Meta-analysis of the efficacy and safety of L-carnitine and N-acetylcysteine monotherapy for male idiopathic infertility

Meta-análisis de la eficacia y seguridad de la monoterapia con L-carnitina y N-acetilcisteína para la infertilidad masculina idiopática

Background: Oral antioxidants especially L-carnitine (LC) and N-Acetylcysteine (NAC) are commonly used as the drug treatment method for idiopathic male infertility (IMI). Methods: Randomized controlled trials (RCTs) of LC and NAC monotherapy for IMI were searched systematically by using MEDLINE, EMBASE and the Cochrane Controlled Trials Register. The reference lists of retrieved studies were also perused. We analyzed the sperm concentration, normal morphology, sperm motility, and ejaculation volume. Results: Seven Randomized controlled trials were included. Four trials compared the efficacy of LC with placebo, and three trials compared the efficacy of NAC with placebo. In the efficacy analysis, LC increased sperm concentration (p < 0.001), normal morphology (p = 0.03), and sperm motility (p = 0.02); NAC improved the first three indicators while also increasing ejaculation volume (p = 0.002). In hormone level analysis, LC increased serum testosterone levels (p < 0.001), but the changes in other hormone levels were not statistically significant. Conclusions: Both LC and NAC can improve sperm motility, sperm concentration, and normal morphology, and increase serum testosterone concentration, but have no significant effect on other serum hormones. The PROSPERO Registration: CRD42024552120.

Resumen

Antecedentes: Los antioxidantes orales, especialmente la L-carnitina (LC) y la N-Acetilcisteína (NAC), se utilizan comúnmente como método de tratamiento farmacológico para la infertilidad masculina idiopática (IMI). Métodos: Se realizaron búsquedas sistemática de ensayos controlados aleatorios (RCTs) de monoterapia con LC y NAC para IMI utilizando MEDLINE, EMBASE y Cochrane Controlled Trials Register. También se revisaron las listas de referencias de los estudios recuperados. Analizamos la concentración de esperma, la morfología normal, la vitalidad del esperma y el volumen de eyaculación. Resultados: Se incluyeron siete ensayos controlados aleatorios. Cuatro ensayos compararon la eficacia de LC con placebo, y tres ensayos compararon la eficacia de NAC con placebo. En el análisis de eficacia, LC aumentó la concentración de esperma (p < 0.001), morfología normal (p = 0.03) y vitalidad del esperma (p = 0.02); NAC mejoró los tres primeros indicadores y también aumentó el volumen de eyaculación (p = 0.002). En el análisis del nivel hormonal, LC aumentó los niveles de testosterona sérica (p < 0.001), pero los cambios en otros niveles hormonales no fueron estadísticamentes significativos. Conclusiones: Tanto LC como NAC pueden mejorar la motilidad del esperma, la concentración de esperma y la morfología normal, y aumentar la concentración de testosterona sérica, pero no tienen un efecto significativo en otros hormonas séricas. El Registro de PROSPERO: CRD42024552120.

L-carnitine; N-acetylcysteine; Antioxidant; Idiopathic male infertility; Randomized controlled trials; Meta-analysis

Palabras Clave

L-carnitina; N-acetilcisteína; Antioxidante; Infertilidad masculina idiopática; Ensayos controlados aleatorios; Meta-análisis

[1] Agarwal A, Baskaran S, Parekh N, Cho CL, Henkel R, Vij S, et al. Male infertility. The Lancet. 2021; 397: 319–333.

[2] Fainberg J, Kashanian JA. Recent advances in understanding and managing male infertility. F1000Research. 2019; 8: F1000 Faculty Rev-670.

[3] Vander Borght M, Wyns C. Fertility and infertility: definition and epidemiology. Clinical Biochemistry. 2018; 62: 2–10.

[4] Barati E, Nikzad H, Karimian M. Oxidative stress and male infertility: current knowledge of pathophysiology and role of antioxidant therapy in disease management. Cellular and Molecular Life Sciences. 2020; 77: 93–113.

[5] Micoogullari U, Cakici MC, Kilic FU, Kisa E, Ozcift B, Caglayan A, et al. Evaluation of the role of thiol/disulfide homeostasis in the etiology of idiopathic male infertility with a novel and automated assay. Systems Biology in Reproductive Medicine. 2022; 68: 162–168.

[6] Sengupta P, Roychoudhury S, Nath M, Dutta S. Oxidative stress and idiopathic male infertility. Advances in Experimental Medicine and Biology. 2022; 62: 181–204.

[7] Gualtieri R, Kalthur G, Barbato V, Longobardi S, Di Rella F, Adiga SK, et al. Sperm oxidative stress during in vitro manipulation and its effects on sperm function and embryo development. Antioxidants. 2021; 10: 1025.

[8] Nowicka-Bauer K, Nixon B. Molecular changes induced by oxidative stress that impair human sperm motility. Antioxidants. 2020; 9: 134.

[9] Takeshima T, Usui K, Mori K, Asai T, Yasuda K, Kuroda S, et al. Oxidative stress and male infertility. Reproductive Medicine and Biology. 2021; 20: 41–52.

[10] Agarwal A, Parekh N, Panner Selvam MK, Henkel R, Shah R, Homa ST, et al. Male oxidative stress infertility (MOSI): proposed terminology and clinical practice guidelines for management of idiopathic male infertility. The World Journal of Men’s Health. 2019; 37: 296–312.

[11] Iliceto M, Stensen MH, Andersen JM, Haugen TB, Witczak O. Levels of L-carnitine in human seminal plasma are associated with sperm fatty acid composition. Asian Journal of Andrology. 2022; 24: 451–457.

[12] Yang K, Wang N, Guo H, Wang J, Sun H, Sun L, et al. Effect of L-carnitine on sperm quality during liquid storage of boar semen. Asian-Australasian Journal of Animal Sciences. 2020; 33: 1763–1769.

[13] Varuzhanyan G, Chan DC. Mitochondrial dynamics during spermatogenesis. Journal of Cell Science. 2020; 133: jcs235937.

[14] Vertika S, Singh KK, Rajender S. Mitochondria, spermatogenesis, and male infertility—an update. Mitochondrion. 2020; 54: 26–40.

[15] Kopets R, Kuibida I, Chernyavska I, Cherepanyn V, Mazo R, Fedevych V, et al. Dietary supplementation with a novel l-carnitine multi-micronutrient in idiopathic male subfertility involving oligo-, astheno-, teratozoospermia: a randomized clinical study. Andrology. 2020; 8: 1184–1193.

[16] Ghorbani F, Nasiri Z, Koohestanidehaghi Y, Lorian K. The antioxidant roles of L-carnitine and N-acetyl cysteine against oxidative stress on human sperm functional parameters during vitrification. Clinical and Experimental Reproductive Medicine. 2021; 48: 316–321.

[17] Majzoub A, Agarwal A. Systematic review of antioxidant types and doses in male infertility: benefits on semen parameters, advanced sperm function, assisted reproduction and live-birth rate. Arab Journal of Urology. 2018; 16: 113–124.

[18] Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. The BMJ. 2021; 372: n71.

[19] Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0. 2008. Available at: https://training.cochrane.org/handbook/archive/v5.1/ (Accessed: 20 March 2011).

[20] Safarinejad MR, Safarinejad S. Efficacy of selenium and/or N-acetyl-cysteine for improving semen parameters in infertile men: a double-blind, placebo controlled, randomized study. The Journal of Urology. 2009; 181: 741–751.

[21] Balercia G, Regoli F, Armeni T, Koverech A, Mantero F, Boscaro M. Placebo-controlled double-blind randomized trial on the use of L-carnitine, L-acetylcarnitine, or combined L-carnitine and L-acetylcarnitine in men with idiopathic asthenozoospermia. Fertility and Sterility. 2005; 84: 662–671.

[22] Ciftci H, Verit A, Savas M, Yeni E, Erel O. Effects of N-acetylcysteine on semen parameters and oxidative/antioxidant status. Urology. 2009; 74: 73–76.

[23] Jannatifar R, Parivar K, Roodbari NH, Nasr-Esfahani MH. Effects of N-acetyl-cysteine supplementation on sperm quality, chromatin integrity and level of oxidative stress in infertile men. Reproductive Biology and Endocrinology. 2019; 17: 24.

[24] Ma L, Sun Y. Comparison of L-Carnitine vs. Coq10 and Vitamin E for idiopathic male infertility: a randomized controlled trial. European Review for Medical and Pharmacological Sciences. 2022; 26: 4698–4704.

[25] Moslemi Mehni N, Ketabchi AA, Hosseini E. Combination effect of Pentoxifylline and L-carnitine on idiopathic oligoasthenoteratozoospermia. Iranian Journal of Reproductive Medicine. 2014; 12: 817–824.

[26] Moradi M, Moradi A, Alemi M, Ahmadnia H, Abdi H, Ahmadi A, et al. Safety and efficacy of clomiphene citrate and L-carnitine in idiopathic male infertility: a comparative study. Urology Journal. 2010; 7: 188–193.

[27] Gunes S, Esteves SC. Role of genetics and epigenetics in male infertility. Andrologia. 2021; 53: e13586.

[28] Sharma A, Minhas S, Dhillo WS, Jayasena CN. Male infertility due to testicular disorders. The Journal of Clinical Endocrinology and Metabolism. 2021; 106: e442–e459.

[29] Jagim AR, Harty PS, Tinsley GM, Kerksick CM, Gonzalez AM, Kreider RB, et al. International society of sports nutrition position stand: energy drinks and energy shots. Journal of the International Society of Sports Nutrition. 2023; 20: 2171314.

[30] Kooshesh L, Nateghian Z, Aliabadi E. Evaluation of L-Carnitine potential in improvement of male fertility. Journal of Reproduction & Infertility. 2023; 24: 69–84.

[31] Khaw SC, Wong ZZ, Anderson R, Martins da Silva S. L-carnitine and L-acetylcarnitine supplementation for idiopathic male infertility. Reproduction & Fertility. 2020; 1: 67–81.

[32] Mongioi L, Calogero AE, Vicari E, Condorelli RA, Russo GI, Privitera S, et al. The role of carnitine in male infertility. Andrology. 2016; 4: 800–807.

[33] Zhou X, Liu F, Zhai SD. Effect of L-carnitine and/or L-acetyl-carnitine in nutrition treatment for male infertility: a systematic review. Asia Pacific Journal of Clinical Nutrition. 2007; 16: 383–390.

[34] Lavranos G, Balla M, Tzortzopoulou A, Syriou V, Angelopoulou R. Investigating ROS sources in male infertility: a common end for numerous pathways. Reproductive Toxicology. 2012; 34: 298–307.

[35] Takalani NB, Monageng EM, Mohlala K, Monsees TK, Henkel R, Opuwari CS. Role of oxidative stress in male infertility. Reproduction & Fertility. 2023; 4: e230024.

[36] Alhasaniah AH. l-carnitine: nutrition, pathology, and health benefits. Saudi Journal of Biological Sciences. 2023; 30: 103555.

[37] Pedre B, Barayeu U, Ezeriņa D, Dick TP. The mechanism of action of N-acetylcysteine (NAC): the emerging role of H2S and sulfane sulfur species. Pharmacology & Therapeutics. 2021; 228: 107916.

[38] Aldini G, Altomare A, Baron G, Vistoli G, Carini M, Borsani L, et al. N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why. Free Radical Research. 2018; 52: 751–762.

[39] Raghu G, Berk M, Campochiaro PA, Jaeschke H, Marenzi G, Richeldi L, et al. The multifaceted therapeutic role of N-Acetylcysteine (NAC) in disorders characterized by Oxidative Stress. Current Neuropharmacology. 2021; 19: 1202–1224.

[40] Wei Y, Geng W, Zhang T, He H, Zhai J. N-acetylcysteine rescues meiotic arrest during spermatogenesis in mice exposed to BDE-209. Environmental Science and Pollution Research International. 2023; 30: 50952–50968.

[41] Zirkin BR. Spermatogenesis: its regulation by testosterone and FSH. Seminars in Cell & Developmental Biology. 1998; 9: 417–421.

[42] Christin-Maitre S, Young J. Androgens and spermatogenesis. Annales D’endocrinologie. 2022; 83: 155–158.

[43] de Kretser DM, Loveland KL, Meinhardt A, Simorangkir D, Wreford N. Spermatogenesis. Human Reproduction. 1998; 13: 1–8.

[44] Raj CJ, Aishwarya CVS, Mounika KVSSN, Mishra B, Sumithra B, Vishal B, et al. Deciphering the nexus between oxidative stress and spermatogenesis: a compendious overview. Advances in Experimental Medicine and Biology. 2022; 1391: 1–16.

[45] Wei G, Zhou Z, Cui Y, Huang Y, Wan Z, Che X, et al. A meta-analysis of the efficacy of L-carnitine/L-acetyl-carnitine or N-acetyl-cysteine in men with idiopathic asthenozoospermia. American Journal of Men’s Health. 2021; 15: 15579883211011371.