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Sexual Dimorphism of the Human Stress Response May Be Due to Estradiol-Mediated Stimulation of Hypothalamic Corticotropin-Releasing Hormone Synthesis¹

Developmental Endocrinology Branch, NICHD, National Institutes of Health Bethesda, Maryland 20892-1862

Kirschbaum et al. (1) reported that short-term estradiol treatment enhanced hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system responses to psychosocial stress in men. Subtle gender differences in human HPA axis responses, such as increased ACTH and cortisol secretion after ovine corticotropin-releasing hormone (CRH) are well established (2). Also, human female hypothalami have increased CRH content relative to male hypothalami (3).

The authors proposed several potential mechanisms for their observation that estradiol enhanced human HPA axis activity, including reduced brain glucocorticoid receptor function, as previously shown in rats (4). Such an effect would reduce the inhibitory effects of glucocorticoid feedback on CRH and ACTH secretion.

A further plausible mechanism for their findings may be direct estradiol receptor-mediated stimulation of CRH synthesis and subsequent secretion. The human CRH gene contains five perfect half-palindromic estrogen responsive elements (EREs) within its 5' flanking region. Specific and reproducible estrogen receptor- and ERE-mediated enhancement of the human CRH gene promoter was observed in chloramphenicol acetyltransferase reporter constructs (5). Indeed, estradiol-induced stimulation of CRH gene transcription could account for the enhanced HPA axis responses to stress observed in men given estrogen. It would also explain the exaggerated sympathetic nervous system responses to stress, as CRH neurons from the paraventricular nuclei and the amygdala innervate and stimulate arousal and autonomic nonadrenergic centers (6, 7, 8).

Estradiol stimulation of CRH gene transcription may also provide, at least in part, the biological basis for the observation that melancholic depression and anorexia nervosa, both disorders associated with central CRH hypersecretion (9), are more prevalent in women than men.

Footnotes

¹ Address correspondence to: David J. Torpy, Developmental Endocrinology Branch, NICHD, NIH, Building 10, Room 10N262, 9000 Rockville Pike, Bethesda, Maryland 20892-1862.

Received November 19, 1996.

References

1. Kirschbaum C, Schommer N, Federenko I, et al. 1996 Short-term estradiol treatment enhances pituitary-adrenal axis and sympathetic responses to psychosocial stress in healthy young men. J Clin Endocrinol Metab. 81:3639–3643.[Abstract]
2. Gallucci WT, Baum A, Laue L, et al. 1993 Sex differences in sensitivity of the hypothalamic-pituitary-adrenal axis. Health Psychol. 12:420–425.[CrossRef][Medline]
3. Frederiksen SO, Ekman R, Gottfries C-G, Widerlov E, Jonsson S. 1991 Reduced concentrations of galanin, arginine vasopressin, neuropeptide Y, and peptide YY in the temporal cortex but not in the hypothalamus of brains from schizophrenics. Acta Psychiatr Scand. 83:273–277.[Medline]
4. Pfeiffer A, Lapointe B, Barden N. 1991 Hormonal regulation of type II glucocorticoid receptor messenger ribonucleic acid in rat brain. Endocrinology. 129:2166–2174.[Abstract/Free Full Text]
5. Vamvakopoulos NC, Chrousos GP. 1993 Evidence of direct estrogenic regulation of human corticotropin releasing hormone gene expression: potential implications for the sexual dimorphism of the stress response and immune/inflammatory reaction. J Clin Invest. 92:1896–1902.
6. Swanson LW, Sawchenko PE, Rivier J, Vale WW. 1983 Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: an immunohistochemical study. Neuroendocrinology. 36:165–186.[Medline]
7. Gray TS. 1989 Autonomic Neuropeptide Connections of the Amygdala. In: Tache Y, Morley JE, Brown MR, eds. Neuropeptides and Stress. New York: Springer-Verlag; 92–106.
8. Valentino RJ, Foote SL. 1988 Corticotropin-releasing hormone increases tonic but not sensory evoked activity of noradrenergic locus ceruleus neurons in unanesthetized rats. J Neurosci. 8:1016–1025.[Abstract]
9. Chrousos GP, Gold PW. 1992 The concepts of stress and stress system disorders: overview of physical and behavioral homeostasis. J Am Med Assoc. 267:1244–1252.[Abstract/Free Full Text]

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