Quality, readability, and transparency of Arabic online health information on temporomandibular disorders: An infodemiological analysis of 408 websites.

The hypothalamic-pituitary-gonadal axis controls reproduction in vertebrates. Gonadotropin-releasing hormone (GnRH) neurons in the medial preoptic area (POA) and hypothalamus project to the median eminence, releasing GnRH in discrete pulses in males and during most of the female reproductive cycle (). GnRH induces the synthesis and release of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), by the anterior pituitary (). The release occurs in a GnRH pulse-frequency-dependent manner, with high frequencies favoring LH release and low frequencies favoring FSH release (, ). Gonadotropins initiate the synthesis of sex steroids, which feedback to regulate the brain and pituitary (). Disruptions in this axis can lead to reduced fertility. Polycystic ovary syndrome (PCOS, which was recently renamed polyendocrine metabolic ovary syndrome, PMOS ()) affects 10% to 13% of reproductive-aged women () according to the Rotterdam diagnostic criteria () and is the leading cause of female infertility (, ). Hyperandrogenemic PCOS, affecting 8% to 20% of reproductive-aged women (, ), is associated with persistent high-frequency LH, and presumably GnRH, pulses () and a higher LH:FSH ratio compared to healthy women (). These disruptions likely begin during the pubertal process; adolescent girls with hyperandrogenemia exhibit elevated LH-pulse frequency (). The underlying causes of PCOS are not fully understood. PCOS is highly heritable with 20% to 40% of first-degree relatives of women with PCOS developing this disorder (, ). Current understanding postulates that PCOS is multifactorial, with genetics and environment both contributing to its etiology. In terms of genetics, genome-wide association studies have linked single nucleotide polymorphisms in over 20 genes to PCOS (). These changes account for <10% of cases, however, suggesting the presence of additional contributing factors (). When considering environmental factors, pregnant women with PCOS have elevated serum testosterone levels in the latter part of gestation (, ), suggesting that fetal exposure to maternal androgens may drive development of PCOS (, ). Supporting this, prenatal androgenization (PNA) of mice, rats, sheep, and non-human primates produces female offspring that display a PCOS-like phenotype: elevated serum LH and testosterone () and elevated LH-pulse frequency (), providing substantial evidence that PNA induces a reprograming of the hypothalamic-pituitary-gonadal axis. Transgenerational transmission of PCOS-like traits was recently reported in both PNA and anti-Müllerian hormone excess models (), underscoring the importance of identifying epigenetic events before adult phenotypes emerge. To determine the effects of PNA on the transcriptional profile of GnRH neurons in mice, translating ribosome affinity purification combined with ribonucleic acid sequencing (TRAP-seq) was performed on female vehicle-control treated (VEH) and PNA dams (). TRAP-seq revealed that PNA altered the transcriptional profile of GnRH neurons. We postulate that as an underlying mechanism, PNA treatment induces epigenetic changes in GnRH neurons. Here, the epigenetic and nuclear-RNA expression profiles of GnRH neurons and surrounding cells were identified in prepubertal mice in an unbiased manner using multiomics: a combination of single-nucleus assay for transposase-accessible chromatin using sequencing (snATACseq) and single-nucleus ribonucleic acid sequencing (snRNAseq). The goals were to determine the epigenetic and gene expression (GEX) profiles of GnRH neurons in VEH vs PNA female mice, and to determine the changes in epigenetic and GEX profiles of non-GnRH cells in the preoptic area to gain insight into the mechanisms underpinning PNA-induced changes in GEX that occur before the onset of adult differences in phenotype arising from that treatment, such as elevated androgens in PNA mice.