Benign prostatic hyperplasia (BPH) is a progressive disease that causes lower urinary tract symptoms (LUTS) in aged men [1]. The 5 alpha reductase inhibitor (5ARI) is widely used as the first-line treatment of BPH with alpha-adrenergic receptor antagonists (α-blockers). α-Blockers, such as terazosin, tamsulosin, doxazosin, or alfuzosin, relax the smooth-muscle tone in the prostate and bladder neck [2], while 5ARIs, such as finasteride or dutasteride, directly reduce the size of the enlarged prostate and alleviate LUTS [3].

However, 5ARI has been shown to cause side effects, such as sexual dysfunction and anxiety, which can adversely affect patients' compliance and continuous treatment [4]. For this reason, some physicians may temporarily stop medication if the prostate volume is sufficiently reduced. After stopping 5ARI, the prostate quickly recovers to its pre-medication size, with individual differences [5]. However, to the best of our knowledge, there are only a few studies evaluating the factors that determine the rate of restoration of prostate volume. Hence, the purpose of this study was to investigate the factors affecting the restoration rate of prostate volume after the discontinuation of 5ARI.

BPH is a progressive disease commonly associated with LUTS in aged men, resulting in in complications, such as acute urinary retention, recurrent urinary tract infection, hematuria, urinary bladder stones, and renal insufficiency [6]. The first lines of treatment for BPH are α-bloker and 5ARI. α-Blockers relax the smooth-muscle tone in the prostate and bladder neck, alleviating LUTS [2]. They show rapid improvement of the maximum flow rate (Qmax) and quality of life with little adverse effects, but have no effect in the prostate growth [7]. For this reason, a single medication of α-Blokers can delay complication of BPH, but may be limited to a reduced prevalence in the long term [8].

The 5-alpha reductases (5-AR) are a family of enzymes, widely distributed in many tissues, including the central nervous system (CNS) [9], and responsible for converting testosterone to dihydrotestosterone (DHT), which is important for the progression of BPH [10]. The 5ARI medication inhibits 5-AR and blocks the formation of DHT, halt or reverse the growth of BPH, and alleviate the symptoms of BPH [3]. A previous study reported that the serum PSA level and prostate volume were decreased by approximately 50% and 20%, respectively, after the treatment with 5ARI [11]. In another study, men taking 5ARI have a 57% reduction in the risk of acute urinary retention compared with those taking placebo and a 34% reduction in the risk of surgery [12].

However, substantial number of patients taking 5ARI experience side effects. In sexual function, studies of Nickel et al. [13] and Tenover et al. [14] showed that the prevalence of erectile dysfunction and ejaculation disorder were higher in the finasteride group than in the placebo group. Hudson et al. [15] reported that the loss of libido is also increased after a 12-month treatment of 5 mg finasteride. In the CNS, since 5-AR also has a role in conversion of precursors into various neurosteroids, such as androstanediol, allopregnanolone, tetrahydrocortisol, tetrahdyrocorticosterone, and tetrahydrodeoxycorticosterone [9], 5ARI medication can reduce neuroactive s teroids in CNS a nd plasma [16]. In particular, a reduction in the level of allopregnanolone, which plays a role in the protection against ischemia, maintenance of blood brain barrier integrity, and in memory and learning, may cause anxiety and depressive symptoms [16]. These adverse effects can lower the patient compliance and continuity of treatment [17].

After discontinuation of 5ARI, the prostate will quickly return to its pre-medication size. Stoner [18] demonstrated that the prostate volume returned to near the baseline values at 12 weeks after discontinuation of 5ARI. In a s tudy by Kim et al. [5], the mean percentage of the prostate regrowth had reached 95.5% of the baseline prostate volume one year after discontinuation of dutasteride. The reason for this rapid recovery of size after stopping the 5ARI medication remains unclear; however, there are several possible hypotheses. The hyperplastic changes in BPH are an androgen-dependent process, and it is possible that the sensitivity to DHT is increased or overly activated as a result of the prolonged pharmacologic inhibition of 5AR by the 5ARI [19]. Another hypothesis has to do with Androgen receptors, which become more sensitive or up-regulated during treatment with 5ARI and may be considered as an alternative mechanism [19].

Although we failed to confirm the statistical significance, the main strength of our study is that we explored the factors involved in the recovery of the prostate size when 5ARI was discontinued. There are a number of clinical trials after discontinuation of 5ARI. Kim et al. [5] demonstrated that the withdrawal of 5ARI during a combination therapy resulted in prostate regrowth, deterioration of LUTS, and increased level of PSA. Liaw et al. [20] showed that the therapeutic effects were maintained without progression of BPH in 64.3% and 62.5% of patients one year after the discontinuation of tamsulosin and finasteride following combination therapy, respectively. However, there were no studies that investigated the factors associated with prostate recovery. Another strength is regular patient's follow up with 6 months of medication and one year of discontinuation. This minimizes the possible bias caused by time difference.

Given that this study is a fragmentary study conducted by a single institution, it has several limitations. First, the number of included patients was small and it took place in only one institution. This may have been the source of lack of statistical significance. Second, we did not consider the difference between the two 5ARI substances-finasteride vs. dutasteride. Because several patients changed drugs due to the lack of efficacy or side effects, it was difficult to statistically analyze this component. Third, it was difficult to verify the patients' past compliance in present time. Fourth, we excluded patients who underwent BPH-related surgery or were diagnosed with prostate cancer due to difficulty in prostate volume measurement and difference in follow up term, and this may have caused selection bias.

In this study, we found a weak positive correlation between patient's age and recovering speed of prostate volume after 5ARI discontinuation, without statistical significance. Other factors, such as PSA, prostate volume before medication, and reduced size after medication, showed to have no association with. When using 5ARI in elderly patients, it seems better to use the medication continuously rather than intermittently; and if discontinuation is needed, short term follow-up is recommended.