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During pregnancy, women with polycystic ovary syndrome (PCOS) display high circulating androgen levels that may affect the fetus and increase the risk of mood disorders in offspring. This study investigated whether maternal androgen excess causes anxiety-like behavior in offspring mimicking anxiety disorders in PCOS. The PCOS phenotype was induced in rats following prenatal androgen (PNA) exposure. PNA offspring displayed anxiety-like behavior in the elevated plus maze, which was reversed by flutamide [androgen receptor (AR) blocker] and tamoxifen [selective estrogen receptor (ER) modulator]. Circulating sex steroids did not differ between groups at adult age. The expression of serotonergic and GABAergic genes associated with emotional regulation in the amygdala was consistent with anxiety-like behavior in female, and partly in male PNA offspring. Furthermore, AR expression in amygdala was reduced in female PNA offspring and also in females exposed to testosterone in adult age. To determine whether AR activation in amygdala affects anxiety-like behavior, female rats were given testosterone microinjections into amygdala, which resulted in anxiety-like behavior. Together, these data describe the anxiety-like behavior in PNA offspring and adult females with androgen excess, an impact that seems to occur during fetal life, and is mediated via AR in amygdala, together with changes in ERα, serotonergic, and GABAergic genes in amygdala and hippocampus. The anxiety-like behavior following testosterone microinjections into amygdala demonstrates a key role for AR activation in this brain area. These results suggest that maternal androgen excess may underpin the risk of developing anxiety disorders in daughters and sons of PCOS mothers. maternal androgen excess | anxiety | behavior | polycystic ovary syndrome | amygdala P olycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by excessive androgen secretion and abnormal insulin activity and affects up to 17% of women worldwide (1). Women with PCOS are at an increased risk of developing symptoms of anxiety and depression. In fact, over 60% of women with PCOS are diagnosed with at least one psychiatric disorder, such as depression, anxiety, or an eating disorder (2). Suicide attempts have also been shown to be seven times more common in women with PCOS than in healthy controls (3). The mechanisms underlying the development of PCOS are poorly understood. Although a genetic basis for PCOS has been suggested, the intrauterine milieu might also affect the reproductive/endocrine function of a child born to a PCOS mother in a manner that is independent of genetic inheritance or sex. It is also known that daughters of mothers with PCOS are at increased risk of developing the syndrome and that sons tend to suffer from obesity and insulin resistance (4). Thus, it has been proposed that PCOS originates during fetal development and that this might be, in part, a result of maternal androgen excess (5).Maternal testosterone levels in humans have been shown to affect br...

Genetic and epigenetic factors may predispose women to polycystic ovary syndrome (PCOS), a common heritable disorder of unclear etiology. Here we investigated differences in genome-wide gene expression and DNA methylation in adipose tissue from 64 women with PCOS and 30 controls. In total, 1720 unique genes were differentially expressed (Q < 0.05). Six out of twenty selected genes with largest expression difference (CYP1B1, GPT), genes linked to PCOS (RAB5B) or type 2 diabetes (PPARG, SVEP1), and methylation (DMAP1) were replicated in a separate case-control study. In total, 63,213 sites (P < 0.05) and 440 sites (Q < 0.15) were differently methylated. Thirty differentially expressed genes had corresponding changes in 33 different DNA methylation sites. Moreover, a total number of 1913 pairs of differentially expressed “gene-CpG” probes were significantly correlated after correction for multiple testing and corresponded with 349 unique genes. In conclusion, we identified a large number of genes and pathways that are affected in adipose tissue from women with PCOS. We also identified specific DNA methylation pathways that may affect mRNA expression. Together, these novel findings show that women with PCOS have multiple transcriptional and epigenetic changes in adipose tissue that are relevant for development of the disease.

Polycystic ovary syndrome (PCOS) is an endocrine-metabolic disorder associated with insulin resistance and compensatory hyperinsulinemia. Scarce information is available on the expression of molecules involved in the insulin pathway in endometria from women with PCOS. Therefore, we examined the protein levels of insulin-signaling molecules, like insulin receptor, insulin-receptor substrate (IRS)-1, pIRS-1Y612, Akt, AS160, pAS160T642 and GLUT4 in endometria from PCOS women with or without hyperinsulinemia. Protein levels were assessed by Western blot and immunohistochemistry in 21 proliferative-phase endometria from control women (CE = 7), normoinssulinemic PCOS women (PCOSE-NI = 7) and hyperinsulinemic PCOS women (PCOSE-HI = 7). The data show no differences in the expression of insulin receptor between all groups as assessed by Western blot; however, IRS-1 and pIRS-1Y612 were lower in PCOSE-HI than controls and PCOSE-NI (P < 0.05). AS160 was detected in all analyzed tissues with similar expression levels between groups. Importantly, PCOSE-HI exhibited lower levels of pAS160T642 (P < 0.05) and of GLUT4 (P < 0.05) compared with CE. The immunohistochemistry for insulin receptor, IRS-1, Akt, AS160 and GLUT4 showed epithelial and stromal localization; IRS-1 staining was lower in PCOSE-HI (P < 0.05). In conclusion, human endometrium has the machinery for glucose uptake mediated by insulin. The diminished expression of GLUT4, as well as the lower level of pIRS-1Y612 and pAS160T642 exhibited by PCOSE-HI, suggests a disruption in the translocation of vesicles with GLUT4 to the cell surface in these patients.

Background: Depletion of ovarian follicles is associated with the end of reproductive function in ageing females. Recently, it has been described that this process parallels increases in the concentration of norepinephrine (NE) in the rat ovary. In sexually mature rats, experimentallyinduced increases in the sympathetic tone of the ovary is causally related to ovarian cyst formation and deranged follicular development. Thus, there is a possibility that increased ovarian NE concentrations represent changes in the activity of sympathetic nerves, which consequently participate in the process of ovarian cyst formation observed during ageing in the human and experimental animal models.

Maternal polycystic ovary syndrome (PCOS), a condition associated with hyperandrogenism, is suggested to increase anxiety-like behavior in the offspring. Because PCOS is closely linked to obesity, we investigated the impact of an adverse hormonal or metabolic maternal environment and offspring obesity on anxiety in the offspring. The obese PCOS phenotype was induced by chronic high-fat-high-sucrose (HFHS) consumption together with prenatal dihydrotestosterone exposure in mouse dams. Anxiety-like behavior was assessed in adult offspring with the elevated-plus maze and open-field tests. The influence of maternal androgens and maternal and offspring diet on genes implicated in anxiety were analyzed in the amygdala and hypothalamus with real-time PCR ( n = 47). Independent of diet, female offspring exposed to maternal androgens were more anxious and displayed up-regulation of adrenoceptor α 1B in the amygdala and up-regulation of hypothalamic corticotropin-releasing hormone ( Crh). By contrast, male offspring exposed to a HFHS maternal diet had increased anxiety-like behavior and showed up-regulation of epigenetic markers in the amygdala and up-regulation of hypothalamic Crh. Overall, there were substantial sex differences in gene expression in the brain. These findings provide novel insight into how maternal androgens and obesity exert sex-specific effects on behavior and gene expression in the offspring of a PCOS mouse model.-Manti, M., Fornes, R., Qi, X., Folmerz, E., Lindén Hirschberg, A., de Castro Barbosa, T., Maliqueo, M., Benrick, A., Stener-Victorin, E. Maternal androgen excess and obesity induce sexually dimorphic anxiety-like behavior in the offspring.

The work was supported by the Swedish Medical Research Council (Project No. 2011-2732 and 2014-2775); Jane and Dan Olsson Foundation, Wilhelm and Martina Lundgrens's Science Fund; Hjalmar Svensson Foundation (E.S.-V and M.M.); Adlerbert Research Foundation; Swedish federal government under the LUA/ALF agreement ALFFGBG-136481 and 429501 and the Regional Research and Development agreement (VGFOUREG-5171, -11296 and -7861). MM thanks the Becas Chile Programme (Chile) and University of Chile for financial support through a postdoctoral fellowship. There are no competing interests.

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