Sex Differences in the Ovine Fetal Cortisol Response to Stress

Abstract

This study tested the hypothesis that the sexually dimorphic adrenocortical response to stress is already established before birth. Chronically instrumented late gestation pregnant sheep carrying 16 male and 15 female age-matched singleton fetuses were subjected to an acute episode of hypoxic stress. Maternal and fetal blood gases, adrenocorticotrophic hormone (ACTH), and cortisol were measured. In addition, six male and six female fetuses received the ACTH analog, Synacthen, and plasma cortisol was measured. During hypoxic stress, the increment in plasma cortisol was 2-fold greater in male versus females fetuses (30.6 Ϯ 3.2 versus 14.3 Ϯ 2.0 ng/mL; p Ͻ 0.001) mediated, in part, by greater adrenocortical sensitivity to ACTH. The data support the hypothesis tested and show that sex-specific differences in the cortisol stress response are present before birth with the output of cortisol being much greater in male than in female fetuses. (Pediatr Res 69: 118-122, 2011) D uring threatening situations, the stress system coordinates adaptive responses that adjust homeostatic mechanisms to increase the individual's chance of survival. The hypothalamic-pituitary-adrenal (HPA) axis constitutes one of the main efferent limbs of the stress system, and measurement of circulating plasma adrenocorticotrophic hormone (ACTH) and cortisol concentrations are established measures of the level of psychological, social, and/or physiological stress (1). An adequate capacity for secretion of adrenal glucocorticoids is essential for fetal development and maintenance of an independent life (2,3); the adrenal glands are thus highly perfused with blood and richly innervated. Adrenocortical secretion of glucocorticoids is often used as an example of classical endocrinology, with the principal control provided by the release of ACTH from the distant anterior pituitary and with excess cortisol production switching off the stimulatory signal through negative feedback.It is widely acknowledged that there are differences in the response to stress between the sexes, but the reason underlying these differences is unclear. The literature is often contradictory due, in part, to variations in the type of stress imposed, the particular species being studied, and the age of the subject. For example, in adult rats, females have greater stress responses (4,5); however, in humans, it is young men and old women who show an increased stress response relative to old men and young women (6). In addition, when compared with agematched women, men showed consistently higher plasma cortisol responses to stress in four independent studies (7). It is also accepted that sex hormones can alter the magnitude of the stress response, with androgens being suppressive and estrogens being stimulatory to the HPA axis (8,9) and that manipulation of gonadal steroids soon after birth can have activational and organizational effects on the function of the stress axis later in life (9). Development of the fetal HPA axis is exquisitely controlled and critical for the a...

Transgenerational programming of fetal nephron deficits and sex-specific adult hypertension in rats

“…Importantly, Control dams from both generations had unaltered sex ratios. Others have reported that exposure to acute hypoxic stress in ewes resulted in a 2-fold greater concentration of plasma cortisol in male compared with female fetuses (Giussani et al 2011). Taken together with our findings, this suggests that males are more sensitive to adverse in utero exposure.…”

Sex differences in cardiorespiratory transition and surfactant composition following preterm birth in sheep

“…As well as finding a strong trend for male fetuses to have a lower arterial pH than female fetuses, the present study demonstrates that female, but not male fetuses, show a rise in circulating plasma cortisol between 131 and 133 days of gestation under control conditions, which may influence lung maturation. However, in response to maternal hypoxia at 130 days of ovine gestation, the increase in circulating cortisol concentration was twice as great in male fetuses compared with females, which was attributed to a greater adrenocortical sensitivity to adrenocorticotrophic hormone (ACTH) in male fetuses (17). This greater adrenal sensitivity to ACTH in the male fetus has previously been shown in male-female twin pairs (33).…”

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Elevated morning cortisol is a stratified population-level biomarker for major depression in boys only with high depressive symptoms

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