The polycystic ovary syndrome evolutionary paradox: a genome-wide association studies-based, in silico, evolutionary explanation.

Objective: In this study we analyze the PCOS phenotype-genotype relationship in silico, using SNPs of representative genes for analysis of genetic clustering and distance, to evaluate the degree of genetic similarity. Data Source: 1000 Genomes, HapMap, and Human Genome Diversity Project databases were used as source of allele frequencies of the SNPs, using data from male and female individuals grouped according to their geographical ancestry. Setting and Design: Genetic clustering was calculated from SNPs data by Bayesian inference. The inferred ancestry of individuals was matched with PCOS phenotype data, extracted from a previous meta-analysis. The measure of genetic distance was plotted against the geographic distance between the populations. Results: The individuals were assigned to five genetic clusters, matching with different world regions (Kruskal-Wallis/Dunn's post test; P < .0001), and converging in two main PCOS phenotypes in different degrees of affinity. The overall genetic distance increased with the geographic distance among the populations (linear regression; R2 = 0.21; P < .0001), in a phenotype-unrelated manner. Conclusions: Phenotype-genotype correlations were demonstrated, suggesting that PCOS genetic gradient results from genetic drift due to a serial founder effect occurred during ancient human migrations. The overall prevalence of the disease supports intralocus sexual conflict as alternative to the natural selection of phenotypic traits in females

Molecular Mechanisms of Action of FSH

The glycoprotein follicle-stimulating hormone (FSH) acts on gonadal target cells, hence regulating gametogenesis. The transduction of the hormone-induced signal is mediated by the FSH-specific G protein-coupled receptor (FSHR), of which the action relies on the interaction with a number of intracellular effectors. The stimulatory Gαs protein is a long-time known transducer of FSH signaling, mainly leading to intracellular cAMP increase and protein kinase A (PKA) activation, the latter acting as a master regulator of cell metabolism and sex steroid production. While in vivo data clearly demonstrate the relevance of PKA activation in mediating gametogenesis by triggering proliferative signals, some in vitro data suggest that pro-apoptotic pathways may be awakened as a “dark side” of cAMP/PKA-dependent steroidogenesis, in certain conditions. P38 mitogen-activated protein kinases (MAPK) are players of death signals in steroidogenic cells, involving downstream p53 and caspases. Although it could be hypothesized that pro-apoptotic signals, if relevant, may be required for regulating atresia of non-dominant ovarian follicles, they should be transient and counterbalanced by mitogenic signals upon FSHR interaction with opposing transducers, such as Gαi proteins and β-arrestins. These molecules modulate the steroidogenic pathway via extracellular-regulated kinases (ERK1/2), phosphatidylinositol-4,5-bisphosphate 3-kinases (PI3K)/protein kinase B (AKT), calcium signaling and other intracellular signaling effectors, resulting in a complex and dynamic signaling network characterizing sex- and stage-specific gamete maturation. Even if the FSH-mediated signaling network is not yet entirely deciphered, its full comprehension is of high physiological and clinical relevance due to the crucial role covered by the hormone in regulating human development and reproduction

Response to letter by Azziz R., et al.

Comment on The polycystic ovary syndrome evolutionary paradox: a genome-wide association studies-based, in silico, evolutionary explanation. [J Clin Endocrinol Metab. 2014] Letter to the editor re: Casarini and Brigante, 2014, from Azziz R., et al. [J Clin Endocrinol Metab. 2015

Is polycystic ovary syndrome a sexual conflict? A review

Several studies have attempted to explain the high overall prevalence of polycystic ovary syndrome among women worldwide (about 4-10%) despite its link to subfertile phenotypes. For this reason, it is considered an evolutionary paradox. In this review, we show that several genetic loci associated with the disease differently modulate the reproductive parameters of men and women. This observation suggests that such genetic variants lead to opposite effects in the two sexes in reproductive success. Intralocus sexual conflict as a cause of the persistence polycystic ovary syndrome genotypes among humans is supported

Monitoring of the immune efficiency of Mytilus galloprovincialis in Adriatic sea mussel farms in 2005

The monthly evaluation of the cytotoxicity of hemolymph from the mussel Mytilus galloprovincialis revealed some variations in the percentage of cytotoxic animals during the year. Cytotoxicity is confirmed to be a dynamic parameter that can be used as an indicator of immune efficiency and, therefore, of the state of health of the animals

Two hormones for one receptor: evolution, biochemistry, actions and pathophysiology of LH and hCG

Luteinizing hormone (LH) and chorionic gonadotropin (CG) are glycoproteins fundamental for sexual development and reproduction. Since they act on the same receptor (LHCGR), there is a general consensus that LH and hCG are equivalent. However, separate evolution of LHβ and hCGβ subunits occurred in primates, resulting in two molecules sharing ∼85% identity and regulating different physiological events. Pituitary, pulsatile LH production results in a ∼90 min half-life molecule targeting the gonads, to regulate gametogenesis and androgen synthesis. Trophoblast hCG, the "pregnancy hormone", exists in several isoforms and glycosylation variants with long half-lives (hours), angiogenic potential, and acts on luteinized ovarian cells as a progestational. The different molecular features of LH and hCG lead to hormone-specific LHCGR binding and intracellular signaling cascades. In ovarian cells, LH action is preferentially exerted through kinases, pERK1/2 and pAKT, resulting in irreplaceable proliferative/anti-apoptotic signals and partial agonism on progesterone production in vitro. In contrast, hCG displays notable cAMP/PKA-mediated steroidogenic and pro-apoptotic potential, which is masked by estrogen action in vivo. In vitro data are confirmed by large dataset from assisted reproduction, since the steroidogenic potential of hCG positively impacts on the number of retrieved oocytes, while LH impacts pregnancy rate (per oocyte number). Interestingly, Leydig cell in vitro exposure to hCG results in qualitatively similar cAMP/PKA and pERK1/2 activation as compared to LH, as well as testosterone. The supposed equivalence of LH and hCG is debunked by such data highlighting their sex-specific functions, thus deeming it an oversight caused by incomplete understanding of clinical data

Efficacy of follicle-stimulating hormone (FSH) alone, FSH + luteinizing hormone, human menopausal gonadotropin or FSH + human chorionic gonadotropin on assisted reproductive technology outcomes in the "personalized" medicine era: A meta-analysis

Setting: Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) act on the same receptor, activating different signal transduction pathways. The role of LH or hCG addition to follicle-stimulating hormone (FSH) as well as menopausal gonadotropins (human menopausal gonadotropin; hMG) in controlled ovarian stimulation (COS) is debated. Objective: To compare FSH + LH, or FSH + hCG or hMG vs. FSH alone on COS outcomes. Design: A meta-analysis according to PRISMA statement and Cochrane Collaboration was performed, including prospective, controlled clinical trials published until July 2016, enrolling women treated with FSH alone or combined with other gonadotropins. Trials enrolling women with polycystic ovarian syndrome were excluded (PROSPERO registration no. CRD42016048404). Results: Considering 70 studies, the administration of FSH alone resulted in higher number of oocytes retrieved than FSH + LH or hMG. The MII oocytes number did not change when FSH alone was compared to FSH + LH, FSH + hCG, or hMG. Embryo number and implantation rate were higher when hMG was used instead of FSH alone. Pregnancy rate was significantly higher in FSH + LH-treated group vs. others. Only 12 studies reported live birth rate, not providing protocol-dependent differences. Patients' stratification by GnRH agonist/antagonist identified patient subgroups benefiting from specific drug combinations. Conclusion: In COS, FSH alone results in higher oocyte number. HMG improves the collection of mature oocytes, embryos, and increases implantation rate. On the other hand, LH addition leads to higher pregnancy rate. This study supports the concept of a different clinical action of gonadotropins in COS, reflecting previous in vitro data

Response: Commentary: Efficacy of Follicle-Stimulating Hormone (FSH) Alone, FSH + luteinizing hormone, human menopausal gonadotropin or FSH + human chorionic gonadotropin on assisted reproductive technology outcomes in the "Personalized" Medicine Era: A meta-analysis

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Nuclear expression of VDR and AHR is mutually exclusive in glandular cells in endometriosis

The vitamin D receptor (VDR) and aryl hydrocarbon receptor (AHR) are two nuclear receptors that exert their effects by binding with ligands and forming a molecular complex. These complexes translocate to the nucleus and activate the expression of a series of genes which have a response element to VDR or AHR. Both receptors have been identified in the pathogenesis of endometriosis, a common disease characterized by the formation of endometrium-like tissue in ectopic zones. Despite numerous therapies, there is no definitive cure for endometriosis at the pharmacological level. Our study aims to describe the location and the expression of VDR and AHR at the protein level. For this purpose, an evaluation was performed using tissue from the three normal phases of the endometrium (proliferative, early, and late secretory) and in endometriosis by immunohistochemistry, using anti-VDR and anti-AHR antibodies. We demonstrate that in the nuclei of glandular cells in endometriosis, the expression of VDR and AHR is mutually exclusive-when the expression of one receptor is high, the other one is low-suggesting a possible target in the treatment of endometriosis. We also identify a significant change in the expression of glandular cytoplasmic AHR between the proliferative and late secretory endometrium