Follicular fluid progesterone downregulated HPGD and COX2 in granulosa cells via suppressing NF-ĸB in endometriosis†.

Increasing evidences showed that ovulatory dysfunction, possibly caused by luteinized unruptured follicular follicle syndrome (LUFS), is one of the reasons for endometriosis-related infertility. The present study was conducted to explore the potential effect of elevated progesterone in follicular fluid (FF) on ovulation in endometriosis. A prospective study including 50 ovarian endometriosis patients and 50 control patients with matched pairs design was conducted with alterations in FF and peritoneal fluid (PF) components identified by metabolomics analyses and differentially expressed genes in granulosa cells (GCs) identified by transcriptome analysis. Patients with endometriosis exhibited a significantly higher progesterone level in serum, FF, and PF. Granulosa cells from endometriosis patients revealed decreased expression of HPGD, COX-2, and suppressed NF-ĸB signaling. Similarly, progesterone treatment in vitro downregulated HPGD and COX2 expression and suppressed NF-ĸB signaling in granulosa tumor-like cell line KGN (Bena Culture Collection, China) and primarily cultured GCs, as manifested by decreased expressions of IL1R1, IRAK3, reduced pIĸBα/IĸBα ratio, and nucleus translocation of p65. On the contrary, TNF-α treatment increased expression of IL1R1, IRAK3, pIĸBα, p65, and HPGD in GCs. One potential p65 binding site was identified in the promoter region of HPGD by chromatin immunoprecipitation. In conclusion, we found that intrafollicular progesterone might downregulate HPGD and COX-2 in GCs via suppressing the NF-ĸB signaling pathway, shedding light on the mechanism underlying the endometriosis-related ovulatory dysfunction.

Effects of dysregulated glucose metabolism on the occurrence and ART outcome of endometriosis.

BACKGROUND: Endometriosis is associated with systemic metabolic indicators, including body mass index (BMI), glucose metabolism and lipid metabolism, while the association between metabolic indexes and the occurrence and assisted reproductive technology (ART) outcome of endometriosis is unclear. We aimed to evaluate the characteristics of systemic metabolic indexes of endometriosis patients with infertility and their effects on pregnancy outcome after ART treatment. METHODS: A retrospective cohort study involve 412 endometriosis patients and 1551 controls was conducted. Primary outcome was metabolic indexes, and secondary measures consisted of the influence of metabolic indexes on the number of retrieved oocytes and ART outcomes. RESULTS: Endometriosis patients had higher insulin (INS) [6.90(5.10-9.50) vs 6.50(4.80-8.90) µU/mL, P = 0.005]. A prediction model for endometriosis combining the number of previous pregnancies, CA125, fasting blood glucose (Glu) and INS, had a sensitivity of 73.9%, specificity of 67.8% and area under curve (AUC) of 0.77. There were no significant differences in ART outcomes and complications during pregnancy. The serum levels of Glu before pregnancy were associated with GDM both in endometriosis group (aOR 12.95, 95% CI 1.69-99.42, P = 0.014) and in control group (aOR 4.15, 95% CI 1.50-11.53, P = 0.006). CONCLUSIONS: We found serum Glu is related to the number of retrieved oocytes in control group, serum INS is related to the number of retrieved oocytes in endometriosis group, while serum Glu and INS before pregnancy are related to the occurrence of GDM in two groups. A prediction model based on metabolic indexes was established, representing a promising non-invasive method to predict endometriosis patients with known pregnancy history.

Conversion from spermatogonia to spermatocytes: Extracellular cues and downstream transcription network.

Spermatocyte (spc) formation from spermatogonia (spg) differentiation is the first step of spermatogenesis which produces prodigious spermatozoa for a lifetime. After decades of studies, several factors involved in the functioning of a mouse were discovered both inside and outside spg. Considering the peculiar expression and working pattern of each factor, this review divides the whole conversion of spg to spc into four consecutive development processes with a focus on extracellular cues and downstream transcription network in each one. Potential coordination among Dmrt1, Sohlh1/2 and BMP families mediates Ngn3 upregulation, which marks progenitor spg, with other changes. After that, retinoic acid (RA), as a master regulator, promotes A1 spg formation with its helpers and Sall4. A1-to-B spg transition is under the control of Kitl and impulsive RA signaling together with early and late transcription factors Stra8 and Dmrt6. Finally, RA and its responsive effectors conduct the entry into meiosis. The systematic transcription network from outside to inside still needs research to supplement or settle the controversials in each process. As a step further ahead, this review provides possible drug targets for infertility therapy by cross-linking humans and mouse model.

Molecular insights into hormone regulation via signaling pathways in Sertoli cells: With discussion on infertility and testicular tumor.

Spermatogenesis is a complex and elaborate differentiation process and is critical for male fertility. The hypothalamic-pituitary-gonadal axis serves as a significant neuroendocrine system to regulate spermatogenesis. As a constitute of the hypothalamic-pituitary-gonadal axis, Sertoli cells promote spermatogenesis via protecting, nourishing, and supporting germ cells upon hormone determination. Here we clarified how the hormones in the hypothalamic-pituitary-gonadal axis, including FSH, testosterone and LH, regulate spermatogenesis via the androgen receptor, cAMP/PKA, PI3k/Akt signaling pathways in Sertoli cells. Other endogenous hormones in higher vertebrates, including ouabain, estradiol, leptin, MIS, PGD2, and thyroid hormone, also regulate spermatogenesis via the AR or cAMP/PKA signaling pathway. Among them, the dynamics of adherens junctions, gap junctions, and blood-testis barrier, glucose uptake, lactate supply and differentiation of Sertoli cells are regulated by more comprehensive hormones and signaling pathways in Sertoli cells. In infertile patients or patients with blocked spermatogenesis, the AR, cAMP/PKA and PI3k/Akt signaling pathways and related components exhibit abnormal activity or disordered content. The clinical specimens from patients with testicular cancer show similar mutated AR genes. According to the existing clinical evidence, it is valuable to study the deep mechanism of male infertility and testicular tumors from the perspective of hormones and signaling pathways in Sertoli cells.

Multiple signaling pathways in Sertoli cells: recent findings in spermatogenesis.

The functions of Sertoli cells in spermatogenesis have attracted much more attention recently. Normal spermatogenesis depends on Sertoli cells, mainly due to their influence on nutrient supply, maintenance of cell junctions, and support for germ cells' mitosis and meiosis. Accumulating evidence in the past decade has highlighted the dominant functions of the MAPK, AMPK, and TGF-ß/Smad signaling pathways during spermatogenesis. Among these pathways, the MAPK signaling pathway regulates dynamics of tight junctions and adherens junctions, proliferation and meiosis of germ cells, proliferation and lactate production of Sertoli cells; the AMPK and the TGF-ß/Smad signaling pathways both affect dynamics of tight junctions and adherens junctions, as well as the proliferation of Sertoli cells. The AMPK signaling pathway also regulates lactate supply. These signaling pathways combine to form a complex regulatory network for spermatogenesis. In testicular tumors or infertile patients, the activities of these signaling pathways in Sertoli cells are abnormal. Clarifying the mechanisms of signaling pathways in Sertoli cells on spermatogenesis provides new insights into the physiological functions of Sertoli cells in male reproduction, and also serves as a pre-requisite to identify potential therapeutic targets in abnormal spermatogenesis including testicular tumor and male infertility.

The dynamics and regulation of chromatin remodeling during spermiogenesis.

The functional sperm is the key factor for species continuation. The process spermatogenesis, to produce mature sperm is quite complex. It begins with the proliferation and differentiation of spermatogonia, which develop from primary spermatocytes to secondary spermatocytes and round spermatids, which eventually develop into fertile mature sperm. Spermiogenesis is the latest stage of spermatogenesis, where the round spermatids undergo a series of dramatic morphological changes and extreme condensation of chromatin to construct mature sperm with species-specific shape. During spermiogenesis, chromatin remodeling is a unique progress. It leads the nucleosome from a histone-based structure to a mostly protamine-based configuration. The main events of chromatin remodeling are the replacement of histone by histone variants, hyperacetylation, transient DNA strand breaks and repair, variants by transition proteins and finally by protamines. In this review, we synthesize and summarize the current knowledge on the progress of chromatin remodeling during spermiogenesis. We straighten out the chronological order of chromatin remodeling and illustrate the possible regulation mechanisms of each step.