Discussion
Testosterone, the main androgenic hormone, is converted by 5alpha-reductase to DHT in many tissues, which binds much more avidly with androgen receptor. Two isoforms of 5alpha-reductase with distinct tissue distribution have been cloned: 5alpha-reductase type1 and type2. 5alpha-reductase type1 is widely distributed in the body, whereas in androgen dependent structures such as prostate, and hair follicles of scalp DHT is mainly formed by 5 alpha-reductase type2. However, according to some studies this isoform is present in many other organs, such as pyramidal cells of cerebral cortex, hepatocytes and bile duct cells. [18,19].
After binding to the androgen receptor, DHT results in stimulation of transcription and protein synthesis. In spite of genomic response, the existence of cell membrane sex steroid receptors was also suggested recently. These receptors exist specially in the brain, and provoke rapid responses [20].
5alpha-reductase is a critical enzyme in the conversion of several steroids such as testosterone, progesterone, aldosterone and corticosterone in the brain. This enzyme converts testosterone to the most natural potent androgen DHT, and also it acts an important role in conversion of progesterone to dihhydroprogesterone (DHP). DHP is further converted to allopregnanolone (5alpha, 3alpha-tetrahydroprogesterone) by 3alpha-HSD [9,21]. Allopregnanolone is a modulator of gamma amino butyric acid type A receptor (GABA-A), and increases chloride conductance. This neurosteroid has been found to exert anti-convulsant, anesthetic and anxiolytic effects [22-24]. Moreover, change in the levels of allopregnanolone is found to be associated with depressive disorders. [25,26]
Our results are in agreement with the past published reports [15], and indicate that finasteride might induce depressive symptoms. The 95% confidence interval, for the difference in the means of the BDI scores, was ranging from 0.34 to 1.04. This shows that the overall change induced by finasteride is minimal, but statistically significant. Anxiety scores were also increased, but the difference was not significant.
A decline in serum DHT level occurs after finasteride administration [27]. This may contribute to finasteride induced depression. Some studies have been shown that serum DHT level, which is in equilibrium with the brain [28], is inversely associated with depression. A study by Barrett-Connor E. et al. showed that BDI scores were inversely associated with bioavailable testosterone and DHT level [29]. Furthermore, it was found that DHT had anti-depressant effects on behavior of male rats and its replacement in castrated rats was able to partially decrease the immobility behavior, which is indicative of depression [30].
Finasteride induced psychiatric dysfunction can also be attributed to its inhibitory effect on androgen and steroid 5alpha-reduction in the brain. Animal studies suggest that finasteride has inhibitory effects on 5alpha-reduction of testosterone and progesterone in the brain and inhibits the formation of allopregnanolone [31,32]. Allopregnanolone has an important role in depressive disorders [26]. In 1998 Romeo E. et al, revealed that episodes of unipolar major depressive disorder in men is associated with a decline in the plasma concentrations of allopregnanolone [25]. Furthermore, a study carried out by Uzunova V. et al. showed that CSF levels of allopregnanolone were significantly lower in depressed patients, and there was negative correlation between allopregnanolone levels in CSF and HAM-D scores. [33].
Since finasteride is a potent 5AR type2 inhibitor and the predominant isoform of the enzyme in human brain is 5AR type1 [34,35], some points should be noted concerning finasteride inhibitory effect on brain steroid metabolism. (i) Although finasteride is a potent 5AR type2 inhibitor, but it has also some inhibitory effects on 5AR type1 [36]. (ii) Finasteride administration in humans has been reported to be associated with some behavioral and mental disorders related to low levels of allopregnanolone in the brain [37]. This may also improve the concept of brain allopregnanolone suppression by finasteride in humans.
However, from the current study, it can not be concluded that the pathophysiology of finasteride-induced mood disorder is attributable to any of the mentioned material.
We couldn't find any significant change in the anxiety scores before and after the treatment (p = 0.061). According to the anxiolytic effects of allopregnanolone and testosterone [38-40], it seems that further investigations with a larger sample size are necessary to determine whether finasteride administration is associated with anxiety.
Finasteride associated side effects were reported by 9.4% of patients in this study. In all cases, the reported side effect was transient and partial libido loss. This side effect was reported by several studies and in different incidences [3,41]. Despite the fact that male sexual function and behavior is related to sex hormone metabolism [42], we couldn't find any relation between libido loss and BDI nor HADS score, before and after the treatment. This may be caused by the sample size effect as there were just 12 subjects in side effect positive group.
Some limitations concerning the study should be raised. The present study didn't have any control group. Excluding the subjects with definitely diagnosed other diseases or positive history of mood disorder, might result in missing some individuals with a high risk for behavioral changes. However, as a preliminary study, we had to exclude these patients to avoid any confounding effects on the results.
Conclusion
In conclusion, this preliminary study suggests that finasteride might induce depressive symptoms. Although our data suggest a slight change, the side effect should be considered specially when the medication is prescribed for patients, who are more susceptible for it.
Finally, we recommend that further studies should be performed to elucidate behavioral effects of finasteride in higher doses and in high risk groups such as elderly patients.
