Furthermore, a metabolite of DHT, 3α-androstanediol (5α-androstan-3α,17β-diol), can bind to neuronal ERβ to have genomic effects , and there is evidence that 3α-androstanediol can enhance memory in male rats through an estrogen-receptor dependent pathway 62,63. In the brain, testosterone either binds directly to androgen receptors (though its affinity for these receptors is relatively low) or is broken down into either dihydrotestosterone (DHT) or estradiol. Although this review will focus on the mammalian condition, some of the first findings of sex differences in neurogenesis came from studies with birds , which will be briefly reviewed. The controversy seems to stem from different methods of measuring sub-populations of proliferating cells, and substantial evidence now indicates that markers of neurogenesis (e.g., doublecortin and PSA-NCAM) are expressed in the hippocampus of adult humans. Other studies using endogenous markers of cell proliferation and neurogenesis suggest that neurogenesis rates decline dramatically after four years of age in humans, becoming nearly undetectable by adolescence 19,20.
Effects of testosterone, whether they are protective or detrimental, are mediated via the androgen receptor and its effect at a cellular level. In this review, we aim to summarize the available data and potential implications related to stroke among young adults. There is approximately 40 percent higher risk of ischemic stroke in females taking only estrogen-based supplements and around 30 percent risk in females taking estrogen-progestin supplements when compared to placebo (19, 20). While risk factors for stroke in young adults are similar to conventional causes for older patients, thrombotic events occurring in this younger patient population warrant investigation of non-traditional etiologies including thrombophilia and hormonal risks (18). In the United States, the incidence of stroke for young adults has increased from 17 per 100,000 in 1993 to 28 per 100,000 in 2015. Conversely, testosterone is known to cause erythrocytosis—leading to possible hyperviscosity and hypercoagulability—as well as a decrease in high-density lipoprotein (HDL), theoretically increasing the risk of cardiovascular disease (11, 12). Previous studies suggested a cardioprotective role of testosterone, as low endogenous testosterone increases cardiovascular morbidity secondary to endothelial dysfunction and increases atherosclerosis (8–10).
An expanding body of research indicates testosterone offers neuroprotective effects, shielding the brain from damage and promoting neural regeneration. These findings position androgens and ARs as promising targets for the therapeutic management of various neurological diseases. Food and Drug Administration issued a black box warning for TRT due to the increased risk of cardiovascular events, like ischemic stroke or myocardial infarction . The role of sex hormones in headache medicine is an emerging area of interest, though current literature largely focuses on female hormones and their association with migraines.
For example, rats that engaged in the hippocampus-dependent Morris water maze had more neurogenesis in the dentate gyrus than did rats engaging in a cued version of the water maze that is hippocampus independent 139,140,141. Similarly, decreased performance on spatial memory tasks correlates with decreased adult neurogenesis among aged rodents 8,134,135. It has long been known that the hippocampus plays a critical role in spatial memory formation 128,129,130, and so it is not surprising that most work testing the function of hippocampal neurogenesis has involved testing rodents in spatial memory tasks . Middle-aged male mice (10–12 months old) given estradiol implants showed an increase in cell proliferation and new neuron production (DCX-expressing cells) but no change in 21-day cell survival . However, blocking DHT production using finasteride caused a decrease in both cell proliferation and DCX-expressing cells within the hippocampus of male mice . DCX is expressed during the cellular migration of synaptic integration stages of development , suggesting that testosterone may influence this critical period.
For example, castrated male rats show elevated release of corticosterone in response to restraint stress compared to intact males exposed to the same stressor . For example, DHT implants caused a significant reduction in neuronal loss in the hippocampus following kainite lesions among castrated male rats . Although some of the neuroprotective properties of testosterone may occur through aromatization to estradiol , evidence indicates that neuroprotection also occurs via androgen-dependent pathways 199,200.
As a result of these physiological effects, supplementation of testosterone poses the risk of vascular events via increased arterial or venous thromboembolism, hyperviscosity of blood, small vessel disease due to endothelial dysfunction, and derangement of lipid panel (Figure 2). Some antiepileptic drugs, namely phenytoin, phenobarbital, carbamazepine, oxcarbazepine, and eslicarbazepine, are known to decrease free testosterone androgen levels in males and can cause potential side effects due to hypogonadism . Future studies should deepen our understanding of TRTs’ effects on MS in men with testosterone deficiency and those with normal levels along with optimizing therapeutic strategies across a broader spectrum of demyelinating diseases. This male predominance, particularly among those with testosterone deficiency, has sparked research into the potential role of androgens in PD pathogenesis and as a therapeutic target. Numerous observational studies have linked anti-androgen therapy, commonly used in prostate cancer, with an elevated risk of AD and other neurodegenerative diseases, like Parkinson disease . A deeper understanding of the mechanisms involved in neuroplasticity could guide therapeutic interventions with androgens such as testosterone replacement therapy (TRT) in neurological recovery in neurodegenerative diseases.
The authors report that no participants in the exposed group and one participant in the unexposed group developed an acute ischemic stroke during the 16-week study period. Patients included in this study were all men aged ≥45 years with documented low testosterone between January 1995 and August 2017, with TRT utilization defined as transdermal or intramuscular use within 90 days of cohort entry. Cheetham et al. provides a retrospective Californian cohort study of men ≥40 years old with pre-requisite low blood testosterone (median at entry 212 ng/dL, interquartile range 160–253 ng/dL).