Alzheimer?s disease: the impact of age-related changes in reproductive hormones

Abstract

Receptors for hormones of the hypothalamic-pituitary-gonadal (HPG) axis that regulate reproductive function are expressed throughout the brain, and in particular the limbic system. The most studied of these hormones, the sex steroids, contain receptors throughout the brain, and numerous estrogenic, progestrogenic and androgenic effects have been reported in the brain related to development, maintenance and cognitive functions. Although less studied, receptors for gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and activins also are found throughout the limbic system on a number of cell types, and they too transduce signals from circulating hormones as demonstrated by their multiple effects on the growth, development, maintenance and function of the brain. This review highlights the point that because of the feedback loops within the HPG axis, it is difficult to ascribe structural and functional changes during development, adulthood and senescence to a single HPG hormone, since a change in the concentration of any hormone in the axis will modulate hormone concentrations and/or receptor expression patterns for all other members of the axis. The most studied of these situations is the change in serum and neuronal concentrations of HPG hormones associated with menopause/andropause. Dysregulation of the HPG axis at this time results in increases in the concentrations of serum GnRH, gonadotropins and activins, decreases in the serum concentrations of sex steroid and inhibin, and increases in GnRH and LH receptor expression. Such changes would result in significantly altered neuronal signaling, with the final result being that there is i.e. increased neuronal GnRH, LH and activin signaling, but decreased sex steroid signaling. Therefore, loss of cognitive function during senescence, typically ascribed to sex steroids, may also result from increased signaling via GnRH, LH or activin receptors. Future studies will be required to differentiate which hormones of the HPG axis regulate/maintain cognitive function. This introductory review highlights the importance of the identification of HPG hormone neuronal receptors and the potential of serum HPG hormones to transduce signals to regulate brain structure and function during development and adult life.