Androgens in polycystic ovary syndrome

Walters, Kirsty A

doi:10.1097/med.0000000000000245

Cited by 38 publications

(12 citation statements)

References 44 publications

(53 reference statements)

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“…A variety of animal models for PCOS have been generated through increased androgen exposure, containing PCOS-like reproductive and metabolic traits in female rodents and nonhuman primates [ 31 , 32 ]. The PCOS models using animals only represent PCOS-like phenotypes since the pathogenesis of human PCOS is complex.…”

Section: Discussionmentioning

confidence: 99%

New insights into the genic and metabolic characteristics of induced pluripotent stem cells from polycystic ovary syndrome women

et al. 2018

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BackgroundPolycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder that affects female fertility. However, with the lack of a corresponding research model, the pathology mechanism of PCOS is poorly understood. Induced pluripotent stem cell (iPSC) technology has been recognized as means to generate patient-specific stem cells for disease modeling.MethodsThe mRNA abundance of iPSCs was analyzed by RNA microarray and real-time polymerase chain reaction (RT-PCR). Karyotyping of iPSCs was performed with cytogenetic analysis. The mitochondrial respiration ability and glycolytic function were measured by the Seahorse Bioscience XF extracellular flux analyzer. The expression of iPSC-associated markers was identified by immunofluorescence and RT-PCR. The teratoma formation of iPSCs was studied using immunochemistry.ResultsA PCOS patient-derived iPSC model was established from somatic cells of PCOS patients. Through comprehensive transcriptional profiling analysis of the RNA microarray, PCOS patient-derived iPSCs showed metabolic abnormalities and mitochondrial dysfunction compared with non-PCOS patient-derived iPSCs in vitro. Specifically, a total of 2904 genes were differentially expressed between the two iPSC populations, of which 1416 genes were upregulated and 1488 genes were downregulated (fold change > 2, p < 0.01). Gene Ontology (GO) term enrichment results showed that upregulated genes were enriched in metabolic processes and mitochondrial activities which participated in the tricarboxylic acid (TCA) cycle, the respiratory electron transport chain (ETC), and glycogenolysis. On the other hand, the downregulated genes were related to cell communication, glucose transport, and uptake. The differentially expressed genes were verified by RT-PCR in PCOS patient-derived iPSCs and granulosa cells from PCOS patients. The PCOS patient-derived iPSCs demonstrated decreased mitochondrial respiration ability and glycolytic function (p < 0.05) but increased mitochondrial copy numbers and biogenesis (p < 0.05). Subsequently, some genes related to glucose metabolism were rescued by treating with metformin in PCOS patient-derived iPSCs. Meanwhile, the ATP production ability of mitochondria and the glycolysis ability of PCOS patient-derived iPSCs also partially returned to normal levels. However, metformin had little effect on mitochondrial maximal respiration ability and maximal glycolytic capacity.ConclusionsWe measured differences in iPSCs from women with and without PCOS in gene transcription and mitochondrial respiratory function. PCOS patient-derived iPSCs showed abnormal expression of metabolic genes and mitochondrial dysfunction in vitro. The study provides a novel cell model in vitro for studying the clinical causes and molecular mechanisms of PCOS.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-0950-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

New insights into the genic and metabolic characteristics of induced pluripotent stem cells from polycystic ovary syndrome women

et al. 2018

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“…Similarly, women born with congenital adrenal hyperplasia, which causes elevated androgen exposure in fetal life, are also more likely to develop PCOS [28]. Animal models of PCOS commonly involve treating pregnant mothers (sheep, monkeys) or newborns (mice and rats) with androgens, with the resulting offspring showing features of PCOS when they reach adulthood [29][30][31][32]. In the absence of any obvious environmental androgens that might cause PCOS by acting on the developing fetus, this area was further advanced when it was discovered that pregnant women with PCOS had elevated anti-Mullerian hormone (AMH) levels [33].…”

Section: Introductionmentioning

confidence: 99%

Could perturbed fetal development of the ovary contribute to the development of polycystic ovary syndrome in later life?

et al. 2020

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Polycystic ovary syndrome (PCOS) affects around 10% of young women, with adverse consequences on fertility and cardiometabolic outcomes. PCOS appears to result from a genetic predisposition interacting with developmental events during fetal or perinatal life. We hypothesised that PCOS candidate genes might be expressed in the fetal ovary when the stroma develops; mechanistically linking the genetics, fetal origins and adult ovarian phenotype of PCOS. In bovine fetal ovaries (n = 37) of 18 PCOS candidate genes only SUMO1P1 was not expressed. Three patterns of expression were observed: early gestation (FBN3, GATA4, HMGA2, TOX3, DENND1A, LHCGR and FSHB), late gestation (INSR, FSHR, and LHCGR) and throughout gestation (THADA, ERBB4, RAD50, C8H9orf3, YAP1, RAB5B, SUOX and KRR1). A splice variant of FSHB exon 3 was also detected early in the bovine ovaries, but exon 2 was not detected. Three other genes, likely to be related to the PCOS aetiology (AMH, AR and TGFB1I1), were also expressed late in gestation. Significantly within each of the three gene groups, the mRNA levels of many genes were highly correlated with each other, despite, in some instances, being expressed in different cell types. TGFβ is a well-known stimulator of stromal cell replication and collagen synthesis and TGFβ treatment of cultured fetal ovarian stromal cells inhibited the expression of INSR, AR, C8H9orf3 and RAD50 and stimulated the expression of TGFB1I1. In human ovaries (n = 15, < 150 days gestation) many of the same genes as in bovine (FBN3, GATA4, HMGA2, FSHR, DENND1A and LHCGR but not TOX3 or FSHB) were expressed and correlated with each other. With so many relationships between PCOS candidate genes during development of the fetal ovary, including TGFβ and androgen signalling, we suggest that future studies should determine if perturbations of these genes in the fetal ovary can lead to PCOS in later life.

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“…Since hyperandrogenism is associated with PCOS, researchers have created animal models to study the role of androgens in the development and pathology of PCOS [reviewed in [38–42]]. Several mouse models were developed using treatment with exogenous dihydrotestosterone but these models did not exhibit the elevated LH levels associated with PCOS [43–47].…”

Section: Introductionmentioning

confidence: 99%

Letrozole treatment of adult female mice results in a similar reproductive phenotype but distinct changes in metabolism and the gut microbiome compared to pubertal mice

Torres

Skarra

et al. 2019

BMC Microbiol

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BackgroundA majority of women with polycystic ovary syndrome (PCOS) have metabolic dysfunction that results in an increased risk of type 2 diabetes. We previously developed a pubertal mouse model using the aromatase inhibitor, letrozole, which recapitulates many of the reproductive and metabolic features of PCOS. To further our understanding of the effects of androgen excess, we compared the effects of letrozole treatment initiated in puberty versus adulthood on reproductive and metabolic phenotypes as well as on the gut microbiome.ResultsLetrozole treatment of both pubertal and adult female mice resulted in reproductive hallmarks of PCOS, including hyperandrogenemia, anovulation and polycystic ovaries. However, unlike pubertal mice, treatment of adult female mice resulted in modest weight gain and abdominal adiposity, minimal elevation in fasting blood glucose and insulin levels, and no detectable insulin resistance. In addition, letrozole treatment of adult mice was associated with a distinct shift in gut microbial diversity compared to letrozole treatment of pubertal mice.ConclusionsOur results indicate that dysregulation of metabolism and the gut microbiome in PCOS may be influenced by the timing of androgen exposure. In addition, the minimal weight gain and lack of insulin resistance in adult female mice after letrozole treatment indicates that this model may be useful for investigating the effects of hyperandrogenemia on the hypothalamic-pituitary-gonadal axis and the periphery without the influence of substantial metabolic dysregulation.Electronic supplementary materialThe online version of this article (10.1186/s12866-019-1425-7) contains supplementary material, which is available to authorized users.

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Androgens in polycystic ovary syndrome

Abstract: Animal models have provided strong evidence to support that androgen receptor-mediated actions are key mediators in the development of PCOS traits.

Cited by 38 publications

References 44 publications

New insights into the genic and metabolic characteristics of induced pluripotent stem cells from polycystic ovary syndrome women

New insights into the genic and metabolic characteristics of induced pluripotent stem cells from polycystic ovary syndrome women

Could perturbed fetal development of the ovary contribute to the development of polycystic ovary syndrome in later life?

Letrozole treatment of adult female mice results in a similar reproductive phenotype but distinct changes in metabolism and the gut microbiome compared to pubertal mice

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