Medical treatment of male infertility encompasses specific and empirical approaches. Specific approaches depend on treating the cause and involve a thorough patient appraisal. In contrast, empirical approaches do not address a specific pathophysiology and do not require accurate patient selection.
Whereas idiopathic male infertility comprises a large sector of male infertility cases 1, the main effective solution by far remains assisted reproduction, a costly option that does not resolve the original pathology. The search for the etiology and an effective treatment for idiopathic male infertility is still ongoing.
One of the medications proposed for treating male infertility is L-carnitine 2. This proposal was based on the fact that L-carnitine represents a cofactor in the transport of long-chain fatty acids inside the mitochondria and their subsequent oxidation, thereby providing the sperm with an energy substrate necessary for propulsion 3.
Several controlled and uncontrolled studies support a potential positive effect of therapy with L-carnitine and its acyl derivatives in treating male subfertility 4–10. However, Agarwal and Said 11 stated that although many clinical trials have been performed in this domain, the majority of these studies lack a placebo-controlled, double-blind design, making it difficult to reach a definite conclusion.
Spermatozoa in the semen use both glycolysis and fatty acid oxidation for generating energy. In contrast, sperm cells in the cervical mucus rely on fatty acid oxidation solely 3. As a cofactor in fatty acid oxidation, L-carnitine may be valuable in enhancing sperm activity in the cervical mucus, an understudied assumption.
This work aimed at studying the effect of L-carnitine on sperm parameters in the ejaculated semen and the cervical mucus, through a randomized, double-blind, placebo-controlled design, in cases of male infertility of various etiologies and seminal parameters of various forms.
The study was presented to and accepted by the internal review board beforehand. A written informed consent was obtained from each patient. Thirty infertile male patients were recruited, and randomized into two groups, one receiving L-carnitine (2 g/day, per oral) and the other receiving placebo for a period of 3 months. Both the investigators and the patients were blinded to the type of therapy administered. All patients provided written informed consents to the experimental nature of the study.
The selection criteria included an age range of 25–40 years (to exclude asthenozoospermia resulting from infrequent coitus in the older age groups) and primary infertility for two years. Selection criteria also entailed that semen analyses were to show asthenozoospermia repeatedly whether isolated or associated with other semen parameter disorders, in the absence of seminal antisperm antibodies and leucocytospermia. A scrotal Duplex study was used to exclude cases with abnormality in testicular size or echogenicity, and to determine the presence or absence of varicocele, excluding cases with grade III varicocele that would possibly indicate surgery rather than medical treatment. The female partners were to have normal ovulation, patent tubes, normal pelvic ultrasound, and favorable cervical mucus.
A 3-month washout period separated the onset of the study from prior therapy for infertility. Three serial semen analyses, 1 month apart, and a postcoital test preceded and followed treatment. The average of the three samples was adopted as the fertility status to avoid bias generated by the natural variations in semen parameters, a drawback in many studies in this domain. Pretreatment and posttreatment semen analyses and postcoital tests were compared in both groups. Analysis was performed according to the WHO guidelines 12.
Posttreatment semen analyses showed that L-carnitine therapy resulted in a nonsignificant increase in the mean concentration, immediate forward progressive motility, and 2-h forward progressive motility, and a decrease in the mean of abnormal forms, which was also nonsignificant compared with the placebo (Table 1).
In contrast, after treatment, the postcoital cervical mucus samples showed significant increases in the mean of the total sperm/high power field (HPF) compared with the placebo (Table 2). This significant positive effect of L-carnitine on sperm cells in the cervical mucus was reproducible in cases of idiopathic infertility (Table 3), in contrast to cases with varicocele (Table 4), where the findings were nonsignificant. No statistical significance was found for the effect on forward progressive motility and sperm morphology in the cervical mucus.
The significant positive effect of L-carnitine on sperm cell concentration in the cervical mucus was also reproducible in cases of oligoasthenozoospermia (Table 5), rather than cases with isolated asthenozoospermia (Table 6), where the improvement was nonsignificant.
In 1965, Marquis and Fritz 13 demonstrated that the epididymis contains an extremely high concentration of carnitine and that spermatozoa have a high activity of carnitine acetyl transferase, which is an effect of testosterone. Lenzi et al.3 suggested the value of L-carnitine as a cofactor in the transport of long-chain fatty acids inside the mitochondria and their subsequent oxidation, thereby enhancing one of the two pathways for energy generation: fatty acid oxidation and glycolysis. Whereas epididymal spermatozoa use fatty acid oxidation for their energy metabolism, ejaculated sperms use the glycolytic process. In contrast, in the cervical mucus, lipids are an important energy source for sperms, and to metabolize these lipids, intrasperm L-carnitine is essential. Mazzilli et al.14 thus reported the possible mechanism of action of L-carnitine as a sperm motility enhancer. In addition to the aforementioned, a secondary role of carnitine as an antioxidant 15 may add to its value in enhancing sperm cell function. Sperm cells take up relatively large amounts of carnitine during their epididymal transit. By the time spermatozoa reach the cauda epididymis, they have lost the ability to take up carnitine, but they now contain high concentrations of carnitine and acetyl carnitine and a high carnitine acetyl transferase activity 16.
Several studies supported a potential positive effect of therapy with L-carnitine and its acyl derivatives in male infertility 4–10. However, the issue remains controversial and open-ended due to contradictory results of those studies in addition to some methodological errors such as a lack of placebo controls in some and ignoring the natural spontaneous variations in semen parameters in others. These shortcomings were well documented by Agarwal and Said 11.
One of the controlled studies affirmed the efficacy of combined treatment with L-carnitine and L-acetyl carnitine in improving sperm motility, especially in patients with lower baseline levels 17. In contrast, Lenzi et al.10 demonstrated that even though increases were seen in all semen parameters after carnitine treatment, they were nonsignificant, which is similar to our finding. In contrast, Sigman et al.18 stated that carnitine supplementation demonstrated neither a significant nor a nonsignificant effect on sperm motility or total motile sperm concentrations in men with idiopathic asthenospermia.
On the scale of sperm-cervical mucus interaction, and in agreement with the current results, Mazzilli et al.14 stated that a strict correlation was found between the L-carnitine content and the sperm motility in the cervical mucus.
The current study confirms the value of L-carnitine in enhancing sperm concentration in the cervical mucus by a double-blind placebo-controlled study, despite its nonsignificant effect on sperm parameters in the semen. In addition, this work is, to our knowledge, the first to demonstrate that L-carnitine therapy is effective in idiopathic, varicocele-free cases, with a resultant recommendation to restrict the use of L-carnitine to cases with idiopathic infertility.
In our study, cases with isolated asthenozoospermia had an associated varicocele; we therefore cannot confirm the inefficacy of carnitine in cases of isolated asthenozoospermia, but can confirm its value in cases of idiopathic oligoasthenozoospermia.
In our opinion, the enhancing effect on sperm concentration could be due to better cervical mucus penetration on account of better metabolism of the cervical mucus lipids as an energy substrate, despite an apparent lack of improvement of forward progressive motility that may be hindered by the nature of the mucus.
In conclusion, and according to the results shown, we recommend the utility of L-carnitine in the management of infertile men with idiopathic oligoasthenozoospermia.
Conflicts of interest
There are no conflicts of interest.
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carnitine; cervical mucus; motility; postcoital; sperm