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. Author manuscript; available in PMC: 2023 Jan 20.
Published in final edited form as: Vitam Horm. 2021;115:89–104. doi: 10.1016/bs.vh.2020.12.005

Luteinizing hormone and the aging brain

Megan Mey a, Sabina Bhatta a, Gemma Casadesus b,*
PMCID: PMC9853463  NIHMSID: NIHMS1859293  PMID: 33706966

Abstract

Fluctuations in luteinizing hormone (LH) release contribute to the development and maintenance of the reproductive system and become dysregulated during aging. Of note, increasing evidence supports extra-gonadal roles for LH within the CNS, particularly as it relates to cognition and plasticity in aging and age-related degenerative diseases such as Alzheimer’s disease (AD). However, despite increasing evidence that supports a link between this hormone and CNS function, the mechanisms underlying LH action within the brain and how they influence cognition and plasticity during the lifespan is poorly understood and, in fact, often in conflict. This chapter aims to provide an up-to-date review of the literature addressing the role of LH signaling in the context of CNS aging and disease and put forward a unifying hypothesis that may explain currently conflicting theories regarding the role of LHCGR signaling in CNS function and dysfunction in aging and disease.

1. Introduction

The role of circulating luteinizing hormone (LH) and its receptor in are well understood in the context of steroid production and reproductive function as well as in changes that the hypothalamic-pituitary-gonadal (HPG) axis undergoes during our lifespan. Furthermore, it is also well known that the loss of any components within this axis such as during menopause, leads to significant dysregulation of the system, affects homeostasis, and results in functional decline throughout the body, including the brain (McEwen, Akama, Spencer-Segal, Milner, & Waters, 2012; Greendale, Derby, & Maki, 2011). These age-related changes, which are more prominent in women, are thought to contribute to the higher incidence of age-related neurodegenerative diseases such as Alzheimer’s disease (Pike, 2017).

Until the last decade the relationship between menopause hormones and CNS alterations has been primarily focused on understanding the role of estrogen loss and replacement in this process. In this regard, classic studies have conclusively demonstrated the beneficial impact of estrogen replacement after ovariectomy in rodents (McEwen et al., 2012 for review). However, the lack of ability of estrogen replacement to improve function in animals (Blair, Bhatta, McGee, & Casadesus, 2015; Bohacek & Daniel, 2010) and humans (Henderson & Sherwin, 2007) when there is a delay between menopause and treatment onset, unveils the complex nature of this system and the likely involvement of multiple HPG axis hormones on brain function.

In connection with the above, emerging studies during the last decade support a new role for LH and its receptor in the CNS. Importantly, the age-related upregulation of LH, more prominent in women than men due to menopause, have been linked to cognitive dysfunction, neuronal plasticity impairment, and increased Alzheimer’s disease risk (Bhatta, Blair, & Casadesus, 2018; Blair et al., 2015; Burnham & Thornton, 2015 for review). At a cellular level, knowledge of broad LH receptor expression (AL-Hader, Lei, & Rao, 1997; Apaja, Harju, Aatsinki, Petäjä-Repo, & Rajaniemi, 2004; Bukovsky et al., 2003; Gallo, Johnson, Kalra, Whitmoyer, & Sawyer, 1972; Lei, Rao, Kornyei, Licht, & Hiatt, 1993; Mak et al., 2007; Yang, Nasipak, & Kelley, 2007; You, Kim, Hsu, El Halawani, & Foster, 2000; Yuan, Peng, Liu, Feng, & Qiu, 2019) and early reports of LH action on neuronal electrophysiology (Gallo et al., 1972) of behavior go as far back as four decades and support receptor functionality within the brain. However, despite multiple reports of LHCGR functionality in the CNS over the years, the precise mechanisms underlying LH’s regulation of neuronal function and plasticity and how its signaling dysregulation during reproductive and neuronal aging impacts these functions remain largely unknown. Furthermore, current findings seem to support both detrimental and beneficial roles for LHCGR activation in age-related CNS function. Therefore, this chapter aims to provide an up to date survey of the work that supports a role for LH in the aging CNS as it pertains to cognition and neuronal plasticity. This chapter also aims to provide critical insight on novel findings that can reconcile current conflicting hypotheses for LHCGR action in the CNS (Fig. 1).

Fig. 1.

Fig. 1

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Hypotheses for LH involvement in age-related cognitive decline and Alzheimer’s disease risk. Conflicting hypotheses explain the mechanism by which increased circulating LH could be influencing associated cognitive decline, and increased risk of Alzheimer’s disease. One hypothesis assumes that LH crosses the BBB, binding LHCGR contributing to cognitive decline. The second hypothesis considers an inverse relationship between circulating and brain LH, suggesting that increased circulating LH leads to decreased synthesis of CNS LH and therefore decreased LHCGR activation contributing to cognitive decline.

1.1. HPG axis regulation and LH release across the lifespan

LH is one of three gonadotropins that regulate gonadal function and are essential for normal growth, sexual development and reproduction. Pituitary-derived LH and follicle stimulating hormone (FSH) and placental-derived chorionic gonadotropin (hCG) are heterodimeric proteins containing two chains. A common alpha chain is shared between the three gonadotropins and a beta chain is unique to each and determines the specific functions of each hormone and the affinity to their corresponding receptor. It is important to note, however, that LH and hCG share 84% homology and share the same receptor, hence the common use of hCG to induce ovulation during assisted reproductive therapy. LH and FSH are under the control of gonadotropin releasing hormone (GnRH), which is released from the hypothalamus in response to circulating levels of gonadal steroids through the kisspeptin system (reviewed in (Lehman, Coolen, & Goodman, 2010; Marques, Skorupskaite, George, & Anderson, 2000). This feedback loop system is termed the hypothalamic-pituitary-gonadal (HPG) axis. Specifically, during reproductive stages, HPG axis action involves the activation of the gonadotropin-releasing hormone receptor (GnRHR) in the pituitary by steroid induced hypothalamic GnRH release. This, in turn, leads to the release of gonadotropins into the bloodstream that reach the gonads and initiate the production of sex steroids. These sex steroids complete the HPG axis by providing negative feedback to shut down further GnRH.

LH has different functions in males and females and its release patterns is therefore also widely different between sexes. In females, LH binds its receptor in ovarian follicles to promote their maturation. Additionally, the mid-cycle surge of LH triggers ovulation and corpus luteum production of progesterone to ensure optimal maturation of the uterine endometrium and implantation of the fertilized egg. In males, LH stimulates production of testosterone by the testes (Rahman & Rao, 2009). Because of its different role a between males and females, its levels remain stable from puberty on in males while in females, LH fluctuates widely with menstrual cycle until reproductive senescence. To this end, with increasing age, males gradually produce less testosterone leading to gradual decreases in negative feedback onto hypothalamic GnRH neurons and gradually rising LH levels (Daniel, Hulst, & Berbling, 2006; Neaves, Johnson, Porter, Parker, & Petty, 1984). In females, however, the rise in circulating is more sudden. The progressive exhaustion of the follicle pool and eventual complete loss of steroid negative feedback onto the pituitary gland during the fourth and fifth decade of life, leads to large increases in gonadotropin hormone synthesis and release (Couzinet, Meduri, & Leese, 2001) that denote the onset of menopause.

1.2. Age-related changes in circulating LH and cognitive decline

The concept that levels of LH or hCG may have an impact on the brain that is reflected in behavior is not new (Berkowitz et al., 1981; Toth et al., 1994). For example, during pregnancy changes in serum hCG are reflected by changes in sleep pattern (Berkowitz et al., 1981). Other studies have suggested that LHCGR may be involved in wakefulness following a decrease in activity after female rats were injected intraperitoneally with hCG (Toth et al., 1994). LHR activation in the CNS of Xenopus laevis is known to affect courtship songs (Yang et al., 2007), and LH receptor activation has been linked to increased neurogenesis in the dentate gyrus of the hippocampus in relation to pheromone-related behaviors (Mak et al., 2007). Furthermore, administration of LH or hCG in rats reduced locomotor activity levels and taste neophobia as well as food intake (Emanuele, Oslapas, Connick, Kirsteins, & Lawrence, 1981; Lukacs, Hiatt, Lei, & Rao, 1995). However, more recently, the relationship between circulating LH and behavior has extended to the realm of memory function and has also been implicated in the development of Alzheimer’s disease (AD).

During the last two decades, multiple clinical studies have shown a correlation between high circulating LH and cognitive decline and AD development (Hogervorst, Combrinck, & Smith, 2003; Short, Bowen, O’Brien, & Graff-Radford, 2001) as well as AD pathology (Bowen et al., 2002; Verdile et al., 2014, 2008). In rodents, earlier studies demonstrated that over-expression of LH in transgenic mice (Casadesus et al., 2007), or exogenous treatment with human LH (Wahjoepramono et al., 2011) without any estrogen manipulations, impaired working memory and/or increased AD pathology. Furthermore, in animal studies, administration of the analog hCG, leads to cognitive decline or increased presence of AD-related neuronal markers (Barron, Verdile, Taddei, Bates, & Martins, 2010; Berry, Tomidokoro, Ghiso, & Thornton, 2008; Burnham, Sundby, Laman-Maharg, & Thornton, 2017). The relationship persists even with the presence of estrogen replacement, suggesting an independent action of the LH peptide on function (Berry et al., 2008).

The clinical associations summarized above have led to a more direct interrogation of the involvement of LH in age-related conditions, namely by suppressing high post-menopausal LH levels. To this end, LH (and gonadal steroids) can be suppressed by GnRH super agonists or antagonists, an approach is commonly used to suppress steroid synthesis in patients with steroid-positive cancers. Interestingly, while such treatments have been linked to cognitive impairments in reproductively active patients (Henderson & Sherwin, 2007). In the context of elderly populations, the reverse seems to be true. To this end, a small phase II trial using leuprolide acetate, a GnRHR negative agonist, to investigate benefits of circulating LH suppression in women with AD showed stabilization of cognition in a subgroup taking acetylcholinesterase inhibitors (Bowen, Perry, Xiong, Smith, & Atwood, 2015). Interestingly, although not all studies concur (Nead, Sinha, & Nguyen, 2017), another study also showed that gonadotropin suppression in prostate cancer patients may shield against AD risk (Bowen et al., 2015).

The findings observed in clinical cohorts have been extensively re-created in rodents. To this end, the use of different types of GnRHR negative modulators to downregulate high circulating ovariectomy/orchiectomy-induced LH levels have consistently shown benefits on learning and memory and associated molecular mechanisms (Bohm-Levine, Goldberg, Mariani, Frankfurt, & Thornton, 2020; Bryan et al., 2010; Telegdy, Adamik, Tanaka, & Schally, 2010). For example, Bryan et al. (2010) demonstrated that improvement in spatial memory in ovariectomized female mice was associated with increased auto-phosphorylation of CAMKII and subsequent phosphorylation of the AMPA GluR1 receptor subunit, required for induction and maintenance of LTP (Hayashi et al., 2000). Similarly, downregulation of LH using comparable approaches have shown increased spine density (Blair et al., 2015). More recently, a study using antide, a GnRHR antagonist, demonstrated that, the neuronal trophic factor, BDNF may be required for such cognitive improvements (Bohm-Levine et al., 2020). Interestingly, the benefits of LH suppression in ovariectomized “menopausal” females extended beyond the window of estrogen replacement effectiveness (Blair et al., 2015), suggesting that some of the neuronal benefits of estrogen replacement are at least partially due to its negative feedback onto pituitary LH synthesis.

Such benefits extend to animal models of AD. To this end early studies showed that LH suppression in aged gonadally-intact AD mouse models (Tg2576) improved function and marginally but significantly reduced AD pathology (Casadesus et al., 2007). More recently, Palm et al. (2014) demonstrated that suppression of circulating LH in ovariectomized 3XADtg mice improved cognitive function and regulated important signaling pathways associated with cognition. However, improvements in cognition in this study were not matched by reductions in amyloid and tau pathology (Palm et al., 2014) suggesting that the neuroprotective effects of lowering circulating LH may occur independently of the regulation of AD pathology. Given that LH suppression has also been shown to mitigate neuronal injury (Mariani, Mojziszek, Curley, & Thornton, 2019), it is likely that the impact of this manipulation on trophic factors such as BNDF (Bohm-Levine et al., 2020; Palm et al., 2014) play as an important role in mediating such benefits.

1.3. LHCGR activation effects on CNS function

The studies cited above suggest that increased levels of circulating ligand during aging and its binding and activation of the LHCGR receptor yield a negative impact in the aging CNS. However, the concept that LHCGR is a negative regulator of memory is difficult to reconcile based on the canonical signaling cascades associated with LHCGR activation. LHCGR is known to signal through Gs and Gq, these cascades are both linked to learning and memory formation, specifically LTP mediated synaptic plasticity (Lisman, Yasuda, & Raghavachari, 2012). For example, LHR is a G-protein coupled receptor that signals through Gs, ultimately leading to increased cAMP, CREB, and extracellular signal-related protein kinase (ERK) (reviewed in Bhatta et al., 2018) or the activating protein kinase A (PKA) (Menon & Menon, 2012). ERK and PKA are critical cascades in long-term potentiation, memory and structural plasticity (Hardingham, Arnold, & Bading, 2001; Hebert & Dash, 2002; Impey et al., 1998). Gq signaling through LHCGR has been shown to drive GSK3β inhibition and β-catenin activation (Breen et al., 2013; Palm et al., 2014), which is also known to be beneficial for cognition, plasticity and is involved in AD neuroprotection (Kleppisch, Voigt, Allmann, & Offermanns, 2001; McQuail et al., 2013; Saudargiene, Cobb, & Graham, 2015).

In addition to the signaling nature implications of the LHCGR, the assertion that a large peptide molecule such as LH can freely cross the blood brain barrier without a transporter must be carefully considered (Ondo, Mical, & Porter, 1972). Also important to consider when formulating a hypothesis involving LH’s impact in the aging brain, is the ability of both LH and hCG to dose-dependently downregulate its own receptor (Peegel, Randolph, Midgley, & Menon, 1994). In light of this, studies testing direct activation of LHCGR through central intracerebroventricular (ICV) delivery of LH or LH analogs like hCG, have yielded contradictory results. For example, hCG ICV treatment directly to the dorsal hippocampus led to impaired memory function (Burnham et al., 2017) and AD-related pheno-type acceleration in and AD mouse model (Barron et al., 2010). ICV hCG administration has also been shown to depress activity and result with motor and cognitive deficits in rats (Lukacs et al., 1995). On the other hand, a recent study using much lower doses of hCG, the LH analog, was able to rescue ovariectomy-related cognitive deficits (Blair, Bhatta, & Casadesus, 2019). These results were paralleled by increased phosphorylation of ERK and increased expression of synaptophysin, a synaptic marker that lies downstream of ERK activation (Giachello et al., 2010; Prekeris & Terrian, 1997). Furthermore, similar neuroprotective findings have been reported for LHCGR activation against hypoxic neuronal injury (Movsas, Weiner, Greenberg, Holtzman, & Galindo, 2017), suggesting that some of this conflict may lie in the doses delivered in the cited studies.

Additional studies are required to identify the role of LHCGR signaling within the brain, its impact on behavior, and its dysregulation during aging. Understanding the dynamics of LHCGR in presence of its ligand could potentially be able to reconcile the contradictory findings discussed above. To this end, it well understood that that LHCGR is quickly internalized and downregulated in the presence of high levels of its ligand (Peegel et al., 1994). Thus, under the hypothesis that LH crosses the blood brain barrier to bind LHCGR, high levels of LH within the brain could downregulate LHCGR expression and lead to cognitive deficits. Reducing circulating LH with GnRHR antagonists could in turn allow LHCGR levels to normalize and resume its normal function. Alternatively, one could also speculate that supra-physiological levels of LH or hCG delivered directly into the brain or delivered to gonadectomized animals (already with high levels of circulating LH) could have similar downregulating effects onto LHCGR expression, which could also impact signaling and function negatively. This would explain why studies using high doses of hCG (Barron et al., 2010; Lukacs et al., 1995) would have detrimental effects on function but studies using lower doses (Blair et al., 2019; Movsas et al., 2017) would have beneficial effects. Thus, precisely characterizing central LHCGR dynamics under different treatment conditions seems to be imperative to understand the nature of the effects of this hormone and its receptor’s potential as a therapeutic target for age-related neurodegenerative disease such as AD.

2. Central LH synthesis in aging and CNS function as a unifying hypothesis

The synthesis and expression of LH within the brain has been reported previously (Emanuele et al., 1981; Glass & McClusky, 1987). Importantly, early studies (Emanuele et al., 1981) and later work (Blair et al., 2019; Palm et al., 2014), indicate an inverse relationship between brain derived LH and pituitary-derived (circulating) LH. To this end, in cycling adult female rats, hypothalamic LH decreased during proestrus, a period where LH release from the pituitary is maximal (Emanuele et al., 1981). Similarly, LH treatment into the median eminence (ME) of the hypothalamus in intact or castrated males and females significantly decreased circulating LH levels.

More recently, such inverse relationship has been directly linked to menopause and AD related functional loss as evidenced by the fact that LH mRNA levels are reduced in both the hippocampus and the cortex in AD brains (Palm et al., 2014), while LH circulating levels are reported to be are increased compared to cognitively normal individuals (Short et al., 2001). Similarly, Palm et al. (2014), demonstrated that brain LH was decreased in ovariectomized 3xTg AD female mice and negatively correlated to circulating LH. Importantly, lower LH immunoreactivity within the brain was reversed when ovariectomy-related high circulating LH levels were normalized and this paralleled cognitive improvements and increases in BDNF transcription, inhibition of GSK3β and upregulation of β-catenin, all important in neuronal plasticity. More recently, another study has shown a strong negative correlation between brain and circulating LH levels in ovariectomized animals that when normalized through low central re-administration of hCG led to cognitive improvements and activation of plasticity-associated signaling (Blair et al., 2019). Taken together, while the mechanism underlying this inverse relationship between circulating and local CNS LH levels is beyond the scope of this chapter, this inverse relationship suggests that, perhaps, chronic upregulation of pituitary LH associated with aging, leads to downregulation of central LH synthesis. This, in turn, results in loss of LHCGR signaling and CNS impairment. Improtantly, these data may provide a reconciling link between data demonstrating that peripheral downregulation of LH is beneficial and the cognition-enhancing (not impairing) signaling pathways that underly LHCGR activation (Fig. 2).

Fig. 2.

Fig. 2

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Luteinizing hormone action in learning and memory. Increased peripheral LH acquired by age related dysregulation of HPG axis is paralleled by decreased synthesis of LH in the CNS and cognitive deficit following impaired plasticity. Treatments that down regulate circulating LH increase LH synthesis in the CNS and rescue cognition. Increased synthesis of CNS LH could be stimulating LHR in the brain. The downstream effects of LHR are associated with improved synaptic plasticity which may underly the rescued cognition following circulating LH downregulation.

3. Conclusion

The tight inter-relationship between hormonal systems and the brain now extends to the understanding of LH signaling in the CNS. This is particularly true for cognition within reproductive senescence-related aging and AD. However, the mechanism of action of LH within the brain continue to be poorly understood. Work stemming from studies using GNRHR-related mechanisms to deplete circulating LH rather than by direct LHCGR inhibition confound the potential conclusions that can be made in relation to the role of this receptor in mediating function. Additionally, conflicting results in studies using analogs such as hCG to drive LHCGR activation further complicate our ability to interpret the impact of LHCGR activation or inhibition on CNS function during reproductive senescence. These conflicts may stem from the nature of LHCGR regulation dynamics upon changing levels of ligand and the lack of clarity as to whether LH or hCG cross the blood brain barrier. Therefore, an in-depth characterization of central LHCGR trafficking and transcription under different treatment and hormonal status conditions seems to be imperative to be able to understand the function of this hormone and its receptor on CNS across the lifespan. Lastly, the potential role of brain LH in mediating LHR receptor activation and its inverse relationship with pituitary-derived LH must be mechanistically probed in depth to develop a comprehensive understanding of this hormone role in the age-related cognitive decline and AD development. However, such understanding poses the potential key to unify the current conflicts in the literature.

List of Abbreviations

AD

Alzheimer’s disease

BBB

blood brain barrier

CamKII

calcium-calmodulin kinase II

cAMP

cyclic AMP

CNS

central nervous system

FSH

follicle stimulating hormone

GnRH

gonadotropin releasing hormone

GnRHR

gonadotropin releasing hormone receptor

GSK3β

glycogen synthase kinase 3 beta

hCG

human chorionic gonadotropin

HPG axis

hypothalamic-Pituitary-Gonadal axis

ICV

intracerebroventricular

LA

leuprolide acetate

LH

luteinizing hormone

LHCGR

luteinizing hormone receptor

OVX

ovariectomy

PKA

protein kinase A

PLC

phospholipase C

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