.6%] versus 27 [11.3%]; P = 0.01] and new infertility (7 [16.3%] versus 6 [2.5%]; P = 0.001]. In logistic regression analysis, infertility was the only symptom associated with an RMT less than 2.5 mm (B = 1.9; P = 0.002). CONCLUSIONS: A reduced RMT was found to be associated with heavy menstrual bleeding and intermenstrual spotting, while values below 2.5 mm were also associated with infertility.

Autologous transplantation of spermatogonial stem cells restores fertility in congenitally infertile mice.

The blood-testis barrier (BTB) is thought to be indispensable for spermatogenesis because it creates a special environment for meiosis and protects haploid cells from the immune system. The BTB divides the seminiferous tubules into the adluminal and basal compartments. Spermatogonial stem cells (SSCs) have a unique ability to transmigrate from the adluminal compartment to the basal compartment through the BTB upon transplantation into the seminiferous tubule. Here, we analyzed the role of Cldn11, a major component of the BTB, in spermatogenesis using spermatogonial transplantation. Cldn11-deficient mice are infertile due to the cessation of spermatogenesis at the spermatocyte stage. Cldn11-deficient SSCs failed to colonize wild-type testes efficiently, and Cldn11-deficient SSCs that underwent double depletion of Cldn3 and Cldn5 showed minimal colonization, suggesting that claudins on SSCs are necessary for transmigration. However, Cldn11-deficient Sertoli cells increased SSC homing efficiency by >3-fold, suggesting that CLDN11 in Sertoli cells inhibits transmigration of SSCs through the BTB. In contrast to endogenous SSCs in intact Cldn11-deficient testes, those from WT or Cldn11-deficient testes regenerated sperm in Cldn11-deficient testes. The success of this autologous transplantation appears to depend on removal of endogenous germ cells for recipient preparation, which reprogrammed claudin expression patterns in Sertoli cells. Consistent with this idea, in vivo depletion of Cldn3/5 regenerated endogenous spermatogenesis in Cldn11-deficient mice. Thus, coordinated claudin expression in both SSCs and Sertoli cells expression is necessary for SSC homing and regeneration of spermatogenesis, and autologous stem cell transplantation can rescue congenital defects of a self-renewing tissue.

Elevated prohibitin 1 expression mitigates glucose metabolism defects in granulosa cells of infertile patients with endometriosis.

Endometriosis is a common disease in women of childbearing age and is closely associated with female infertility. However, the pathogenesis of endometriosis-related infertility is still not fully understood. Prohibitin 1 (PHB1), a highly conserved protein related to mitochondrial function, is differentially expressed in the endometrium of patients with endometriosis. However, the role of PHB1 in glucose metabolism in granulosa cells remains unclear. In this study, we investigated whether PHB1 expression and glucose metabolism patterns differ in the granulosa cells of patients with endometriosis and those of patients serving as controls. We then evaluated these changes after PHB1 was upregulated or downregulated in the human granulosa cell line (KGN) using a lentivirus construct. In the granulosa cells of patients with endometriosis, significantly elevated PHB1 expression, increased glucose consumption and lactic acid production, as well as aberrant expression of glycolysis-related enzymes were found compared to those without endometriosis (P < 0.05). After PHB1 expression was upregulated in KGN cells, and the expression of enzymes related to glucose metabolism, glucose consumption and lactic acid production was strikingly increased compared to controls (P < 0.05). The opposite results were found when PHB1 expression was downregulated in KGN cells. Additionally, the cell proliferation and apoptosis rates, ATP synthesis, reactive oxygen species (ROS) levels and mitochondrial membrane potential (MMP) were significantly altered after down-regulation of PHB1 expression in KGN cells (P < 0.05). This study suggested that PHB1 plays a pivotal role in mitigating the loss of energy caused by impaired mitochondrial function in granulosa cells of patients with endometriosis, which may explain, at least in part, why the quality of oocytes in these patients is compromised.

Functioning gonadotroph adenomas in premenopausal women: clinical and molecular characterization and review of the literature.

PURPOSE: To summary the clinical features of premenopausal women with functioning gonadotroph adenomas (FGAs) and preliminarily explore their molecular characterization. METHODS: 12 premenopausal females with FGAs in our center were retrospectively analyzed. Previously reported cases were also summarized. The patients were clinically divided into FSH- or LH-predominant types according to their preoperative serum FSH/LH ratio. The expressions of related genes in the tumor tissues of female FGAs, non-functioning gonadotroph adenomas (NFGAs), and silent corticotropin adenomas were evaluated by RT-qPCR. RESULTS: Of all the 12 patients with FGAs from our center, 11 (91.7%) were diagnosed as FSH-predominant type, and they all had menstrual disorders, including 9 with spontaneous ovarian hyperstimulation syndrome (sOHSS). Their hormonal profiles showed non-suppressed FSH (12.45 ± 7.34 IU/L) with hyperestrogenemia [median estradiol level 1353.0 pg/mL (636.0, 3535.0)]. The other patient (8.3%) with LH-predominant type mainly manifested with infertility and sustained elevated serum LH without FSH or estradiol increasing. 65 premenopausal FGAs patients were systematic reviewed. 60 patients (92.3%) were FSH-predominant type, including 86.7% presented with menstrual disorders, 16.7% reported infertility, and 98.2% (55/56) showed sOHSS. No sOHSS or hyperestrogenemia were found in the 5 patients (7.7%) with LH-predominant type. Pituitary imaging data revealed macroadenomas and microadenomas accounted for 89.2% and 10.8%, respectively. Of 63 patients (96.9%) who underwent pituitary adenoma resection, 77.8% had complete tumor resection and no recurrence at the last follow-up. The relative expressions of KISS1 mRNA were significantly higher in FGA group than in NFGA group (p = 0.018), and significantly positively correlated with the preoperative serum estradiol levels (p = 0.004). CONCLUSIONS: Different clinical features were observed in premenopausal women with FGAs of FSH- or LH-predominant types. The elevated KISS1 expression in tumor tissues might involve in the secretion function of FGAs.

Uterine double-conditional inactivation of Smad2 and Smad3 in mice causes endometrial dysregulation, infertility, and uterine cancer.

SMAD2 and SMAD3 are downstream proteins in the transforming growth factor-ß (TGF ß) signaling pathway that translocate signals from the cell membrane to the nucleus, bind DNA, and control the expression of target genes. While SMAD2/3 have important roles in the ovary, we do not fully understand the roles of SMAD2/3 in the uterus and their implications in the reproductive system. To avoid deleterious effects of global deletion, and given previous data showing redundant function of Smad2 and Smad3, a double-conditional knockout was generated using progesterone receptor-cre (Smad2/3 cKO) mice. Smad2/3 cKO mice were infertile due to endometrial hyperproliferation observed as early as 6 weeks of postnatal life. Endometrial hyperplasia worsened with age, and all Smad2/3 cKO mice ultimately developed bulky endometrioid-type uterine cancers with 100% mortality by 8 months of age. The phenotype was hormone-dependent and could be prevented with removal of the ovaries at 6 weeks of age but not at 12 weeks. Uterine tumor epithelium was associated with decreased expression of steroid biosynthesis genes, increased expression of inflammatory response genes, and abnormal expression of cell cycle checkpoint genes. Our results indicate the crucial role of SMAD2/3 in maintaining normal endometrial function and confirm the hormone-dependent nature of SMAD2/3 in the uterus. The hyperproliferation of the endometrium affected both implantation and maintenance of pregnancy. Our findings generate a mouse model to study the roles of SMAD2/3 in the uterus and serve to provide insight into the mechanism by which the endometrium can escape the plethora of growth regulatory proteins.

[Receptive status of the endometrium in patients with benign ovarian tumors before and after organ-preserving operations]. / Retseptivnyi status endometriya pri dobrokachestvennykh opukholyakh yaichnikov do i posle organosokhranyayushchikh operatsii.

Background. Benign ovarian tumors (BOT) occupy the 2nd place in the structure of diseases of the female genital organs. In 20% of women of reproductive age, BOT are associated with infertility. One of the causes of infertility caused by ovarian tumors is morphofunctional inferiority with impaired endometrial receptivity. OBJECTIVE: To reveal the morphological and functional features of the endometrium and the level of receptivity to sex hormones in patients with BOT before and after organ-preserving operations. MATERIAL AND METHODS: The study included 77 patients with epithelial ovarian tumors (EOT) - I group, 52 with mature teratomas (MT) - II group. Before and 6-12 months after laparoscopic cystectomy aspiration biopsy of endometrium was performed in the middle stage of secretory phase. The percentage and degree of maturity of pinopodes were determined, and the level of expression of estrogen (ER) and progesterone (PR) receptors in the glands and stroma of the endometrium was assessed. RESULTS: At the preoperative stage, a decrease in the number of mature pinopodes in patients with EOT was revealed. Normal levels of ER were determined in glands and stroma of endometrium, PR was reduced both in stroma and glands of uterine mucosa. In patients with MT all markers corresponded to those of healthy women. In the postoperative period an increase in the number of developed pinopodes on the apical surface of endometrium in patients of I group was found. The ER level did not differ from control values, PR remained reduced in stroma. In II group a persistent decrease in quantity of mature pinopodes, ER in stroma, PR in glands and stroma of uterine mucosa was recorded. CONCLUSION: The presence of BOT and unintentional intraoperative removal of healthy ovarian tissue lead to indirect disorders of the morphofunctional state and endometrial receptivity.

A heterozygous hypomorphic mutation of Fanca causes impaired follicle development and subfertility in female mice.

Reduced fertility is a common clinical feature of the individuals with Fanconi anemia (FA), a rare autosomal recessive disorder due to deficiency in FA pathway during DNA repair. Our previous study reported that the heterozygous pathogenic variants in FANCA (Fanconi anemia complementation group A) induced premature ovarian insufficiency (POI). However, the genotype-phenotype correlation in POI caused by FANCA variants remains considerably uncertain. Herein, a heterozygous non-frameshift Fanca-mutated mouse strain (Fanca+/hypo) carrying a 9-bp deletion (c.3581del9, p.QEA1194-1196del) was generated. The mutant mice exhibited slightly decreased Fanca protein level in ovaries, suggesting the non-frameshift deletion mutant is hypomorphic. Female fertility test showed decreased number of litters, litter sizes and prolonged litter interval time in the female Fanca+/hypo mice compared to wild-type mice. Follicle counting revealed a consistent decreasing pattern of follicle numbers in Fanca+/hypo females compared to that in wild-type mice with aging. Furthermore, embryonic fibroblasts of Fanca+/hypo mice were hyper-responsive to Mitomycin C in vitro, demonstrating a partial loss of function of this hypomorphic Fanca mutant in DNA repair. Collectively, our experimental observations suggest that the hypomorphic Fanca allele is sufficient to reduce female fertility in mice, providing new insights into the genetic counseling of FANCA variants in subfertile women.

Endometrial thickness in the prediction of neonatal adverse outcomes in frozen cycles for singleton pregnancies.

RESEARCH QUESTION: Does endometrial thickness (EMT) predict adverse neonatal outcomes in singleton pregnancies after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) frozen embryo transfer (FET)? DESIGN: This retrospective study involved 13,383 women undergoing IVF/ICSI FET cycles between January 2010 and December 2018 in Women's Hospital of Zhejiang University. The primary outcome was preterm delivery (PTD). The secondary outcomes were small for gestational age (SGA), large for gestational age (LGA) and low birthweight (LBW). RESULTS: A total of 13,383 FET cycles resulting in 5220 singleton live births and 8163 failed cycles were included. Multiple spline regression visualization showed an increasing risk of PTD and LBW for a thin EMT. By comparing multiple cut-off points using area under the curve, a cut-off point of 8 mm was identified, which was used to categorize EMT. A reference point of EMT greater than 8 mm was used; after adjusting for covariates, individuals with EMT less than 8 mm had an adjusted odds ratio of 1.75 (95% CI 1.30 to 2.34) for PTD, 1.57 (95% CI 1.09 to 2.26) for LBW, 0.97 (95% CI 0.63 to 1.50) for SGA and 1.04 (95% CI 0.79 to 1.37) for LGA. Additional analyses showed similar increasing risk with a thin endometrium for both PTD with and without caesarean section, and PTD with low and normal birthweight percentiles. CONCLUSION: A clinical cut-off point of 8 mm has been identified, below which risk of PTD and LBW increases in women undergoing IVF/ICSI.

The Inferto-Sex Syndrome (ISS): sexual dysfunction in fertility care setting and assisted reproduction.

PURPOSE: Infertility represents a peculiar social burden affecting more than 15% of couples, provoking it a real threat to the general quality of life and to the sexual health. The medicalization (diagnosis, therapy and follow up) of the lack of fertility is frequently a challenge in term of personal and couple's involvement. In particular, while the Assisted Reproductive Technology (ART) has allowed many infertile couples to achieve pregnancy, the therapeutic process faced by the couple bears a strong psychological stress that can affect the couple's quality of life, relationship and sexuality. Despite infertility affects both female and male sexual health, only recently the interest in the effects of ART on the couple's sexuality has grown, especially for women. METHODS: A literature research on the sexual dysfunction in fertility care and particularly in ART setting was performed. RESULTS: Literature largely found that intimacy and sexuality appear specifically impaired by intrusiveness of treatments and medical prescriptions. Moreover, there is a close relationship between emotional, psychological and sexual aspects, which can be integrated in the new concept of Inferto-Sex Syndrome (ISS) that can impair the ART treatment outcomes. Evidence demonstrates that the assessment of sexual function is necessary in couples undergoing diagnosis of infertility and ART. CONCLUSION: A close relationship between infertility and sexuality, both in the female and male partners, was detected. ART treatments may heavily impact on the couple's psychosexual health. A couple-centred program for the integrated management of psychological and sexual dysfunction should be considered in the context of ART programs.

The female medical workforce.

In the UK, the proportion of female medical students has remained static over the last decade, at around 55%; however, at consultant level, only 36.6% of doctors are women. The reasons for this drop in numbers are not clear. Given the increase in number of female doctors in training, the proportion of female doctors at consultant level is lower than might be expected. This article discusses issues affecting the female medical workforce in anaesthesia, intensive care and pain medicine. It explores how gender stereotypes and implicit gender bias can affect the way women are perceived in the workplace, especially in leadership positions, and discusses health issues particular to the female medical workforce. While the issues in this article may not affect all women, the cumulative effect of being subject to gender stereotypes within a workplace not designed to accommodate the health needs of women may contribute to a work environment that may promote the attrition of women from our specialties.

The efficiency of progesterone/estradiol and progesterone/follicle ratio without elevated trigger-day progesterone levels on the reproductive outcomes of GnRH antagonist IVF/ICSI cycles.

AIM: To assess the predictive value of serum progesterone/estradiol (P/E2) and serum progesterone/follicle (P/F) ratios on the reproductive outcomes of women without elevated trigger-day progesterone levels undergoing GnRH-antagonist IVF (in vitro fertilization)/ICSI (intracytoplasmic sperm injection) cycles. MATERIALS AND METHODS: This was a retrospective cohort study in a university teaching hospital conducted between January 2017 and December 2019. Couples who underwent assisted reproduction cycles were evaluated. Initially, 978 cycles were evaluated and only GnRH antagonist cycles (n = 505) without elevated trigger-day progesterone levels were analyzed after respecting exclusion criteria. RESULTS: A total of 505 cycles were analyzed after the exclusion criteria were met. The clinical pregnancy rate, ongoing pregnancy rate, and live birth rate were 45.5%, 30.9%, and 27.8%, respectively. Cutoff values of P/E2 and P/F ratios that were discriminative for achieving or not achieving clinical pregnancy were 0.36 and 0.17, respectively. The clinical pregnancy rates were found to be significantly different between below and above P/E2 cutoff values (49.8% vs. 40.1%, respectively, p = .031), while there were no significant differences between below and above P/F cutoff values regarding the pregnancy outcomes. CONCLUSION: The P/E2 and P/F ratios were found to be more efficient and reliable markers than serum progesterone level alone in predicting the reproductive outcomes of assisted reproduction cycles without a premature rise in serum progesterone levels. A P/E2 ratio ≤0.36 and a P/F ratio ≤0.17 significantly improved the cycle outcomes.

The impact of the female genital tract microbiome in women health and reproduction: a review.

PURPOSE: The aim of this review is to gather the available research focusing on female genital tract (FGT) microbiome. Research question focuses in decipher which is the role of FGT microbiota in eubiosis, assisted reproduction techniques (ARTs), and gynaecological disorders, and how microbiome could be utilised to improve reproduction outcomes and to treat fertility issues. METHODS: PubMed was searched for articles in English from January 2004 to April 2021 for "genital tract microbiota and reproduction", "endometrial microbiome", "microbiome and reproduction" and "microbiota and infertility". Manual search of the references within the resulting articles was performed. RESULTS: Current knowledge confirms predominance of Lactobacillus species, both in vagina and endometrium, whereas higher variability of species is both found in fallopian tubes and ovaries. Microbial signature linked to different disorders such endometriosis, bacterial vaginosis, and gynaecological cancers are described. Broadly, low variability of species and Lactobacillus abundance within the FGT is associated with better reproductive and ART outcomes. CONCLUSION: Further research regarding FGT microbiome configuration needs to be done in order to establish a more precise link between microbiota and eubiosis or dysbiosis. Detection of bacterial species related with poor reproductive outcomes, infertility or gynaecological diseases could shape new tools for their diagnosis and treatment, as well as resources to assess the pregnancy prognosis based on endometrial microbiota. Data available suggest future research protocols should be standardised, and it needs to include the interplay among microbiome, virome and mycobiome, and the effect of antibiotics or probiotics on the microbiome shifts.

Time-lapse technology improves total cumulative live birth rate and shortens time to live birth as compared to conventional incubation system in couples undergoing ICSI.

PURPOSE: The improvement of clinical outcome provided by time-lapse technology (TLT) in IVF over conventional incubation (CI) still remains controversial. This study aimed at evaluating whether the exclusive use of time-lapse technology (TLT) during whole IVF care improves total cumulative live birth rate (TCLBR) and shortens time to live birth (TTLB) as compared to the use of CI in couples undergoing ICSI. METHODS: This retrospective cohort study was conducted in couples with male infertility undergoing their first ICSI cycle in 2014-2015 and for whom embryo culture system remained the same during their whole IVF care, i.e., TLT or CI. Couples were followed up up to 2020, including all following frozen-embryo transfers and ICSI cycles (if any). Survival analysis was used to compare clinical outcome and time-related endpoints between both groups. RESULTS: A total of 151 and 250 couples underwent their whole IVF care with the exclusive use of TLT and CI, respectively. Survival analysis showed that TCLBR after whole IVF care was significantly higher in TLT than in CI group (66.9 vs 56.4%, p=0.02, log-rank test). Median live birth time was significantly shorter in TLT than CI group (464 vs 596 days, p=0.01). CONCLUSIONS: We found that TCLBR and TTLB were significantly improved with TLT over CI in couples undergoing ICSI for male factor. This study fuels the debate on the clinical benefit of using TLT. The use of time-related endpoints adds important information for both patients and practitioners.

Challenging cases in oncofertility: insights from a national specialized e-meeting for fertility preservation specialists.

PURPOSE: To determine the use of a new specialized E-Meeting for Complex Cases in Oncofertility by fertility preservation specialists (FPSs) MATERIAL AND METHODS: We present 3 years of activity of the E-Meeting for Complex Cases in Oncofertility, a new tool created in September 2016 which allows national oncofertility experts to share viewpoints about challenging cases for which they do not have experience or sufficient data in order to provide them an emergency advice within 48 h. Second, a survey was conducted to evaluate the use of this e-meeting for participating FPSs. RESULTS: One hundred and four experts have joined the e-meeting since its set-up, and 109 challenging cases have been submitted. The mean age of the patients was 22.4 ± 8.9 years, and 87.0% were female. Each submitted case received on average of 1.8 ± 1.1 different strategies for FP and the opinions of 7.1 ± 3.4 experts. Among the FPSs who submitted cases, seeking opinions from other FPSs allowed them to confirm their care plan (N = 49, 84.4%), to offer different options to their patients (N = 34, 58.6%), and to compare their practices with those of other specialists (N = 23, 39.6%). All respondents reported a self-perceived improvement in their practice of oncologic FP (n = 80, 100.0%). CONCLUSION: Specific attention should be paid to challenging cases for which the experiences of only a few individuals exist. Enhancing communication between FPSs through oncofertility networks, pooling experiences, and collecting the most complex cases is required to improve the management of these patients.

Expanded carrier screening for recessively inherited disorders: economic burden and factors in decision-making when one individual in a couple is identified as a carrier.

PURPOSE: When undergoing expanded carrier screening (ECS), couples are often screened sequentially to reduce need for a second individual's test. It is unknown how often partners of individuals found to be carriers complete the recommended testing with a sequential approach and what factors contribute to decision-making regarding partner testing. Additionally, the economic burden placed on individuals by ECS testing and its effect on partner testing has not been evaluated. METHODS: In part 1, all individuals at a university-affiliated reproductive endocrinology and infertility practice identified to be carriers of a recessively inherited mutation using the Counsyl/Foresight ECS were included. Conditions were categorized by severity according to a previously described classification system. In part 2, all individuals who underwent ECS with a single test provider between September 1, 2013 and February 1, 2020 were contacted via email to complete a confidential and anonymized online survey. RESULTS: In part 1, a total of 2061 patients were screened. 36.9% were carriers of one or more recessively inherited disorders. Twenty-seven percent of positively screened individuals did not have their partner screened. Carriers of a moderate condition had a trend towards a reduced odds for having their partner screened compared to a profound condition (OR 0.36, 95% CI 0.12-1.05, p = 0.06). Number of conditions was not predictive of subsequent partner screening (OR 0.95, 95% CI 0.72-1.25, p = 0.72). In part 2, the cost of ECS was not covered by insurance for 54.5% (103/189) and most paid over $300 out-of-pocket for testing (47.6%). The most common reason for not completing partner testing was that the results would not alter their course when seeking conception (33.3%). 73.5% of patients knew that the largest benefit of ECS comes from knowing a partner's results as well as their own. CONCLUSIONS: Not all carriers of recessively inherited disorders choose to undergo partner screening. Patients found to be carrier of more debilitating genetic disorders may be more likely to screen their reproductive partners. For many, ECS testing is not covered by insurance, and this test may impose a significant economic burden. For some patients, the results of ECS would not change what they would do when seeking conception. Providers should evaluate whether a patient's ECS result would change their treatment course prior to testing.

Functional Ambivalence of Dendritic Cells: Tolerogenicity and Immunogenicity.

Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs) and inducers of T cell-mediated immunity. Although DCs play a central role in promoting adaptive immune responses against growing tumors, they also establish and maintain peripheral tolerance. DC activity depends on the method of induction and/or the presence of immunosuppressive agents. Tolerogenic dendritic cells (tDCs) induce immune tolerance by activating CD4+CD25+Foxp3+ regulatory T (Treg) cells and/or by producing cytokines that inhibit T cell activation. These findings suggest that tDCs may be an effective treatment for autoimmune diseases, inflammatory diseases, and infertility.

The Roles of Luteinizing Hormone, Follicle-Stimulating Hormone and Testosterone in Spermatogenesis and Folliculogenesis Revisited.

Spermatogenesis and folliculogenesis involve cell-cell interactions and gene expression orchestrated by luteinizing hormone (LH) and follicle-stimulating hormone (FSH). FSH regulates the proliferation and maturation of germ cells independently and in combination with LH. In humans, the requirement for high intratesticular testosterone (T) concentration in spermatogenesis remains both a dogma and an enigma, as it greatly exceeds the requirement for androgen receptor (AR) activation. Several data have challenged this dogma. Here we report our findings on a man with mutant LH beta subunit (LHß) that markedly reduced T production to 1-2% of normal., but despite this minimal LH stimulation, T production by scarce mature Leydig cells was sufficient to initiate and maintain complete spermatogenesis. Also, in the LH receptor (LHR) knockout (LuRKO) mice, low-dose T supplementation was able to maintain spermatogenesis. In addition, in antiandrogen-treated LuRKO mice, devoid of T action, the transgenic expression of a constitutively activating follicle stimulating hormone receptor (FSHR) mutant was able to rescue spermatogenesis and fertility. Based on rodent models, it is believed that gonadotropin-dependent follicular growth begins at the antral stage, but models of FSHR inactivation in women contradict this claim. The complete loss of FSHR function results in the complete early blockage of folliculogenesis at the primary stage, with a high density of follicles of the prepubertal type. These results should prompt the reassessment of the role of gonadotropins in spermatogenesis, folliculogenesis and therapeutic applications in human hypogonadism and infertility.

Cryopreservation of Gametes and Embryos and Their Molecular Changes.

The process of freezing cells or tissues and depositing them in liquid nitrogen at -196 °C is called cryopreservation. Sub-zero temperature is not a physiological condition for cells and water ice crystals represent the main problem since they induce cell death, principally in large cells like oocytes, which have a meiotic spindle that degenerates during this process. Significantly, cryopreservation represents an option for fertility preservation in patients who develop gonadal failure for any condition and those who want to freeze their germ cells for later use. The possibility of freezing sperm, oocytes, and embryos has been available for a long time, and in 1983 the first birth with thawed oocytes was achieved. From the mid-2000s forward, the use of egg vitrification through intracytoplasmic sperm injection has improved pregnancy rates. Births using assisted reproductive technologies (ART) have some adverse conditions and events. These risks could be associated with ART procedures or related to infertility. Cryopreservation generates changes in the epigenome of gametes and embryos, given that ART occurs when the epigenome is most vulnerable. Furthermore, cryoprotective agents induce alterations in the integrity of germ cells and embryos. Notably, cryopreservation extensively affects cell viability, generates proteomic profile changes, compromises crucial cellular functions, and alters sperm motility. This technique has been widely employed since the 1980s and there is a lack of knowledge about molecular changes. The emerging view is that molecular changes are associated with cryopreservation, affecting metabolism, cytoarchitecture, calcium homeostasis, epigenetic state, and cell survival, which compromise the fertilization in ART.

Infertility and ovarian cancer risk: Evidence from nine prospective cohort studies.

Epidemiological studies have investigated the relationship between infertility and the risk of ovarian cancer (OC); however, the results have been inconsistent. We therefore conducted the first meta-analysis to update and quantify the aforementioned association based on prospective cohort studies. Studies were identified by searching PubMed, EMBASE and Web of Science databases up to January 8, 2020. We extracted data from the studies and performed quality assessments. Summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Publication bias, and subgroup, meta-regression and sensitivity analyses were also conducted. Nine prospective cohort studies with a total of 10 383 OC cases and 6 278 830 participants were included in the present study. The summary RR of the association between infertility and the risk of OC was 1.51 (95% CI: 1.35-1.69), with low heterogeneity. Positive associations were observed in most subgroup analyses stratified by predefined factors, including region, duration of follow-up, study quality, causes of infertility, invasiveness of OC, infertility treatment status and adjustment of potential confounding parameters. No significant publication bias was detected. Our findings suggest that infertility in women were associated with an increased risk of OC.