Metformin versus metformin plus pioglitazone on gonadal and metabolic profiles in normal-weight women with polycystic ovary syndrome: a single-center, open-labeled prospective randomized controlled trial.

OBJECTIVE: To investigate the effects of metformin (MET) monotherapy and pioglitazone plus MET (PIOMET) therapy on gonadal and metabolic profiles in normal-weight women with polycystic ovary syndrome (PCOS). METHODS: Sixty normal-weight women with PCOS were recruited between January and September 2022 at the Shengjing Hospital of China Medical University. They were randomly assigned to the MET or PIOMET groups for 12 weeks of MET monotherapy or PIOMET therapy. Anthropometric measurements, menstrual cycle changes, gonadal profiles, and the oral glucose insulin-releasing test (OGIRT) were performed at baseline and after the 12-week treatment. RESULTS: Thirty-six participants completed the trial. MET and PIOMET therapies improved menstrual cycles after the 4- and 12-week treatments; however, there was no statistical difference between the two groups. PIOMET therapy improved luteinizing hormone (LH), luteinizing hormone/follicle stimulating hormone (LH/FSH) ratio, and free androgen index (FAI) levels after the 4-week treatment, whereas MET monotherapy only improved total testosterone (TT) levels compared to baseline (P < 0.05). Both MET and PIOMET therapies improved TT and anti-Mullerian hormone (AMH) levels after the 12-week treatment (P < 0.05). In addition, only PIOMET therapy significantly improved sex hormone-binding globulin (SHBG), FAI, and androstenedione (AND) levels than the baseline (P < 0.05). PIOMET therapy improved SHBG and AMH levels more effectively than MET monotherapy (P < 0.05). Furthermore, PIOMET treatment was more effective in improving blood glucose levels at 120 and 180 min of OGIRT compared to MET monotherapy (P < 0.05). CONCLUSIONS: In normal-weight women with PCOS, PIOMET treatment may have more benefits in improving SHBG, AMH, and postprandial glucose levels than MET monotherapy, and did not affect weight. However, the study findings need to be confirmed in PCOS study populations with larger sample sizes.

HIF1α-glycolysis engages activation-induced cell death to drive IFN-γ induction in hypoxic T cells.

The role of HIF1α-glycolysis in regulating IFN-γ induction in hypoxic T cells is unknown. Given that hypoxia is a common feature in a wide array of pathophysiological contexts such as tumor and that IFN-γ is instrumental for protective immunity, it is of great significance to gain a clear idea on this. Combining pharmacological and genetic gain-of-function and loss-of-function approaches, we find that HIF1α-glycolysis controls IFN-γ induction in both human and mouse T cells activated under hypoxia. Specific deletion of HIF1α in T cells (HIF1α-/-) and glycolytic inhibition significantly abrogate IFN-γ induction. Conversely, HIF1α stabilization in T cells by hypoxia and VHL deletion (VHL-/-) promotes IFN-γ production. Mechanistically, reduced IFN-γ production in hypoxic HIF1α-/- T cells is due to attenuated activation-induced cell death but not proliferative defect. We further show that depletion of intracellular acetyl-CoA is a key metabolic underlying mechanism. Hypoxic HIF1α-/- T cells are less able to kill tumor cells, and HIF1α-/- tumor-bearing mice are not responsive to immune checkpoint blockade (ICB) therapy, indicating loss of HIF1α in T cells is a major mechanism of therapeutic resistance to ICBs. Importantly, acetate supplementation restores IFN-γ production in hypoxic HIF1α-/- T cells and re-sensitizes HIF1α-/- tumor-bearing mice to ICBs, providing an effective strategy to overcome ICB resistance. Taken together, our results highlight T cell HIF1α-anaerobic glycolysis as a principal mediator of IFN-γ induction and anti-tumor immunity. Considering that acetate supplementation (i.e., glycerol triacetate (GTA)) is approved to treat infants with Canavan disease, we envision a rapid translation of our findings, justifying further testing of GTA as a repurposed medicine for ICB resistance, a pressing unmet medical need.

Androgens exacerbate hepatic triglyceride accumulation in rats with polycystic ovary syndrome by downregulating MTTP expression.

PURPOSE: Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder, which is closely associated with insulin resistance, glucose and lipid metabolism disorders. Patients with PCOS have a significantly higher risk of non-alcoholic fatty liver disease and are associated with hyperandrogenemia (HA). However, the exact mechanism by which HA exacerbates hepatic steatosis in PCOS has not yet been fully elucidated. This work aims to investigate the effects and underlying mechanisms of androgens on hepatic triglyceride (TG) metabolism in rats with PCOS. METHODS: Twenty-four female Sprague-Dawley rats were randomly divided into four groups (6 rats/group): control, high-fat diet (HFD), PCOS, and PCOS + flutamide (Flu). Changes in the estrous cycle, liver and ovarian tissue sections, serum total testosterone, serum and liver biochemical indicators, and key enzymes involved in TG metabolism were studied. RESULTS: Hepatocyte steatosis and TG accumulation were more evident in the PCOS group than in the control and HFD groups. The PCOS group showed apparent increases in the levels of serum alanine aminotransferase, aspartate aminotransferase, TG, free fatty acid, fasting insulin, and homeostasis model assessment of insulin resistance. Hepatic VLDL and apoB-100 levels decreased in the PCOS group. After Flu was administered to block the actions of androgens, the above abnormalities had been improved. The expression of MTTP was greatly decreased in the PCOS group and significantly increased after Flu administration. CONCLUSION: Hepatic steatosis in PCOS rats was correlated with HA. Androgens may exacerbate hepatic TG accumulation by downregulating MTTP expression in PCOS.

Aerobic exercise and metformin on intermuscular adipose tissue (IMAT): insights from multimodal MRI and histological changes in prediabetic rats.

BACKGROUND: Physical exercise is the first-line intervention for prediabetes, and metformin is the most widely used oral insulin-sensitizing agent. Moreover, intermuscular adipose tissue (IMAT) directly affects insulin resistance by helping maintain glucose homeostasis. Here, we evaluated the effects of moderate aerobic exercise and/or metformin on histological IMAT parameters in non-streptozotocin-induced prediabetes. METHODS: Male Wistar rats with prediabetes fed a high-fat diet and high-sugar drinks were randomly assigned to high-fat diet (PRE), metformin (MET), moderate aerobic exercise (EXE), combined therapy (EMC), or EMC + compound-c (EMA) groups for 4 weeks. Multimodal magnetic resonance imaging (MRI) was then performed, and tissue-specific inflammation and energy and lipid metabolism were evaluated in IMAT. RESULTS: The EXE group had lower inflammatory factor levels, lipid metabolism, and mitochondrial oxidative stress, and shorter IMAT adipocyte diameters than the MET group. The MET group exhibited lower IL-1ß and Plin5 expression than the PRE group. Furthermore, the IMAT of the EMC group had lower TNF-α and phosphorylated NF-κB levels and higher GLUT1 and GLUT4 expression than the PRE group. Multimodal MRI revealed significant changes in transverse-relaxation time 2, apparent diffusion coefficient, and fractional anisotropy values in the IMAT and muscles, as well as lower IMAT% values in the EXE and EMC groups than in the MET and PRE groups. CONCLUSION: Moderate aerobic exercise training can effectively improve IMAT function and structure via the AMP-activated protein kinase pathway in prediabetes. Combining metformin with moderate aerobic exercise might elicit modest synergy, and metformin does not counterbalance the beneficial effects of exercise.

Genome-Wide Analysis of the Odorant Receptor Gene Family in Solenopsis invicta, Ooceraea biroi, and Monomorium pharaonis (Hymenoptera: Formicidae).

Olfactory systems in eusocial insects play a vital role in the discrimination of various chemical cues. Odorant receptors (ORs) are critical for odorant detection, and this family has undergone extensive expansion in ants. In this study, we re-annotated the OR genes from the most destructive invasive ant species Solenopsis invicta and 2 other Formicidae species, Ooceraea biroi and Monomorium pharaonis, with the aim of systematically comparing and analyzing the evolution and the functions of the ORs in ant species, identifying 356, 298, and 306 potential functional ORs, respectively. The evolutionary analysis of these ORs showed that ants had undergone chromosomal rearrangements and that tandem duplication may be the main contributor to the expansion of the OR gene family in S. invicta. Our further analysis revealed that 9-exon ORs had biased chromosome localization patterns in all three ant species and that a 9-exon OR cluster (SinvOR4-8) in S. invicta was under strong positive selection (Ka/Ks = 1.32). Moreover, we identified 5 S. invicta OR genes, namely SinvOR89, SinvOR102, SinvOR352, SinvOR327, and SinvOR135, with high sequence similarity (>70%) to the orthologs in O. biroi and M. pharaonis. An RT-PCR analysis was used to verify the antennal expression levels of these ORs, which showed caste-specific expression. The subsequent analysis of the antennal expression profiles of the ORs of the S. invicta workers from the polygyne and monogyne social forms indicated that SinvOR35 and SinvOR252 were expressed at much higher levels in the monogyne workers than in the polygyne workers and that SinvOR21 was expressed at higher levels in polygyne workers. Our study has contributed to the identification and analysis of the OR gene family in ants and expanded the understanding of the evolution and functions of the ORs in Formicidae species.

Pioglitazone can improve liver sex hormone-binding globulin levels and lipid metabolism in polycystic ovary syndrome by regulating hepatocyte nuclear factor-4α.

Polycystic ovary syndrome (PCOS) is a common reproductive and metabolic disorder that is closely correlated with insulin resistance. Sex hormone-binding globulin (SHBG) is an important carrier for regulating androgen activity and is affected by insulin level, which is related to metabolic abnormalities and long-term prognosis of PCOS. Insulin sensitizer pioglitazone can improve the SHBG level and dyslipidaemia in PCOS, but the mechanism remains unclear. We investigated liver SHBG expression, liver lipid levels, and the effects and potential mechanisms of pioglitazone on reproductive and metabolic disorders in a rat model of polycystic ovary syndrome with insulin resistance (PCOS-IR). PCOS-IR was induced by letrozole and a high-fat diet. Metformin was used as a positive control. Additionally, dihydrotestosterone and oleic acid combined with palmitic acid were used to induce the HepG2 cell models with IR. The cells were exposed to pioglitazone alone or in combination with a hepatocyte nuclear factor (HNF)- 4α inhibitor. Changes in biochemical characteristics were analysed using an enzyme-linked immunosorbent assay. Vaginal smears were used to analyse the oestrous cycle, and ovarian histology was used to analyse the changes in ovarian morphology. The degree of IR in vivo and in vitro was measured using the hyperinsulinaemic-euglycaemic clamp and glucose oxidase techniques. The levels of key anabolism-related proteins, including SHBG, HNF-4α, and peroxidase proliferator-activated receptor (PPAR-γ), were measured using western blots. Pioglitazone and metformin significantly increased the SHBG levels in the sera and livers. Compared to metformin, pioglitazone significantly improved the lipid droplet deposition, triglyceride (TG) and total cholesterol (TC) levels, HNF-4α protein expression, and weights of the livers in the PCOS-IR rats. After applying pioglitazone with an HNF-4α inhibitor in the PCOS-IR cell models, we found that pioglitazone may increase SHBG and improve IR, TG, and TC levels by upregulating HNF-4α. Similar to metformin, pioglitazone also restored the oestrous cycle and ovarian morphology, ameliorated IR and hyperandrogenaemia in the PCOS-IR rats. Our findings hint at the value of HNF-4α in the treatment of PCOS by PIO, which could shed light on potential targets that may be used in treatments for PCOS with metabolic disorders.

Effect of metformin versus metformin plus liraglutide on gonadal and metabolic profiles in overweight patients with polycystic ovary syndrome.

Objective: To observe the effect of metformin (MET) monotherapy versus MET plus liraglutide (LIRA) on gonadal and metabolic profiles in overweight patients with polycystic ovary syndrome (PCOS). Methods: Sixty overweight patients with PCOS were recruited from January 2021 to January 2022 in Shengjing Hospital of China Medical University and were randomly assigned to the MET or combination (COM) group to receive 12 weeks of MET monotherapy or MET plus LIRA therapy. Anthropometric measurements, menstrual cycle changes, gonadal profiles, and oral glucose tolerance tests (OGTT) were conducted at baseline and after the 12-week treatment. Results: Fifty-two subjects completed the trial while eight were lost during the follow-up. Both MET and COM improved menstrual cycles, anthropometric parameters, and glucose metabolism after the 12-week treatment; however, there was no statistical difference between the two groups. MET plus LIRA therapy improved hyperandrogenemia, including TT (total testosterone), SHBG (sex hormone binding globulin) and FAI (free androgen index), whereas MET monotherapy only improved SHBG and FAI when compared with baseline. Furthermore, both MET monotherapy and MET plus LIRA therapy improved E2 (estradiol) while only MET plus LIRA therapy improved LH (luteinizing hormone), FSH (follicle stimulating hormone) and Prog (progesterone) more effectively than baseline. Additionally, MET plus LIRA therapy may improve TT, SHBG, FAI, LH and Prog more effectively than MET monotherapy; however, there were no significant differences on E2, FSH and LH/FSH between the two groups. Conclusions: In overweight patients with PCOS, both MET monotherapy and MET plus LIRA therapy improved glucose metabolism and relieved insulin resistance (IR). Additionally, MET plus LIRA therapy was more effective than MET monotherapy in improving reproductive abnormalities and hyperandrogenemia, potentially by modulating the hypothalamic-pituitary-ovarian axis.

Congenital lipoid adrenal hyperplasia with Graves' disease: A case report.

BACKGROUND: Congenital adrenal hyperplasia (CAH), which is caused by a mutation of the steroidogenic acute regulatory (StAR) gene. Affected patients are usually characterized by adrenal insufficiency in the first year of life, salt loss, glucocorticoid and mineralocorticoid deficiency, and female external genitalia, regardless of chromosomal karyotype. Patients with non-classical lipoid CAH usually develop glucocorticoid deficiency and mild mineralocorticoid deficiency at 2-4 years of age. CASE SUMMARY: Herein, We report the case of a woman with non-classic lipoid CAH combined with Graves' disease. Her chromosome karyotype was 46, XX, and high-throughput sequencing revealed two missense variants in the StAR gene: c.229C > T (p.Q77X) and c.814C > T (p.R272C), which were inherited from both parents (non-close relatives). The patient was treated for Graves' disease in a timely manner and the dosage of glucocorticoid was adjusted during the treatment of Graves' disease. CONCLUSION: This is the first case of non-classic lipoid CAH combined with Graves' disease reported in the Chinese population. In addition to conventional glucocorticoid replacement therapy, timely adjustments were made to the dosages of thyroid hormone and glucocorticoid to avoid adrenal crisis as a consequence of the increased demand and accelerated metabolism of glucocorticoids when the patient was diagnosed with Graves' disease.

Canagliflozin combined with metformin versus metformin monotherapy for endocrine and metabolic profiles in overweight and obese women with polycystic ovary syndrome: A single-center, open-labeled prospective randomized controlled trial.

Objectives: Canagliflozin (CANA), a kind of sodium-glucose cotransporter-2 (SGLT-2) inhibition, study in which the role of CANA monotherapy in polycystic ovary syndrome (PCOS) has been investigated, and it could become a novel option in the PCOS treatment. Nevertheless, trials focused on SGLT-2 combination therapy's efficacy, and safety in PCOS patients are limited. This randomized controlled trial compared the efficacy and safety of CANA and metformin (MET) combination therapy and MET monotherapy in endocrine and metabolic profiles of overweight and obese women with polycystic ovary syndrome (PCOS). Methods: Fifty-one overweight or obese non-diabetic PCOS women between 18 and 40 years old were enrolled. Patients were randomly allocated to receive either CANA/MET or MET treatment. The CANA/MET group received CANA 100 mg once daily plus MET 1000 mg twice daily, while the MET group received MET 1000 mg twice daily for three months. Changes in menstrual pattern, anthropometric parameters, gonadal parameters, glucose and lipid homeostasis, and adverse events (AEs) were evaluated. Results: Compared with the MET group, women have a significantly lower level of total testosterone (TT), area under the curve for glucose (AUCGlu), and area under the curve for insulin (AUCIns) to AUCGlu ratio in the combination group. There were no significant differences in menstrual frequency, body weight, body mass index, follicle-stimulating hormone, luteinizing hormone, free androgen index, sex hormone-binding globulin, androstenedione, fasting blood glucose, fasting insulin, AUCIns, homeostasis model assessment-insulin resistance (HOMA-IR), triglycerides, total cholesterol, low-density lipoprotein cholesterol, apolipoprotein A1 (Apo A1), apolipoprotein B (Apo B), and APO B/A1 ratio. AEs were seen in 57.70% (15/26) and 68.00% (17/25) of patients in the CANA/MET and MET groups, respectively. Conclusions: In overweight and obese women with PCOS, CANA and MET combination therapy may be similar to MET monotherapy in improving menstrual frequency, weight control, hyperandrogenemia, and relieving insulin resistance. CANA/MET may have more benefits in reducing TT, AUCGlu, and the AUCIns/AUCGlu ratio within three months than MET monotherapy. Trial registration: ClinicalTrials.gov, NCT04973891.

An in vivo model of glioblastoma radiation resistance identifies long noncoding RNAs and targetable kinases.

Key molecular regulators of acquired radiation resistance in recurrent glioblastoma (GBM) are largely unknown, with a dearth of accurate preclinical models. To address this, we generated 8 GBM patient-derived xenograft (PDX) models of acquired radiation therapy-selected (RTS) resistance compared with same-patient, treatment-naive (radiation-sensitive, unselected; RTU) PDXs. These likely unique models mimic the longitudinal evolution of patient recurrent tumors following serial radiation therapy. Indeed, while whole-exome sequencing showed retention of major genomic alterations in the RTS lines, we did detect a chromosome 12q14 amplification that was associated with clinical GBM recurrence in 2 RTS models. A potentially novel bioinformatics pipeline was applied to analyze phenotypic, transcriptomic, and kinomic alterations, which identified long noncoding RNAs (lncRNAs) and targetable, PDX-specific kinases. We observed differential transcriptional enrichment of DNA damage repair pathways in our RTS models, which correlated with several lncRNAs. Global kinomic profiling separated RTU and RTS models, but pairwise analyses indicated that there are multiple molecular routes to acquired radiation resistance. RTS model-specific kinases were identified and targeted with clinically relevant small molecule inhibitors. This cohort of in vivo RTS patient-derived models will enable future preclinical therapeutic testing to help overcome the treatment resistance seen in patients with GBM.

A Chinese boy with familial Duchenne muscular dystrophy owing to a novel hemizygous nonsense mutation (c.6283C>T) in an exon of the DMD gene.

Duchenne muscular dystrophy is a severe, X-linked, progressive neuromuscular disorder clinically characterised by muscle weakening and extremely high serum creatine kinase levels. A 1-year-old Chinese patient was diagnosed with early-onset Duchenne muscular dystrophy. Next-generation gene sequencing was conducted and the Sanger method was used to validate sequencing. We identified a novel nonsense mutation (c.6283C>T) in DMD that caused the replacement of native arginine at codon 2095 with a premature termination codon (p.R2095X), which may have had a pathogenic effect against dystrophin in our patient's muscle cell membranes. We discovered a novel nonsense mutation in DMD that will expand the pathogenic mutation spectrum for Duchenne muscular dystrophy.

The Association of CYP17A1, CYP19A1, and SHBG Gene Polymorphisms in Polycystic Ovary Syndrome Susceptibility: A Systematic Review and Meta-Analysis.

Objective: To elucidate the relationship between CYP17A1/CYP19A1/SHBG gene polymorphisms and PCOS susceptibility. Methods: We searched multiple databases from inception to December 2020 and meta analysis was conducted to elucidate the relationship between gene polymorphisms and PCOS risk. Results: 26 studies were included, comprising 4860 PCOS and 4043 controls. CYP17A1 rs743572 polymorphisms were found to be negatively associated with PCOS risk under dominant model (p = 0.017, OR = 0.83, 95%CI 0.72-0.97, I 2 = 74.80%, P heterogeneity = 0.000) in the general population while neither CYP19A1 rs2414096 polymorphisms (p = 0.578, OR = 0.87, 95%CI 0.54-1.41, I 2 = 95.90%, P heterogeneity = 0.000) nor SHBG rs6529 polymorphisms (p = 0.752, OR = 0.99, 95%CI 0.94-1.05, I 2 = 60.90%, P heterogeneity = 0.012) was associated with PCOS susceptibility under dominant model in the general population. Conclusion: CYP17A1 rs7435721 polymorphisms might be protective factors against PCOS in general populations. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/#myprospero, identifier CRD4202122640.

Sodium-glucose cotransporter-2 inhibitors for improving endocrine and metabolic profiles in overweight and obese individuals with polycystic ovary syndrome: a meta-analysis protocol.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a heterogeneous reproductive endocrine disorder. Several ongoing trials test sodium-glucose cotransporter-2 (SGLT-2) inhibitors for women with PCOS. However, their effectiveness has not been fully elucidated owing to the lack of high-confidence evidence. Our group agrees with the statement that SGLT-2 inhibition could treat PCOS as it is supported by reports demonstrating the benefits of SGLT-2 inhibition on metabolic status and weight control. Moreover, the functions of chronic inflammation amelioration and cardiovascular system protection make it a more attractive candidate for PCOS therapy. Therefore, to provide physicians with a reference, we intend to perform a meta-analysis on the efficacy and safety of SGLT-2 inhibitors on the endocrine and metabolic profiles of patients with PCOS. METHODS AND ANALYSIS: We will search for randomised controlled trials performed until September 2022 using PubMed, Web of Science, EMBASE, the Cochrane Library, Google Scholar, the PhRMA Clinical Study Results Database (www. CLINICALTRIALS: gov), the China National Knowledge Infrastructure, the Wanfang, the Weipu and the Chinese biomedical literature databases. The outcomes will include androgen-associated outcomes, body fat, glucose and lipid homoeostasis, inflammatory outcomes and adverse events. In addition, two investigators will independently assess methodological quality using the revised Cochrane risk-of-bias tool 2. The analysis will be performed using RevMan V.5.3 software, and subgroup and sensitivity analyses and a meta-regression will be used to determine the heterogeneity source. ETHICS AND DISSEMINATION: Ethical approval is not required because this is a meta-analysis. We will disseminate these results by publishing them in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42021281176.

Poly(N-vinylpyrrolidone)-block-Poly(dimethylsiloxane)-block-Poly(N-vinylpyrrolidone) Triblock Copolymer Polymersomes for Delivery of PARP1 siRNA to Breast Cancers.

Nearly 20% of HER2-positive breast cancers develop resistance to HER2-targeted therapies requiring the use of advanced therapies. Silencing RNA therapy may be a powerful modality for treating resistant HER2 cancers due to its high specificity and low toxicity. However, the systemic administration of siRNAs requires a safe and efficient delivery platform because of siRNA's low stability in physiological fluids, inefficient cellular uptake, immunoreactivity, and rapid clearance. We have developed theranostic polymeric vesicles to overcome these hurdles for encapsulation and delivery of small functional molecules and PARP1 siRNA for in vivo delivery to breast cancer tumors. The 100 nm polymer vesicles were assembled from biodegradable and non-ionic poly(N-vinylpyrrolidone)14-block-poly(dimethylsiloxane)47-block-poly(N-vinylpyrrolidone)14 triblock copolymer PVPON14-PDMS47-PVPON14 using nanoprecipitation and thin-film hydration. We demonstrated that the vesicles assembled from the copolymer covalently tagged with the Cy5.5 fluorescent dye for in vivo imaging could also encapsulate the model drug with high loading efficiency (40%). The dye-loaded vesicles were accumulated in tumors after 18 h circulation in 4TR breast tumor-bearing mice via passive targeting. We found that PARP1 siRNA encapsulated into the vesicles was released intact (13%) into solution by the therapeutic ultrasound treatment as quantified by gel electrophoresis. The PARP1 siRNA-loaded polymersomes inhibited the proliferation of MDA-MB-361TR cells by 34% after 6 days of treatment by suppressing the NF-kB signaling pathway, unlike their scrambled siRNA-loaded counterparts. Finally, the treatment by PARP1 siRNA-loaded vesicles prolonged the survival of the mice bearing 4T1 breast cancer xenografts, with the 4-fold survival increase, unlike the untreated mice after 3 weeks following the treatment. These biodegradable, non-ionic PVPON14-PDMS47-PVPON14 polymeric nanovesicles capable of the efficient encapsulation and delivery of PARP1 siRNA to successfully knock down PARP1 in vivo can provide an advanced platform for the development of precision-targeted therapeutic carriers, which could help develop highly effective drug delivery nanovehicles for breast cancer gene therapy.

Effect of Sex Hormone-Binding Globulin on Polycystic Ovary Syndrome: Mechanisms, Manifestations, Genetics, and Treatment.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases causing infertility in women of childbearing age. It is characterized by hyperandrogenemia (HA), chronic anovulation, and polycystic ovary morphology (PCOM). Most women with PCOS have metabolic abnormalities. Sex hormone-binding globulin (SHBG), a transport carrier that binds estrogen and androgens and regulates their biological activity, is usually used as an indicator of hyperandrogenism in women with PCOS. Low serum SHBG levels are considered a biomarker of metabolic abnormalities and are associated with insulin resistance (IR), HA, and abnormal glucose and lipid metabolism in PCOS patients. SHBG is also related to the long-term prognosis of PCOS, whereas SHBG gene polymorphism is associated with PCOS risk. In addition, the administration of metformin (MET), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), thiazolidinediones (TZDs), compound oral contraceptives (COCs), as well as nutrient supplements such as inositol (MI), vitamin D, and synbiotics can regulate SHBG levels to ameliorate PCOS complications and improve prognosis. This review focuses on the interaction between SHBG and various PCOS complications as well as the regulation of SHBG by various drugs and nutrients and its therapeutic effects on PCOS.

Effects of bariatric surgery on the menstruation- and reproductive-related hormones of women with obesity without polycystic ovary syndrome: a systematic review and meta-analysis.

BACKGROUND: Bariatric surgery is an effective treatment for severe obesity. Several studies have been conducted on the effects of bariatric surgery on the reproductive function of women with obesity who do not have polycystic ovary syndrome (PCOS). OBJECTIVES: To evaluate the effects of bariatric surgery on the menstruation and reproductive related hormones of women of childbearing age with who do not have PCOS. SETTING: A systematic review and meta-analysis at a university hospital. METHODS: Online databases were searched for all studies reporting the efficacy of bariatric surgery for women with obesity until March 2021. The language of publication was limited to English and Chinese. Incidence of abnormal menstruation and reproductive-related hormone levels were the primary outcomes. RESULTS: Fifteen studies comprising 725 patients were enrolled in this meta-analysis. Results showed a significantly lower incidence of abnormal menstruation (relative risk: .40, 95% confidence interval [CI]: .20-.79, P = .008) after bariatric surgery. Moreover, bariatric surgery led to a decrease in serum insulin levels (mean difference [MD] = -13.12 mIU/L, 95% CI: -15.03 to -11.22, P < .00001), glucose (MD = -.91 mmol/L, 95% CI: -1.26 to -.56, P < .00001), triglyceride (MD = -.61 g/L, 95% CI: -.76 to -.46, P < .00001), total testosterone (MD = -.22 ng/mL, 95% CI: -.24 to -.20, P < .00001), dehydroepiandrosterone (DHEA) (MD = -25.34 µg/dL, 95% CI: -31.19 to -19.49, P < .00001), estradiol (MD = -25.13 pg/mL, 95% CI: -34.13 to -16.13, P < .00001), and anti-Mullerian hormone (AMH) (MD = -.40 ng/mL, 95% CI: -.67 to -.13, P = .003). Serum sex hormone binding globulin (SHBG) levels increased after bariatric surgery (MD = 43.99 nmol/L, 95% CI: 34.99-52.99, P < .00001). CONCLUSION: Bariatric surgery can lower fasting insulin, glucose, and triglyceride levels, reduce the incidence of abnormal menstruation, decrease total serum testosterone, DHEA, estradiol, and AMH levels, and increase SHBG level for women with obesity of childbearing age who do not have PCOS. This meta-analysis indicated that bariatric surgery could be effective in improving reproductive function for women with severe obesity.

Analysis of Endocrine and Metabolic Indexes in Non-Obese Patients with Polycystic Ovary Syndrome and Its Compare with Obese Patients.

PURPOSE: To compare the endocrine and metabolic indexes of obese and normal body mass index (BMI) polycystic ovary syndrome (PCOS) patients, and explore factors affecting the pathogenesis and progression of PCOS. METHODS: This study included obese (n=79) and normal BMI (n=40) PCOS patients, and obese (n=30) and normal BMI (n=30) non-PCOS controls. Blood glucose, insulin (INS), blood lipids, sex hormones, and other metabolic and endocrine indicators were measured, and the correlations between the indicators were analyzed. RESULTS: HOMA-IR, 0min INS, 60min INS, 120min INS, 180min INS, FAI, TG, TC, LDL-C and sd-LDL in obese PCOS group were higher, while SHBG, LH, LH/FSH and HDL-C were lower than those in normal weight PCOS group (P <0.05). 120min PBG, HOMA-IR, FAI, T, LH, LH/FSH, AMH, TC and LDL-C in obese PCOS group were higher than those in obese control group (P <0.05). 0min PBG, 60min PBG, 120min PBG, 180min PBG, 0min INS, 60min INS, 120min INS, 180min INS, HOMA-IR, LH, LH/FSH and T in normal weight PCOS group were higher than those in normal weight control group (P <0.05). In both normal weight group and obesity group, HOMA-IR entered the regression equation with FAI as dependent variable, and the absolute value of HOMA-IR standardized partial regression coefficient was higher than that of hs-CRP and AMH. In PCOS patients, FAI in the obese and non-obese PCOS groups was positively correlated with HOMA-IR. CONCLUSION: Endocrine metabolic disorders in women with PCOS were more obvious than that in women with non-PCOS with matched BMI. The abnormality of glucose and lipid metabolism in obese PCOS patients is more serious than that in PCOS patients with normal BMI. Both obese and normal BMI PCOS patients were affected by hyperinsulinemia, and IR may play a key role in the pathogenesis and development of PCOS.

Metformin and exenatide upregulate hepatocyte nuclear factor-4α, sex hormone binding globulin levels and improve hepatic triglyceride deposition in polycystic ovary syndrome with insulin resistance rats.

OBJECTIVE: To explore the efficacy and underlying mechanisms of metformin and exenatide in reversing reproductive and metabolic disturbances in letrozole combined with high-fat diet-induced polycystic ovary syndrome (PCOS) rats. METHODS: Rats with PCOS and insulin resistance (IR) were induced by intra-gastric instillation of letrozole combined with a high-fat diet and verified by histological screening of vaginal exfoliated cells. After metformin and exenatide supplementation, body weight, chow intake and ovarian morphology were observed. Serum biochemical profiles were analyzed using ELISA, while the levels of key anabolism-related proteins, including sex hormone binding globulin (SHBG), hepatocyte nuclear factor-4α (HNF-4α), PI3K, and AKT, were determined using western blotting. RESULTS: The estrus cycle and ovarian morphology of rats with PCOS and IR were significantly recovered following metformin and exenatide treatment, with decreased body weight and chow intake. Furthermore, PCOS-induced changes in metabolic disorders including IR and hepatic triglyceride (TG) deposition, and hyperandrogenemia were reversed by treatment with both drugs. Specifically, the levels of HNF-4α and SHBG in liver tissue of rats with PCOS and IR were upregulated significantly. CONCLUSIONS: Both metformin and exenatide could recover the estrous cycle and ovarian morphology, reduce body weight and high-fat chow intake, and improve glycolipid metabolism disorders and hyperandrogenemia in PCOS with IR rat models. Interestingly, our findings also highlight the potential of both therapeutic agents for improving IR by regulating the liver PI3K/AKT pathway, reducing the deposition of hepatic TG, as well as upregulating the levels of SHBG and HNF-4α in PCOS with IR rat liver tissue.

Comparative efficacy of oral insulin sensitizers metformin, thiazolidinediones, inositol, and berberine in improving endocrine and metabolic profiles in women with PCOS: a network meta-analysis.

BACKGROUND: Multiple oral insulin-sensitizing agents, such as metformin, thiazolidinediones, inositols, and berberine, have been proven safe and efficacious in improving the endocrine, metabolic, and reproductive abnormalities seen in polycystic ovary syndrome (PCOS), providing more options for healthcare providers and patients. These oral insulin sensitizers are more convenient, practical, and economic than agents that need to be injected. A comparison of the clinical effectiveness of the four different classes of oral insulin sensitizers in PCOS has not been explored, leading to clinical uncertainty about the optimal treatment pathway. The present study aims to compare the effects of oral insulin sensitizers on endocrine and metabolic profiles in women with PCOS. METHODS: We identified randomized controlled trials for PCOS from a variety of databases, published from January 2005 to October 2020. Outcomes included changes in menstrual frequency, improvements in hyperandrogenism and glucolipid metabolism and adverse side effects. A random-effects network meta-analysis was performed. RESULTS: Twenty-two trials comprising 1079 patients with PCOS were included in this study. Compared with metformin, treatment with myo-inositol + D-chiro-inositol was associated with a greater improvement in menstrual frequency (odds ratio 14.70 [95% confidence interval (CI) 2.31-93.58]). Myo-inositol + D-chiro-inositol and metformin + thiazolidinediones combination therapies were superior to respective monotherapies in reducing total testosterone levels. Thiazolidinediones, metformin + thiazolidinediones, and myo-inositol + D-chiro-inositol were associated with a lower insulin resistance index (HOMA-IR) compared with that in metformin alone (mean differences: - 0.72 [95% CI (- 1.11)-(- 0.34)] to - 0.89 [95% CI (- 1.460)-(- 0.32)]). Metformin + thiazolidinediones treatment was associated with lower triglyceride levels compared with that in metformin and thiazolidinediones monotherapy, while thiazolidinediones was superior to metformin in increasing high-density lipoprotein cholesterol and decreasing fasting plasma glucose, triglycerides, low-density lipoprotein cholesterol, and gastrointestinal adverse events. CONCLUSIONS: Ours is the first study to report that for women with PCOS, myo-inositol combined with D-chiro-inositol and metformin combined with thiazolidinediones appear superior to metformin alone in improving insulin resistance and decreasing total testosterone. Myo-inositol combined with D-chiro-inositol is particularly efficacious in menstrual recovery. Thiazolidinediones and metformin combined with thiazolidinediones improve lipid metabolism better than metformin alone. Trial registration PROSPERO CRD42020211524.

This study aimed to compare the effects of oral insulin sensitizers on endocrine and metabolic profiles in women with polycystic ovary syndrome (PCOS). A random-effects network meta-analysis including 22 trials was conducted. For women with PCOS, myo-inositol combined with D-chiro-inositol and metformin combined with thiazolidinediones appear superior to metformin alone in improving insulin resistance and decreasing total testosterone level. Myo-inositol combined with D-chiro-inositol is particularly efficacious in menstrual recovery. Thiazolidinediones and metformin combined with thiazolidinediones improve lipid metabolism better than metformin alone.