Reproductive Biology and Endocrinology最新文献

Breast cancer (BrCa) is a complex and heterogeneous disease with diverse molecular subtypes, leading to varied clinical outcomes and posing significant treatment challenges. The increasing global burden of BrCa, particularly in low- and middle-income countries, underscores the urgent need for more effective therapeutic strategies. The androgen receptor (AR), expressed in a substantial proportion of breast cancer cases, has emerged as a potential biomarker and therapeutic target. In breast cancer, AR exhibits diverse functions across subtypes, often interacting with other hormone receptors, thereby influencing tumor progression and treatment responses. This intricate interplay is further complicated by the presence of constitutively expressed AR splice variants (AR-Vs) that drive resistance to AR-targeting therapies through structural rearrangements in the domains and activation of aberrant signaling pathways. Although AR-targeting drugs, initially developed for prostate cancer (PCa), have shown promise in AR-positive breast cancer, significant gaps remain in understanding AR's precise functions and therapeutic potential. The systemic management of breast cancer is guided primarily by theranostic biomarkers; ER, PR, HER2, and Ki67 which also dictate the breast cancer classification. The ubiquitous expression of AR in BrCa and the emergence of AR-Vs can assist the management of disease complementing the standard of care. This article provides a comprehensive overview of AR and its splice variants in the context of breast cancer, highlighting their prognostic and predictive value across different subtypes looking beyond the conventional ER, PR, and HER2 status. This review also raises the possibility of using AR splice variants in predicting tumor aggressiveness. From the settings of developing nations, this may provide useful insight by integrating recent advances in AR-targeted therapies and exploring their translational potential, emphasizing the critical need for further research to optimize AR-based therapeutic strategies for breast cancer management.

Background: Preimplantation embryos in vivo are exposed to various growth factors in the female reproductive tract that are absent in in vitro embryo culture media. Cell-free fat extract exerts antioxidant, anti-ageing, and ovarian function-promoting effects. However, its effects on embryo quality are yet to be investigated.

Methods: We assessed the effect of cell-free fat extract supplementation on embryo culture using a naturally ageing mouse model. We assessed the model's efficacy in influencing embryo development and pregnancy rates in older women with in vitro fertilization failure. In addition, we performed immunofluorescence staining, multiplex immunoassay, whole-genome amplification and DNA sequencing, time-lapse embryo monitoring, and in vitro experiments.

Results: Cell-free fat extract-supplemented media has a suitable osmolarity and pH and contains high levels of bioactive growth factors. Cell-free fat extract promoted embryo development and implantation in aged mice, probably by increasing embryo growth rate, inhibiting cell apoptosis, and promoting blastocyst adhesion. Clinical results showed that the cell-free fat extract group had significantly higher rates of the day 3 available and high-quality embryos than the control group, and the rate of usable embryos tended to be higher in the cell-free fat extract group. Furthermore, implantation and clinical pregnancy rates improved in the cell-free fat extract group than in the control group.

Conclusions: Our study implies that cell-free fat extract supplementation can promote embryo development and clinical outcomes and may serve as a rescue strategy for older women with in vitro fertilization failure.

Background: Despite the growing use of social egg freezing (SEF), research focusing on its psychological aspects is lacking. This study aimed to investigate possible psychological predictors, reasons, and outcomes of SEF in German-speaking countries.

Methods: The cross-sectional study included 1,131 women (average age 31 years) who had never used medical egg freezing. The participants were at different stages of SEF decision-making: women who cannot imagine using SEF (SEF-non-use), women who can imagine using SEF (SEF-possible-use), women who plan to use SEF (SEF-planned-use), women who have used SEF (SEF-use), and women who have used their oocytes frozen during SEF for assisted reproduction (SEF + ART-use). Data on sociodemographic and psychological characteristics, attitudes towards motherhood, well-being, and reasons for SEF were assessed. We used multinomial logistic regression to identify predictors of SEF decision-making stages, principal components analysis to examine motives for SEF, and multiple linear regression to analyze associations between motives and psychological variables.

Results: The probability of belonging to the SEF-use group rather than SEF-non-use was higher among childless single women with tertiary education, high levels of employment, and high importance placed on the genetic relationship to the child, and rose with increasing age and importance of motherhood. The probability of belonging to the SEF-use group rather than SEF-planned-use was higher among childless women with a high importance placed on the genetic relationship to the child, and increased with age. The probability of belonging to the SEF + ART-use group rather than SEF-use depended mainly on the presence of infertility. The women froze eggs mainly to gain time to fulfill their desire for conventional parenthood (59%), including finding the right partner and enabling a genetic relationship to the child. Using SEF to actively shape one's life and family planning was rather associated with positive psychological outcomes, whereas relying on SEF in the hope of personal and societal changes (e.g. improving fertility) was associated with negative outcomes.

Conclusion: SEF users might be characterized as mainly single, career-oriented, and greatly valuing genetic motherhood. As the motives for SEF, rather than its use per se, might be linked to psychological variables, these should be considered when counseling and supporting women.

The production of spermatozoa, a process known as spermatogenesis, is primarily controlled by follicle-stimulating hormone (FSH) and luteinizing hormone (LH)-driven testosterone. LH acts on the Leydig cells, stimulating steroid production, predominantly testosterone, and activating critical inter-related spermatogenesis regulatory pathways. Despite evidence that exogenous gonadotropins containing LH activity can effectively restore spermatogenesis in males with hypogonadotropic hypogonadism, the use of these drugs to treat other forms of male infertility is the subject of an ongoing debate. In this review, we delve into the molecular properties and functions of LH activity in spermatogenesis regulation and explore available preparations for therapeutic use. We also examine the evidence regarding the effectiveness of LH-containing drugs in treating specific male infertility conditions and identify the main areas for future research. Our review highlights the critical role of LH in spermatogenesis and emphasizes the potential of LH-containing drugs in treating male infertility. However, further research is required to completely elucidate the mechanisms underlying the effects of LH activity on sperm production and to establish the most effective dosages and treatment durations.

Ovarian stimulation (OS) is a crucial component of clinical IVF treatment that strongly influences outcomes. As such, it is useful to understand the indicators for successful OS during IVF. As OS leads to multiple follicular recruitment, it can be quantified as number of oocytes retrieved. Optimal OS should help to maximize the number of oocytes, thus improving preclinical laboratory outcomes. Optimal preclinical outcomes should ultimately lead to clinical outcomes with maximal efficacy, safety, and cost-effectiveness. To help guide successful OS, this review details prognostic factors and appropriate endpoints for an optimal OS at each stage of the IVF cycle.

Background: This study aims to investigate the association of pre-conception vitamin D levels on adverse pregnancy outcomes in women undergoing in vitro fertilization with fresh embryo transfer.

Methods: This was a retrospective cohort study using archived serum 25-hydroxyvitamin D measured in the pre-conception period before ovarian stimulation in patients undergoing in vitro fertilization with fresh autologous embryo transfer. A total of 306 women were included and adverse pregnancy outcomes in their resulting pregnancy were recorded. Patients who were vitamin D deficient (< 20ng/ml) were compared with those who were non-deficient (≥20ng/ml) and analysed for any association with adverse pregnancy outcomes.

Results: A total of 16/306 (5.3%) patients had hypertensive disorders of pregnancy (gestational hypertension and/or pre-eclampsia). The adjusted odds ratio for hypertensive disorders of pregnancy using vitamin D deficiency as a reference was 0.190 (95% CI 0.042-0.852) (p = 0.030). Other pregnancy complications were not significantly different with regards to pre-conception vitamin D status.

Conclusions: Pre-conception vitamin D deficiency is associated with an increased risk of hypertensive disorders in pregnancy in women undergoing in vitro fertilization with fresh embryo transfer.

Trial registration: HKUCTR 2361 (9th March 2018).

Background: Heterogeneous nuclear ribonucleoprotein M (HnRNPM) is a key splicing factor involved in various biological processes, including the epithelial‒mesenchymal transition and cancer development. Alternative splicing is widely involved in the process of spermatogenesis. However, the function of hnRNPM as a splicing factor during spermatogenesis remains unknown.

Methods: The expression of hnRNPM in germ cells at different stages was detected by polymerase chain reaction, western blotting, a single-cell database, and chromosome spreading assays. Conditional hnRNPM knockout mice were generated to observe the development of testes and germ cells in male mice. Histological staining, immunofluorescence staining and transmission electron microscopy were used to observe the abnormal development of sperm from conditional hnRNPM-deficient mice. Coimmunoprecipitation and mass spectrometry analyses revealed the proteins that interact with hnRNPM. RNA sequencing was performed to analyse the different alternative splicing events in the testes of control and hnRNPM-deficient mice.

Results: In this study, we revealed that hnRNPM is highly expressed in spermatocytes and round spermatids, with the exception of XY bodies and metaphase. Therefore, we generated a germ cell-specific hnRNPM conditional knockout mouse model to investigate the role of hnRNPM in spermatogenesis. A lack of hnRNPM led to male infertility under natural conditions. Male hnRNPM-deficient mice presented lower numbers of sperm, lower motility, significantly more malformed sperm and even tailless sperm. Moreover, we found that hnRNPM interacted with PTBP1 to collectively regulate the process of spermatogenesis. In addition, we found that hnRNPM deficiency caused 1617 different alternative splicing events, and we detected abnormal exon skipping events in Cep152, Cyld, Inpp4b and Cd59b.

Conclusions: Together, our results suggest that hnRNPM regulates the alternative splicing of mRNAs during spermatogenesis by recruiting PTBP1 and is required for male mouse fertility.

Background: A didelphic uterus represents a unique and infrequent congenital condition in which a woman possesses two distinct uteri, each with its own cervix. This anomaly arises due to partial or incomplete merging of the Müllerian ducts during the developmental stages in the womb. Accounting for uterine malformations, a didelphic uterus is a relatively rare condition, affecting approximately 0.5-2% of the population and is considered one of the more uncommon types of uterine abnormalities.

Methods: This case report aims to study the physical separation in uterine didelphys and its impact on endometrial microbiome and inflammation, and the patterns of endometrial receptivity observed.

Results: Endometrial receptivity analyses revealed a similar receptive state in both uteri, both in the early receptive phase. Differential markers of chronic endometritis, including CD138, and MUM1-positive cells, were observed when comparing endometrial biopsies from both uteri. The right uterus exhibited a higher prevalence of these positive cells. Regarding the microbiome, significant differences were found between the uteri, notably in the right uterus, a clear non-dominance of lactobacilli and the presence of genera such as Staphylococcus, Streptococcus, and Acinetobacter. Additionally, the right uterus presented a less 'favourable' microenvironment, a characteristic that was also reflected in the right cervix; both sites presenting less lactobacilli than the left side samples. A distinct metabolomic signature associated with the physical separation of the uteri contributed to the differences in endometrial milieu.

Conclusions: Our study revealed that physical separation, among other factors in uterus didelphys, affects the endometrial microbiome, metabolome, and inflammatory state, with significant microbiome variation observed between the uteri, although similar endometrial receptivity patterns were noted.

Polycystic ovary syndrome (PCOS), as a common endocrine and metabolic disorder, is often regarded as a primary cause of anovulatory infertility in women. The pathogenesis of PCOS is complex and influenced by multiple factors. Emerging evidence highlights that energy metabolism dysfunction and oxidative stress in granulosa cells (GCs) are pivotal contributors to aberrant follicular development and impaired fertility in PCOS patients. Mitochondrial dysfunction, increased oxidative stress, and disrupted glucose metabolism are frequently observed in individuals with PCOS, collectively leading to compromised oocyte quality. This review delves into the mechanisms linking oxidative stress and energy metabolism abnormalities in PCOS, analyzing their adverse effects on reproductive function. Furthermore, potential therapeutic strategies to mitigate oxidative stress and metabolic disturbances are proposed, providing a theoretical basis for advancing clinical management of PCOS.