Steroid hormone regulation of neurons in the hypothalamic arcuate nucleus

Abstract

Menopause is accompanied by neuronal hypertrophy and increased neurokinin B (NKB) gene expression in the human infundibular (arcuate) nucleus. We have hypothesized that these changes are secondary to withdrawal of gonadal steroids. In the present study, a rat model is used to determine if orchidectomy and hormone replacement alter the size and gene expression of arcuate NKB neurons. Compared to intact animals, gonadectomy significantly increased the mean profile area and number of neurons/section expressing NKB mRNA in the rat arcuate nucleus. Both the increase in NKB neuron size and number of neurons was prevented by implantation of estradiol- or testosterone-containing capsules. These data provide strong support for the hypothesis that the hypertrophy and increased numbers of neurons expressing NKB gene transcripts in postmenopausal women are secondary to ovarian failure. Studies were also conducted to determine if the conditions that induce neuronal hypertrophy and enhanced gene expression in the arcuate nucleus are accompanied by other morphological changes. To achieve this end, a fixed slice preparation was used to examine the morphology of neuroendocrine neurons in the rat arcuate nucleus. In comparison to intact controls, arcuate neuroendocrine neurons in the orchidectomized group had significantly larger somatic profile areas and exhibited significant increases in dendrite length, dendrite volume, terminal branch number, and spines per unit length of dendrite. These results provide evidence for hormonal regulation of dendritic morphology of arcuate neuroendocrine neurons in adult mammals. To assess the role of testosterone withdrawal in inducing these dendritic changes, hormone replacement studies were conducted. Testosterone treatment of castrate animals prevented increases in dendrite length and volume when compared to untreated castrate rats. Testosterone treatment also prevented the castration induced increase in the number of branches per dendrite. Finally, immunohistochemical studies indicate that approximately 22% of arcuate neuroendocrine neurons contain estrogen receptors, while 16% contain androgen receptors, indicating that these neurons can respond directly to changes in steroid hormone levels. These findings clearly demonstrate a role for testosterone in modulating the dendritic morphology of arcuate neuroendocrine neurons in adult rats.