Hypothalamic–Pituitary–Gonadal Axis Involvement in Learning and Memory and Alzheimer’s Disease: More than “Just” Estrogen

Abstract

Accumulating studies affirm the effects of age-related endocrine dysfunction on cognitive decline and increasing risk of neurodegenerative diseases. It is well known that estrogens can be protective for cognitive function, and more recently androgens and luteinizing hormone have also been shown to modulate learning and memory. Understanding the mechanisms underlying hypothalamic–pituitary–gonadal axis-associated cognitive dysfunction is crucial for therapeutic advancement. Here, we emphasize that reproductive hormones are influential in maintaining neuronal health and enhancing signaling cascades that lead to cognitive impairment. We summarize and critically evaluate age-related changes in the endocrine system, their implications in the development of Alzheimer’s disease, and the therapeutic potential of endocrine modulation in the prevention of age-related cognitive decline.

Spatial memory is impaired by peripubertal GnRH agonist treatment and testosterone replacement in sheep

“…Finally, the suppression of LH signaling that is associated with GnRHa-treatment, may also play a role in the observed changes in learning and memory, as LH receptors are expressed in the CNS, including the hippocampus (Blair et al, 2015). In addition, it has been shown in human and rodent studies that the age-related increase in circulating LH and decline in gonadal steroid production, correlates with impaired cognitive function (Blair et al, 2015).…”

“…In addition, it has been shown in human and rodent studies that the age-related increase in circulating LH and decline in gonadal steroid production, correlates with impaired cognitive function (Blair et al, 2015). However, the route through which circulating LH could reach receptors in the central nervous system is not yet characterized.…”

Role of Hypothalamic-Pituitary-Adrenal Axis, Hypothalamic-Pituitary-Gonadal Axis and Insulin Signaling in the Pathophysiology of Alzheimer’s Disease

“…Hormones of the HPG axis with hippocampal receptors (GnRH, LH/human chorionic gonadotropin and sex steroids) regulate neuronal development, structure and the functions of the adult brain [38, 39]. Receptors for these HPG hormones are mainly concentrated in the limbic system, particularly the pyramidal neurons of the hippocampus which are vulnerable to AD pathology [40, 41].…”

“…Gender has been reported as an independent risk factor for AD; females have a higher risk of developing AD compared to males because of the changes in reproductive hormones during menopause [38]. Females exhibit an AD endophenotype characterized by the brain hypometabolism, loss of gray and white matter, and elevated depositions of Aβ [47, 48].…”

Vitamin D, Cognition and Alzheimer’s Disease: The Therapeutic Benefit is in the D-Tails

“…Moreover, we have shown that vitamin D likely interacts with the estrogen receptor, Esr1, to regulate molecular pathways relevant to AD pathogenesis [ 64 ]. A number of studies suggest a strong link between the drop in estrogen levels occurring during menopause and the development of AD [ 135–137 ]. Animal studies could help clarify this matter; however, future clinical trials might consider stratifying results in a gender-specific manner.…”