Baseline Levels of Seminal Reactive Oxygen Species Predict Improvements in Sperm Function Following Antioxidant Therapy in Men With Infertility

Wayne Vessey; Shaghayegh Saifi; Aditi Sharma; Cassandra McDonald; Paula Almeida; Monica Figueiredo; Suks Minhas; Ashraf Virmani; Waljit S. Dhillo; Jonathan W. Ramsay; Channa N. Jayasena


Clin Endocrinol. 2021;94(1):102-110. 

In This Article

Abstract and Introduction


Background: Poor sperm function is a major cause of infertility. There is no drug therapy to improve sperm function. Semen oxidative stress is a recently identified pathway for sperm damage. Commercial antioxidants such as L-carnitine and acetyl-L-carnitine (LAL) are commonly self-administered by infertile men. However, concerns have been raised whether inappropriate LAL therapy causes reductive stress-mediated sperm damage. It is imperative to investigate whether: (1) LAL improves sperm function by reducing reactive oxidative species (ROS); (2) LAL has differential effects on sperm function between men with normal and elevated ROS.

Methods: A prospective cohort study of routine clinical practice was performed in infertile men with abnormal sperm quality. Changes in sperm function and semen ROS levels following three months of oral LAL therapy were compared between participants with baseline seminal normal ROS (≤10RLU/SEC/106sperm; n = 29) and High ROS (>10 RLU/SEC/106sperm; n = 15) levels measured using an established colorimetric-luminol method.

Results: In normal ROS group, sperm function did not change following LAL therapy. In high ROS group, LAL therapy reduced semen ROS fivefold, increased sperm count by 50% (mean count in mill/ml: 21.5 + 7.2, baseline; 32.6 + 9.5, post-treatment, P = .0005), and total and progressive sperm motility each by 30% (mean total sperm motility in % 29.8 + 5.0, baseline: 39.4 + 6.2, post-treatment, P = .004; mean progressive sperm motility in % 23.1 + 4.6, baseline: 30.0 + 5.5, post-treatment, P = .014 vs. baseline).

Conclusions: We report for the first time that LAL only improves sperm quality in infertile men who have baseline high-ROS levels prior to treatment. These data have important potential implications for couples with male infertility and their clinicians.


Infertility affects 10% of couples, and nearly half of cases are due to sperm defects in the male partner.[1] There are currently no available drug therapies to improve sperm function. Reactive oxygen species (ROS) are unstable products of metabolism causing cellular damage[2] produced in the semen by leukocytes and the oxidative metabolism of spermatozoa.[3] ROS generation is a recently identified mechanism for sperm damage and measurement of ROS is a potential tool of added value in the investigation of male infertility. Previous studies have suggested that elevated semen ROS levels are associated with reduced sperm function in men with idiopathic infertility[4] and recurrent miscarriage.[5] Furthermore, many exogenous factors such as genito-urinary infections, varicocele and adverse lifestyle choices have been observed to increase semen ROS.[6] However, no current clinical guidelines support its use in routine practice. There is extensive research in the area with antioxidant therapy observed to improve semen parameters and live-birth rates in men with idiopathic infertility and varicocele-associated infertility.[7,8] Accordingly, antioxidant therapy is a novel, potential therapy to improve sperm function in men with infertility.

Nutritional supplements containing the antioxidant, L-carnitine and acetyl-L-carnitine, are readily available over the counter for men to use as empirical therapies for improving sperm function. However, published data suggest that the effects of carnitines on sperm function are unclear. Some studies suggest that the orally administered amino acid-derived antioxidant L-carnitine and acetyl-L-carnitine (LAL) increase sperm concentration and motility parameters in men with infertility;[9,10] however, other studies suggest that carnitines do not alter sperm function.[11,12] Furthermore, some clinicians harbour concerns that infertile men without elevated semen ROS might suffer paradoxical impairment of sperm function following antioxidant therapy due to reductive stress.[13] In summary, it is common practice that men with infertility often take antioxidant therapy, but the balance of potential benefit and/or harm from such therapy is not known.

In the absence of any pharmacological therapy for male infertility, it is important to identify which (if any) men with infertility could clinically benefit from self-administering the antioxidant carnitines to improve sperm function. We therefore conducted a single-centre prospective cohort study of routine clinical practice in men with infertility associated with reduced sperm function. Specifically, we compared changes in sperm function following carnitines therapy between participants with normal and elevated baseline semen ROS levels.