Browse
Submit Data
Databases
API
Help

Dataset Information

24 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Impact of SGLT-2 Inhibition on Cardiometabolic Abnormalities in a Rat Model of Polycystic Ovary Syndrome.

ABSTRACT: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS is characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS have a high prevalence of obesity, insulin resistance (IR), increased blood pressure (BP), and activation of the renin angiotensin system (RAS). Effective evidence-based therapeutics to ameliorate the cardiometabolic complications in PCOS are lacking. The sodium-glucose cotransporter-2 (SGLT2) inhibitor Empagliflozin (EMPA) reduces BP and hyperglycemia in type 2 diabetes mellitus. We hypothesized that hyperandrogenemia upregulates renal SGLT2 expression and that EMPA ameliorates cardiometabolic complications in a hyperandrogenemic PCOS model. Four-week-old female Sprague Dawley rats were treated with dihydrotestosterone (DHT) for 90 days, and EMPA was co-administered for the last three weeks. DHT upregulated renal SGLT2, SGLT4, and GLUT2, but downregulated SGLT3 mRNA expression. EMPA decreased DHT-mediated increases in fat mass, plasma leptin, and BP, but failed to decrease plasma insulin, HbA1c, or albuminuria. EMPA decreased DHT-mediated increase in renal angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE2), and angiotensin II type 1 receptor (AGT1R) mRNA and protein expression. In summary, SGLT2 inhibition proved beneficial in adiposity and BP reduction in a hyperandrogenemic PCOS model; however, additional therapies may be needed to improve IR and renal injury.

SUBMITTER: Pruett JE

PROVIDER: S-EPMC7962009 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Metformin Ameliorates Uterine Defects in a Rat Model of Polycystic Ovary Syndrome.

Project description:Adult rats treated concomitantly with insulin and human chorionic gonadotropin exhibit endocrine, metabolic, and reproductive abnormalities that are very similar to those observed in polycystic ovary syndrome (PCOS) patients. In this study, we used this rat model to assess the effects of metformin on PCOS-related uterine dysfunction. In addition to reducing androgen levels, improving insulin sensitivity, and correcting the reproductive cycle, metformin treatment induced morphological changes in the PCOS-like uterus. At the molecular and cellular levels, metformin normalized the androgen receptor-mediated transcriptional program and restored epithelial-stromal interactions. In contrast to glucose transport, uterine inflammatory gene expression was suppressed through the PI3K-Akt-NF?B network, but without affecting apoptosis. These effects appeared to be independent of AMPK subunit and autophagy-related protein regulation. We found that when metformin treatment partially restored implantation, several implantation-related genes were normalized in the PCOS-like rat uterus. These results improve our understanding of how metformin rescues the disruption of the implantation process due to the uterine defects that result from hyperandrogenism and insulin resistance. Our data provide insights into the molecular and functional clues that might help explain, at least in part, the potential therapeutic options of metformin in PCOS patients with uterine dysfunction.

| S-EPMC5405166 | biostudies-literature

Long-Lasting Androgen-Induced Cardiometabolic Effects in Polycystic Ovary Syndrome.

Project description:Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, is characterized by androgen excess and ovarian dysfunction and presents with increased cardiometabolic risk factors such as obesity, insulin resistance, and elevated blood pressure (BP). We previously reported that administration of dihydrotestosterone (DHT) to female rats elicits cardiometabolic derangements similar to those found in women with PCOS. In this study, we tested the hypothesis that the DHT-mediated cardiometabolic derangements observed in PCOS are long lasting despite DHT withdrawal. Four-week-old female Sprague Dawley rats were treated with DHT (7.5 mg/90 days) or placebo for 6 months. DHT was discontinued (ex-DHT), and rats were followed for 6 additional months. After 6 months of DHT withdrawal, food intake, body weight, fat and lean mass, fasting plasma insulin, leptin, and adiponectin were elevated in ex-DHT rats. BP remained significantly elevated, and enalapril, an angiotensin-converting enzyme (ACE) inhibitor, normalized BP in ex-DHT rats. Expression of components of the intrarenal renin-angiotensin system was increased in ex-DHT rats. The cardiometabolic features found in ex-DHT rats were associated with lower plasma androgen levels but increased expression of renal and adipose tissue androgen receptors. In summary, androgen-induced cardiometabolic effects persisted after DHT withdrawal in a PCOS experimental model. Activation of intrarenal renin-angiotensin system plays a major role in the androgen-mediated increase in BP in ex-DHT. Upregulation of the renal and adipose tissue androgen receptor may explain the long-lasting effects of androgens. In clinical scenarios characterized by hyperandrogenemia in women, prompt normalization of androgen levels may be necessary to prevent their long-lasting cardiometabolic effects.

| S-EPMC6065488 | biostudies-literature

Use of Bao Gui capsule in treatment of a polycystic ovary syndrome rat model.

Project description:The present study was designed to elucidate the underlying mechanisms of Bao Gui capsule (BGC) against hyperandrogenism, insulin resistance and leptin resistance of PCOS. Letrozole was used to induce a PCOS model in rats, which were then randomly divided into four groups (n=9): Control, Model, high‑dose BGC (BGC‑H) and low‑dose BGC (BGC‑L) group. Serum levels of follicle‑stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), estradiol (E2), insulin, leptin, and interleukin (IL)‑1β, IL‑6 and tumor necrosis factor‑α (TNF‑α) in the hypothalamus were determined by ELISA. Protein levels of cytochrome P450c17α and cytochrome P450 aromatase (P450arom) in ovaries were determined by immunohistochemistry and western blot analysis. Additionally, the expression of GLUT4 in uterus and muscle tissue, and NF‑κB, IKKβ and SOCS3 mRNA levels in the hypothalamus were evaluated. BGC significantly reduced body weight gain and decreased serum levels of LH/FSH, T, log T/E2, insulin and leptin compared with the PCOS model rats. Furthermore, BGC markedly reduced the expression of P450c17α and significantly increased the expression of P450arom in ovaries, and increased the expression of GLUT4 in uterus and muscle tissues. BGC also effectively reduced the level of IL‑6 and TNF‑α, and the expression of IKKβ, NF‑κB and SOCS3 in the hypothalamus of PCOS model rats. These results suggest that BGC may effectively improve hyperandrogenism, insulin resistance, endometrial receptivity and the low‑grade chronic inflammation in the hypothalamus.

| S-EPMC7002974 | biostudies-literature

The Goto-Kakizaki rat is a spontaneous prototypical rodent model of polycystic ovary syndrome.

Project description:Polycystic ovary syndrome (PCOS) is characterized by an oligo-anovulation, hyperandrogenism and polycystic ovarian morphology combined with major metabolic disturbances. However, despite the high prevalence and the human and economic consequences of this syndrome, its etiology remains unknown. In this study, we show that female Goto-Kakizaki (GK) rats, a type 2 diabetes mellitus model, encapsulate naturally all the reproductive and metabolic hallmarks of lean women with PCOS at puberty and in adulthood. The analysis of their gestation and of their fetuses demonstrates that this PCOS-like phenotype is developmentally programmed. GK rats also develop features of ovarian hyperstimulation syndrome. Lastly, a comparison between GK rats and a cohort of women with PCOS reveals a similar reproductive signature. Thus, this spontaneous rodent model of PCOS represents an original tool for the identification of the mechanisms involved in its pathogenesis and for the development of novel strategies for its treatment.

| S-EPMC7886868 | biostudies-literature

Does polycystic ovary syndrome affect morphokinetics or abnormalities in early embryonic development?

Project description:ObjectivesThis study aimed to investigate whether oocyte retrieval from PCOS patients affects the morphokinetics or the incidence of abnormalities in early embryonic development, using time-lapse imaging analysis.MethodsThis was a prospective study in total of 39 PCOS patients and 67 women with normal ovarian function, underwent a GnRH antagonist protocol of controlled ovarian stimulation and fertilization by ICSI. 402 zygotes from the PCOS group and 449 zygotes from the control group were observed by time-lapse monitoring for 48?h following sperm injection.ResultsPatients with PCOS showed a significantly higher number of retrieved oocytes, and a significantly higher number of metaphase II oocytes per cycle than that of the non-PCOS group (18.85?±?9.41 vs. 11.48?±?5.51 and 14.97?±?7.43 vs. 9.51?±?4.7, respectively). However, oocyte maturation rate and morphologically assessed embryo quality did not differ between two groups. After 48?h of the embryo culture using time-lapse video recording, most of the embryos in both groups had reached the 4-cell stage (353/449 vs. 314/402 embryos). There were no significant differences between the control and PCOS group regarding the time-points of the successive events in early embryonic development from the appearance of 2 polar bodies to the 6-cell stage. However, the percentage of t2 stages which fell in "optimal range" (>24?h and ?28?h) was significantly lower in the PCOS group than in the control group (37.8% vs. 48.1%, P?=?0.004). The proportion of embryos manifesting abnormal fertility, multinucleation, direct cleavage and reverse cleavage were not significantly different between the two groups.ConclusionOur data indicated that PCOS does not affect the morphokinetics or incidence of abnormalities in early embryonic development.

| S-EPMC6687388 | biostudies-literature

Multiomics Analysis Reveals Molecular Abnormalities in Granulosa Cells of Women With Polycystic Ovary Syndrome.

Project description:Polycystic ovary syndrome (PCOS) is the most common complex endocrine and metabolic disease in women of reproductive age. It is characterized by anovulatory infertility, hormone disorders, and polycystic ovarian morphology. Regarding the importance of granulosa cells (GCs) in the pathogenesis of PCOS, few studies have investigated the etiology at a single "omics" level, such as with an mRNA expression array or methylation profiling assay, but this can provide only limited insights into the biological mechanisms. Here, genome-wide DNA methylation together with lncRNA-miRNA-mRNA profiles were simultaneously detected in GCs of PCOS cases and controls. A total of 3579 lncRNAs, 49 miRNAs, 669 mRNAs, and 890 differentially methylated regions (DMR)-associated genes were differentially expressed between PCOS cases and controls. Pathway analysis indicated that these differentially expressed genes were commonly associated with steroid biosynthesis and metabolism-related signaling, such as glycolysis/gluconeogenesis. In addition, we constructed ceRNA networks and identified some known ceRNA axes, such as lncRNAs-miR-628-5p-CYP11A1/HSD17B7. We also identified many new ceRNA axes, such as lncRNAs-miR-483-5p-GOT2. Interestingly, most ceRNA axes were also closely related to steroid biosynthesis and metabolic pathways. These findings suggest that it is important to systematically consider the role of reproductive and metabolic genes in the pathogenesis of PCOS.

| S-EPMC8168535 | biostudies-literature

Change in Androgenic Status and Cardiometabolic Profile of Middle-Aged Women with Polycystic Ovary Syndrome

Project description:Understanding the cardiovascular disease (CVD) risk for women with polycystic ovary syndrome (PCOS) at reproductive age is crucial. To investigate this, we compared the cardiometabolic profiles of different PCOS groups over a median interval of 15.8 years. The study focused on three groups: (1) women with PCOS who were hyperandrogenic at both initial and follow-up screening (HA-HA), (2) those who transitioned from hyperandrogenic to normoandrogenic (HA-NA), and (3) those who remained normoandrogenic (NA-NA). At initial and follow-up screenings, both HA-HA and HA-NA groups showed higher body mass indexes compared to the NA-NA group. Additionally, at follow-up, the HA-HA and HA-NA groups exhibited higher blood pressure, a higher prevalence of hypertension, elevated serum triglycerides and insulin levels, and lower levels of HDL cholesterol compared to the NA-NA group. Even after adjusting for BMI, significant differences persisted in HDL cholesterol levels and hypertension prevalence among the groups (HA-HA: 53.8%, HA-NA: 53.1%, NA-NA: 14.3%, p < 0.01). However, calcium scores and the prevalence of coronary plaques on CT scans were similar across all groups. In conclusion, women with PCOS and hyperandrogenism during their reproductive years exhibited an unfavorable cardiometabolic profile during their post-reproductive years, even if they changed to a normoandrogenic status.

| S-EPMC10455407 | biostudies-literature

Soy isoflavones exert beneficial effects on letrozole-induced rat polycystic ovary syndrome (PCOS) model through anti-androgenic mechanism.

Project description:ContextSoy is the main source of phytoestrogens, which has long been used as traditional food. One major subtype of phytoestrogens includes isoflavones and they are scientifically validated for their beneficial actions on many hormone-dependent conditions.ObjectiveThe present study examines the effect of soy isoflavones on letrozole-induced polycystic ovary syndrome (PCOS) rat model.Materials and methodsPCOS was induced in Sprague-Dawley rats with of 1?mg/kg letrozole, p.o. once daily for 21 consecutive days. Soy isoflavones (50 and 100?mg/kg) was administered for 14 days after PCOS induction. Physical parameters (body weight, oestrous cycle determination, ovary and uterus weight) metabolic parameters (oral glucose tolerance test, total cholesterol), steroidal hormone profile (testosterone and 17?-oestradiol), steroidogenic enzymes (3?-hydroxy steroid dehydrogenase (HSD) and 17?-HSD), oxidative stress and histopathology of ovary were studied.ResultsSoy isoflavones (100?mg/kg) treatment significantly altered the letrozole-induced PCOS symptoms as observed by decreased body weight gain (p?<?0.05), percentage diestrous phase (p?<?0.001), testosterone (p?<?0.001), 3?-HSD (p?<?0.01) and 17?-HSD (p?<?0.001) enzyme activity and oxidative stress. Histological results reveal that soy isoflavones treatment in PCOS rats resulted in well-developed antral follicles and normal granulosa cell layer in rat ovary.DiscussionTreatment with soy isoflavones exerts beneficial effects in PCOS rats (with decreased aromatase activity) which might be due to their ability to decrease testosterone concentration in the peripheral blood.ConclusionAnalysis of physical, biochemical and histological evidences shows that soy isoflavones may be beneficial in PCOS.

| S-EPMC6130471 | biostudies-literature

Influence of Vitamin D on the Vasoactive Effect of Estradiol in a Rat Model of Polycystic Ovary Syndrome.

Project description:We examined the vasoactive effect of estradiol in a rat model of early PCOS and the influence of vitamin D deficiency (VDD). We created a model of chronic hyperandrogenism and VDD in adolescent female Wistar rats (N = 46) with four experimental groups: vitamin D supplemented (T-D+), VDD (T-D-), hyperandrogenic and vitamin D supplemented (T+D+), and hyperandrogenic and VDD (T+D-). T+ groups received an 8-week-long transdermal Androgel treatment, D-animals were on vitamin D-reduced diet and D+ rats were supplemented orally with vitamin D3. Estrogen-induced vasorelaxation of thoracic aorta segments were measured with a wire myograph system with or without the inhibition of endothelial nitric oxide synthase (eNOS) or cyclooxygenase-2 (COX-2). The distribution of estrogen receptor (ER), eNOS and COX-2 in the aortic wall was assessed by immunohistochemistry. VDD aortas showed significantly lower estradiol-induced relaxation independently of androgenic status that was further decreased by COX-2 inhibition. COX-2 inhibition failed to alter vessel function in D+ rats. Inhibition of eNOS abolished the estradiol-induced relaxation in all groups. Changes in vascular function in VDD were accompanied by significantly decreased ER and eNOS staining. Short-term chronic hyperandrogenism failed to, but VDD induced vascular dysfunction, compromised estrogen-dependent vasodilatation and changes in ER and eNOS immunostaining.

| S-EPMC8431242 | biostudies-literature

Polycystic ovary syndrome phenotype does not have impact on oocyte morphology.

Project description:PurposeThe primary objective of the present study of women participating in an ICSI program was to determine whether the morphologic quality of oocytes was related to the polycystic ovary syndrome (PCOS) phenotype.MethodsWe performed a retrospective cohort study in the IVF unit at the Lille University Medical Center (Lille, France) between 2006 and 2015. Oocyte morphology (fragmented first polar body, abnormal zona pellucida, large perivitelline space, material in perivitelline space, abnormal shape of oocyte, granular cytoplasm and intracytoplasmic vacuoles) was evaluated in PCOS women and according to different subgroup (depending on the presence or absence of the cardinal features polycystic ovarian morphology (PCOM), hyperandrogenism (HA), and oligo-anovulation (OA)).ResultsA total of 1496 metaphase II oocytes (n = 602 for phenotype A combining PCOM + HA + OA, n = 462 oocytes for phenotype C: PCOM + HA, and n = 432 for phenotype D: PCOM + OA) were assessed. The phenotypes A, C and D did not differ significantly with regard to the proportion of normal oocytes (adjusted percentages (95%CI): 35.2% (31.5 to 39.1%), 25.8% (21.9 to 29.9%) and 34.0% (29.7 to 38.6%), respectively: adjusted p = 0.13). Likewise, there were no significant intergroup differences in oocyte morphology. The ICSI outcome was not significantly associated with the PCOS phenotype.ConclusionThe present study is the first to show that the PCOS phenotype (notably the presence vs. absence of OA and/or HA) is not significantly associated with the morphological quality of oocytes.

| S-EPMC8729101 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data