Sex, stress, and mood disorders: at the intersection of adrenal and gonadal hormones

Abstract

The risk for neuropsychiatric illnesses has a strong sex bias, and for major depressive disorder (MDD), females show a more than 2-fold greater risk compared to males. Such mood disorders are commonly associated with a dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis. Thus, sex differences in the incidence of MDD may be related with the levels of gonadal steroid hormone in adulthood or during early development as well as with the sex differences in HPA axis function. In rodents, organizational and activational effects of gonadal steroid hormones have been described for the regulation of HPA axis function and, if consistent with humans, this may underlie the increased risk of mood disorders in women. Other developmental factors, such as prenatal stress and prenatal overexposure to glucocorticoids can also impact behaviors and neuroendocrine responses to stress in adulthood and these effects are also reported to occur with sex differences. Similarly, in humans, the clinical benefits of antidepressants are associated with the normalization of the dysregulated HPA axis, and genetic polymorphisms have been found in some genes involved in controlling the stress response. This review examines some potential factors contributing to the sex difference in the risk of affective disorders with a focus on adrenal and gonadal hormones as potential modulators. Genetic and environmental factors that contribute to individual risk for affective disorders are also described. Ultimately, future treatment strategies for depression should consider all of these biological elements in their design.

Fig. 1

Chronic restraint stress in male rats reduces spine number of apical primary dendrites from hippocampal CA1 pyramidal neuron. After 14 days of restraint stress (2.5 h/day), brains were processed for rapid Golgi staining and the number of spines along a segment of primary apical dendrite (80 µm) from pyramidal neurons of the CA1 hippocampal area was scored. Protrusions, irrespective of their morphological characteristics were counted as spines only if they were in direct connection with the dendritic shaft. a Representative images of the primary branch of hippocampal CA1 pyramidal neurons under 100 × magnifications to show spines arrows) from control and stressed animals. Note the greater density of spines along the shafts in control compared to stressed animal. b Total number of spines in an 80 µm segment from the origin of the branch, was then averaged across all neurons in control and stressed animals (4–5 neurons per animal were used in each experimental group). Data show means ± S.D. Unpaired t-test: **p < 0.005.

Fig. 2

Daily rhythm in core body temperature (CBT) in prenatal dexamethasone (DEX)-treated adult female rats. Pregnant dams were treated with DEX (0.4 mg/kg BW) from gestation age 18–21. Offspring were raised to adulthood. CBT was determined by in vivo telemetry (Mini mitter, Bend, OR) and temperature was recorded throughout the Dark:Light (D:L) cycle. Data shown are 30-min means from 4 females in each group recorded over a 24-h period on a day of diestrus. Controls are shown in black, DEX treated in gray. A 2-h moving average was used to plot the data. Prenatal DEX-treated females showed a significant 0.2–0.5 °C temperature decrease throughout the day compared to vehicle treated females (p < 0.05). All individuals tested arose from different litters. DEX- and vehicle-treated males were not different from each other and not different from vehicle treated-females (data not shown) indicating a sex-difference in susceptibility to hypothalamic disruption by prenatal glucocorticoids. Black bars on bottom indicate the dark period of the D:L cycle.

Fig. 3

Effect of subchronic treatment with fluoxetine (2.5, 5 and 10 mg/kg) on females’ (left panel) and males’ (right panel) immobility in the forced swimming test. Control- and neonatally-virilized (testosterone propionate, 60 µg/rat subcutaneously (s.c.) at day 5) females were tested in estrus. Neonatally-orchidectomized (orx) males were castrated on day 5 of life under cryo-anesthesia. Data show means ± S.E.M. of number of counts of 8–10 rats per group (within bars). One way ANOVAs for: control females: F_(3,31) = 4.01, p < 0.05; virilized females: F_(3,32) = 6.8, p < 0.001; control males: F_(3,31) = 2.93, p < 0.05, neonatally castrated males: F_(3,34) = 5.15, p < 0.01, Fisher Least Significant Difference (LSD): *p < 0.05; **p < 0.01 vs. its respective nontreated control group. t-test: ++ p < 0.01 between control and neonatally orchidectomized groups. Note that without treatment under control conditions females in estrus display lower levels of immobility than males.