The roles of GnRH in the human central nervous system

Alzheimer’s disease (AD) is an age-related neurodegenerative disease that affects approximately 15 % of the population over the age of 65. It is marked by progressive cognitive decline with early and prominent memory deficits. Neuropathologically, AD is defined by the presence of amyloid plaques and tau tangles, with early atrophy of basal forebrain and hippocampus visible on clinical neuroimaging ( Raji et al., 2009 ). After menopause, the risk of AD rises significantly. This effect has been attributed to the dysregulation of the HPG axis ( Atwood and Bowen, 2015 ) with loss of estrogen considered to play a major role. There is strong evidence from animal models that estrogen is neuroprotective, by maintaining neurons within the basal forebrain, cortex and especially hippocampus ( McEwen, 2002 ; Gibbs and Aggarwal, 1998 ) However, there is also strong evidence that post-reproduction, elevated levels of luteinizing hormone (LH) and FSH - which are controlled by GnRH - promote neurodegeneration ( Atwood and Bowen, 2015 ), and gonadotropin elevation may be more important than loss of estrogen in mediating neurodegeneration. LH and FSH are elevated in serum and CSF of AD patients as compared to controls, and cortical and hippocampal neurons with LH receptors follow a degenerative pattern after menopause ( Rao, 2016 ). Decreasing LH improves cognitive performance and decreases amyloid deposition and tau phosphorylation in multiple animal models of AD ( Bowen et al., 2004 ; Wilson et al., 2007 ). LH is considered toxic to the brain because it serves as a signal for post-mitotic neurons to attempt to enter the cell cycle, which leads to cell death. This theory, termed the Cell Cycle Theory of Aging and AD is reviewed by Herrup (2012) and Atwood and Bowen (2015) . GnRH agonists/antagonists are one method for decreasing circulating gonadotropin concentrations in humans, and this motivated a clinical trial of GnRH analogues in AD ( Bowen et al., 2015 ; Butler et al., 2021 ). GnRH agonists initially have a stimulatory effect on LH and FSH along with subsequent estrogen and/or testosterone release, however, the continuous administration of the drug leads to it becoming a potent antagonist that downregulates GnRH receptors on the anterior pituitary and thereby LH and FSH and sex hormone secretion ( Wilson et al., 2007 ). Reduction or alteration of gonadotropin concentrations is the basis for clinical uses of GnRH analogues listed in Table 1 . In postmenopausal woman, who already have low estrogen levels, the main effect of GnRH analogues is to lower LH and FSH. As noted above, lowering LH and FSH reduces amyloid, tau and neurodegeneration in animal models of AD. To investigate this effect in humans, a 48-week randomized double-blind placebo-controlled clinical trial was conducted to test the effect of the GnRH analogue leuprolide acetate (LA) in women (n = 109) with mild to moderate AD ( Bowen et al., 2015 ). Upon primary analysis, although no significant differences were observed between the high-dose LA (22.5 mg/3 months), low-dose (11.5 mg/3 months) LA and the placebo group, a trend towards clinical improvement was noted with the high dose LA. In a planned subgroup analysis involving the 70 % of women who were also taking the acetylcholinesterase inhibitor donepezil, a standard therapy for AD, the effect of high dose LA was significant, and the progression of cognitive decline was halted. A potential mechanism of synergy between a GnRH analogue and a cholinesterase inhibitor - unknown at the time the trial was conducted - can now be understood in the context of the very recent demonstration that in humans but not rodents, the majority of GnRH neurons are also cholinergic ( Skrapits et al., 2021 ). A follow-up trial called LUCINDA (Leuprolide + Cholinesterase Inhibition to reduce Neurologic Decline In Alzheimer’s) is currently being conducted to confirm a synergistic effect of combined GnRH and cholinergic modulation in women with AD ( Butler et al., 2021 ). GnRH also may have neurotrophic effects on spinal cord lesions. GnRH and mRNA receptor expression have been found more recently in human spinal cords with 90 % of receptor expression on the gray matter of motor neurons ( Martínez-Moreno et al., 2018 ; Díaz-Galindo et al., 2020 ). GnRH agonist administered to rats with induced spinal cord injury (SCI) showed increased recovery of locomotor activity including gait, improved urinary dysfunction, decreased histopathological damage with increased number and caliber of neuronal axons at the level of the SCI ( Calderón-Vallejo and Quintanar, 2012 ; Quintanar et al., 2009 ; Calderón-Vallejo et al., 2015 ). Another study reported improvement in external sphincter activity in neurogenic bowel for rats with induced SCI ( Altamira-Camacho et al., 2019 ). In a human clinical trial administering GnRH agonists for individuals with chronic SCI improved sensitivity, motor activity and independence ( Quintanar et al., 2018 ). Overall, these studies suggest the potential neurotrophic role GnRH has on the spinal cord. However, although the exact mechanism of action is yet to be deduced it has been proposed that GnRH agonist upregulates LH which is the basis of the neurotrophic effect observed ( Martínez-Moreno et al., 2018 ; Quintanar et al., 2018 ; Calderón-Vallejo and Quintanar, 2012 ; Calderón-Vallejo et al., 2015 ).

Due to the essential role GnRH I plays in reproductive function, GnRH analogues have a wide-array of uses in medicine including prostate cancer, breast/ovarian cancer, endometriosis and leiomyoma, central precocious puberty, hyperandrogenism/hirsutism, menorrhagia, chemical castration to reduce paraphilias in sex offenders, and in vitro fertilization ( Wilson et al., 2007 ). Table 1 summarizes the current clinical applications of GnRH. Most of these effects are through chronic GnRH agonist treatment except for in vitro fertilization, which uses GnRH agonists acutely to produce a surge of FSH and LH to increase estrogen levels and facilitate ovulation ( Wilson et al., 2007 ).

In conclusion, as observed GnRH and its receptor gene expression are widespread within human central nervous systems and are multifaceted neuromodulators that not only play a pivotal role in reproduction but also in the aging processes, cognition and motor functions. Their roles within the human brain should be further investigated. A clinical trial of a GnRH analogue is underway as a potential treatment for AD. Additional study of GnRH systems is likely to advance therapeutic options in other human brain disorders.

Gonadotropin-releasing hormone (GnRH), formerly referred to as the luteinizing hormone-releasing hormone (LHRH), is produced and secreted primarily by the hypothalamus in a pulsatile fashion, and acts on the anterior pituitary gland to release luteinizing hormone (LH) and follicle stimulating hormone (FSH). These two gonadotropins have downstream effects on the peripheral reproductive organs essential for maturation and fertility (reviewed in Veldhuis, 1996 ). In addition to this traditional understanding of GnRH functioning in reproduction, roles for GnRH in CNS functioning are beginning to be appreciated ( Jones, 1987 ; Casoni et al., 2016 ; Skrapits et al., 2021 ; Martínez-Moreno et al., 2018 ). It has been discovered that GnRH receptors and GnRH producing neurons, originally thought to be concentrated within the hypothalamic-pituitary-gonadal (HPG) axis, are present in many other regions of the central nervous system (CNS) and the periphery ( Jones, 1987 ; Wilson et al., 2006 ; Casoni et al., 2016 ; Skrapits et al., 2021 ). In this review we will focus only on the human brain unless stated otherwise. We will review the traditional understanding of GnRH in regulating sex hormones through the HPG axis along with current clinical uses of GnRH analogue medications. We will then look at GnRH neurons and receptors external to the pituitary and the hypothalamus including a brain-wide quantification of GnRH gene expression, with a focus on their potential function. Lastly, we will explore the therapeutic potential of GnRH modulation in terms of neurodegenerative disease such as Alzheimer’s disease (AD) and on spinal cord lesions.

To complement individual studies of GnRH neuron location and function we utilized the Allen Brain Atlas to quantify GnRH I and II mRNA expression across the entire brain. As detailed in Fig. 1 and the subregions presented in Appendix A , the Allen Brain Atlas provides microarray data from multiple adult control brains. To evaluate GnRH 1 and 2 mRNA expression, we extrapolated data from the Allen Brain and compared GnRH I and GnRH II gene expression across multiple brain regions using microarray data. Three different genetic probes targeting distinct exons were used to measure the amount of GnRH I or GnRH II cRNA in each brain region. The amount of detected GnRH I or GnRH II cRNA for each brain region was normalized to the average detected level of GnRH I or GnRH II cRNA across the entire brain in the form of a normalized z-score for each genetic probe. The normalized z-score across all three genetic probes and across all six donor brains was averaged to produce an average z-score for GnRH I and GnRH II genetic expression in each brain region, providing a measure of GnRH gene expression within each brain region relative to the whole brain mean. Overall, both GnRH I and II are widely expressed within the human brain. As expected based on traditional understanding of the role of GnRH in the HPG axis, GnRH I is highly expressed in the hypothalamus, especially the arcuate nucleus. GnRH I is also expressed in basal forebrain and striatum, in accord with recent studies summarized above ( Skrapits et al., 2021 ). In addition, there is prominent GnRH I and II expression in the cerebellum. While cerebellar GnRH I has been reported previously ( Martínez-Moreno et al., 2018 ), such high expression, exceeding that found in hypothalamus, has not to our knowledge been reported. GnRH I expression in the choroid plexus of the lateral ventricle may relate to GnRH I found in the CSF, discussed below. Increased GnRH I expression in dentate gyrus of hippocampus in humans may be a novel finding, and is potentially of great interest given recent appreciation of the role of hippocampal GnRH receptors in memory and other functions ( Skrapits et al., 2021 ; Wilson et al., 2006 ). It has been noted previously that the endogenous source of GnRH acting on hippocampal neurons was unknown ( Skrapits et al., 2021 ); current findings suggest the dentate gyrus as a possible local source. In this respect, it is relevant that, like hypothalamic neural progenitor cells, hippocampal neural progenitor cells are capable of differentiating into GnRH neurons in vitro , though to our knowledge this has not been demonstrated in vivo ( Markakis, 2004 ). Also notable is that GnRH II expression is highest in the Edinger–Westphal nucleus and oculomotor nucleus. The significance of this finding is uncertain, but it may relate to interplay between autonomic and reproductive function. Other regions of above average GnRH I expression are the epithalamus, hippocampus, and the pons (please see the GnRH I and II expressions of the subregions in Appendix A ).