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.

In female mammals, mechanisms have been developed, throughout evolution, to integrate environmental, nutritional and hormonal cues in order to guarantee reproduction in favorable energetic conditions and to inhibit it in case of food scarcity. This metabolic strategy could be an advantage in nutritionally poor environments, but nowadays is affecting women’s health. The unlimited availability of nutrients, in association with reduced energy expenditure, leads to alterations in many metabolic pathways and to impairments in the finely tuned inter-relation between energy metabolism and reproduction, thereby affecting female fertility. Many energetic states could influence female reproductive health being under- and over-weight, obesity and strenuous physical activity are all conditions that alter the profiles of specific hormones, such as insulin and adipokines, thus impairing women fertility. Furthermore, specific classes of nutrients might affect female fertility by acting on particular signaling pathways. Dietary fatty acids, carbohydrates, proteins and food-associated components (such as endocrine disruptors) have per se physiological activities and their unbalanced intake, both in quantitative and qualitative terms, might impair metabolic homeostasis and fertility in premenopausal women. Even though we are far from identifying a “fertility diet”, lifestyle and dietary interventions might represent a promising and invaluable strategy to manage infertility in premenopausal women.

In female animals, energy metabolism and fertility are tightly connected, and reciprocally regulated. However, the relative contributions of metabolic and reproductive pathways have changed over the course of evolution. In oviparous animals, metabolic factors take precedence over fertility, enabling egg production to be inhibited in a nutritionally poor environment. By contrast, in placental mammals, the opposite occurs: the need to feed a developing embryo and neonate forces metabolic pathways to adapt to these reproductive needs. This physiological necessity explains why in female mammals alterations of gonadal activity, including age-dependent cessation of ovarian functions, are associated with a disruption of metabolic homeostasis and consequent inflammatory reactions that trigger the onset of metabolic, cardiovascular, skeletal and neural pathologies. This Review discusses how metabolic homeostasis and reproductive functions interact to optimize female fertility and explains the pathogenic mechanisms underlying the disordered energy metabolism associated with human ovarian dysfunction owing to menopause, polycystic ovary syndrome and Turner syndrome. Finally, this article highlights how hormone replacement therapy might aid the restoration of metabolic homeostasis in women with ovarian dysfunction.

Sex impacts on liver physiology with severe consequences for energy metabolism and response to xenobiotic, hepatic, and extra-hepatic diseases. The comprehension of the biology subtending sex-related hepatic differences is therefore very relevant in the medical, pharmacological, and dietary perspective. The extensive application of metabolomics paired to transcriptomics here shows that, in the case of short-term fasting, the decision to maintain lipid synthesis using amino acids (aa) as a source of fuel is the key discriminant for the hepatic metabolism of male and female mice. Pharmacological and genetic interventions indicate that the hepatic estrogen receptor (ERα) has a key role in this sex-related strategy that is primed around birth by the aromatase-dependent conversion of testosterone into estradiol. This energy partition strategy, possibly the result of an evolutionary pressure enabling mammals to tailor their reproductive capacities to nutritional status, is most important to direct future sex-specific dietary and medical interventions.

Lipoprotein synthesis is controlled by estrogens, but the exact mechanisms underpinning this regulation and the role of the hepatic estrogen receptor α (ERα) in cholesterol physiology are unclear. Utilizing a mouse model involving selective ablation of ERα in the liver, we demonstrate that hepatic ERα couples lipid metabolism to the reproductive cycle. We show that this receptor regulates the synthesis of cholesterol transport proteins, enzymes for lipoprotein remodeling, and receptors for cholesterol uptake. Additionally, ERα is indispensable during proestrus for the generation of high-density lipoproteins efficient in eliciting cholesterol efflux from macrophages. We propose that a specific interaction with liver X receptor α (LXRα) mediates the broad effects of ERα on the hepatic lipid metabolism.