Maternal androgen excess reduces placental and fetal weights, increases placental steroidogenesis, and leads to long-term health effects in their female offspring

Sun, Miao; Maliqueo, Manuel; Benrick, Anna; Johansson, Julia; Shao, Ruijin; Hou, Lihui; Jansson, Thomas; Wu, Xiaoke; Stener-Victorin, Elisabet

doi:10.1152/ajpendo.00421.2012

Cited by 90 publications

(87 citation statements)

References 54 publications

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“…These results are in line with a recent study in the offspring of female PNA mice that used liquid chromatography tandem (LC)-MS/MS (29). In contrast, higher circulating testosterone has previously been reported in female rat PNA offspring (12). This discrepancy may be a result of the higher doses of maternal testosterone (5 mg) used in the previous study compared with the present study (0.5 mg).…”

Section: Discussionsupporting

confidence: 90%

“…One possible explanation may be an effect of maternal testosterone exposure on the organization of the brain, which may permanently alter brain morphology and subsequently give rise to altered behavioral responses (27). Another possibility is that high testosterone in the mother alters steroid production in the placenta (12), which may affect the fetus. We found that placental weight was reduced in androgenized rats.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the effects of testosterone on pregnancy are partly mediated by estrogen (11). Women with PCOS exhibit high circulating androgen levels during pregnancy, which hypothetically could be related to the increased risk of mood disorders in their offspring (12).…”

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confidence: 99%

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Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring

Richard

Maliqueo

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring

Richard

Maliqueo

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The slides were rinsed in distilled water for 5 min and counterstained with Mayer's hematoxylin (#01820; Histolab, Sweden) before mounting with medium containing glycerol (50%) and gelatin (7%). The samples were classified into positive (+), possible early (+/−), and negative (−) fatty liver (61). Adipocyte size measurement.…”

Section: Methodsmentioning

confidence: 99%

Adiponectin protects against development of metabolic disturbances in a PCOS mouse model

Benrick

Chanclón

Micallef

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Adiponectin, together with adipocyte size, is the strongest factor associated with insulin resistance in women with polycystic ovary syndrome (PCOS). This study investigates the causal relationship between adiponectin levels and metabolic and reproductive functions in PCOS. Prepubertal mice overexpressing adiponectin from adipose tissue (APNtg), adiponectin knockouts (APNko), and their wild-type (WT) littermate mice were continuously exposed to placebo or dihydrotestosterone (DHT) to induce PCOS-like traits. As expected, DHT exposure led to reproductive dysfunction, as judged by continuous anestrus, smaller ovaries with a decreased number of corpus luteum, and an increased number of cystic/atretic follicles. A two-way between-groups analysis showed that there was a significant main effect for DHT exposure, but not for genotype, indicating adiponectin does not influence follicle development. Adiponectin had, however, some protective effects on ovarian function. Similar to in many women with PCOS, DHT exposure led to reduced adiponectin levels, larger adipocyte size, and reduced insulin sensitivity in WTs. APNtg mice remained metabolically healthy despite DHT exposure, while APNko-DHT mice were even more insulin resistant than their DHT-exposed littermate WTs. DHT exposure also reduced the mRNA expression of genes involved in metabolic pathways in gonadal adipose tissue of WT and APNko, but this effect of DHT was not observed in APNtg mice. Moreover, APNtg-DHT mice displayed increased pancreatic mRNA levels of insulin receptors, Pdx1 and Igf1R, suggesting adiponectin stimulates beta cell viability/hyperplasia in the context of PCOS. In conclusion, adiponectin improves metabolic health but has only minor effects on reproductive functions in this PCOS-like mouse model. polycystic ovary syndrome | insulin resistance | adipose tissue P olycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder occurring in females (1). PCOS is one of the leading causes of poor fertility and is associated with abdominal obesity, metabolic syndrome, and an increased risk of developing type 2 diabetes (1, 2). Indeed, it has been demonstrated that 30-40% of women with PCOS have impaired glucose tolerance, and as many as 10% develop diabetes by the age of 40 y (3, 4). Despite the negative effect of PCOS on women's health, very little is known about its etiology, including the causal relationship between the reproductive and metabolic features of PCOS. Adipose tissue dysfunction is implicated as a key feature, and both lean and obese women with PCOS have aberrant adipose tissue morphology (5-7). Specifically, we have found that large adipocyte size, low circulating adiponectin levels, and increased waist circumference, but surprisingly, not androgen excess, are factors that are most strongly associated with insulin resistance in women with PCOS (8). Others have shown that hyperandrogenism is associated with intra-abdominal fat deposition (9). Adiponectin is an adipocyte-derived hormone exerting potent positive effec...

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“…Their role seems to be multifactorial and is believed to be implicated in multiple steps of hepatic physiology. Their impact may be apparent even in intrauterine stages of life by modifying liver metabolism and signaling [24,25].…”

Section: Discussionmentioning

confidence: 99%

Impact of Androgen and Dietary Advanced Glycation End Products on Female Rat Liver

Palioura

Palimeri

Piperi

et al. 2015

Cell Physiol Biochem

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Background/Aims: Advanced glycation end products (AGEs) have been related to a wide range of liver disorders including hyperandrogenic states such as the Polycystic Ovary Syndrome (PCOS). The aim of the present study is to evaluate the potential impact of dietary glycotoxins exposure and androgen excess on hepatic histology and biochemistry in an androgenized female rat model. Methods: The study population consisted of 80 female Wistar rats, divided in 3 groups, a group of prepubertal (Group A, n=30) and adult rats (Group B, n=20) that were androgenized via subcutaneous implantation of dihydrotestosterone-containing pellets as well as a group of adult non-androgenized rodents (Group C, n=30). All groups were randomly assigned either to a high-AGE or low-AGE diet for 3 months. Results: Rats fed with a high-AGE diet exhibited significantly elevated levels of gamma-glutamyl transferase (γGT) (p≤0.0002) and indices of AGE immunostaining in liver tissue (p<0.01) when compared to the respective low-AGE group, while aspartate aminotransferase (AST) levels were affected only in non-androgenized animals (p=0.0002). Androgenization per se constitutes an aggravating factor as demonstrated by the elevated γGT levels in adult androgenized animals compared to non-androgenized, independent of diet content (p=0.0002) and by the elevated AST and alanine aminotransferase (ALT) levels in low-AGE subgroups (adult androgenized vs. non-androgenized, p=0.0002) followed by increased immunohistochemical AGE deposition in hepatocytes of the latter categories (p=0.0007). Conclusion: The present study suggests that androgens and glycotoxins may contribute synergistically to distort hepatic physiology and function as observed in hyperandrogenic conditions.

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Maternal androgen excess reduces placental and fetal weights, increases placental steroidogenesis, and leads to long-term health effects in their female offspring

Cited by 90 publications

References 54 publications

Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring

Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring

Adiponectin protects against development of metabolic disturbances in a PCOS mouse model

Impact of Androgen and Dietary Advanced Glycation End Products on Female Rat Liver

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