Regulatory Mechanisms Affecting Gonadal Hormone Action

Author : Matthew Green
Publisher :
ISBN 13 :
Total Pages : pages
Book Rating : 4.:/5 (124 download)

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Download or read book Developmental and Gonadal Regulation of Hypothalamic-pituitary-adrenal Axis Function in Adolescent and Adult Rats written by Matthew Green and published by . This book was released on 2017 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The hypothalamic-pituitary-adrenal (HPA) axis regulates the release of stress hormones and its function is dependent on various factors including prior exposure to stressors, circulating gonadal hormones, and developmental status. The overarching goal of this thesis was to uncover the potential mechanisms mediating developmental changes in HPA function and its regulation by gonadal hormones during adolescence and early adulthood. In Chapter 2, I found that pre-pubertal (postnatal day [P]35) and post-pubertal (P45) adolescents responded to an acute stressor with greater release of corticosterone (the main stress hormone in rodents) compared with adults (P75). To determine whether differences in corticosterone release were related to ongoing maturation of HPA feedback, I investigated glucocorticoid receptor (GR) activity and mRNA expression of receptors (Nr3c1, Nr3c2) and their co-chaperones (Fkbp5, Fkbp4, Bag1) in the hippocampus. I provide novel evidence that P35 males have more, not less, GR translocation from the cytosol to the nucleus in response to stress compared with P75 males. Gene expression remained relatively stable across development, except for Fkbp4, which codes for a pro-translocation protein and was up-regulated in P35 males relative to expression in P75 males. Thus, there are developmental shifts in the hormonal response to stress that are likely unrelated to GR activity in the hippocampus. In Chapter 3, I investigated whether differences in HPA function are explained by gonadal status; in adult males, testosterone reduces HPA function. Age-related differences in corticosterone release persisted when orchiectomized (OCX) males at each age were administered testosterone. Moreover, the effect of testosterone changed across the adolescent period; relative to those that got blank implants, testosterone had no effect on post-stress concentrations of corticosterone at P35, increased concentrations at P45, and tended to reduce concentrations at P75. Testosterone reduced expression of AVP in the PVN at all ages, but did not affect Fos (a marker of neuronal activation) expression. I hypothesized that the age-specific effects of testosterone on corticosterone were related to differential conversion to metabolites (e.g., estradiol), which I tested using androgen receptor (AR) and estrogen receptor (ER) antagonists (flutamide and tamoxifen, respectively) in the presence of testosterone or dihydrotestosterone (DHT). Testosterone produced a similar, albeit non-significant, age-specific pattern of effects on corticosterone as described above, and I found little evidence for effects of receptor antagonists. Androgens reduced post-stress concentrations of progesterone in all age groups, and flutamide prevented the effect. Together, this study provides evidence for developmental shifts in stress responses and their regulation by gonadal hormones. In Chapter 4, I examined the influence of estradiol on HPA function in adult female rats as a first step toward understanding developmental shifts. Ovariectomy (OVX) reduced post-stress concentrations of corticosterone compared with sham OVX and OVX females given estradiol alone or in combination with progesterone. I also found that OVX females had greater cytosolic expression of GR, possibly increasing sensitivity to corticosterone. In a second experiment, I found that progesterone partially mitigated the effect of estradiol on corticosterone release and that gene expression of stress hormone receptors (Nr3c1, Nr3c2), their co-chaperones (Fkbp5, Fkbp4, Bag1), and a co-activator (Src-1) did not change as a function of ovarian hormones. Together, these studies build on previous research investigating developmental and gonadal regulation of HPA activity and provide novel findings regarding potential mechanisms underlying their actions.