This is a very small investigation coming from a two cases analyses. But the discussion is very interesting.
“… experienced a decreased libido, erectile dysfunction and less morning erections, as well as penoscrotal morphological changes, particularly penile and scrotal shrinking, and hypospermia, that lasted for more than 3 months. All of these symptoms are consistent with different studies that evaluated them in these patients [22-26]. Many experimental publications in animals have left clear the importance of DHT in the erectile function [27-29]. Park et al. showed that androgens, without differences between Testosterone and DHT, are crucial for the proper maintenance of the expression of nitric oxide synthetase, which explains the differences in response to phosphodiesterase inhibitors between normo and hypogonadic patients [30]. The patient in case 1 presented a severe anxiety syndrome, associated with suicidal ideation, that required for an interdisciplinary management with a psychiatrist. Many studies suggest that different neurosteroids, like allopregnenolone (among others) could be involved in different neuronal circuits, such as anxiety and depression regulation [31-35]. 5AR is fundamental for the biosynthesis of these neurosteroids, followed by a second enzymatic step mediated by a 3-alpha reductase. In fact, finasteride reduces not only the plasma levels, but also the cephalorraquid fluid levels of these neurosteroids [35]. Because not all of the patients that withdrew finasteride after experiencing its sexual adverse effects persisted with these symptoms, there could be some type of genetic predisposition. This is why several authors have put their focus on disorders of the 5AR and of the androgen receptor. Di Loreto et al. showed their experience in patients with persistent symptoms after withdrawing finasteride 1mg/day for androgenetic alopecia who had undergone a foreskin biopsy in order to determine androgen receptor density, resulting much higher in cases than in controls. This data could imply a fundamental role of 5AR in the expression of the androgen receptor18. However, evidence differs in some in vitro studies with prostate cancer cells exposed to finasteride, in which the expression of the androgen receptor is downregulated [36], although the physiopathology could differ with a different population or target. On the other hand, different polymorphisms of the exon 1 of the androgen receptor gene are implicated in its affinity to androgens. Cecchin et al. showed an association between the expansion mutation of CAG and GGN triplets, androgenetic alopecia and the possibility of developing a post-finasteride syndrome, resulting in a higher number of triplet repetitions in those patients with androgenetic alopecia and, especially, in those who developed the syndrome (Table 1) [37].
The polymorphism of this exon of the gene is directly related to its overexpression and inversely related to the sensitivity of the androgen receptor [38,39]. However, in an up to date of Shukla et al. [40] about androgen receptor related diseases, it’s well established the inverse relationship between the number of CAG repetitions and the sensitivity of the androgen receptor, but isn’t that clear for GGN repetitions. In fact, controversially, a study by Gao et al. showed a lower sensitivity of this receptor when there’s a deletion of this gene region [41]. The number of repetitions is a fundamental factor not only because it determines the sensitivity of the androgen receptor, but also for its association (usually above 40 repetitions) with the bulbospinal muscular atrophy or Kennedy disease, a neurodegenerative disease due to toxicity secondary to overexpression of the androgen receptor in the motoneurons [42]. These patients can experience, besides the neurologic symptoms, microrchidia, gynecomastia and oligo or azoospermia, among other sexual and reproductive symptoms. This is why it is hypothesized that post-finasteride syndrome patients could carry an expansion mutation of the CAG and/or GGN triplet of exon 1 of the androgen receptor gene, although lower than 40 repetitions, resulting in a silent mutation, becoming evident after the inhibition of the 5AR. When the levels of DHT drop drastically, Testosterone becomes the main androgen, with a lower affinity to an already defective receptor. Because this doesn’t explain the persistence of the symptoms after the discontinuation of the drug, other cofactors may be involved. This is why the focus is also onto the expression and activity of the 5AR. Bechis et al. reported the development of resistance to the treatment of benign prostatic hyperplasia with finasteride 5 mg/day in a subgroup of patients, that after a prostatic biopsy showed a lower density of epithelial and stromal 5AR by immunohistochemistry, probably due to epigenetic changes of the gene[19]. Berman et al. had already reported that, in the urogenital tract of the adult rat, Testosterone and DHT positively regulate 5AR-2, data corroborated by Torres et al. in the adult brain of the rat [43,44]. Therefore, DHT seems to be a positive regulator of the expression of the 5AR, and its downregulation due to lack of DHT could explain the persistence of the symptoms. Also, proapoptotic effects of finasteride may be involved, as showed by Traish et al. not only in the corpora cavernosa but also in the central nervous system [45]. These results seem counterintuitive in respect to the classic feedback mechanisms, and opens a field of investigation into the regulation of the expression of the 5AR that could clarify the physiology of androgen action and the physiopathology of this syndrome. It’s logical to interpret that the neuropsychiatric symptoms that are constantly reported by these patients could be due to a negative impact of the physical symptoms in their mood. However, as previously mentioned, many neurosteroids such as allopregnenolone, whose metabolism depends of the 5AR (among other enzymes), have a fundamental role in mood regulation, among other neurologic functions [46]. In fact, Melcangi et al. demonstrated a lower concentration of these neurosteroids in the cephalorraquid fluid compared to controls [35]. Also, it’s not clear if the diminished levels of these neurosteroids in the cephalorraquid fluid were present before the installation of the syndrome, given that patients without post-finasteride syndrome (but with depressive symptoms) also have low cephalorraquid levels of neurosteroids, especially allopregnenolone [5]. The presence of mood disorders, and even suicidal ideation that is observed in these patients is a fundamental aspect to have in mind for their interdisciplinary management. Suicidal ideation is especially important when the persistence and progression of the symptoms lasts more than 3 months [47]. Recently, Basaria et al. didn’t find evidence of sequence variation in AR, SRD5A1, or SRD5A2 genes, or of significant alterations in expression of AR-dependent genes in the skin, but they can’t exclude the possibility of variations in other genes, like epigenetic effects, or in the gene expression levels in other tissues or specific brain regions involved in regulation of mood and sexual function. Therefore, symptomatic finasteride users are unlikely to benefit from treatment with testosterone, DHT, or any other androgen because these patients didn’t show evidence of androgen deficiency, persistent SRD5A inhibition or androgen insensitivity [48]. In our experience, both patients reported adverse effects attributable to the use of finasteride, being both cases very similar between them, except for the fact that one of them only needed one pill of finasteride 1 mg to experience its adverse effects and, after the withdrawal of the drug, its persistence and progression, warning about a possible time and/or dose independent characteristic of the syndrome. Another fundamental difference between both patients is that one of them reported to have developed a penile curvature, later evidencing a plaque on the right corpus cavernosum and an ultrasound showing an apparent intracaversonal fibrosis, that we couldn’t corroborate with an MRI. Although the patient did mention that the curvature developed after the use of finasteride, we can’t be sure about this. However, some studies associate the state of hypogonadism as a risk factor for the development of Peyronie’s disease, so the drop in the levels of DHT could have been a factor in the development of his curvature [49,50].”