Invited ReviewAssessing gonadal hormone contributions to affective psychopathologies across humans and animal models
Introduction
The clinical picture of hormonal dysfunction of the gonads (hyper- or hypogonadism) is frequently accompanied by some presentation of psychopathology, most notably in forms of anxiety and/or depression. Awareness of comorbid psychopathology is important for the clinical care and management of affected individuals, but it may also provide valuable information on the fundamental contributions of gonadal hormones, specifically androgens, oestrogens, and progesterone, to affective cognition. Conversely, some manifestations of mood disorders, such as premenstrual dysphoric disorder or postmenopausal depression have been intimately linked to underlying imbalances of the hormonal milieu. While research on basic cognitive-affective processes in human endocrine conditions is slowly increasing (Mueller, 2013), parallel research employing animal models indicates important relationships between gonadal dysfunction and the presentation of anxiety-like and depressive-like behaviours in non-human species (ter Horst et al., 2012). Surprisingly, few attempts to reconcile how human and animal literatures can inform one another have been made despite the possibility that findings obtained in one species may provide insights into the basic mechanisms that are better addressed in the other species. Such cross-species comparisons and validation of animal models are essential when aiming to develop effective therapeutic and/or pharmacological interventions for various disorders.
This review focuses on recent developments of affective processing in humans suffering from perturbations of gonadal hormones and corresponding models in non-human species, particularly rodents. As will be shown, these conditions may serve as an essential intermediary between behavioural neuroscience in animal models and basic neuroscience in human populations. To limit its scope, this review primarily focuses on changes in gonadal hormones and the HPG (hypothalamic-pituitary-gonadal) axis, however, some conditions presented here also affect HPA (hypothalamic-pituitary-adrenal) axis functioning. Given the breadth of this topic and the number of disorders and species being involved, and to emphasize similarities rather than differences, we decided to selectively focus on perturbations in sex hormones. To maintain this focus, the review will not address underlying biology or aetiology or examine possible interactions between hormones and other molecular systems including neurotransmitters or immunochemistry. Instead, it will address the relevance of sex hormones for behavioural aspects of anxiety and depression. In this sense, the reviewed literature has to be regarded as being limited and only constituting one aspect of a broader, complicated scenario.
First, conditions of hypogonadism in women and men will be reviewed followed by discussion of conditions of hypergonadism in both sexes. Given the current scarcity of research in this area, inclusion of published reports in the review was guided by available studies. To obtain these available studies, we searched PubMed from 1970 onwards with the search terms for the disorder or the rodent equivalent, i.e., Klinefelter, XXY, TFM and testicular feminization model, CAH and congenital adrenal hyperplasia, PMDD and premenstrual dysphoric disorder, postmenopausal syndrome, ovariectomy, Turners Syndrome, hypogonadal, castration PLUS anxiety OR depression AND/OR psychopathology AND human OR rodent. In addition, reference lists of identified articles were also searched for relevant literature. Thus, while some conditions are not included in this article, a secondary purpose of this review is to highlight the need for further studies of the consequences of hormonal imbalances. Following these sections, we highlight consistencies in the reviewed literature and discuss methodological challenges for future research, including the need for valid behavioural tasks that can be applied across human and rodent species.
Section snippets
Premenstrual dysphoric disorder
Roughly affecting 3–8% of women of childbearing age, symptoms of premenstrual dysphoric disorder (PMDD) include depression, irritability, mood swings, and feelings of tension and anxiety (Halbreich et al., 2003). These symptoms typically occur within 5–11 days before the beginning of a woman's menstrual cycle, thus during the luteal phase, and usually cease during or after menstruation. A strong contribution of gonadal hormones in PMDD has been proposed although it may not be the sole
Testosterone deficiency
Human males with androgen deficiency due to a supernumerary X chromosome, such as in men carrying the 47 XXY genotype or Klinefelter Syndrome (KS), show high rates of various psychopathologies, particularly language disorders (65%), attention deficit hyperactivity disorder (63%), autism spectrum disorder (27%), depression, (24%) and anxiety disorders (18%) (Bruining et al., 2009). In an interesting series of studies, van Rijn and colleagues have assessed affective processing, emotion
Polycystic ovary syndrome
One in five women of reproductive age suffer from polycystic ovary syndrome (PCOS), which includes symptoms of anovulation, irregular menstrual periods, exposure to large amounts of androgens, and insulin resistance. Frequent associated psychopathologies include anxiety and depression as well as eating disorders relative to women without this condition (Barry et al., 2011, Mansson et al., 2008). Importantly, a 7-fold increased risk for suicide attempts in affected individuals relative to
Congenital adrenal hyperplasia and familial male precocious puberty
Similar to hypogonadism in males, evidence also supports increased rates of psychopathologies associated with exposure to excess androgen, particularly during early developmental stages of life. Pathogenesis of hyperandrogenism can have different origins. In congenital adrenal hyperplasia (CAH), both males and female foetuses are exposed to abnormally high levels of androgens in-utero. While CAH may affect both sexes, effects are particularly severe in females who may be born with ambiguous
Androgen insensitivity
Although humans can experience both over- and under-production of gonadal steroids, another form of gonadal hormone perturbation occurs when sufficient levels of gonadal steroids are present but dysfunction of hormone receptors precludes their effects. A well-known form of insensitivity in humans is androgen insensitivity syndrome (AIS), which presents in partial or complete forms. Despite having a 46, XY karyotype and the presence of a Y chromosome, individuals with the complete form of this
Synthesis of human and animal data across the life-span on hormonal effects on affective and neurocognitive function
In this review, several consistencies across the surveyed literature emerged. In humans, low androgens in males with Klinefelter Syndrome (KS), low oestrogen in females with Turner Syndrome (TS), and low progesterone in females with premenstrual dysphoric disorder (PMDD) increased manifestations of depression and anxiety (Bruining et al., 2009, Downey et al., 1989, Halbreich et al., 2003). Each of these disorders was reported to be associated with difficulties in labelling emotional facial
A proposed model of gonadal hormone effects on anxious/depressed behaviour
Summarizing the findings of this review, the model displayed in Fig. 2 proposes a U-shaped relationship to describe the role of gonadal steroid hormone perturbations in the manifestations of depression and anxiety. The reviewed literature consistently indicates higher levels of depression and anxiety across conditions with a strong, inherent hormonal component. While most studies documented the presence of psychopathology in affected individuals (Barry et al., 2011, Bruining et al., 2009,
A continuing search for translatable paradigms and open questions for future research
One issue for enabling straightforward comparisons across species to facilitate future research is the search for valid and translatable paradigms of interest to psychoneuroendocrinology. As shown in Fig. 3, a variety of paradigms currently are available to compare humans and rodents that tap into learning and memory processes (panel a) and fear conditioning and startle response (panel b), or other behaviours such as sexual function and arousal (kinky picture not shown). In areas of learning
General summary
In summary, studies investigating affective processes in humans indicate higher rates of mood and anxiety disorders in pathologies that express abnormalities in gonadal hormone levels or tissue sensitivities. Rodent models parallel many of the hormonal and behavioural characteristics of these human pathologies, offering experimental approaches to gain a better understanding of these conditions and the underlying mechanism. Nevertheless, there continues to be a dearth of research that applies
Role of the funding source
This study was funded by Ghent University (Multidisciplinary Research Partnership “The integrative neuroscience of behavioural control”) and the Society for Endocrinology (Early Career Grant).
Conflict of interest
None of the authors has a conflict of interest to declare.
Acknowledgements
SCM is supported by Ghent University (Multidisciplinary Research Partnership “The integrative neuroscience of behavioural control”) and an Early Career Grant from the Society for Endocrinology.
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