The Role of Sex and Sex Hormones in Neurodegenerative Diseases

Abstract

Neurodegenerative diseases (NDs) are a wide class of disorders of the central nervous system (CNS) with unknown etiology. Several factors were hypothesized to be involved in the pathogenesis of these diseases, including genetic and environmental factors. Many of these diseases show a sex prevalence and sex steroids were shown to have a role in the progression of specific forms of neurodegeneration. Estrogens were reported to be neuroprotective through their action on cognate nuclear and membrane receptors, while adverse effects of male hormones have been described on neuronal cells, although some data also suggest neuroprotective activities. The response of the CNS to sex steroids is a complex and integrated process that depends on (i) the type and amount of the cognate steroid receptor and (ii) the target cell type—either neurons, glia, or microglia. Moreover, the levels of sex steroids in the CNS fluctuate due to gonadal activities and to local metabolism and synthesis. Importantly, biochemical processes involved in the pathogenesis of NDs are increasingly being recognized as different between the two sexes and as influenced by sex steroids. The aim of this review is to present current state-of-the-art understanding on the potential role of sex steroids and their receptors on the onset and progression of major neurodegenerative disorders, namely, Alzheimer’s disease, Parkinson’s diseases, amyotrophic lateral sclerosis, and the peculiar motoneuron disease spinal and bulbar muscular atrophy, in which hormonal therapy is potentially useful as disease modifier.

Progesterone in the Brain: Hormone, Neurosteroid and Neuroprotectant

“…For more information regarding the effects of 3α,5α-THPROG on inflammation see [125,126]. For readers interested in the role of sex and sex hormones and their neuromodulatory effects and underlying mechanisms in the context of neurodegenerative diseases, we recommend two excellent recent reviews [127,128].…”

A Crucial Role for the Protein Quality Control System in Motor Neuron Diseases

“…ALS has a very high variability in terms of both age of onset and disease progression, and it seems to occur earlier in males compared to females (Vegeto et al, 2020), with a male/female ratio of 1-3 in the geographic region and population evaluated in the study (Kurtzke, 1982;Haverkamp et al, 1995;Manjaly et al, 2010). The two sexes also show different symptomatology, since in males the disease predominantly begins in the lumbar tract of the spinal cord, while in females ALS mainly begins in the bulbar region (see Blasco et al, 2012 for an extensive review).…”

Trimethyl Chitosan Hydrogel Nanoparticles for Progesterone Delivery in Neurodegenerative Disorders

“…In recent years, research has focused on the potential repurposing of sex hormones, particularly progesterone (PG), for the treatment of neurodegenerative disorders, including Parkinson's disease (PD), stroke, and Alzheimer's disease [1,2]. Use of PG in PD initially raised interest following evidence of the higher incidence in men than in women [3,4].…”