Reproductive Sciences

Contemporary claims that mitotically active female germ line or oogonial stem cells (OSCs) exist and support oogenesis during postnatal life in mammals have been debated in the field of reproductive biology since March 2004, when a mouse study posed the first serious challenge to the dogma of a fixed pool of oocytes being endowed at birth in more than 50 years. Other studies have since been put forth that further question the validity of this dogma, including the isolation of OSCs from neonatal and adult mouse ovaries by 4 independent groups using multiple strategies. Two of these groups also reported that isolated mouse OSCs, once transplanted back into ovaries of adult female mice, differentiate into fully functional eggs that ovulate, fertilize, and produce healthy embryos and offspring. Arguably, one of the most significant advances in this emerging field was provided by a new research study published this year, which reported the successful isolation and functional characterization of OSCs from ovaries of reproductive age women. Two commentaries on this latest work, one cautiously supportive and one highly skeptical, were published soon afterward. This article evaluates the current literature regarding postnatal oogenesis in mammals and discusses important next steps for future work on OSC biology and function.

Potential roles of gonadotropin-releasing hormone (GnRH) antagonists on GnRH/GnRH receptor systems and their effects on the extrapituitary tissues are largely elusive. In this narrated review, we summarized the systemic effects of GnRH antagonists on ovary, endometrium, embryo implantation, placental development, fetal teratogenicity, reproductive tissue cancer cells, and heart while briefly reviewing the GnRH and GnRH receptor system. GnRH antagonists may have direct effects on ovarian granulosa cells. Data are conflicting regarding their effects on endometrial receptivity. The GnRH antagonists may potentially have detrimental effect on early placentation by decreasing the invasive ability of cytotrophoblasts if the exposure to them occurs during early pregnancy. The GnRH antagonists were not found to increase the rates of congenital malformations. Comparative clinical data are required to explore their systemic effects on various extrapituitary tissues such as on cardiac function in the long term as well as their potential use in other human cancers that express GnRH receptors.

Blood vessels are necessary for development and maintenance of the endometriosis and blood flow supplies oxygen and essential nutrient to the disease. Local angiogenesis is regulated by vascular endothelial growth factor (VEGF) and inhibitors of VEGF may be a novel therapeutic approach. We inducted endometriosis in 43 rats and they were randomly allocated into 4 groups. The rats in group I (control n = 11) were given no medication. The rats in group II (n = 11) were given bevacizumab. The rats in group III (n = 11) were given Sorafenib, and the rats in group IV (n = 10) were given retinoic acid (RA). Then groups were compared for microvessel density, VEGF, soluble tyrosine-kinase receptor, ovarian reserve, and treatment effectivity. All these medications were effective on endometriosis and we detected that volume of endometriotic implants were significantly decreased. Ovarian reserve was not affected from the medication, in addition RA have induced reproductive capacity.

We used logistic regression analysis to investigate the relationship between serum anti-Mullerian hormone (AMH) levels and the rate of ongoing pregnancy. Retrospective data were collected from 1043 women who had undergone their first cycle of in vitro fertilization (IVF), including 540 cycles of fresh embryo transfer and 503 cycles of frozen-thawed embryo transfer. The patients were divided into 4 groups based on the cutoff values from a receiver–operating characteristic curve: 0.0 to 12.4, 12.5 to 25.5, 25.6 to 44.1, and >44.2 pmol/L. After adjustment for multiple confounders, the serum AMH group was found to be significantly related to the rate of ongoing pregnancy in total cycles (0.0-12.4 vs 12.5-25.5 pmol/L; P = .0088, odds ratio, 1.909: vs 25.6-44.1 pmol/L; P = .0281, odds ratio, 2.109: vs >44.2 pmol/L; P = .0008, odds ratio, 2.840). In conclusion, there appears to be a significant relationship between serum AMH levels and the ongoing pregnancy rate in first IVF treatment cycles after adjustment for multiple confounders.

We investigated whether microRNA (miRNA) polymorphisms (miR-146aC>G, miR-196a2T>C, and miR-499A>G) confer risk of premature ovarian failure (POF) in Korean women. DNA samples from 136 patients with POF and 234 controls were genotyped for the 3 miRNA single-nucleotide polymorphisms by polymerase chain reaction–restriction fragment length polymorphism. The miR-146aCG/miR-196a2TC combined genotype was less frequent in patients than in controls (P < .05), conferring less susceptibility. Using haplotype-based multifactor dimensionality reduction analysis, the C-C-A and G-T-A inferred haplotypes (miR-146a/miR-196a2/miR-499) were less frequent in patients, suggesting protective effects (P < .05 for each), whereas the C-T-A and G-C-A haplotypes were more frequent in patients (P < .05 for each). The C-T and G-C haplotypes (miR-146a/miR-196a2) were more frequent in patients, whereas the C-C and G-T haplotypes were less frequent in patients (P < .05 for each). However, none of the 3 miRNA polymorphisms alone was associated with POF risk. Our findings suggest that putative gene–gene interaction between miR-146 and miR-196a2 may be involved in POF development.

We postulate that protein kinase C α (PKCα) may contribute to the maintenance of pregnancy myometrial quiescence in humans. We studied the changes in myometrial PKCα gene products (messenger RNA [mRNA] and protein) in 4 groups of women: preterm not in labor (PT-NL), preterm in labor (PT-L), term not in labor (T-NL), and term in labor (T-L). The degree of PKCα activation was studied by comparing the levels of particulate (active) PKCα with the total PKCα protein levels and by measuring PKCα activity in the cytosolic and particulate fractions. Protein kinase Cα abundance (mRNA and protein) did not increase during myometrial quiescence (PT-NL), whereas the level of PKCα activity significantly increased during quiescence. The activity of PKCα significantly decreased in the T-NL, T-L, and PT-L groups. These findings suggest that PKCα plays a significant role in the maintenance of myometrial quiescence and that PKCα activity must decrease at the end of pregnancy allowing myometrial activation. Additionally, our data demonstrate an association between reduced PKCα activity and preterm labor, which merits further investigation.

HOXA10 is an important gene for endometrial receptivity and plays a regulatory role in the adult female reproductive tract. It is regulated by epigenetic modulation in the CpG clusters of promoter in some cases. The aim of this study was to investigate HOXA10 expression and the epigenetic regulation in the eutopic endometrium of fertile women with endometriosis by quantitative real-time polymerase chain reaction (RT-PCR) and Western blot. The effect of 5-azacytidine (5-ac), a demethylation agent on HOXA10 expression was determined on endometrium stromal cells (ESCs) from these women with endometriosis. Results revealed that in normal endometrium (NE), HOXA10 messenger RNA (mRNA) and protein expression at the secretory phase were significantly higher than that at the proliferative phase. The HOXA10 mRNA and protein expression in the eutopic endometrium of endometriosis were significantly lower than in NE. The HOXA10 mRNA and protein levels in cultured stromal cells from endometriosis in vitro were significantly increased in a 5-ac treatment group compared with a nontreatment group. Our results indicated that the level of HOXA10 decrease in the eutopic endometrium of patients with endometriosis. Upregulation of HOXA10 in ESCs after treatment with 5-ac suggests that HOXA10 expression is controlled by methylation of the promoter. An epigenetic aberration is likely the main cause of endometriosis.

We identified differentially expressed genes comparing peritoneal endometriosis lesions (n = 18), eutopic endometrium (n = 17), and peritoneum (n = 22) from the same patients with complete menstrual cycles using microarrays (54 675 probe sets) and immunohistochemistry. Peritoneal lesions and peritoneum demonstrated 3901 and 4973 significantly differentially expressed genes compared to eutopic endometrium, respectively. Peritoneal lesions significantly revealed no correlation with a specific menstrual cycle phase by gene expression and histopathology, exhibited low expressed proliferation genes, and constant levels of steroid hormone receptor genes. Tissue remodeling genes in cytoskeleton, smooth muscle contraction, cellular adhesion, tight junctions, and O-glycan biosynthesis were the most significant to lesions, including desmin and smooth muscle myosin heavy chain 11. Protein expression and location of desmin, alpha-actin, and h-caldesmon in peritoneal lesions discriminated between smooth muscle hyperplasia and metaplasia. Peritoneal lesions demonstrate no menstrual cycle phasing but constant steroid hormone receptor expression where a slow but steady growth is linked with tissue remodeling. Our study contributes to the molecular pathology of peritoneal endometriosis and will help to identify clinical targets for treatment and management.

To understand the regulation of Na(+)/H(+) exchanger regulatory factor (NHERF1) in polycystic ovarian syndrome, we studied the expression of NHERF1 in uterus of Wistar rats injected with (6 mg/kg) of dehydroepiandrosterone (DHEA) for 7 and 20 days. Immunohistochemistry analysis of NHERF1 showed a substantial shift in the intracellular localization of NHERF1 in endometrial glands and areas of luminal epithelium as early as 7 days of DHEA administration. The NHERF1 accumulated in the “Golgi apparatus area” virtually in all the glands in the 7-day protocol, and in the majority of the glands of 20-day protocol. In contrast, NHERF1 is expressed in the apical membrane and slightly in the cytoplasm of the control epithelium. The subcellular redistribution of NHERF1 could affect the sorting of proteins to the apical membrane and the organization of the apical compartment.