Melatonin and Testosterone: Is there a connection?

It seems two pandemics are occurring simultaneously in the world today: low testosterone levels in men and widespread insomnia caused by circadian disruption, but is there any connection?

What is testosterone?

Testosterone, the primary male sex hormone, is crucial in maintaining various bodily functions, including muscle mass, bone density, and sperm production. However, as men age, their testosterone levels naturally decline, leading to a plethora of health issues. 

What is melatonin?

Melatonin is widely acknowledged as a pivotal hormone responsible for regulating sleep-wake cycles¹ and seasonal rhythms in vertebrates. Studies have also explored its impact on testosterone levels, particularly among adult males. Furthermore, melatonin plays a crucial yet often overlooked role as an antioxidant.² 

For more information about melatonin, read our blog “What is melatonin and how does it work.”

Sleep and why it is Important

Sleep is crucial for anabolic processes that facilitate the body’s repair and rejuvenation at night. Additionally, it serves a neuroprotective role by allowing the brain to rid itself of harmful free radicals and undergo reorganisation through the glymphatic system. Studies conducted in rodents have demonstrated that sleep deprivation results in cellular damage, which may culminate in replication errors and metabolic irregularities.³ Conditions characterised by impaired sleep, such as insomnia, are associated with adverse alterations in cognition, behaviour, and/or judgment.⁴ 

Insomnia, a prevalent condition affecting approximately 30% of the population, maintains consistent prevalence rates across various nations.⁵ It encompasses challenges in initiating sleep, maintaining sleep, and attaining restorative sleep. Often accompanied by comorbidities like diabetes, sleep apnoea, and medication-related side effects, insomnia poses a considerable public health concern.⁶

Due to the prevalence of sleep disturbances, melatonin supplementation has become widely sought after to enhance sleep quality and promote restorative sleep. Nonetheless, there is considerable curiosity surrounding the efficacy of melatonin, its potential impact on testosterone levels, and whether it may even decrease them.

Does melatonin supplementation cause low testosterone levels?

Due to increasing use of melatonin supplementation there were concerns after press reports stated that melatonin could lower testosterone levels and testosterone secretion. However, a cross-sectional study from 2022 demonstrated that low-dose melatonin (approximately 1mg per day for more than 30 days) had no association with testosterone levels in males over the age of 18 in the US.⁷ These findings confirm an older study which found no impact of oral melatonin, which was tested at a larger dose of 6mg daily for one month, on testosterone secretion and levels in men.⁸

So, we now know that melatonin supplementation does not effect testosterone levels, but is there any evidence to suggest that there could some kind of synergy between the two? 

Does melatonin increase testosterone levels?

Researchers discovered that melatonin receptors are found not only in the brain but are distributed around the body in other tissues and organs, such as the testes.⁹ 

In several animal species, there is evidence to suggest that melatonin increases testosterone levels.¹⁰ Animal studies also demonstrated that melatonin was able to ameliorate the decrease in testosterone levels resulting from agents with known testicular toxicity.¹¹ Whilst in some human clinical trials there has been evidence of an increase in testosterone levels after supplementation with this hormone. The mechanism for this increase remains unknown but can be inferred from animal studies which found that melatonin has a protective effect on Leydig cells by suppressing the mitochondrial signaling of Bax/Bcl-2 apoptosis and increasing testosterone production and enhancing sperm quality in mammals.¹²

Due to the anti oxidant activity of melatonin, it can mop up reactive oxygen species (ROS), this ability has found that it protects against testicular toxicity induced by etoposide, cisplatin, and bleomycin regimen by attenuating nitro-oxidative stress, apoptosis, and inflammation in rats.¹¹

Summary

In simple terms, animal studies have demonstrated that testosterone, which is the primary male hormone, is mainly produced by cells called Leydig cells in the testicles. Its production is largely controlled by signals (cytokines) from another type of cells called Sertoli cells. Melatonin, a hormone produced by the body, plays a role in regulating the activity of Leydig cells, which affects testosterone production. Additionally, melatonin can also influence the growth and energy use of Sertoli cells, ultimately impacting testosterone production. This highlights the significant role of melatonin in regulating the production of testosterone.

Furthermore, melatonin has been discovered to possess antioxidant properties, which serve to safeguard testes and hence testosterone production from oxidative stress. Melatonin functions as a scavenger of free radicals, intercepting them and preventing them from harming the testes and testosterone and sperm production.

So, although the positive protective effects of melatonin on testosterone production has been demonstrated in numerous studies we are still waiting for these initial results to be seen in larger human trials.

References:

1. M. Emet, H. Ozcan, L. Ozel, M. Yayla, Z. Halici, A. Hacimuftuoglu, A Review of Melatonin, Its Receptors and Drugs, Eurasian J Med. 48 (2016) 135–141. https://doi.org/10.5152/eurasianjmed.2015.0267.
2. R. Hardeland, Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance, Endocrine. 27 (2005) 119–130. https://doi.org/10.1385/endo:27:2:119.
3. C. Pieri, M. Marra, F. Moroni, R. Recchioni, F. Marcheselli, Melatonin: a peroxyl radical scavenger more effective than vitamin E, Life Sci. 55 (1994) PL271-276. https://doi.org/10.1016/0024-3205(94)00666-0.
4. A.R. Eugene, J. Masiak, The Neuroprotective Aspects of Sleep, MEDtube Sci. 3 (2015) 35–40.
5. T. Roth, Insomnia: definition, prevalence, etiology, and consequences, J Clin Sleep Med. 3 (2007) S7-10.
6. S. Bhaskar, D. Hemavathy, S. Prasad, Prevalence of chronic insomnia in adult patients and its correlation with medical comorbidities, J Family Med Prim Care. 5 (2016) 780–784. https://doi.org/10.4103/2249-4863.201153.
7. J. Zizzo, R. Reddy, N. Kulkarni, R. Blachman-Braun, R. Ramasamy, Impact of Low-Dose Melatonin Supplementation on Testosterone Levels in U.S. Adult Males, Urology. 169 (2022) 92–95. https://doi.org/10.1016/j.urology.2022.07.048.
8. R. Luboshitzky, M. Levi, Z. Shen-Orr, Z. Blumenfeld, P. Herer, P. Lavie, Long-term melatonin administration does not alter pituitary-gonadal hormone secretion in normal men, Human Reproduction. 15 (2000) 60–65. https://doi.org/10.1093/humrep/15.1.60.
9. Slominski, R.M., Reiter, R.J., Schlabritz-Loutsevitch, N., Ostrom, R.S. and Slominski, A.T., 2012. Melatonin membrane receptors in peripheral tissues: distribution and functions. Molecular and cellular endocrinology, 351(2), pp.152-166.
10. Yang M, Guan S, Tao J, et al. Melatonin promotes male reproductive performance and increases testosterone synthesis in mammalian leydig cells. Biol Reprod 2021;104(6):1322–1336; doi: 10.1093/biolre/ioab046
11. Moradi M, Goodarzi N, Faramarzi A, et al. Melatonin protects rats testes against bleomycin, etoposide, and cisplatin-induced toxicity via mitigating nitro-oxidative stress and apoptosis. Biomed Pharmacother 2021;138:111481; doi: 10.1016/j.biopha.2021.111481
12. Yang M, Guan S, Tao J, et al. Melatonin promotes male reproductive performance and increases testosterone synthesis in mammalian leydig cells. Biol Reprod 2021;104(6):1322–1336; doi: 10.1093/biolre/ioab046