Effect of isotretinoin consumption on spermatogenesis and semen quality
DOI:
https://doi.org/10.48193/6r19tr95Keywords:
Isotretinoin, Spermatogenesis, Semen, Spermatozoa, FertilityAbstract
Introduction: the use of isotretinoin, a derivative of vitamin A, to treat severe acne has been reported to have contradictory effects on spermatogenesis and semen quality. This literature review evaluates the impact of isotretinoin on semen quality.
Relevance & discussion: in humans, administration of isotretinoin at therapeutic doses has consistently shown improvement in semen parameters, increasing sperm concentration, motility, and viability. In contrast, studies in other animal models, mainly rats, show reproductive toxicity. Higher doses result in testicular degeneration, increased apoptosis, and reduced Sertoli and Leydig cell populations. Although the concentrations of isotretinoin detected in human semen are low, the known teratogenic potential of the drug highlights the importance of continuing to take strict precautions to prevent fetal exposure, given the severity of the associated congenital malformations.
Conclusion: in conclusion, isotretinoin has specific effects on semen quality, and although better results are observed in humans using low therapeutic doses, data obtained in animal models with high doses suggest possible adverse effects on the reproductive system.
References
Bassas L. Espermatogénesis e infertilidad. Revista Iberoamericana de fertilidad. 2001;18(4): 11–17.
Cirakoglu A, Onder S, Hancı H, Benli E, Yüce A, Kasko Arici Y, et al. Does isotretinoin affect spermatogenesis in the long term? A rat model. Archivio Italiano Di Urologia, Andrologia: Organo Ufficiale [di] Societa Italiana Di Ecografia Urologica E Nefrologica. 2023;95(3): 11502. https://doi.org/10.4081/aiua.2023.11502.
Hogarth CA, Griswold MD. The key role of vitamin A in spermatogenesis. The Journal of Clinical Investigation. 2010;120(4): 956–962. https://doi.org/10.1172/JCI41303.
Sharpe RM, McKinnell C, McLaren T, Millar M, West TP, Maguire S, et al. Interactions Between Androgens, Sertoli Cells and Germ Cells in the Control of Spermatogenesis. In: Verhoeven G, Habenicht UF (eds) Molecular and Cellular Endocrinology of the Testis. Berlin, Heidelberg: Springer; 1994. p. 115–142. https://doi.org/10.1007/978-3-662-22189-1_6.
Zhao Y, Deng S, Li C, Cao J, Wu A, Chen M, et al. The Role of Retinoic Acid in Spermatogenesis and Its Application in Male Reproduction. Cells. 2024;13(13). https://doi.org/10.3390/cells13131092.
Gudas LJ. Retinoids induce stem cell differentiation via epigenetic changes. Seminars in Cell & Developmental Biology. 2013;24(10–12): 701–705. https://doi.org/10.1016/j.semcdb.2013.08.002.
Blomhoff R, Blomhoff HK. Overview of retinoid metabolism and function. Journal of Neurobiology. 2006;66(7): 606–630. https://doi.org/10.1002/neu.20242.
Kunchala SR, Suzuki T, Murayama A. Photoisomerization of retinoic acid and its influence on regulation of human keratinocyte growth and differentiation. Indian Journal of Biochemistry & Biophysics. 2000;37(2): 71–76.
Kapała J, Lewandowska J, Placek W, Owczarczyk-Saczonek A. Adverse Events in Isotretinoin Therapy: A Single-Arm Meta-Analysis. International Journal of Environmental Research and Public Health. 2022;19(11): 6463. https://doi.org/10.3390/ijerph19116463.
Khalil NY, Darwish IA, Al-Qahtani AA. Isotretinoin. Profiles of Drug Substances, Excipients, and Related Methodology. 2020;45: 119–157. https://doi.org/10.1016/bs.podrm.2019.10.005.
Paichitrojjana A, Paichitrojjana A. Oral Isotretinoin and Its Uses in Dermatology: A Review. Drug Design, Development and Therapy. 2023;17: 2573–2591. https://doi.org/10.2147/DDDT.S427530.
Melnik BC. Apoptosis May Explain the Pharmacological Mode of Action and Adverse Effects of Isotretinoin, Including Teratogenicity. Acta Dermato-Venereologica. 2017;97(2): 173–181. https://doi.org/10.2340/00015555-2535.
Draghici CC, Miulescu RG, Petca RC, Petca A, Dumitrașcu MC, Șandru F. Teratogenic effect of isotretinoin in both fertile females and males (Review). Experimental and Therapeutic Medicine. 2021;21(5): 534. https://doi.org/10.3892/etm.2021.9966.
Reigada C, Valera-Vera EA, Sayé M, Errasti AE, Avila CC, Miranda MR, et al. Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi. PLOS Neglected Tropical Diseases. 2017;11(3): e0005472. https://doi.org/10.1371/journal.pntd.0005472.
Silva FSG, Oliveira H, Moreiras A, Fernandes JC, Bronze-da-Rocha E, Figueiredo A, et al. The in vitro and in vivo genotoxicity of isotretinoin assessed by cytokinesis blocked micronucleus assay and comet assay. Toxicology in vitro: an international journal published in association with BIBRA. 2013;27(2): 900–907. https://doi.org/10.1016/j.tiv.2013.01.002.
Al-Othman SI, Bin-Jumah MN, Alkosome RA. Deleterious Effects of Perinatal Exposure to Isotretinoin Drug on the Offspring of Pregnant Mice. International Journal of Pharmacology. Invalid date;15(6): 706–715. https://doi.org/10.3923/ijp.2019.706.715.
Bispo ACC, GalvãO TC, Tamoyese VM, Costa GA, Ramos SP, Salles MJS. Effects of Isotretinoin on the Reproduction of Pubertal Male Mice and Malformations in the Offspring. American Journal of Biomedical Sciences. 2017; 225–236. https://doi.org/10.5099/aj170400225.
Amory JK, Ostrowski KA, Gannon JR, Berkseth K, Stevison F, Isoherranen N, et al. Isotretinoin administration improves sperm production in men with infertility from oligoasthenozoospermia: a pilot study. Andrology. 2017;5(6): 1115–1123. https://doi.org/10.1111/andr.12420.
Kumaş M, Eşrefoğlu M, Kumaş M, Eşrefoğlu M. Investigation of the Effects of Isotretinoin on Spermatogenesis in Balb/c Mice. Bezmialem Science. 2020; https://doi.org/10.14235/bas.galenos.2019.2542.
Millsop JW, Heller MM, Eliason MJ, Murase JE. Dermatological medication effects on male fertility. Dermatologic Therapy. 2013;26(4): 337–346. https://doi.org/10.1111/dth.12069.
Khoo KC, Reik D, Colburn WA. Pharmacokinetics of isotretinoin following a single oral dose. Journal of Clinical Pharmacology. 1982;22(8–9): 395–402. https://doi.org/10.1002/j.1552-4604.1982.tb02692.x.
Kamm JJ. Toxicology, carcinogenicity, and teratogenicity of some orally administered retinoids. Journal of the American Academy of Dermatology. 1982;6(4 Pt 2 Suppl): 652–659. https://doi.org/10.1016/s0190-9622(82)70054-4.
Stinson SF, Reznik-Schüller H, Reznik G, Donahoe R. Atrophy induced in the tubules of the testes of Syrian hamsters by two retinoids. Toxicology. 1980;17(3): 343–353. https://doi.org/10.1016/0300-483x(80)90015-3.
Çinar L, Kartal D, Ergin C, Aksoy H, Karadag MA, Aydin T, et al. The effect of systemic isotretinoin on male fertility. Cutaneous and Ocular Toxicology. 2016;35(4): 296–299. https://doi.org/10.3109/15569527.2015.1119839.
Eyada MMK, Mostafa RM, Mahgoub SR, Azab M. Effect of systemic isotretinoin on semen parameters and sperm ultrastructure in male patients treated for acne vulgaris : An electron microscope study. Human Andrology. 2020;10(Published Articles): 1–9. https://doi.org/10.21608/ha.2020.37010.1066.
Amory JK, Muller CH, Walsh TJ. Isotretinoin for the treatment of nonobstructive azoospermia: a pilot study. Asian Journal of Andrology. 2021;23(5): 537. https://doi.org/10.4103/aja.aja_18_21.
Gurel A, Gurel G, Fırat F, Ozgul E, Turkoglu IND, Aladag T, et al. Effect of systemic isotretinoin therapy on semen parameters. Annals of Medicine. 2023;55(1): 2207038. https://doi.org/10.1080/07853890.2023.2207038.
Jessup CM, Amory JK, Turek PJ. Treatment with isotretinoin can improve de novo sperm production in nonobstructive azoospermia or cryptozoospermia. Journal of Assisted Reproduction and Genetics. 2025;42(8): 2793–2799. https://doi.org/10.1007/s10815-025-03567-6.
Al-Shahed FAZN, Shoeb HH, El-Shawwa MM. Effect of isotretinoin (Netlook) on the testis of adult male albino rats and the role of omega 3 supplementation: A histological and biochemical study. Journal of Cellular and Molecular Medicine. 2022;26(20): 5213–5221. https://doi.org/10.1111/jcmm.17546.
Khalil A, Daradkeh M, Alrabie A, Abo Siam H. Assessment of the In Vivo Reprotoxicity of Isotretinoin in Sprague-Dawley Male Rat. Current Drug Discovery Technologies. 2024;21(1): e160823219865. https://doi.org/10.2174/1570163820666230816155855.
Arnold SL, Kent T, Hogarth CA, Schlatt S, Prasad B, Haenisch M, et al. Importance of ALDH1A enzymes in determining human testicular retinoic acid concentrations. Journal of Lipid Research. 2015;56(2): 342–357. https://doi.org/10.1194/jlr.M054718.
Akman TC, Yazici M, Atila A, Mertoglu C. Analysis of Isotretinoin-Induced Alterations in the Levels of Plasma Trace Elements: Investigation of the Relationship Between Magnesium, Phosphorus, Potassium, Zinc, and Treatment-Related Side Effects. Biological Trace Element Research. 2024;202(11): 4858–4868. https://doi.org/10.1007/s12011-023-04053-9.
Clouthier DE, Avarbock MR, Maika SD, Hammer RE, Brinster RL. Rat spermatogenesis in mouse testis. Nature. 1996;381(6581): 418–421. https://doi.org/10.1038/381418a0.
Jan SZ, Hamer G, Repping S, de Rooij DG, van Pelt AMM, Vormer TL. Molecular control of rodent spermatogenesis. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2012;1822(12): 1838–1850. https://doi.org/10.1016/j.bbadis.2012.02.008.
Gilbert SF, Gilbert SF. Biología del desarrollo.. 6.a. Sinauer Associates; 2000.
Schmitt-Hoffmann AH, Roos B, Sauer J, Brown T, Weidekamm E, Meyer I, et al. Low levels of alitretinoin in seminal fluids after repeated oral doses in healthy men. Clinical and Experimental Dermatology. 2011;36 Suppl 2: 12–17. https://doi.org/10.1111/j.1365-2230.2011.04032.x.
Choi JS, Koren G, Nulman I. Pregnancy and isotretinoin therapy. CMAJ: Canadian Medical Association journal = journal de l’Association medicale canadienne. 2013;185(5): 411–413. https://doi.org/10.1503/cmaj.120729.
Dai WS, LaBraico JM, Stern RS. Epidemiology of isotretinoin exposure during pregnancy. Journal of the American Academy of Dermatology. 1992;26(4): 599–606. https://doi.org/10.1016/0190-9622(92)70088-w.
Sladden MJ, Harman KE. What Is the Chance of a Normal Pregnancy in a Woman Whose Fetus Has Been Exposed to Isotretinoin? Archives of Dermatology. 2007;143(9): 1187–1188. https://doi.org/10.1001/archderm.143.9.1187.
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Revista Mexicana de Urología
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
