Men, not rats. And most important, brain and cerebrospinal fluid, not merely Blood level.
5α-R reaction is the rate limiting step in the conversion of testosterone, progesterone, cortisol, corticosterone, and DOC into their respective 5α-dihydro-deratitves, which serve as precursors for 3α-hydroxysteroid dehydrogenase which transfroms such precursors into their respective neurosteroids (androstanediol, allopregnanolone [AP], tetrahydrocortisol, tetrahdyrocorticosterone, and tetrahydrodeoxycorticosterone) (Fig. 1) [1, 2]. All three isoforms of 5α-R are expressed in the various regions of brain and are thought to be critical for brain development since fetal brain express high concentrations of 5α-R [1, 2].
It has recently been shown that patients who had been treated with finasteride have reduced or undetectable levels of neuroactive steroids in their cerebro-spinal fluid and plasma, and exhibited higher levels of precursor steroids [75]. This observation strongly suggests that 5α-RIs have a deleterious effect on the biosynthesis and function of neurosteroids in the central nervous system. Finasteride treatment resulted in decreased levels of 5α-DHT and 3α, 5α-tetrahydroprogesterone (AP) and increased levels of testosterone supporting the hypothesis that deleterious effects of finasteride may be persistent or irreversible. This may explain some of the noted symptoms such as anxiety, depression and suicide in patients who have been treated with finasteride [76].
NEUROPROTECTIVE EFFECTS OF NEUROSTEROIDS
Neuroactive steroids elicit important neuroprotective effects during trauma and injury to the central nervous system [75]. AP is shown to be beneficial in the treatment of traumatic brain injury, attenuating edema, trauma, stress, inflammation, apoptosis, and reducing oxidative stress [76, 77, 78]. AP is not only a protective agent in ischemia, but also in maintaining blood brain barrier integrity, and in memory and learning [78, 79, 80, 81]. Studies on CNS injury in which asphyxiation was induced in fetal sheep to stimulate neurological stressors, in the presence or absence of finasteride, showed an increase in apoptotic cell death in the cerebellum and hippocampus in the animals treated with finasteride (Fig. 5) [82]. Furthermore, treatment with an AP analogue, alfaxalone, prevented cell death as assessed by the increase in activity of caspace-3 and expression of ki-67 protein. This observation suggests that AP exerts a neuroprotective role in the brain, which is inhibited by finasteride.
The neuroprotective effect of AP was further illustrated during injury to the rat hippocampus slices induced by tributyltin treatment, which resulted in significant cell death. Administration of progesterone (P) with finasteride showed similar cell death to that induced by tributyltin treatment, in the various regions of the hippocampus. In contrast, P treatment without finasteride provided a protective effect. This is attributed to the conversion of P to 5α-DHP by 5α-Rs and to AP by 3α-HSD. To confirm that this is due to the neuroprotective effect of AP, the latter was administered with or without finasteride. While the tributyltin induced cell death was significant, administration of AP with and without finasteride produced a markedly protective effect as assessed by the reduced cell death [83]. These findings suggest that 5α-Rs play a pivotal role in neuroprotection.
Neurosteroid synthesis in the hippocampus is suggested to be critical for neuroplasticity in the brain [84]. Inhibition of 5α-R by finasteride is thought to contribute to reduced neuroplasticity due to structural changes resulting from inhibition of neurogenesis in the hippocampus. Finasteride treatment in mice showed decreased cell proliferation in the hippocampus, suggesting that inhibitors of 5α-R blocks neurogenesis [84].
As reported by Mellon [85] in an adult animal model of Niemann-Pick disease type C the biosynthesis of AP is significantly reduced, and this was supported by significant reduction in the activity of 5α-R and 3α-HSD in the brain of these animals [85]. The activity of 5α-R was markedly reduced with the progression of the disease. This reduced 5α-R activity may contribute to the observed accumulation of cholesterol in neurons and gangliosides, cerebro, perkinje cell degeneration, dysmyelination and neurodegeneration [85]. Thus, loss of 5α-R and 3α-HSD activity is attributed to loss of neurons expressing these enzymes. Treatment with AP early at postanatal day 7 was found most effective in preventing neurodegeneration and correlates with reduced tremor, ataxia, and increased lifespan. In the animal model, these findings indicate that the loss of neurosteroid biosynthesis may be responsible for the disease state and its progression. Therefore inhibition of 5α-R by finasteride and dutasteride in the course of treatment of nonlife threatening conditions, such as male pattern baldness (alopecia) or BPH may have detrimental effects on the CNS.
It has been reported that AP levels were significantly decreased in postmortem human brains of Alzheimer disease (AD) patients [86]. An inverse correlation was noted between AP levels and the degree of neurological degeneration in pathological section of AD patient [86]. One of the interesting findings was that pregnenolone levels were greater in the temporal cortex of AD patients suggesting that this may be a compensating mechanism for reduced 5α-R activity. We speculate that 5α-RIs may contribute to reduced levels of neurosteroids in the CNS and this may enhance the progression of neurodegenerative disease, such as AD.
Conversion of polyprenol into dolichol is critical for N-glycosylation of membrane proteins [3]. 5α-R type 3 was shown to be critical for catalyzing this reaction [3]. A mutation in this enzyme lead to mental retardation and opthamologic and cerebral defects [3]. Intraoperative Floppy Iris Syndrome (IFIS) is also a complication experienced during cataract extraction. The syndrome is defined by floppy, or flaccid iris. Studies have indicated a correlation between finasteride and the occurrence of cataracts and IFIS indicating inhibition of glycosylation may contribute to this pathology