Long-term use of dutasteride to treat androgenic alopecia in young men may lead to persistent abnormalities in semen parameters
Article information
Abstract
Objective
To evaluate the long-term effects of dutasteride on male fertility and determine the cutoff treatment duration that causes significant and persistent decreases in semen parameters.
Methods
This was a single-center, randomized, controlled study that evaluated 200 men (ages 28 to 39 years). Forty men were allocated to each study group, divided according to the duration of dutasteride treatment, as follows: <6 months (group 1), 6–12 months (group 2), 13–18 months (group 3), 19–24 months (group 4), and >24 months (group 5). All subjects received dutasteride 0.5 mg/day for management of androgenetic alopecia then discontinued dutasteride for 6 months.
Results
The baseline mean testosterone level in the study subjects was 4.8 ng/mL. No significant differences were found between study groups in sperm concentration, normal morphology, and vitality. Semen volume and sperm total/progressive motility were significantly reduced as the duration of dutasteride treatment increased. All study groups showed an increase in total sperm motility and semen volume after discontinuation of dutasteride. Compared with group 1, groups 2–5 showed significant decreases in semen volume and sperm total motility, with the odds ratios becoming smaller as the duration of dutasteride treatment increased. Receiver operating characteristic analysis showed the cutoff values for persistent impairment of semen volume and total sperm motility to be 17.8 and 20.3 months, respectively.
Conclusion
Long-term use of dutasteride may lead to male infertility by persistently impairing semen volume and sperm motility.
Introduction
Dutasteride is a steroid-derived medication that belongs to the class of 5α-reductase inhibitors. Intracellular 5α-reductase is an enzyme responsible for converting testosterone into a more potent form of androgen known as dihydrotestosterone (DHT), whereas dutasteride competitively and irreversibly inhibits both types I and II of 5α-reductase by forming a stable complex with α-reductase [1]. Approximately 33% of serum DHT is synthesized by type I 5α-reductase, which is mainly found in keratinocytes, sebaceous glands, and sweat glands within skin tissue. The remaining 66% of serum DHT is primarily produced by the type II 5α-reductase isozyme within genital tissues, including the prostate, seminal vesicles, vas deferens, and epididymis [2]. DHT is the primary androgen responsible for prostate gland growth, and reducing serum DHT levels accelerates prostate volume reduction by enhancing apoptosis in prostatic epithelial cells [3]. Dutasteride can reduce serum DHT levels by more than 90%, while another 5α-reductase inhibitor available on the market, finasteride, decreases serum DHT levels by approximately 70% [4]. Dutasteride 0.5 mg daily was approved in 2001 by the United States Food and Drug Administration (FDA) for the treatment of symptomatic benign prostatic hyperplasia, either as monotherapy or in combination with alpha-blockers [5].
The global dutasteride market size reached 1.1 billion US dollars in 2023, driven by its increasing applications in the treatment of androgenetic alopecia (AGA) [6]. Although some studies have shown promising results regarding the treatment of AGA with dutasteride, it has not yet been approved by the U.S. FDA [7]. However, its use for AGA treatment has been approved in South Korea and Japan [8]. In contrast, finasteride has received official approval from the U.S. FDA for low-dose (1 mg) treatment of AGA [9]. Due to the fetal teratogenic effects of dutasteride, men undergoing dutasteride treatment should avoid donating blood for up to 6 months after discontinuing the medication [10]. Since dutasteride is prescribed off-label for the treatment of AGA, many young male patients take the medication without proper background knowledge, including the contraindications and potential complications of dutasteride [11]. Previous studies, including one by Amory et al. [12], have indicated that some decrease in semen parameters may occur during dutasteride treatment. However, the influence of dutasteride on semen parameters has not been widely explored, particularly in cases involving extended treatment durations. Therefore, the current study primarily aimed to evaluate the long-term effects of dutasteride on male fertility. Our secondary focus was on the association between the duration of dutasteride treatment and its potential to cause significant and persistent decreases in semen parameters.
Methods
1. Patients and baseline evaluations
This was a single-center, randomized, controlled study that evaluated a total of 314 men who visited the Fertility Center of CHA Bundang Medical Center between January 2021 and November 2023 for a fertility workup. Approval was obtained from the Ethics Committee of CHA Medical University (approval number 2024-11-012-002), and all study participants provided informed consent for the use of their medical information. Moreover, personal medical data collection and all clinical procedures were conducted according to recent relevant guidelines. All study subjects had been undergoing treatment with dutasteride 0.5 mg/day for management of AGA for at least 3 months prior to their inclusion in the study. Among the 314 patients initially evaluated, those with the following conditions were removed from the final analysis: insufficient medical data; a history of chronic prostatitis; active urinary tract infection confirmed by urine or semen cultures or multiplex real-time polymerase chain reaction assays; a history of antimicrobial (antibacterial or antiviral) treatment within 6 months prior to the first clinic visit; a history of treatment with alpha-blockers, finasteride, minoxidil, spironolactone, clomiphene, or testosterone replacement within 6 months prior to the first clinic visit; an initial prostate specific antigen level ≥3.0 ng/dL (or ≥1.5 ng/dL if the duration of dutasteride treatment was ≥6 months); suspicion of urologic malignancy based on radiologic examinations; or a history of invasive genitourinary surgeries, including transurethral resection of the prostate and urethrotomy (Figure 1). After excluding 114 men who met these criteria, a total of 200 patients were included in the final analysis. The participants were then randomly divided into five groups, with a 1:1 allocation ratio, based on the duration of dutasteride treatment prior to their initial clinic visit: <6 months (group 1), 6–12 months (group 2), 13–18 months (group 3), 19–24 months (group 4), and >24 months (group 5). While the patients were under dutasteride treatment, no participants had discontinued the medication. Each study participant underwent an evaluation of their underlying medical and surgical history, current medications, baseline hormone levels, and semen parameters. All study subjects were instructed to follow these guidelines: discontinue dutasteride and adopt strict lifestyle modifications, including minimizing caffeine intake, getting 6 to 8 hours of sleep daily, quitting smoking and alcohol consumption, drinking 2 L of water per day, and exercising for 1 to 2 hours per day on 2 to 3 days per week.
Consolidated Standards for Reporting of Trials (CONSORT) flow chart. PSA, prostate specific antigen; Hx, history.
2. Semen collection and parameter analysis
At the initial clinic visit, all study participants underwent semen analysis and were instructed to strictly discontinue dutasteride until the next semen analysis, which was conducted 6 months after discontinuation. The study participants provided semen samples in sterile containers after 3 to 5 days of sexual abstinence. The samples were then placed on a clean bench at room temperature for 30 minutes to allow for liquefaction. Semen analysis included the following parameters: semen volume, sperm concentration, motility (total/progressive), morphology, vitality, and deoxyribonucleic acid (DNA) fragmentation of spermatozoa.
3. Statistical analysis
Clinical variables were compared between study groups using the analysis of variance test for normally distributed variables and the Kruskal-Wallis test for non-normally distributed variables. To evaluate the effect of dutasteride treatment duration on sperm parameter improvement after discontinuation, multivariate logistic regression analyses were undertaken, describing odds ratios and 95% confidence intervals, with a p-value of ≤0.05 considered statistically significant. The optimal cutoff value for dutasteride treatment duration, which could lead to persistent impairment in sperm parameters, was determined using receiver operating characteristic (ROC) curve analysis. All statistical analyses were performed using MedCalc statistical software ver. 20.1.4 (MedCalc Software Ltd.) and SPSS ver. 24.0 (IBM Corp.).
Results
1. Baseline characteristics
The baseline clinical variables of the study participants are presented in Table 1. The duration of dutasteride treatment for the study subjects ranged from 3 to 60 months, with a mean duration of 14.1 months. The mean age of the study subjects was 34.3 years, with no significant differences observed between study groups in terms of age and underlying disease history. All men included in the study had received 0.5 mg of daily dutasteride treatment for the management of AGA. Of the participants, 28.0% had a history of minoxidil use, and 13.5% had a history of spironolactone use; however, none had used these medications in the 6 months prior to inclusion in the study. Genitourinary abnormalities were evaluated, and two subjects (4.0%) had hydrocele. No anatomical abnormalities affecting male fertility, such as varicocele or cryptorchidism, were found in any study subject. There were no significant differences between the study groups in terms of testis volume and initial hormone levels. The mean testosterone level of the study subjects was 4.8 ng/mL, and none of the study groups exhibited signs of hypogonadism. No significant differences were found in semen parameters between the study groups, including sperm concentration, normal morphology, and vitality. However, semen volume and sperm total/progressive motility were significantly reduced as the duration of dutasteride treatment increased. In addition, a longer duration of dutasteride treatment was associated with a greater increase in the mean DNA fragmentation rate (Table 1, Figure 2).
Basic characteristics of males treated with dutasteride (n=200)
Sperm parameters before and after 6 months of dutasteride discontinuation: (A) sperm concentration (×106 sperm/mL), (B) semen volume (mL), and (C) sperm total motility (%). Data are presented as mean values.
2. Semen parameters and hormone levels after dutasteride discontinuation
Comparisons between baseline and 6-month post-dutasteride hormone levels and semen parameters are shown in Table 2. The mean sperm concentration increased insignificantly in all study groups after dutasteride was discontinued for 6 months (Table 2, Figure 2A). Six months after discontinuing dutasteride, the mean total and progressive sperm motilities of the study cohort were 35.7% and 26.2%, respectively, representing improvements from baseline of 22.3% and 35.1% (Table 2, Figure 2C). All study groups showed an increase in total sperm motility after discontinuation of dutasteride, but groups 4 and 5 showed statistically insignificant improvements (group 4, 7.8% improvement, p=0.159; group 5, 5.7% improvement, p=0.521) (Table 2, Figure 2C). Progressive motility improved significantly after dutasteride was discontinued for 6 months in all study groups, but the degree of improvement decreased as the duration of dutasteride treatment increased. Regarding sperm vitality, DNA fragmentation, and normal morphology, no study group showed a significant improvement after 6 months without dutasteride. Group 5 showed no significant improvement in semen volume after dutasteride was discontinued, whereas the other study groups showed a significant increase in semen volume (Table 2, Figure 2B).
Semen parameters and hormonal changes 6 months after discontinuing dutasteride
As for hormone levels, all study groups showed a decrease in follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and prolactin, though the changes were not statistically significant.
3. Multivariate logistic regression analysis of sperm parameter improvement after dutasteride discontinuation
Multivariate logistic regression analyses were conducted to evaluate the association between the duration of dutasteride treatment and significant impairment of sperm parameters, and the results are presented in Table 3. Significant impairment was defined as at least one semen parameter (sperm concentration, semen volume, sperm motility, or normal morphology rate) falling below the World Health Organization’s (WHO) recommended levels, even after 6 months of drug discontinuation. Compared with group 1, groups 2, 3, 4, and 5 showed significant decreases in semen volume and sperm total motility, with the OR becoming smaller as the duration of dutasteride treatment increased. For other semen parameters, including sperm concentration, DNA fragmentation, normal morphology, and vitality, the duration of dutasteride treatment did not result in significant differences.
Multivariate logistic analysis of the impact of dutasteride treatment duration on semen parameters following 6 months discontinuation
4. ROC analysis of the cutoff value for dutasteride treatment duration
The estimated cutoff values for dutasteride treatment duration that persistently impair semen volume and total sperm motility, even after discontinuation of dutasteride, are presented in Table 4. The cutoff values for persistent impairment of semen volume and total sperm motility were 17.8 months (sensitivity 83.1%, specificity 63.4%, area under the curve [AUC] 0.742, p=0.035) and 20.3 months (sensitivity 85.5%, specificity 71.0%, AUC 0.790, p=0.019), respectively.
Predicted cutoff scores and AUC values obtained by ROC analyses for dutasteride treatment duration and persistent decrease in semen parameters
Discussion
AGA is the most common cause of hair loss in men, with 30% of Caucasian men affected by the age of 30 years. The current treatment guideline for AGA recommends oral dutasteride 0.5 mg/day due to its superior effect on hair growth when compared with finasteride 0.1 mg/day [13]. Previous studies have looked at the long-term safety and efficacy of dutasteride, but few have evaluated changes in sperm parameters after an extended period of dutasteride treatment. This study is the first to evaluate the restorability of sperm parameters in men who discontinue dutasteride after long-term treatment. This study showed that chronic administration of dutasteride significantly decreased sperm parameters, including sperm motility and semen volume. This study aimed to minimize differences in baseline infertility risk factors between study groups. The environmental and clinical factors that affect male fertility, including medications, underlying disease history, and testicular size, showed no significant differences between the groups. Moreover, the participants had not taken medications other than dutasteride for at least 6 months prior to the initial visit, and no medications were taken after dutasteride was discontinued.
The initial semen analysis showed that semen volume, sperm concentration, and DNA fragmentation decreased significantly as the duration of dutasteride treatment increased. However, sperm concentration decreased only slightly in men exposed to dutasteride for >24 months (group 5), remaining above the value recommended in the WHO 2021 manual (16×106 sperm/mL). Dutasteride inhibits cell proliferation and induces apoptosis of prostatic cells, causing a reduced prostate volume [14]. In an animal study, male Sprague-Dawley rats exposed to dutasteride had fibrotic changes in the prostate and penis compared with unexposed control mice [15]. Since the prostate contributes 20% of the fluid to each ejaculate [16], apoptotic and fibrotic changes in the prostate could be related to the reduction of semen volume in men undergoing dutasteride treatment. The negative impact of dutasteride on semen volume was described in a study by Amory et al. [12], which reported that ≥20% of men undergoing dutasteride treatment experienced at least a 50% reduction in semen volume, and 15% of men showed a significant decrease (≥50%) in semen volume even after discontinuing the medication for 6 months. The current study showed similar findings, with groups 1, 2, and 3 experiencing a significant increase in semen volume after discontinuing dutasteride for 6 months, while groups 4 and 5 showed an insignificant increase. These results suggest that fibrosis of prostate tissue and the associated reduction in semen volume may become extensive and irreversible after a certain duration of dutasteride treatment. However, further investigation with histologic evaluations of the prostate and seminal vesicles is required to confirm this postulation.
The current study showed that mean sperm concentration decreased as the duration of dutasteride treatment increased, but the difference between groups was not significant, and values remained above the WHO-recommended level in all groups. Moreover, recovery of sperm concentration was observed in all study groups after dutasteride was discontinued, although the extent of improvement was not significant and decreased as the duration of dutasteride treatment increased. These results were consistent with previous studies, including those by Amory et al. [12]. In addition, Gul et al. [17] demonstrated that Sprague-Dawley rats treated with dutasteride showed no significant change in spermatogenesis when compared with a normal control group, as indicated by similar Johnsen’s scores for testicular tissue. Therefore, it can be assumed that the negative impact of dutasteride on sperm parameters may result from changes in sperm transport within the ejaculatory duct or alterations in epididymal function rather than from effects on spermatogenesis itself.
The mean total and progressive sperm motility in the current study decreased as the duration of dutasteride treatment increased. Groups with a treatment duration ≥13 months (groups 3, 4, and 5) showed mean total sperm motility below the WHO-recommended value (≥42%). A study by Amory et al. [12] demonstrated that sperm motility in healthy men decreased during 52 weeks of dutasteride treatment but returned close to baseline levels (pre-treatment levels) after 24 weeks of dutasteride discontinuation. However, the current study showed that groups with ≥19 months of dutasteride treatment had an insignificant recovery of sperm motility after discontinuation, with motility values remaining below the WHO-recommended level.
To our knowledge, this is the first study to evaluate the duration of dutasteride treatment that might cause persistent and significant impairment of sperm parameters even after discontinuation. The ROC analysis in this study suggested that persistent impairment of semen volume and sperm motility may occur after 17.8 and 20.3 months of continuous dutasteride treatment, respectively. Since current fertility guidelines are relatively broad and lack specificity in describing the correlation between the degree of impairment in specific semen parameters and fertility rates [18-20], it is difficult to establish a definitive duration of dutasteride treatment that impacts fertility rates. However, as shown by the results of the current study and previous studies [12,18], semen parameters can decrease with dutasteride treatment. Therefore, we believe that treatment duration should be carefully managed, with regular semen analysis, when young men with future pregnancy plans are taking dutasteride for AGA treatment.
Like the study by Amory et al. [12], our study found no significant improvement in the mean sperm normal morphology after dutasteride was discontinued. As previous studies [21] suggest, the percentage of morphologically normal sperm is relatively vulnerable in reproducibility. Therefore, further research on the spermatogenesis mechanism with a larger sample size is needed to confirm the effect of dutasteride on sperm morphology.
In this study, serum FSH, LH, and testosterone levels decreased after dutasteride discontinuation, but the changes were not significant. As suggested by Maeda et al. [22], dutasteride treatment reduces DHT levels, which may affect the hypothalamic-pituitary axis by promoting negative feedback. Therefore, discontinuation of dutasteride might interrupt this negative feedback on the hypothalamic-pituitary axis, leading to a subsequent decrease in FSH, LH, and testosterone levels.
This study had some limitations. Due to the relatively small sample size, a larger cohort and longer follow-up period might have yielded different outcomes. In addition, since this study primarily focused on the impact of dutasteride treatment duration on sperm parameters, other male fertility factors such as potency and libido were not assessed. Therefore, it would be valuable to explore the correlations with other clinical factors to better understand the long-term impact of dutasteride treatment on male fertility. The lack of participants’ clinical information prior to the study prevented inclusion of their sperm parameters before dutasteride treatment. The inclusion of pre-dutasteride sperm parameters could help achieve a more thorough interpretation of the overall effect of dutasteride on sperm parameters. Despite these limitations, this study is the first to suggest an estimated duration of dutasteride treatment that can irreversibly impair semen parameters.
In conclusion, as the duration of dutasteride treatment increased, semen parameters including semen volume, sperm motility, and DNA fragmentation, showed statistically significant negative effects. Although 6 months after dutasteride was discontinued, semen volume and sperm motility were restored, treatment durations longer than 17.8 and 20.3 months significantly and persistently impaired semen volume and sperm motility, respectively. Sperm concentration, vitality, normal morphology, and DNA fragmentation rates were minimally impacted after discontinuation. Young men planning to have children in the future should be carefully managed when treated with dutasteride.
Notes
Conflict of interest
No potential conflict of interest relevant to this article was reported.
Author contributions
Conceptualization: YJK, YDY. Methodology: YJK, SRL, YDY. Formal analysis: YJK, SRL, YDY. Data curation: YJK, SRL, YDY. Project administration: SRL, YDY. Writing-original draft: YJK, YDY. Writing-review & editing : YDY. Approval of final manuscript: YJK, SRL, YDY.