Age, Sex, and Reproductive Hormone Effects on Brain Serotonin-1A and Serotonin-2A Receptor Binding in a Healthy Population

Abstract

There is a need for rigorous positron emission tomography (PET) and endocrine methods to address inconsistencies in the literature regarding age, sex, and reproductive hormone effects on central serotonin (5HT) 1A and 2A receptor binding potential (BP). Healthy subjects (n ¼ 71), aged 20-80 years, underwent 5HT1A and 2A receptor imaging using consecutive 90-min PET acquisitions with [ 11 C]WAY100635 and [18 F]altanserin. Logan graphical analysis was used to derive BP using atrophy-corrected distribution volume (V T ) in prefrontal, mesiotemporal, occipital cortices, and raphe nucleus (5HT1A only). We used multivariate linear regression modeling to examine BP relationships with age, age 2 , sex, and hormone concentrations, with post hoc regional significance set at po0.008. There were small postsynaptic 5HT1A receptor BP increases with age and estradiol concentration in women (p ¼ 0.004-0.005) and a tendency for small 5HT1A receptor BP declines with age and free androgen index in men (p ¼ 0.05-0.06). Raphe 5HT1A receptor BP decreased 4.5% per decade of age (p ¼ 0.05), primarily in men. There was a trend for 15% receptor reductions in prefrontal cortical regions in women relative to men (post hoc p ¼ 0.03-0.10). The significant decline in 5HT2A receptor BP relative to age (8% per decade; po0.001) was not related to sex or hormone concentrations. In conclusion, endocrine standardization minimized confounding introduced by endogenous hormonal fluctuations and reproductive stage and permitted us to detect small effects of sex, age, and endogenous sex steroid exposures upon 5HT1A binding. Reduced prefrontal cortical 5HT1A receptor BP in women vs men, but increased 5HT1A receptor BP with aging in women, may partially explain the increased susceptibility to affective disorders in women during their reproductive years that is mitigated in later life. 5HT1A receptor decreases with age in men might contribute to the known increased risk for suicide in men over age 75 years. Low hormone concentrations in adults o50 years of age may be associated with more extreme 5HT1A receptor BP values, but remains to be studied further. The 5HT2A receptor declines with age were not related to sex or hormone concentrations in this sample. Additional study in clinical populations is needed to further examine the affective role of sex-hormone-serotonin receptor relationships.

Gender Differences in Neurologic Emergencies Part I: A Consensus Summary and Research Agenda on Cerebrovascular Disease

“…Persistent alterations of serotonin systems may lead to chronic migraine headaches, a finding of particular importance when noting that serotonin receptor binding decreases with advancing age in women. 83 Patients who have been identified as such may respond to estrogen treatment. 80 Human and animal studies suggest a genetic etiology for headache prevalence in women.…”

Depression and Serotonergic Changes during the Climacteric and Postmenopausal Stages: Hormonal Influences

“…The 5-HT1A receptors have an age-dependent increase in neocortical regions in women, associated with decreased estrogen. In the same study, they identiied that increase in 5-HT2A receptors is associated with the establishment of disorders such as neurosis, depression, suicide, and eating disorders [28], suggesting that age tends to reduce these receptors, since they are expressed in the neuropil of pyramidal neurons located mainly in the neocortex which are related to the release of glutamate and gamma-aminobutyric acid (GABA) regulating the postsynaptic excitatory impulses that project to the hippocampus and spinal cord neurons [29]. So, it is hypothesized that its reduction associated with age may be related to sleep disorder, cognition, and mood disorders [30].…”

“…A study developed by Kranz et al [56] did not detect diferences on the 5-HT1A receptor density on structures such as the hippocampus, the frontal cortex, and the raphe on postmenopausal woman [56]. After the administration of HRT with 17β-valerate ester alone or combined with progesterone, no mater the fact exist, a signiicant increase of estradiol and progesterone, an efect that has been identiied on postmenopausal women [28]. This suggests that plasma concentrations of estradiol that are still elevated in premenopausal women compared to postmenopausal women seem to determine the 5-HT 1A receptor expression on the estrogenic treatment response.…”

“…Moses-Kolko et al [28] reported that in depressed women going through premenopause and postmenopause, there is a 15% decrease in 5-HT1A receptors in the orbitofrontal cortex compared to adult men with depression. The foregoing after performing an endocrine standardization to minimize the inluence introduced by endogenous hormonal luctuations and reproductive stage.…”

A influência da percepção visual de movimento sobre desempenho em tarefa tomada de decisão

“…Outras evidências sugerem diferenças entre circuitos cerebrais entre homens e mulheres como a observação de que mulheres teriam melhor performance em memória, linguagem, atenção e cognição social enquanto homens teriam melhor performance no processamento espacial com a velocidade motora e sensório motora. Desta forma, os melhores escores obtidos pelo sexo masculino na tarefa de rastreio podem estar relacionados a diferenças entre os tempos de reação e de previsibilidade de movimentos, na coordenação da recepção de estímulo visual e execução motora da tarefa de rastreamento (Amunts et al, 2007;Clayson et al, 2011;Ingalhalikar et al, 2014;Moses-Kolko et al, 2011;Sacher et al, 2013;Satterthwaite et al, 2015;Tomasi & Volkow, 2012;Vanston & Strother, 2017 Existem evidências de que, em algumas situações, diferenças de gênero em diversos âmbitos desaparecem após a menopausa, sugerindo um papel relevante da modulação hormonal sobre a expressão comportamental de todos os indivíduos (Faravelli et al, 2013). As flutuações de estrogênio e progesterona aumentam respostas de stress, consequentemente aumentando as respostas de ansiedade e depressão, por exemplo (Seeman, 1997).…”