Androgen Deprivation Therapy for Prostate Cancer: Focus on Cognitive Function and Mood

Abstract

Prostate cancer is the second leading cause of cancer death in men in the United States. Androgen deprivation therapy (ADT) is currently the primary treatment for metastatic prostate cancer, and some studies have shown that the use of anti-androgen drugs is related to a reduction in cognitive function, mood changes, diminished quality of life, dementia, and possibly Alzheimer's disease. ADT has potential physiological effects such as a reduction in white matter integrity and a negative impact on hypothalamic functions due to the lowering of testosterone levels or the blockade of downstream androgen receptor signaling by first- and second-generation anti-androgen drugs. A comparative analysis of prostate cancer patients undergoing ADT and Alzheimer patients identified over 30 shared genes, illustrating common ground for the mechanistic underpinning of the symptomatology. The purpose of this review was to investigate the effects of ADT on cognitive function, mood, and quality of life, as well as to analyze the relationship between ADT and Alzheimer's disease. The evaluation of prostate cancer patient cognitive ability via neurocognitive testing is described. Future studies should further explore the connection among cognitive deficits, mood disturbances, and the physiological changes that occur when hormonal balance is altered.

Keywords: androgen deprivation therapy; cognitive function; hormonal therapies; management strategies; prostate cancer; testosterone.

Figure 1

Mechanisms of action of anti-androgen drugs frequently used in ADT. Testosterone is converted to DHT by 5-α-reductase. DHT binds to the AR, causing a conformational change in the receptor that leads to its homodimerization and translocation to the nucleus. In the nucleus, the AR binds to the ARE and acts as a transcription factor to signal downstream targets. Second-generation anti-androgens such as apalutamide, darolutamide, and enzalutamide competitively suppress binding of androgens to the AR (indicated by a red “X”) and inhibit AR translocation to the nucleus (indicated by a red “X”). DHT, dihydrotestosterone; AR, androgen receptor; ARE, androgen response element.

Figure 2

Mechanisms of action of abiraterone. Abiraterone blocks the activity of CYP17A1, a key enzyme in the production of testosterone. By inhibiting CYP17A1, it prevents conversion of pregnenolone to DHEA and progesterone to androstenedione, resulting in decreased testosterone biosynthesis. CYP17A1, cytochrome P450, family 17, subfamily A, polypeptide 1; DHEA, dehydroepiandrosterone.