Sex hormones differentially contribute to Parkinson disease in males: A multimodal biomarker study

Abstract

Background and purpose: Parkinson disease (PD) presents relevant sex-related differences in epidemiology, pathophysiology, and clinical features, with males being more vulnerable to the disease. Sex hormones might have a role, as the experimental models suggest; however, human-based evidence is scarce. Here, we integrated multimodal biomarkers to investigate the relationships between circulating sex hormones and clinicalpathological features in male PD patients. Methods: A cohort of 63 male PD patients underwent comprehensive clinical evaluation of motor and nonmotor disturbances; measurement of estradiol, testosterone, folliclestimulating hormone (FSH), and luteinizing hormone (LH) blood levels; and cerebrospinal fluid (CSF) assay of total α-synuclein, amyloidβ-42, amyloidβ-40, total tau, and phosphorylated-181 tau levels. A subgroup of 47 PD patients underwent brain volumetry by 3-T magnetic resonance imaging for further correlations. A control group of 56 age-matched individuals was enrolled for comparative analyses. Results: Male PD patients had higher estradiol and testosterone levels than controls. Estradiol had independent inverse associations with Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part 3 score and disease duration; it was also lower in nonfluctuating patients. Testosterone had inverse independent correlations with CSF αsynuclein and right globus pallidus volume. FSH and LH had age-dependent correlations with cognitive impairment and CSF amyloidβ-42/amyloidβ-40 ratio. Conclusions:The study suggested that sex hormones could differentially contribute to clinical-pathological features of PD in male patients. Whereas estradiol might have a protective role in motor impairment, testosterone might be involved in male vulnerability to PD neuropathology. Gonadotropins instead might mediate age-dependent phenomena of amyloidopathy and cognitive decline.

Combined detrimental effect of male sex and GBA1 variants on cognitive decline in Parkinson’s Disease

“…The dopamine system contains a high density of oestrogen receptors, through which hormones exert their protective role on dopaminergic functions 35 . Such protective effects of oestrogens are achieved by reducing oxidative stress and mitochondrial dysfunction, limiting neuroinflammation, and preventing the deposition of α-synuclein and neural injury 36 . Another aspect under investigation is related to the detrimental role of GBA1 mutations on sphingolipid homeostasis, the latter found to be modulated by means of oestrogen receptor 37 .…”

Gender differences in non-motor fluctuations in Parkinson’s disease

“…Although we have not a clear explanation for the higher frequency of NMF among women a possible role of sex hormones cannot be ruled out. As a matter of fact, preclinical studies have shown a possible neuroprotective role of estrogens and, according to literature evidence, lower levels are associated with a greater risk of developing motor fluctuations (Bovenzi et al 2023 ).…”

Pregnancy, fertile life factors, and associated clinical course in PRKN early-onset Parkinson’s disease

“…Such fluctuations can be essentially related to hormonal changes, since estrogen and progesterone levels rise during pregnancy and dramatically drop with puerperium. While the neuroprotective and pro-dopaminergic effects of estradiol (E2) are well-known [30], the properties of estriol (E3), the dominant estrogen during pregnancy, and progesterone are not clear yet [17]. Apart from sex hormones, other factors, including altered pharmacokinetics, diet changes, and variations in intestinal absorption, as well as physical and psychosocial aspects, might also contribute to motor fluctuations during pregnancy [17].…”