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Dutasteride: Mechanism, Side Effects and Dosage

Mechanism of Action

Dutasteride is a synthetic steroid similar to testosterone; it leads to a competitive inhibition of the 5α-reductase 1–3. Among other things, 5α-reductase is responsible for converting testosterone into dihydrotestosterone (DHT); the further function of 5α-reductase on other steroids is still insufficiently understood. Dihydrotestosterone is the most potent natural androgen with effects on numerous organs, especially during fetal development. In adult men, inhibition of 5α-reductase is used to treat benign prostatic hyperplasia and androgenetic alopecia. In a direct comparison in BPH therapy, there are no significant differences between finasteride and dutasteride (Park et al., 2014); 5α-reductase inhibitors can be combined with alpha blockers to improve efficacy.

Indications for Dutasteride in Urology

• Benign prostate hyperplasia: lower urinary tract symptoms or bleeding due to significant BPH (>30 ml prostate volume). The inhibition of the 5α-reductase causes shrinkage of the prostate (24% in 12 months), improves LUTS and IPSS score (-1.8), improves the urinary stream (+1,3 ml/s compared to placebo), and lowers the risk for urinary retention (2% vs. 4%), hematuria or surgical interventions (2% vs. 4%) after two years of treatment Dutasteride can be combined with alpha blockers to improve its effectiveness.
• Androgenetic alopecia: dutasteride stops hair loss and stimulates hair growth. However, in many countries there is no approval for this despite probably better efficiency (Gupta et al., 2022).

Pharmacokinetics of Dutasteride

Good oral absorption of dutasteride independent of meals, high plasma protein binding, hepatic elimination, excretion of metabolites via the faeces. Very long half-life of 3–5 weeks, steady state concentration is only reached after six months.

Side Effects of Dutasteride

Dihydrotestosterone is the most potent natural androgen with effects on numerous organs, especially during fetal development. Furthermore, the function of 5α-reductase on other steroids is poorly understood. Long-term use of dutasteride can lead to serious side effects. The extent and frequency are controversial and underreported in the approval studies (Traish et al., 2020).

PSA concentration:

Dutasteride reduces the PSA concentration by 50% within a year. The ratio fPSA/tPSA is not affected.

Prostate cancer:

The incidence of prostate cancer was reduced (25% compared to placebo) in long-term studies with 5α-reductase inhibitors. However, the rate of undifferentiated prostate carcinoma was higher in the verum group without an effect on overall survival (Goodman et al., 2019).

Sexual side effects:

Often reduced ejaculate volume, decreased libido, gynecomastia (1–2%), and erectile dysfunction (<2%). Infertility (reduced sperm count, worsening of OAT syndrome) is possible but usually only mild and temporary (Samplaski et al., 2013).

Neuropsychiatric side effects:

Neurosteroid interference increases the risk of depression, anxiety disorders, suicidality, and cognitive impairment (Giatti et al., 2024). The FDA and EMA have published warnings regarding neuropsychiatric side effects of dutasteride.

Metabolic side effects:

Dutasteride increases the risk of insulin resistance and metabolic syndrome.

Post-finasteride syndrome:

Sexual and neuropsychiatric side effects of dutasteride may persist in some patients even after discontinuation (Giatti et al., 2024). The mechanism, extent, and frequency are controversial.

Other:

Rarely allergic skin reactions. Controversial: increased risk of breast cancer.

Drug Interactions with Dutasteride

Clinically significant interactions with dutasteride are not known.

Contraindications of Dutasteride

• Severe hepatic insufficiency
• Women, pregnancy (risk of malformations), children
• Caution in patients with intolerance, side effects, and desire to have children.

Dosage of Dutasteride

0,5 mg dutasteride orally once daily.

References

Andriole u.a. 2004 ANDRIOLE, G. ; BRUCHOVSKY, N. ; CHUNG, L. W. ; MATSUMOTO, A. M. ; RITTMASTER, R. ; ROEHRBORN, C. ; RUSSELL, D. ; TINDALL, D.: Dihydrotestosterone and the prostate: the scientific rationale for 5alpha-reductase inhibitors in the treatment of benign prostatic hyperplasia.
In: J Urol
172 (2004), Nr. 4 Pt 1, S. 1399–403

Chapple 2004 CHAPPLE, C. R.: Pharmacological therapy of benign prostatic hyperplasia/lower urinary tract symptoms: an overview for the practising clinician.
In: BJU Int
94 (2004), Nr. 5, S. 738–44

J. M. Hirshburg, P. A. Kelsey, C. A. Therrien, A. C. Gavino, and J. S. Reichenberg, “Adverse Effects and Safety of 5-alpha Reductase Inhibitors (Finasteride, Dutasteride): A Systematic Review.,” J Clin Aesthet Dermatol., vol. 9, no. 7, pp. 56–62, 2016.

Giatti S, Diviccaro S, Cioffi L, Cosimo Melcangi R. Post-Finasteride Syndrome And Post-Ssri Sexual Dysfunction: Two Clinical Conditions Apparently Distant, But Very Close. Front Neuroendocrinol. 2024 Jan;72:101114. doi: 10.1016/j.yfrne.2023.101114.

Gupta AK, Talukder M, Williams G. Comparison of oral minoxidil, finasteride, and dutasteride for treating androgenetic alopecia. J Dermatolog Treat. 2022 Nov;33(7):2946-2962. doi: 10.1080/09546634.2022.2109567

J. D. McConnell et al., “The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety Study Group,” vol. 338, no. 9, pp. 557–63, 1998.

Samplaski MK, Lo K, Grober E, Jarvi K. Finasteride use in the male infertility population: effects on semen and hormone parameters. Fertil Steril. 2013 Dec;100(6):1542-6. doi: 10.1016/j.fertnstert.2013.07.2000. Epub 2013 Sep 4. PMID: 24012200.

A. M. Traish, “Health Risks Associated with Long-Term Finasteride and Dutasteride Use: It’s Time to Sound the Alarm.,” World J Mens Health., vol. 38, no. 3, pp. 323–337, 2020, doi: 10.5534/wjmh.200012.

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