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

Abstract

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...

Female infertility, infertility-associated diagnoses, and comorbidities: a review

“…The relationship between PCOS and mental health is not yet clear but may be independent of a strict diagnosis of infertility. Ongoing research has suggested that testosterone levels may play a role in brain development, which could provide a possible explanation for this association [41]. Health care providers who care for women with infertility or PCOS should be aware that their patients may face challenges either at time of consultation for infertility or in the future related to anxiety, depression, and substance abuse.…”

Cross-generational influences on childhood anxiety disorders: pathways and mechanisms

“…For example, it is not clear how effectively candidate hormones such as cortisol or noradrenaline cross the placental barrier. This question is also being investigated in animal studies, and there is evidence that maternal exposure to testosterone during pregnancy can impact the limbic system of offspring in rats, and contribute to elevated anxiety-like behavior (Hu et al 2015). It is also unclear to what extent changes in fetal blood flow, related to maternal anxiety, actually explain psychological outcomes in the babies.…”

Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome

“…Support for AR-mediated androgen actions influencing the progression of PCOS includes that variation in androgen sensitivity via the CAG triplet repeat length polymorphism of the AR (11) is associated with PCOS prevalence (12), and alternative splicing of the AR in granulosa cells is associated with aberrant follicle development (13,14). Treatment with the AR antagonist flutamide is reported to restore ovulation in some women with PCOS (15) and rescue acyclicity (16) and anxiety-like behavior (17) in PCOS mouse models. Moreover, we recently identified that loss of AR signaling protects female mice from induction of PCOS features by prenatal hyperandrogenism (18).…”