Organizational and Activational Effects of Testosterone on Masculinization of Female Physiological and Behavioral Stress Responses

Abstract

The prevalence of affective disorders is two times greater in women than in men. The onset of anxiety and depression occurs at different ages that may correspond to key developmental periods when the brain is more vulnerable to hormonal and exogenous influences. Because stressful life events can precipitate disease onset, the development of greater stress sensitivity in females may contribute to their increased vulnerability. Gonadal hormone exposure in males during early development and again from puberty onward plays a prominent role in sexually dimorphic brain formation, possibly contributing to sex differences in stress responsivity. Therefore, organizational effects of testosterone propionate (TP) administered postnatally and activational effects of TP administered beginning at puberty on adult female physiological and behavioral stress responses were examined in mice. Although the activational effects of TP in females ameliorated the sex difference in the hypothalamic-pituitary-adrenal axis stress response, there was no effect of postnatal TP. Similarly, higher immobile time in intact females in the tail suspension test was blunted by activational TP in the absence of postnatal TP. However, in the marble-burying test of anxiety-like behaviors, organizational and activational TP independently resulted in increased burying behaviors. These results show that TP administration has distinct effects on reducing physiological and behavioral stress responsivity in rodent models and suggest that sex differences in these responses may partially result from the absence of testosterone in females.

Hippocampal gene expression induced by cold swim stress depends on sex and handling

“…Sex differences in stress sensitivity are often attributed to differences in HPA axis function (Bangasser and Valentino, 2012;Handa et al, 1994). Indeed, our results confirm previous reports showing that females generally have higher resting levels of corticosterone, and have a more pronounced increase in corticosterone secretion in response to stress (Goel and Bale, 2008;Handa et al, 1994). However, we demonstrate here that the rapid changes in gene expression in response to stress are not mediated by corticosterone.…”

Sex as a Biological Variable: Who, What, When, Why, and How

“…For instance, adult sex differences in hippocampal expression of the glucocorticoid receptor, critical for the negative feedback and modulation of the HPA stress axis, was disrupted in females masculinized at birth by a single injection of testosterone, supporting the importance of the male testosterone surge in normal wiring of sex differences in stress pathways (Bingham and Viau, 2008;Goel and Bale, 2008;Goel et al, 2011). In addition to this early critical period of programming, the rise in gonadal hormones beginning in puberty interacts with these organizational changes and exerts modulatory actions on neurotransmitter systems critical in regulation of sex differences in stress responsivity.…”

“…This variability comparison has now similarly been completed in rats as well . In addition, many behavioral studies have similarly reported that when estrous cycle stage was included as a variable, no significant differences in outcome measures were found, including for the Barnes maze, tail suspension test, forced swim test, elevated plus maze, light-dark box, and open-field tests (Mueller and Bale, 2007;Goel and Bale, 2008;Goel and Bale, 2009;Goel and Bale, 2010;Goel et al, 2011). This is not to say that gonadal hormones are not important in behavioral responses, but rather that the variability within females when comparing their outcomes to males does not explain sex differences.…”

“…Knowing this, you might design your study to ask about differences within sex for a given manipulation rather than between sexes. As another example, in post-puberty rodents, the HPA stress axis has a significant sex difference in the amount of ACTH and corticosterone produced in response to a given acute stressor Romeo et al, 2004;Romeo and McEwen, 2006;Goel and Bale, 2007;Goel and Bale, 2008;Goel and Bale, 2009;Handa et al, 2009;Weiser and Handa, 2009). This would be an example of a sex difference that is along a continuum, with females producing the same hormones and in the same direction as males (increased following stress), but just at higher levels (Joel and McCarthy, 2016).…”

Sex differences in animal models of psychiatric disorders

“…However, others have found that in this test, female rats in prooestrous are more sensitive to diazepam, than male and female rats in dioestrous (Fernandez-Guasti and Picazo, 1990). Finally, in a study where the marble burying test was used as an anxiety model, female rats tended to bury fewer objects than male rats (Goel and Bale, 2008).In another model of OCD, the deer mice, which are characterized by stereotypical behaviours, mice of both sexes have been used but no sex differences have been reported to date (Korff et al, 2008). With regard to genetic models, male ArKO mice, which lack oestrogens, show enhanced OCD-like behaviours, such as grooming and wheel running, whereas females do not (Hill et al, 2007).…”