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Project 3: Handa (P.I.)

Sex-Specific Programming of the HPA Axis by Glucocorticoids

The overarching goal of this project is to describe the long-term consequences of fetal/neonatal exposure to stress on the developing hypothalamic-pituitary- adrenal (HPA) axis. It has been shown that fetal and neonatal insults, specifically to exposure to glucocorticoids, the corticosteroids produced by the adrenal gland in response to stress, can affect the developing HPA axis, resulting in neuroendocrine stress hyper-reactivity and increased anxiety in adulthood. Though glucocorticoids exist in order to regulate several cardiovascular, immunological, and metabolic processes, excess levels of glucocorticoid exposure during development can have detrimental effects on body and brain tissues. Females are more susceptible to these effects on the developing HPA axis than males. Furthermore, early exposure of the developing brain to glucocorticoids has been shown to produce lasting changes in HPA function, yet the cellular mechanisms responsible for programming the memory of early glucocorticoid exposure to adult stress responsiveness remain unknown.

We have demonstrated that exposure to excess glucocorticoids during development of the rodent brain that corresponds to late 2nd / early 3rd trimester in human development causes an increase in the number of dying cells within the lateral paraventricular nucleus of the hypothalamus (PVN), in female but not male neonates, and increase expression of some genes that promote cell death (called pro-apoptotic genes) in the neonatal brain. This raises the possibility that perinatal exposure to glucocorticoids can permanently change the function of the adult HPA axis by altering the numbers of some neurons within or around the PVN. Alternatively, long-term changes in gene expression may be due to altered DNA methylation as a result of neonatal glucocorticoid or gonadal steroid hormone effects. We have also demonstrated that prenatal glucocorticoid exposure can result in metabolic dysregulation in adulthood.  Adult female rats that were exposed to dexamethasone in utero develop fatty liver disease that is more profound than that of males.  This is also characterized by changes in Growth Hormone and IGF-1 expression and altered mitochondrial function.

Studies in this project test two hypotheses in rodents regarding the fetal programming of adult stress responsiveness:

1) that prenatal/neonatal exposure to stress causes permanent changes in the function of the HPA axis by either increasing the incidence of death in a select neuronal phenotype in the PVN, or by causing permanent changes in gene expression in PVN neurons through DNA methylation;

2) that there are sex-specific effects of fetal/neonatal glucocorticoid exposure on the developing PVN as a result of molecular interactions between glucocorticoid receptors (GR) and estrogen receptors (ER).

Such investigations have implications for the study of major depressive disorder (MDD) in humans as well as its comorbidity with cardiovascular disease and obesity, which are also much greater in women than in men. Clinical and preclinical studies show a causal link between the dysregulation of the HPA axis and behavioral pathology. Furthermore, depression is more prevalent in females, with female-to-male ratios of greater than 2:1. Clinical studies of depressed patients demonstrate that gender differences arise during adolescence as reflected by an increased incidence of MDD in girls and decreased incidence in boys. Preliminary data collected by our lab indicate that the HPA axis of rodents is sexually differentiated and, if extrapolated to humans, such a sex difference may underlie the sex differences in the prevalence of MDD in humans as well.


  • Prenatal glucocorticoid exposure programs metabolism causing increased hepatic steatosis in adult females, but not males after they are placed on a high fat diet
    • This is accompanied by female specific reductions in circulating growth hormone, IGF-1 and other adipocytokines
  • Prenatal glucocorticoid exposure increases naturally occurring cell death in the amygdala and is are greater in GABAergic neuron
  • Prenatal glucocorticoid excess increases apoptosis in the hippocampus and is greater in females compared to males
  • An estrogen receptor beta agonist inhibits inflammatory markers and reduces p-glycoprotein expression, a component of the blood brain barrier, in human microvascular endothelial cell cultures from brain
  • Prenatal dexamethasone exposure decreases core body temperature in female, but not male rats
    • The changes in core body temperature are accompanied by decreases in expression of trh mRNA in the PVN


Goldstein, JM, Handa RJ, Tobet SA. Disruption of fetal hormone programming (prenatal stress) implicates shared risk for sex differences in depression and cardiovascular function. Front. Neuroendocrinol 2014 Jan; 35(1): 140-58. PMCID: PMC3917309

Carbone DL, Handa RJ.   (2013). Sex and Stress Hormone Influences on the Expression and Activity of Brain Derived Neurotrophic Factor. Neuroscience, 2013 Jun 3; 239:295-303. PMCID: PMC3609934 

Carbone DL, Zuloaga DG, Lacagnina AF, Handa RJ.  2012. A unique population of prepro-thyrotropin releasing hormone expressing neurons in the lateral hypothalamus that are activated by leptin and altered by prenatal glucocorticoid exposure. Brain Res 1477;19-26. PMID:22981312

Carbone DL, Zuloaga DG, Lacagnina AF, McGivern RF, Handa RJ. Exposure to dexamethasone during late gestation causes female-specific decreases in core body temperature and prepro-thyrotopin-releasing hormone expression in the paraventricular nucleus of the hypothalamus in rats.  Physiol Behav 2012 Dec; 108: 6-12. PMCID: PMC3513498

Zuloaga DG, Carbone DL, Handa RJ. Prenatal dexamethasone selectively decreases calretinin expression in the adult female lateral amygdala. Neurosci. Lett 2012 Jul; 521(2):109-14.   PMCID: PMC3395764 

Zuloaga KL, Swift SN, Gonzales RJ, Wu TJ, Handa RJ. 2012.  The androgen metabolite, 5-androstane-3b,17b diol decreases cytokine induced cyclooxygenase-2 and vascular cell adhesion molecule-1 expression and reduces P-glycoprotein expression in Human Brain Microvascular Endothelial Cells. Endocrinology 2012 Dec; 153(12): 5949-60. PMCID: PMC3512076 

Zuloaga, KL, O’Connor, Handa, RJ, Gonzales, RJ. Estrogen Receptor Beta Dependent Attenuation of Cytokine-Induced Cyclooxygenase-2 by Androgens in Human Brain Vascular Smooth Muscle Cells and Rat Mesenteric Arteries. Steroids 2012 Jul; 77(8-9):835-844. PMCID: PMC3809122

Larco DO, Cruthirds DF, Weiser MJ, Handa RJ, Wu TJ. The interaction of 17b-estradiol and chronic immobilization stress to regulate body weight in the ovariectomized (OVX) rat. Endocrine 2012 Dec; 42(3): 717-25. PMID: 22706604

Fernandez Guasti A, Fiedler J, Herrera L, Handa RJ. Sex, Stress and Mood Disorders: At the intersection of Adrenal and Gonadal Hormones. Horm. Metab Res. 2012 Jul; 44(8):607-618. PMCID: PMC3584173 

Zuloaga, DG, Carbone DL, Quihuis A, Chong DL, Handa RJ. Perinatal dexamethasone-induced alterations in apoptosis within the hippocampus and paraventricular nucleus of the hypothalamus are age- and sex-dependent. J. Neurosci. Res 2012 Jul; 90(7): 1403-1412. PMID: 22388926

Carbone, DL, Zuloaga, DG, Hiroi R, Foradori, CD, LeGare, ME, Handa, RJ. Prenatal dexamethasone exposure potentiates diet-induced hepatosteatosis and decreases plasma IGF-1 in a sex specific fashion. Endocrinology 2012 Jan; 153(1): 295-306. PMCID: PMC3249671

Zuloaga, DG, Carbone DL, Hiroi R, Chong DL, Handa RJ. Dexamethasone induces apoptosis in the developing rat amygdala in an age, region and sex specific manner.  Neuroscience 2011 Dec; 199:535-547. PMCID: PMC3237835