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. 2024 Apr 29;43(1):41–49. doi: 10.5534/wjmh.230291

Role of Lipoic Acid in Testosterone Production in Males

Saleem Ali Banihani 1,✉
PMCID: PMC11704161  PMID: 38772537

Abstract

Testosterone extends its impact beyond sexual function, playing a crucial role in shaping overall male health, including aspects such as muscle mass, bone density, mood regulation, and energy levels. Lipoic acid, a cofactor for specific enzymes, particularly dehydrogenases involved in cellular energy production, has been studied for its impact on testosterone. This comprehensive review systematically scoured PubMed and Scopus databases using the keywords “lipoic acid” and “testosterone.” It encompassed all relevant English papers published from November 1971 to the present, including full texts and abstracts, along with research elucidating the biochemical mechanisms linking lipoic acid to testosterone. In summary, lipoic acid consistently restores testosterone levels, offering promise as an intervention in testicular health, especially in cases of testicular toxicity caused by various harmful agents. Its mechanisms encompass nitric oxide enhancement, fortification of testicular antioxidants, elevation of luteinizing hormone, enhancement of steroidogenesis, and the maintenance of energy production. These mechanisms underscore the therapeutic potential of lipoic acid for testicular health.

Keywords: Spermatozoa, Testicular diseases, Testosterone, Thioctic acid

INTRODUCTION

Lipoic acid, also known as thioctic acid or 6,8-Dithiooctanoic acid, is a sulfur-containing molecule derived from octanoic acid, specifically caprylic acid. Its IUPAC name is R-5-(1,2-Dithiolan-3-yl) pentanoic acid. The conjugate base of lipoic acid is referred to as lipoate or alpha-lipoate. Lipoic acid exists as two enantiomers: S-(–)-lipoic acid and R-(+)-lipoic acid; however, only the latter is naturally occurring. Physically, lipoic acid appears as a yellow crystalline powder.

Lipoic acid, discovered to function as a cofactor for essential metabolic enzymes within the dehydrogenase family in the human body, includes alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase. These enzymes play a vital role in the citric acid cycle and are crucial for normal aerobic respiration. Additional enzymes subject to lipoylation comprise branched-chain keto acid dehydrogenase, alpha-oxo-(keto) adipate dehydrogenase, and the glycine cleavage system, the latter being in regulating glycine concentration within the body [1]. It is noteworthy that lipoic acid forms a covalent bond with these enzymes, imparting potent antioxidant properties crucial for their catalytic activities.

Currently available as a nutritional supplement, lipoic acid is predominantly chemically synthesized due to its low natural occurrence in dietary sources recognized for various beneficial effects, including anticancer [2,3,4,5], antidiabetic [6,7], antiviral [8,9], anti-inflammatory [10,11] activities.

Maintaining adequate testosterone levels is a central objective in scientific research, given its profound impact on male health. Beyond its role as the primary steroid hormone governing sexual arousal and development in men [12], testosterone significantly influences overall men’s health, affecting functions like muscle development, bone density, mood regulation, and energy levels [13,14]. Studies have linked low levels of testosterone in males to various health problems such as cancer [15,16], diabetes [17,18,19,20], cardiovascular diseases [21,22], osteoporosis, Alzheimer’s disease [23,24,25], Parkinson’s disease [26,27], depression [28,29], and constant fatigue [30,31]. Clinical trials have endorsed testosterone as one of the therapeutic strategies to manage such chronic aging diseases [19,21,26,32]. Thus, maintaining optimum levels of testosterone in males is very critical for men’s health.

This comprehensive review explores the role of lipoic acid in testosterone production in males. We systematically examined papers published in the main databases PubMed and Scopus that directly link between lipoic acid and testosterone using the keywords (“lipoic acid” and “testosterone”) to include relevant studies published in English since November 1971. Additionally, we reviewed research studies to discuss the biochemical mechanisms of lipoic acid's effect on testosterone, providing a conclusive summary.

EFFECT OF LIPOIC ACID ON TESTOSTERONE IN TESTICULAR TOXICITY CONDITIONS

Table 1 presents a comprehensive overview of 20 distinct studies [33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52], that directly explore the impact of lipoic acid on testosterone levels in various male reproductive toxicity contexts. Notably, all of these investigations were conducted post-2006 and spanned different countries worldwide, with a predominant focus on Middle Eastern nations, including eight studies from Egypt.

Table 1. Principal research studies investigating the impact of lipoic acid on testosterone levels in induced testicular toxicity conditions in males.

Origin of the study (year) Population of the study Dose (mode) Duration Effect on testosterone Reference
India (2006) Male rats with adriamycin-ITT 35 mg/kg per week (i.v.) 10 weeks (+) [36]
Egypt (2010) Male rats with cyclophosphamide-ITT 35 mg/kg (orally) 2 weeks (+) [37]
Egypt (2011) Male rats with cadmium-ITT 35 mg/kg (p.o) 4 weeks (+) [38]
Egypt (2012) Male rats with 4-tert-octylphenol-ITT 50 mg/kg (p.o) 3 times a week 5 weeks (+) [39]
Argentina (2013) Male rats with pesticide-ITT 25, 50, and 100 mg/kg (i.p.) 5 weeks (+) [40]
Saudi Arabia (2013) Male rats with Bisphenol A-ITT 20 mg/kg (orally) 2 weeks (+) [41]
Egypt (2014) Male rats with acrylamide-ITT 1% of basal diet (orally) 3 weeks (+) [42]
Saudi Arabia (2014) Male rats with bi-n-butyl phthalate-ITT 20 mg/kg per day (orally) 2 weeks (+) [43]
Turkey (2016) Male rats with polychlorobiphenyl (aroclor 1260)-ITT 25 mg/kg (orally) 30 days (+/–) [34]
Saudi Arabia (2017) Male rats with polychlorobiphenyl (aroclor 1260)-ITT 35 mg/kg per day (orally) 15 days (+) [35]
India (2017) Male rats with carbimazole-ITT 70 mg/kg per day (orally) Embryonic days 9-21 (+) [44]
Turkey (2018) Male rats with methotrexate-ITT 100 mg/kg (i.p.) Single dose (+) [45]
India (2018) Male rats with arsenic-ITT 70 mg/kg-3 times a week (i.p.) 8 weeks (+) [46]
Iran (2019) Male mice with radiation-ITD 200 mg/kg 2 days (+/–) [33]
Iran (2020) Male rats with di-(2-ethylhexyl) phthalate-ITT 20 mg/kg (p.o.) 2 weeks (+) [47]
Egypt (2020) Male rats with cyclosporine-ITT 100 mg/kg 45 days (+) [48]
Egypt (2020) Male rats with ionizing radiation-ITD 50 mg/kg (p.o.) 1 week before and 3 days post-irradiation (+/-) [49]
Egypt (2021) Male rats with carbimazole-ITT 60 mg/kg per day (orally) 30 days (+) [50]
Turkey (2021) Male rats with doxorubicin-ITT 50 mg/kg every other day (orally) 28 days (+) [51]
Egypt (2022) Male rats with silver nanoparticles-ITD 100 mg/kg per day (orally) 30 days (+) [52]
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ITT: Induced testicular toxicity, ITD: Induced testicular damage.

It is crucial to highlight that all these studies utilized male rats as the primary subjects, exposing them to a range of reproductive toxicants, including pharmaceuticals, toxic metals, pesticides, and various organic chemicals frequently encountered in industrial settings. As per our comprehensive search strategy, no clinical studies have been identified within this particular research paradigm to date.

In these in-vivo system studies (summarized in Table 1), lipoic acid was administered at varying doses and durations. The highest administered dose was 100 mg/kg of body weight, which, when extrapolated to humans, is approximately equivalent to 16.7 mg/kg of body weight [53]. Conversely, the lowest administered dose of lipoic acid was approximately 20 mg/kg of body weight, which, in human terms, corresponds to approximately 3.3 mg per kg of body weight [53]. Moreover, the duration of lipoic acid administration in these studies varied significantly, ranging from a single dose to a duration of up to 10 weeks.

Additionally, as outlined in Table 1, the prevailing trend across the majority of studies underscores lipoic acid's remarkable capacity to substantially reverse the diminished testosterone levels observed in testicular toxicity induced by various toxic agents. It is noteworthy that only three studies reported no discernible effect of lipoic acid on testosterone levels in this context. Interestingly, two of these studies, aligned with our search strategy, specifically investigated radiation-induced testicular damage. This suggests that lipoic acid may not effectively preserve testosterone levels against radiation-induced testicular injury. The complexity of radiation-induced testicular injury involves various molecular and cellular pathways that could potentially surpass the antioxidative activity of lipoic acid. This limitation is not unique to lipoic acid but extends to other potential antioxidants such as resveratrol and Q10 [33].

In the third study, lipoic acid did not improve testosterone levels in male rats subjected to polychlorobiphenyl (aroclor 1260)-induced testicular toxicity [34]. This lack of improvement might be attributed to the dosage of lipoic acid used (25 mg/day), as the protective effect was observed when subjected to a higher dose of 35 mg/day [35].

Collectively, the administration of lipoic acid, particularly in the context of testicular toxicity conditions, appears to hold significant therapeutic promise.

HUMAN STUDIES

Human studies examining the direct impact of lipoic acid on testosterone levels in men are notably limited. A randomized clinical trial conducted in 2019 involving infertile men who received a daily dosage of 600 mg of lipoic acid for twelve weeks, revealing improvement in serum testosterone levels [54]. Furthermore, a recently published study demonstrated that the oral combination of alpha-lipoic acid (800 mg), folic acid (400 mg), apple SelectSIEVE® (300 mg), and myo-inositol (2000 mg), administered twice daily for three months, significantly enhanced testosterone production in men with subclinical hypogonadism [55]. Considering the limited nature of studies directly investigating the impact of lipoic acid on testosterone in men, future research endeavors should prioritize in-depth and well-designed clinical trials.

MECHANISMS BY WHICH LIPOIC ACID ENHANCES TESTOSTERONE PRODUCTION

1. Increasing nitric oxide production

A decrease in blood flow to the testis has been observed to have a detrimental impact on testosterone production [56]. One potential mechanism for enhancing testosterone production involves promoting testicular nitric oxide, a signaling molecule and vasodilator synthesized by nitric oxide synthase [57]. Increasing testicular nitric oxide levels has been linked to potential improvements in testosterone production [58]. Lipoic acid has demonstrated the ability to enhance the activity of nitric oxide synthase, particularly the endothelial [59,60], and facilitate the production of nitric oxide [61]. The mechanism through which lipoic acid enhances nitric oxide production may involve the activation of the PI3K/Akt signaling pathway [62]. Consequently, it is plausible that lipoic acid could elevate testosterone levels in males, potentially enhancing spermatogenesis efficacy by promoting nitric oxide production.

2. Enhancing testicular antioxidant defense mechanism

The antioxidant properties of lipoic acid were first proposed back in 1959 by Rosenberg and Culik [63]. They observed that administering lipoate prevented the development of symptoms related to alpha-tocopherol deficiency in rats subjected to a specialized diet lacking vitamin E. Additionally, lipoic acid prevented scurvy symptoms in ascorbic acid-deficient pigs [64]. Up to the present, a search of PubMed databases reveals a substantial body of over five thousand articles that directly or indirectly link lipoic acid to its antioxidant capabilities. From a chemical standpoint, the reduced form of lipoic acid, known as dihydrolipoic acid, contains two thiol (R-SH) groups. These thiol groups can readily undergo oxidation by donating two electrons along with two protons (as depicted in Fig. 1) [65]. Consequently, lipoic acid serves as a potent reducing agent, effectively donating electrons, and has the capacity to counteract the oxidative and potentially damaging effects of various types of prooxidants. Once introduced into cellular systems, lipoic acid takes on the role of a potent quencher and stabilizer of free radicals [64,66].

Fig. 1. Reduced and oxidized forms of lipoic acid.

Fig. 1

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Exposing testes to external toxic substances, such as drugs, toxic metals, and organic chemicals is known to elevate the production of reactive oxygen species, including hydroxyl radicals (HO.), superoxide ions (O2−.), and hydrogen peroxide (H2O2). The accumulation of these species within testicular cells results induces oxidative stress, signifying an impaired ability to counteract the generated reactive oxygen species [67,68]. In such unfavorable conditions, oxidative damage to cell components such as enzymes is increasing [69]; and, as a consequence, this may lead to a reduction in testicular function [69], including testosterone production [70]. It is important to note that the extent of oxidative stress, and hence the testicular oxidative damage, in response to induced toxicity may vary in proportion to type of toxicant, the used dose, and the duration of exposure. In this experimental context, numerous studies have explored lipoic acid's potential to ameliorate such induced oxidative damage, primarily through direct quenching of generated free radicals or enhancing the antioxidant defense mechanisms, both enzymatic and non-enzymatic. Specifically, lipoic acid has demonstrated its ability to restore the reduction in the testicular antioxidant enzymes, including catalase, superoxide dismutase, glutathione reductase, and glutathione peroxidase. Additionally, it reinstates the testicular content glutathione that results from induced testicular toxicity [34,39,42,43,44,45,52]. Furthermore, lipoic acid exhibits the capability to reduce the level of malonaldehyde moieties, byproducts of oxidative damage, particularly resulting from peroxidation of polyunsaturated fatty acids (i.e., lipid peroxidation) [42,45,47].

Moreover, in a setting of normal reproductive conditions, aging broiler breeder roosters that were administered a daily dose of 95 mg of lipoic acid for a duration of 8 weeks exhibited reduced levels of seminal malondialdehyde in comparison to the control group [71]. Furthermore, the inclusion of lipoic acid at a concentration of 300 mg/kg in the basal diet led to significant improvements in the activities of superoxide dismutase, glutathione peroxidase, and catalase, resulting in increased total antioxidant activities. Additionally, this supplementation reduced malondialdehyde levels in ROSS 308 breeder roosters [72].

The mechanism underlying lipoic acid's enhancement of the antioxidant defense system is believed, in part, to involve the Nrf2-signaling pathway, along with exerting an antiapoptotic effect [72]. In summary, it can be hypothesized that one of the mechanisms through which lipoic acid boosts testosterone production in males is by fortifying the antioxidant defense mechanisms within the testes while concurrently reducing oxidative damage in this crucial reproductive organ.

3. Stimulating the production of luteinizing hormone

Testosterone, a pivotal hormone primarily synthesized in the Leydig cells of the testes, undergoes intricate regulation by luteinizing hormone (LH), a glycoprotein released from the anterior pituitary gland in response to gonadotropin-releasing hormone. Biochemically, LH plays a crucial role in regulating the gene expression of 17β-hydroxysteroid dehydrogenase (17β-HSD), the enzyme responsible for catalyzing the final step in testosterone synthesis.

Numerous studies have revealed the capacity of lipoic acid supplementation to enhance LH levels in males [40,47,50]. For instance, in rats exposed to carbimazole and subsequently administered oral lipoic acid supplementation at a dose of 60 mg/kg per day for a duration of one month, significantly elevated LH levels were observed when compared to the control group [50]. Similarly, male mice subjected to testicular toxicity induced by di-(2-ethylhexyl) phthalate and treated with lipoic acid at a dosage of 20 mg/kg (p.o.) displayed higher LH levels in comparison to normal animals [47]. Furthermore, lipoic acid demonstrated its capability to restore LH levels in male rats afflicted with pesticide-induced testicular toxicity [40].

Conversely, a randomized clinical trial conducted in 2019 involving infertile men who received a daily dosage of 600 mg of lipoic acid for a twelve-week period revealed an improvement in serum testosterone levels. However, it did not yield a statistically significant effect on LH levels [54]. In combination, these findings suggest that lipoic acid may play a role in enhancing LH production or the restoration of reduced LH levels following reproductive toxicity conditions in experimental animals. Nonetheless, it is crucial to note that this effect requires further investigation in human subjects. Consequently, it can be postulated that the elevation of LH levels could be a contributing factor to the observed positive impact of lipoic acid on testosterone production.

4. Enhancing testicular steroidogenesis

Testosterone is synthesized from cholesterol through a complex enzymatic process. In men, over 95% of testosterone is produced in the testes, primarily within Leydig cells, with the remaining fraction generated in the adrenal gland.

External factors such as medications, chemicals, and dietary components can influence testosterone synthesis, impacting overall testosterone production. In conditions of induced testicular toxicity, pivotal enzymes like 3β-HSD and 17β-HSD play a crucial role in the final stages of testosterone synthesis from precursor molecules, such as androstenediol and androstenedione. Additionally, the expression of steroidogenic acute regulatory protein (StAR), a transport protein responsible for transferring cholesterol between the outer and inner mitochondrial membranes, serves as an indicator of steroidogenesis efficiency in the testes.

Lipoic acid's impact on HSDs and its consequences on testosterone production are active areas of research. Current evidence suggests that lipoic acid may indeed have an impact on testosterone metabolism. Specifically, lipoic acid has been shown to modulate the activity of 3β-HSD and 17β-HSD type 3, while also enhancing the expression and activity of StAR. These actions collectively contribute to the enhancement of testosterone production [73].

In addition, oxidative stress can negatively impact steroidogenesis by disrupting enzymatic pathways and damaging testicular tissue [46]. Lipoic acid, with potent antioxidant properties [74], protects testicular cells from oxidative stress, preserving their functionality and supporting optimal testosterone production [75].

Moreover, chronic inflammation can impair testicular steroidogenesis. Lipoic acid exhibits anti-inflammatory properties by inhibiting pro-inflammatory cytokines and modulating immune responses [76]. By reducing inflammation, lipoic acid supports the proper functioning of the testes and enhances testosterone production.

However, it is important to note that the effects of lipoic acid on testosterone production may depend on various factors, including the concentration of lipoic acid, the specific HSDs enzyme being targeted, and the context in which it is studied. Individual variations in response to lipoic acid can also play a role.

5. Maintaining adequate level of energy production

As previously mentioned, lipoic acid plays a role in maintaining energy production [65]. Serving as a cofactor for several enzymes involved in key metabolic processes, including pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, lipoic acid is essential for the citric acid cycle [65]. These enzymes play a pivotal role in breaking down nutrients and producing energy in the form of adenosine triphosphate. By actively supporting these enzymatic processes, lipoic acid contributes to efficient energy production within the cells, including those involved in testosterone synthesis. This highlights the multifaceted role of lipoic acid in ensuring optimal cellular energy levels, particularly in processes crucial for the synthesis of testosterone.

CONCLUSION AND FUTURE PERSPECTIVES

In conclusion, the substantial body of research consistently indicates that lipoic acid has a notable capacity to effectively restore diminished testosterone levels in the context of testicular toxicity resulting from various toxic agents. It is noteworthy that only three studies reported no discernible impact of lipoic acid on testosterone levels. Consequently, the administration of lipoic acid, particularly in cases of testicular toxicity, emerges as a valuable and promising intervention.

Lipoic acid exerts its influence on testosterone through a multifaceted array of mechanisms. These encompass the augmentation of nitric oxide production, reinforcement of the testicular antioxidant defense mechanism, elevation of LH levels, enhancement of testicular steroidogenesis, and the crucial maintenance of an optimal energy production level. These intricate processes collectively underscore the potential therapeutic significance of lipoic acid in the management of testicular toxicity and its beneficial role in supporting testosterone levels and overall testicular health.

Looking ahead, future perspectives in this field should encompass exploring personalized treatment approaches, tailoring lipoic acid therapy to individual patient profiles, and investigating potential long-term benefits and safety considerations. Furthermore, research efforts should aim to elucidate the precise molecular pathways involved in lipoic acid's impact on testicular health, paving the way for the development of targeted therapies and improved clinical outcomes.

Acknowledgements

None.

Footnotes

Conflict of Interest: The authors have nothing to disclose.

Funding: None.

Data Sharing Statement

All data generated or analyzed during this study are included in this published article.

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Data Availability Statement

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