Androgen Therapy in Neurodegenerative Diseases

Abstract

Neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington disease, are characterized by the loss of neurons as well as neuronal function in multiple regions of the central and peripheral nervous systems. Several studies in animal models have shown that androgens have neuroprotective effects in the brain and stimulate axonal regeneration. The presence of neuronal androgen receptors in the peripheral and central nervous system suggests that androgen therapy might be useful in the treatment of neurodegenerative diseases. To illustrate, androgen therapy reduced inflammation, amyloid-β deposition, and cognitive impairment in patients with AD. As well, improvements in remyelination in MS have been reported; by comparison, only variable results are observed in androgen treatment of PD. In ALS, androgen administration stimulated motoneuron recovery from progressive damage and regenerated both axons and dendrites. Only a few clinical studies are available in human individuals despite the safety and low cost of androgen therapy. Clinical evaluations of the effects of androgen therapy on these devastating diseases using large populations of patients are strongly needed.

Keywords: Alzheimer’s disease; Multiple sclerosis; Parkinson’s disease; androgens; neuroregeneration; remyelination; testosterone.

Figure 1.

Neurosteroids: biosynthesis in the human brain and their function. Progesterone, testosterone, and deoxycorticosterone are converted by 5α-reductase into 5-dihydro-reduced steroids, which are then reduced further to 3α-hydroxylated neurosteroids by 3-HSOR in allopregnenolone, THDOC, and androstendiol. All these metabolites activate GABA-A receptors that regulate anxiety, depression, and seizure. Testosterone is converted by aromatase into 17β-estradiol that activates ERα and ERβ improving mitochondrial function, anti-inflammatory effect, and neurotransmission. DHEAS and testosterone activate NMDA and can converted in testosterone and estradiol. NMDA activation is involved in memory, learning impairments, and psychosis. DHEAS, dehydroepiandrosterone sulfate; DHT, dihydrotestosterone; ER, estrogen receptor; GABA, gamma-aminobutyric acid; HSOR, 3alpha-hydroxysteroid oxide reductase; NMDA, N-methyl-D-aspartate; THDOC, 5α-pregnane-3α, 21-diol-20-one.

Figure 2.

Effect of androgens on neuron and myelin regeneration. Androgens (testosterone, DHT, and DHEAS) activate ARs, which are located on the membrane of neurons and mitochondria. The activation of ARs promotes the trophism and growth of neurons and the formation of new myelin following the OPCs activation and axonal regeneration. Testosterone, after its aromatization in 17β-estradiol, activates the ERα and Erβ, improving mitochondrial function, anti-inflammatory and neurotransmission effects and protecting astrocytes. Testosterone is converted in DHT by 5α-reductase and then in androstendiol for which the metabolites 3α and 3β-diol then have a weak effect on ARs but are more active on ERβ. AR, androgen receptor; DHEAS, dehydroepiandrosterone sulfate; DHT, dihydrotestosterone; ER, estrogen receptor; OPC, oligodendrocyte precursor cell.