Sodium-glucose cotransporter 2 inhibitor ameliorates high fat diet-induced hypothalamic-pituitary-ovarian axis disorders.

High-fat diet (HFD) consumption is known to be associated with ovulatory disorders among women of reproductive age. Previous studies in animal models suggest that HFD-induced microglia activation contributes to hypothalamic inflammation. This causes the dysfunction of the hypothalamic-pituitary-ovarian (HPO) axis, leading to subfertility. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of lipid-soluble antidiabetic drugs that target primarily the early proximal tubules in kidney. Recent evidence revealed an additional expression site of SGLT2 in the central nervous system (CNS), indicating a promising role of SGLT2 inhibitors in the CNS. In type 2 diabetes patients and rodent models, SGLT2 inhibitors exhibit neuroprotective properties through reduction of oxidative stress, alleviation of cerebral atherosclerosis and suppression of microglia-induced neuroinflammation. Furthermore, clinical observations in patients with polycystic ovary syndrome (PCOS) demonstrated that SGLT2 inhibitors ameliorated patient anthropometric parameters, body composition and insulin resistance. Therefore, it is of importance to explore the central mechanism of SGLT2 inhibitors in the recovery of reproductive function in patients with PCOS and obesity. Here, we review the hypothalamic inflammatory mechanisms of HFD-induced microglial activation, with a focus on the clinical utility and possible mechanism of SGLT2 inhibitors in promoting reproductive fitness.

Variation in genes and hormones of the hypothalamic-pituitary-ovarian axis in female mood disorders - A systematic review and meta-analysis.

Women's increased risk for depression during reproductive transitions suggests an involvement of the hypothalamic-pituitary-ovarian (HPO) axis. This is the first systematic review and meta-analysis of HPO functioning in female mood disorders. Inclusionary criteria were: i) women suffering from premenstrual dysphoric disorder (PMDD) or a depressive disorder, ii) assessment of HPO-axis related biomarkers, iii) a case-control design. Sixty-three studies (N = 5,129) were included. There was evidence for PMDD to be paralleled by lower luteal oestradiol levels. Women with depression unrelated to reproductive transition showed lower testosterone levels than healthy controls and there was some evidence for lower dehydroepiandrosterone sulfate levels. There were no differences in HPO-related parameters between women with pregnancy, postpartum, and perimenopausal depression and controls. Women with PMDD and depression unrelated to reproductive transitions exhibit specific changes in the HPO-axis, which potentially contribute to their symptoms. Further research into reproductive mood disorders characterised by extreme endocrine changes is warranted.

Effects of ammonia on hypothalamic-pituitary-ovarian axis in female rabbits.

BACKGROUND: As one of the most harmful gases in the livestock house, ammonia is recognized as an environmental stressor by Environmental Protection Agency (United States). The study aimed to explore the effect of ammonia on hypothalamic-pituitary-ovarian (HPO) axis of rabbits. A total of ninety two-month-old female IRA rabbits were randomly divided into three groups, and were kept in animal environment control rooms for four weeks at college of animal science and technology, Hebei Agricultural University (Baoding, China). The rabbits in the control group were kept under ammonia concentration of < 3 ppm. The two treatment groups were kept under ammonia concentration of 30 ppm and 50 ppm. Hypothalamus, pituitary, and ovary were collected for hematoxylin and eosin (HE) staining, immunohistochemistry, terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Serum was collected for enzyme-linked immunosorbent assay (ELISA). RESULTS: Histopathological examination revealed that exposed to excess ammonia damaged the morphology and structure of hypothalamus, pituitary, and ovary. TUNEL assay revealed that apoptosis rate increased in hypothalamus, pituitary, and ovary. The protein expression levels of Bcl-2associated X protein (Bax) and Caspase-9 increased, while B-cell lymphoma-2 (Bcl-2) decreased, resulting in apoptosis. Moreover, the concentration of gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and progesterone (PROG) reduced in plasma. The mRNA expression of FSH and LH in pituitary and follicle-stimulating hormone receptor (FSHR), E2, PROG in ovary as well as decreased, indicated hormone secretion disorder. CONCLUSIONS: The results indicated that ammonia exposure damaged hypothalamus, pituitary, and ovary, caused hormone secretion disorder and apoptosis.

Orcinol glucoside improves the depressive-like behaviors of perimenopausal depression mice through modulating activity of hypothalamic-pituitary-adrenal/ovary axis and activating BDNF- TrkB-CREB signaling pathway.

Orcinol Glucoside (OG), a phenolic glucoside isolated from C. orchioides, showed the antidepressant-like effect on chronic unpredictable mild stress (CUMS)-induced rats previously. This study was designed to determine whether OG could improve the depressive-like symptoms of perimenopausal depression (PMD) and the possible mechanisms involved. This research was performed on a PMD mice model established by a two-steps method of ovariectomy (OVX) followed CUMS. OG treatment effectively improved the depressive-like behaviors of OVX-CUMS mice, as indicated by increased sucrose intake in sucrose preference test (SPT), reduced immobility time in forced swimming test (FST), and tail suspension test (TST), lower frequency of grooming and defecation, increased actions of rearing, and prolonged duration in the center in open field test (OFT). OG treatment alleviated the OVX-CUMS induced dysfunction of hypothalamic-pituitary-ovarian (HPO) axis by increased serum estradiol (E2) and decreased ovarian hormones follicle stimulating hormone (FSH), luteinizing hormone (LH), and gonadotropin-releasing hormone (GnRH) in serum. Meanwhile, OG reversed the hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis as evidenced by decreased CORT and ACTH in serum, reduced as well as the mRNA and protein expression of corticotropin-releasing hormone (CRH) in hypothalamus and hippocampus. Moreover, OG up-regulated the protein expression of BDNF, TrkB, and phosphorylation level of CREB and ERK1/2 in hippocampus. These findings demonstrated that OG improves depressive behaviors of OVX-CUMS mice by modulating of HPO/HPA axis dysfunction, and activating BDNF-TrkB-CREB signaling pathway.

Marijuana, the Endocannabinoid System and the Female Reproductive System.

Marijuana use among women is highly prevalent, but the societal conversation on marijuana rarely focuses on how marijuana affects female reproduction and endocrinology. This article reviews the current scientific literature regarding marijuana use and hypothalamic-pituitary-ovarian (HPO) axis regulation, ovarian hormone production, the menstrual cycle, and fertility. Evidence suggests that marijuana can reduce female fertility by disrupting hypothalamic release of gonadotropin releasing hormone (GnRH), leading to reduced estrogen and progesterone production and anovulatory menstrual cycles. Tolerance to these effects has been shown in rhesus monkeys, but the effects of chronic marijuana use on human female reproduction are largely unknown. Marijuana-induced analgesia, drug reinforcement properties, tolerance, and dependence are influenced by ovarian hormones, with estrogen generally increasing and progesterone decreasing sensitivity to marijuana. Carefully controlled regulation of the Endocannabinoid System (ECS) is required for successful reproduction, and the exogenous cannabinoids in marijuana may disrupt the delicate balance of the ECS in the female reproductive system.

The naturally occurring luteinizing hormone surge is diminished in mice lacking estrogen receptor Beta in the ovary.

Female ESR2-null mice (betaERKO) display defects in ovarian function and are subfertile. Follicular maturation is impaired and explains smaller litters, but betaERKO also produce fewer litters, which may be partially due to inadequate ovulatory signals. To test this, the amplitude and timing of the naturally occurring luteinizing hormone (LH) surge was measured in individual intact betaERKO and wild-type (WT) mice. Vaginal cytology was evaluated daily, and blood samples were taken from mice in proestrus. The amplitude of the LH surge was severely blunted in betaERKO mice compared to WT, but pituitary LH levels revealed no differences. The betaERKO mice did not produce a preovulatory estradiol surge. To determine if the smaller LH surges and the reduced number of litters in betaERKO were due to the lack of ESR2 in the hypothalamic-pituitary axis or due to the absence of ESR2 in the ovary, ovaries were transplanted from WT into betaERKO mice and vice versa. The size of the LH surge was reduced only in mice lacking ESR2 within the ovary, and these mice had fewer litters. Fertility and size of the LH surge were rescued in betaERKO mice receiving a WT ovary. These data provide the first experimental evidence that the LH surge is impaired in betaERKO females and may contribute to their reduced fertility. ESR2 is not necessary within the pituitary and hypothalamus for the generation of a normal LH surge and for normal fertility, but ESR2 is essential within the ovary to provide proper signals.

Molecular mechanisms of hypothalamic-pituitary-ovarian/thyroid axis regulating age at first egg in geese.

Age at first egg (AFE) has consistently garnered interest as a crucial reproductive indicator within poultry production. Previous studies have elucidated the involvement of the hypothalamic-pituitary-ovarian (HPO) and hypothalamic-pituitary-thyroid (HPT) axes in regulating poultry sexual maturity. Concurrently, there was evidence suggesting a potential co-regulatory relationship between these 2 axes. However, as of now, no comprehensive exploration of the key pathways and genes responsible for the crosstalk between the HPO and HPT axes in the regulation of AFE has been reported. In this study, we conducted a comparative analysis of morphological differences and performed transcriptomic analysis on the hypothalamus, pituitary, thyroid, and ovarian stroma between normal laying group (NG) and abnormal laying group (AG). Morphological results showed that the thyroid index difference (D-) value (thyroid index D-value=right thyroid index-left thyroid index) was significantly (P < 0.05) lower in the NG than in the AG, while the ovarian index was significantly (P < 0.01) higher in the NG than in the AG. Furthermore, between NG and AG, we identified 99, 415, 167, and 1182 differentially expressed genes (DEGs) in the hypothalamus, pituitary, thyroid, and ovarian stroma, respectively. Gene ontology (GO) analysis highlighted that DEGs from 4 tissues were predominantly enriched in the "biological processes" category. Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that 16, 14, 3, and 26 KEGG pathways were significantly enriched (P < 0.05) in the hypothalamus, pituitary, thyroid, and ovarian stroma. The MAPK signaling pathway emerged as the sole enriched pathway across all 4 tissues. Employing an integrated analysis of the protein-protein interaction (PPI) network and correlation analysis, we found GREB1 emerged as a pivotal component within the HPO axis to regulate estrogen-related signaling in the HPT axis, meanwhile, the HPT axis influenced ovarian development by regulating thyroid hormone-related signaling mainly through OPN5. Then, 10 potential candidate genes were identified, namely IGF1, JUN, ERBB4, KDR, PGF, FGFR1, GREB1, OPN5, DIO3, and THRB. These findings establish a foundation for elucidating the physiological and genetic mechanisms by which the HPO and HPT axes co-regulate goose AFE.

Tao-Hong-Si-Wu-Tang Improves the Depressive-like Behaviors in Mice Experiencing Perimenopausal Depression Through Modulating Activity of the Hypothalamic-Pituitary-Adrenal-Ovary Axis and Activating the BDNF-TrkB-CREB Signaling Pathway.

Tao-Hong-Si-Wu-Tang (THSWT), a traditional Chinese herbal remedy, is commonly utilized for the treatment of female perimenopausal depression through regulating menstruation, but the mechanism remains unknown. In this study, ICR mice were randomly divided into six groups: low, medium, and high dose of THSWT (0.5, 1.5, and 4.5 g/kg), soy isoflavone (250 mg/kg), ovariectomy group, and control group. All mice, except the control group, had ovaries removed and were exposed to hypoxic stimulation for 28 days to establish a perimenopausal depression mice model. The mice, having unrestricted access to food and water, were administered THSWT treatment for a duration of 14 days. The Western blotting and Enzyme linked immunosorbent assay kits were used to determine protein and hormone levels, respectively. Experimental results showed that THSWT reduced the immobility time of mice from 150.8 s to 104.9 s in the tail suspension test, and it decreased the immobility time of mice from 165.7 s to 119.0 s in the forced swimming test, outperforming the results obtained with soy isoflavones. In addition, THSWT upregulated the protein expression of follicle-stimulating hormone receptor and downregulated the protein expression of corticotropin-releasing hormone-receptor 1 in the hippocampus. Compared with the oophorectomized group, treatment with THSWT decreased the levels of corticosterone and adrenocorticotropic hormone in serum by 173.7 and 23.4 ng/mL, respectively. These findings showed that THSWT could stimulate the perimenopausal nerve tissue and regulate the level of serum hormones in mice. THSWT exhibited promising potential as a viable alternative drug for hormone treatment of perimenopause in clinical use.

Combined exposure of beta-cypermethrin and emamectin benzoate interferes with the HPO axis through oxidative stress, causing an imbalance of hormone homeostasis in female rats.

The impact of pesticides on reproductive health has been increasingly recognized. ß-cypermethrin (ß-CYP) and emamectin benzoate (EMB) are commonly used with agricultural workers. There are few published studies on the effects of combined poisoning of these two pesticides on the reproductive system. This study investigated the toxic effects and mechanism of ß-CYP and EMB on the reproductive system of female rats based on the hypothalamic-pituitary-ovarian (HPO) axis. The hypothalamic GnRH content tended to decrease, and Kiss-1 and GPR-54 mRNA and protein expression tended to increase in exposed rats. FSH content was elevated for the pituitary gland, and Kiss-1 and GPR-54 mRNA and protein expression were enhanced in all experimental groups compared with the control group. E2 content in rat ovaries and ERα mRNA and protein expression were reduced by ß-CYP and EMB. Furthermore, there were interactive effects of ß-CYP and EMB on FSH and E2 release, pituitary GPR-54 mRNA and protein, and ovarian ERα mRNA expression. To investigate causes of damage, oxidative damage indicators were tested and showed that exposure to ß-CYP and EMB decreased GSH-Px and SOD activities in the HPO axis, increased MDA levels in the hypothalamus and ovary together with LDH activities in the HPO axis, with an interaction effect on GSH-Px and SOD activities in the hypothalamus and pituitary gland as well as on MDA in the ovary. The above results support the screening of sensitive molecular biomarkers and evaluation of the adverse effects of pesticide exposure in greenhouse operations on reproductive health.

The cycle of stress: A systematic review of the impact of chronic psychological stress models on the rodent estrous cycle.

Stress is known to impair reproduction through interactions between the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes. However, while it is well accepted that stress can alter estrous cycle regularity, a key indicator of female's HPG axis function, effects of different types of psychological stress have been inconsistent. This systematic review evaluated the impact of rodent models of psychological stress on estrous cyclicity, while reporting biological parameters pertaining to HPA or HPG axis function assessed within these studies. We performed a systematic database search and included articles that implemented a psychological stress model in rodents and reported estrous cyclicity for at least two cycles after initiation of stress. Of the 32 studies included, 62.5% reported post-stress alterations to estrous cyclicity, with Chronic Mild Stress (CMS) models showing the most conclusive effects. Twenty-five studies measured HPG or HPA axis markers, with cycle disruptions being commonly observed in parallel with altered estradiol and increased corticosterone levels. Our review highlights gaps in reporting estrous cyclicity assessments and makes recommendations to improve comparability between studies.

Aberrant HPO Axis Alterations and Autoimmune Abnormalities in PCOS Patients with DOR: A Retrospective Analysis.

BACKGROUND: There is a group of polycystic ovary syndrome (PCOS) patients in clinic who have diminished ovarian reserve (DOR) in combination. This study was designed to evaluate the differences in glucolipid metabolism, hypothalamic-pituitary-ovarian (HPO) axis-related parameters, and autoimmune antibodies in PCOS patients with and without DOR. METHODS: A total of 2307 PCOS patients, including 1757 patients with PCOS alone and 550 patients who have both PCOS and DOR, were enrolled in this retrospective study. Parameters of glucolipid metabolism, HPO axis-related parameters, and autoimmune antibodies were measured and analyzed. RESULTS: The prevalence of DOR among all patients with PCOS was 23.84%. Many HPO axis-related parameters, such as follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and prolactin (PRL) were significantly different in PCOS with DOR compared with PCOS without DOR. The FSH levels were positively correlated with LH, testosterone (T), and androstenedione (AD) levels, but had no association with glucolipid metabolism after adjusting for body mass index (BMI). Moreover, anti-ovarian antibody (AOAb) and anti-21-OH antibody (21-OHAb) levels were significantly elevated in PCOS patients with DOR. CONCLUSIONS: PCOS patients with DOR showed more chaotic HPO axis hormone levels and elevated autoimmune antibodies, suggesting that autoimmune factors may be the cause of DOR in women with PCOS.

Prophylactic Effects of Hemp Seed Oil on Perimenopausal Depression: A Role of HPA Axis.

Hemp seed, the dried fruit of Cannabis sativa L. (Moraceae), has been extensively documented as a folk source of food due to its nutritional and functional value. This study evaluated the antidepressant effect of hemp seed oil (HSO) during its estrogen-like effect in Perimenopausal depression (PMD) rats induced by ovariectomy combined with chronic unpredictable mild stress (OVX-CUMS). Female SD rats (SPF, 10 weeks, sham operated group, ovariectomy (OVX) model group, ovariectomy - chronic unpredictable mild stress (OVX-CUMS) group, HSO + OVX-CUMS group, fluoxetine (FLU) + OVX-CUMS group, n=8) were subjected to treatment with HSO (4.32 g/kg) or fluoxetine (10 mg/kg) for 28 days (20 mL/kg by ig). Sucrose preference test (SPT), forced swimming test (FST), open field test (OFT), estrogen receptor α (ERα) and estrogen receptor ß (ERß) expression, estradiol (E2), follicle stimulating hormone (FSH), luteinizing hormone (LH), cortisol (CORT), adrenocorticotropic hormone (ACTH), corticotropin releasing hormone (CRH), norepinephrine (NE), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5HIAA) levels are measured to evaluate the function of the hypothalamic-pituitary-ovarian (HPO) and hypothalamic-pituitary-adrenal (HPA) axis. The results showed that OVX-CUMS significantly decrease sucrose preference rate in SPT, increase immobility time in FST and OFT, and decrease movement distance and stand-up times in OFT. HSO treatment significantly improves depression-like behaviors, upregulates the expression of ERα and ERß, improves HPO axis function by increasing E2 levels and decreasing FSH and LH levels, reverses HPA axis hyperactivation by decreasing CORT, ACTH, and CRH levels, and upregulates NE, 5-HT, and 5HIAA levels in model rats. The findings suggested that HSO could improve depression-like behavior in OVX-CUMS rats by regulating HPO/HPA axis function and neurotransmitter disturbance.

The prolactin receptor gene (PRLR) is linked and associated with the risk of polycystic ovarian syndrome.

The prolactin receptor gene (PRLR) may contribute to polycystic ovarian syndrome (PCOS) since it plays important roles in physiological ovarian functions. PRLR-knockout mice have irregular cycles and subfertility and variants in or around the PRLR gene were associated in humans with female testosterone levels and recurrent miscarriage. We tested 40 variants in the PRLR gene in 212 Italian families phenotyped by type 2 diabetes (T2D) and PCOS and found two intronic PRLR-variants (rs13436213 and rs1604428) significantly linked to and/or associated with the risk of PCOS. This is the first study to report PRLR as a novel risk gene in PCOS. Functional studies are needed to confirm these results.

A Chinese herbs complex ameliorates gut microbiota dysbiosis induced by intermittent cold exposure in female rats.

Cold is a common source of stress in the alpine areas of northern China. It affects the microbial community, resulting in the invasion of pathogenic microorganisms and intestinal diseases. In recent years, studies have reported that Chinese herbal extracts and their fermentation broth have a significant beneficial effect on gut microbiota. This study aimed to investigate the probiotic effect of a self-designed Chinese herbs complex on the gut microbiota of rats exposed to cold. The rats were treated with intermittent cold exposure and Chinese herbs complex for 14 days, and the gut microbiota composition and other parameters were assayed. The 16s ribosomal DNA high-throughput sequencing and analysis confirmed that the Chinese herbs complex positively improved the gut microbiota. We found that cold exposure could lead to significant changes in the composition of gut microbiota, and affect the intestinal barrier and other physiological functions. The relative abundance of some probiotics in the genus such as Roseburia, Parasutterella, and Elusimicrobium in rats treated with Chinese herbs complex was significantly increased. Serum D-lactic acid (D-LA) and lipopolysaccharide (LPS) were increased in the cold exposure group and decreased in the Chinese herbs complex-treated group. Moreover, the Chinese herbs complex significantly increased the protein expression of occludin. In conclusion, the Chinese herbs complex is effective in restoring the gut microbiota caused by cold exposure, improving the function of the intestinal barrier, and may act as a prebiotic in combatting gut dysbiosis.

[Effects of nutritional preparation on HPO axis function and energy metabolism in uterus and ovary of rats exposed to intermittent cold].

Objective: To investigate the effects of a self-designed nutritional preparation on hypothalamic-pituitary-ovarian (HPO) axis function and energy metabolism in female SD rats exposed to intermittent cold. Methods: Female SD rats were divided into control group, cold exposure group and nutritional preparation group. The control group and cold exposure group were given distilled water by daily gavage, and the nutritional preparation group was given nutritional preparation intragastrically. After the treatment, the cold exposure group and nutritional preparation group were exposed to -10℃ in a cabin for 4 h every day. After being treated for 14 days, the serum, uterus and ovary of rats were collected. The serum follicle stimulating hormone (FSH), luteinizing hormone (LH) and other hormone indicators were detected by enzyme-linked immunosorbent assay (ELISA) and colorimetry was used to detect ATPase and other energy metabolism related indicators. Results: Compared with the control group, cold exposure significantly up-regulated the protein expressions of FSHR and LHR, and notably enhanced the activity of Na+-K+-ATPase and Ca2+-Mg2+-ATPase in ovary and uterus (P<0.05). Nutritional preparation down-regulated the protein expressions of FSHR and LHR, and inhibited the activity of ATPase in ovary and uterus (P<0.05) compared with the cold exposure group. Conclusion: Nutritional preparations can effectively improve the expressions of HPO axis related receptors and abnormal energy metabolism in uterus and ovary caused by intermittent cold exposure.

Expression and localization of adiponectin and its receptors (AdipoR1 and AdipoR2) in the hypothalamic-pituitary-ovarian axis of laying hens.

Adiponectin is a hormone secreted by adipose tissue that is involved in the regulation of energy homeostasis and reproduction. In this study, the expression levels of adiponectin and its receptors in the hypothalamic-pituitary-ovarian (HPO) axis of laying hens were investigated using quantitative real-time PCR (qRT-PCR) and Western blotting, and the localization of these proteins was explored using immunohistochemistry. The morphological relationships between adiponectin receptors and gonadotropin-releasing hormone (GnRH) neurons were analyzed using double immunofluorescence labeling. The results showed that adiponectin mRNA and protein were widely expressed in all tissues involved in the HPO axis in laying hens, with especially high expression in the hypothalamus. Both AdipoR1 and AdipoR2 were more highly expressed in the pituitary than in other tissues and exhibited similar mRNA and protein expression patterns. The immunohistochemistry results showed that adiponectin and AdipoR2 were localized in the major hypothalamic nuclei that regulate food intake and energy balance (i.e., the lateral hypothalamic area (LHA), infundibular nucleus (IN), dorsomedial nucleus (DMN), and paraventricular nucleus (PVN)). Immunostaining revealed that adiponectin and its receptors were also localized in the cytoplasm of cells in the adenohypophysis. In the ovaries, adiponectin was localized in the granulosa layer, in the theca externa of follicles and in basal cells, while AdipoR1 and AdipoR2 were localized in basal cells. In the double immunofluorescence labeling experiment, AdipoR1 and AdipoR2 were localized in GnRH neurons in the IN and DMN. These results suggest that adiponectin and its receptors may play major roles in the endocrine network, which integrates energy balance and reproduction.

Novel Regulatory Factors in the Hypothalamic-Pituitary-Ovarian Axis of Hens at Four Developmental Stages.

Ovarian follicular development is an extremely complex and precise process in which the hypothalamic-pituitary-ovarian (HPO) axis plays a crucial role. However, research on the regulatory factors of the HPO axis is sparse. In this study, transcriptomes of the tissues in the entire HPO axis at 15, 20, 30, and 68 w of age were analyzed. In total, 381, 622, and 1090 differentially expressed genes (DEGs) were found among the hypothalamus, pituitary, and ovary, respectively. In particular, the greatest number of DEGs (867) was identified from the comparison of ovary at 30 and 15 w, which might be related to ovarian development and function at high ovulation capacity. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that most of these DEGs in the significantly enriched biological process (BP) terms and pathways were primarily involved in tissue development and the regulation of reproductive hormone biosynthesis and secretion. The latter is highly related to the HPO axis. Therefore, a number of hub candidate genes strongly associated with the HPO axis in each tissue were filtered by analyzing the Protein-protein interaction (PPI) network and seven known reproductive hormone-associated key genes were obtained: PGR, HSD3B2, CYP17A1, CYP11A1, CYP21A2, STS, and CYP19A1, and 12 novel genes: ROCK2, TBP, GTF2H2, GTF2B, DHCR24, DHCR7, FDFT1, LSS, SQLE, MSMO1, CYP51A1, and PANK3. These will be utilized for further research into the function of the HPO axis. This study has highlighted the major role of the HPO axis in the reproduction of hens at the four developmental stages and explored the novel factors that might regulate reproduction, thus providing new insights into the function of the HPO axis on the reproductive system.

Metformin administration during pregnancy attenuated the long-term maternal metabolic and cognitive impairments in a mouse model of gestational diabetes.

BACKGROUND: Gestational diabetes mellitus (GDM) is a metabolic disease that can have long-term adverse effects on the cognitive function of mothers. In our study, we explored the changes in metabolic health and cognitive function in mice of middle- and old- age after exposure to GDM, and whether metformin therapy during pregnancy provided long-term benefits. RESULTS: Mice with GDM demonstrated significant cognitive impairment in old age, which was associated with insulin resistance. Gestational metformin therapy was shown to increase insulin sensitivity and improve cognition. The ovarian aging rate was also accelerated in mice exposed to GDM during pregnancy, which may be related to fatty acid metabolism in the ovaries. CONCLUSION: Treatment with metformin during pregnancy was shown to improve fatty acid metabolism in ovarian tissues. METHOD: During pregnancy, mice were fed with a high-fat diet (GDM group) or a low-fat diet (Control group), and a third group received metformin while receiving a high-fat diet (Treatment group). At 12 months old, the mice completed an oral glucose tolerance test, insulin tolerance test, Morris water maze test, female sex hormones were measured, and metabolite profiles of tissue from the ovaries, hypothalamus, and pituitary glands were analysed using gas chromatography-mass spectrometry.

Chronic exposure to low dose of bisphenol A causes follicular atresia by inhibiting kisspeptin neurons in anteroventral periventricular nucleus in female mice.

Bisphenol-A (BPA) is an estrogenic chemical extensively used in industrial and household applications. The present study was conducted to investigate the effect of chronic exposure to BPA on the adult female neuroendocrine system. Herein, we found that expose of adult female mice to BPA (50 µg/kg) by oral gavage for 60 days (BPA mice) prolonged diestrus and decreased serum 17ß-estradiol (E2) concentration by reducing the number of antral follicles and corpora luteum. In comparison with controls, the levels of serum luteinizing hormone (LH), follicle stimulating hormone (FSH), hypothalamic gonadotrophin releasing hormone (GnRH) and the expression of kisspeptin in anteroventral periventricular nucleus (AVPV) decreased in BPA mice, which could be reversed by injecting kisspeptin-10 (i.c.v.). Treatment with BPA or estrogen receptor α (ERα) antagonist MPP, but not ERß antagonist PHTPP inhibited E2-induced AVPV-kisspeptin expression in ovariectomized mice. Use of ERα agonist PPT rather than ERß agonist DPN enhanced AVPV-kisspepetin expression, which decreased after treatment with BPA. The amplitude of the proestrus LH surge decreased in mice exposed to BPA, but was recovered by administering kisspeptin-10. The present study provides in vivo evidence that chronic exposure to a low dose of BPA suppressed ERα-induced activation of AVPV-kisspeptin neurons, leading to prolonged diestrus and reduced ovulation in adult female mice.

The role of miR-7 as a potential switch in the mouse hypothalamus-pituitary-ovary axis through regulation of gonadotropins.

The hypothalamus-pituitary-ovary (HPO) axis plays fundamental roles in female neuroendocrinology and reproduction. Pituitary gonadotropins are located in the center of this axis. Previous investigation suggested that miR-7 is closely linked with gonadotropins. However, the interaction between miR-7 and the HPO axis remains unclear. This study aims to determine whether and how miR-7 functions in this axis. A mouse ovariectomy model and mouse primary pituitary cells were used in this study. The results showed that miR-7 is localized to gonadotrophs and somatotrophs. miR-7 can inhibit the expression, synthesis and secretion of gonadotropins, but not growth hormones. Gonadotropin-releasing hormone (GnRH) has inhibitory effects on miR-7, while estrogen enhances miR-7 expression. miR-7 is vital for the pathway by which GnRH and estrogen regulate gonadotropins by targeting v-raf-leukemia viral oncogene 1 (Raf1). Together, these results indicate that miR-7 acts as a potential switch in the feedback loop of the HPO axis by regulating gonadotropins.