Introduction
It’s widely recognised that hormones play an important role in the develop of acne. It’s no coincidence that acne is most prevalent during the teenagehood, where the body rapidly develops under the sudden flood of hormones released from the sex organs (testes or ovaries) as well as the pituitary gland. These hormones play a vital role in guiding the body to develop key secondary sexual characteristics, such as broad shoulders in a male, or widening of hips in females.
Whilst some of these changes are desirable, others are less so, and in particular the sudden develop of acne. Acne is especially driven by androgens, which are the typically male hormones such as testosterone, however women’s bodies also produce testosterone in much lower quantities. Androgens are vital, particularly during puberty, so acne treatments that don’t involve hampering androgen signalling are clearly desirable.
Isotretinoin (brand name Accutane) is a retinoid, and for the longest time was believed to be a non-hormonal approach to treating acne by instead acting on the target receptors of Vitamin A. However, in the 40 years since its release, more evidence has come to light to show that Accutane has a number of endocrine (hormone) disrupting effects, including changes to pituitary and gonadal hormones (read more) as well as directly impacting the androgen receptor itself (read more).
The exact nature of these hormonal changes isn’t consistent across studies, and appears to highly depend on the dose and duration of treatment. A study on 47 acne vulgaris patients, with a mean age of 21 years old, identified a suppression in Thyroid Stimulating Hormone (TSH), Luteinising Hormone (LH), and total testosterone. [1]
The samples were taken three months after a five-month course of Accutane at doses ranging from 0.5–0.75 mg/kg body weight. This effect on total testosterone, a 30% drop, might be especially concerning for young men, for whom testosterone is necessary for the development of secondary sexual characteristics such as body hair and muscle development.
This result was slightly less pronounced than that found in a 2019 study by Nasrallah et al. These researchers measured an average 40% reduction in total testosterone across 113 male patients following six months of 0.5 mg/kg per day. [5]
Acta Derm Venereol 2011; 91: 31–34 [1] This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License
Hypothalamic-Pituitary-Testicular axis
Luteinising Hormone (LH), which is released from the pituitary gland, stimulates the synthesis of testosterone in the testes. A drop in LH levels could possibly explain the statistically significant reduction in total testosterone by disrupting the Hypothalamic-Pituitary-Testicular Axis (HPTA). This is the complex feedback mechanism by which the body regulates hormone production to achieve homeostasis.
Interestingly, when the researchers divided the cohort by sex, they found that the drop in LH in men was not statistically significant—although they attribute this to a loss of statistical power. Nonetheless, this presents the possibility that the drop in total testosterone is instead a consequence of primary hypogonadism, where the issue originates from the testes.
Artoria2e5, CC BY 3.0 https://creativecommons.org/licenses/by/3.0, via Wikimedia Commons
Testosterone production is highly sensitive to oxidative stress in the testicles, and increased oxidative stress is one of the triggers of declining testosterone with age. [2] It should not be too surprising, therefore, that Accutane, with its extensive evidence of elevating ROS (Reactive Oxygen Species), could be having a similarly harmful effect on the testes. [3] In fact, in previous articles I’ve highlighted the significance of Accutane in down regulating key enzymes involved in the body’s detoxification processes, namely the Aldehyde Dehydrogenase (ALDH).
These enzymes are involved in a variety of processes throughout the body, including the synthesis of neurosteroids, to the metabolism of dopamine byproducts (read more) – but most pertinently, they are needed to synthesise Retinoic Acid from dietary sources of vitamin A. When the body is exposed to a massive increase in Retinoic Acid signalling during Accutane treatment, these ALDH isoforms downregulate through a negative feedback mechanism. One of the effects of ALDH suppression is an increase in Reactive Oxygen Species and cytotoxicity (read more). This effect is so profound that Accutane can even be used to make chemo cancer treatments more toxic to cancer cells (as well as healthy ones too).
ROS cause DNA damage and trigger cell death. A 2022 study in rats sought to elucidate this possibility by directly examining the tissue samples of testes following 21 days of treatment with the acne drug. [4] The dose used was equivalent to a very low dose in humans, approximately 0.2 mg/kg. At the end of the treatment, the Accutane group had dramatically lower testosterone compared to the control, with 0.6 ng/ml in the Accutane cohort against 1.54 ng/ml in the control. Interestingly, the Accutane group also experienced an increase in LH production, which could be explained as the body attempting to achieve homeostasis.
Examining tissue samples under an electron microscope revealed damage to the testes, with the Accutane group having disturbances in the seminiferous tubules (which generate sperm). Compared to the control group, the Accutane group had decreased tubular diameter and increased inter-tubular distance.
OMEGA- 3 Fatty Acids
Al-Shahed et al. were able to substantiate the notion that these changes to testicular tissue—and subsequently testosterone—are a consequence of increased oxidative stress. They did this by including a third cohort that, as well as being treated with Accutane, were also supplemented with omega-3 polyunsaturated fatty acids.
This was dosed at 400 mg/kg each day, which is equivalent to 70 mg/kg in humans—or around 5 g for a 70 kg man. This cohort experienced a more minor suppression in testosterone levels, measured at 1.1 ng/ml post-treatment compared to 0.6 ng/ml in the Accutane-only group. This difference was also borne out in the tissue samples.
This third group had almost the exact same tubular structures as the control group. This normalisation in tissue health was matched with the appearance of healthy sperm with the characteristic flagella. This group also had only a slight elevation in LH compared to control, which further confirms a restoration in the HPTA axis.
To determine the increase in oxidative stress in response to acne treatment, the researchers also sampled malondialdehyde (MDA). The Accutane group was found to have 3.5 times the serum concentration compared to control; however, the omega-3 supplemented group only had a minor elevation. These findings strongly implicate the toxic effects of Accutane on testicular tissue, and the remediating role of omega-3 fatty acids by reducing oxidative stress.
Article Summary
- Accutane and hormone production: Accutane treatment can have harmful effects on hormone production, particularly on pituitary hormones like Thyroid Stimulating Hormone (TSH), Luteinising Hormone (LH), and testosterone.
- Testosterone reduction: In a study on acne patients, testosterone dropped by 30% following a 5-month course of Accutane, with a similar study showing a 40% reduction in men after six months. This is concerning for young men, as testosterone is essential for development.
- Pituitary-gland impact: LH, which stimulates testosterone production, was suppressed, possibly due to disruptions in the Hypothalamic-Pituitary-Testicular Axis (HPTA).
- Primary hypogonadism possibility: A drop in LH wasn’t statistically significant in men, hinting at primary hypogonadism (testes-originated issue) rather than pituitary problems as a cause for low testosterone.
- Oxidative stress: Oxidative stress, heightened by Accutane, is linked to testicular damage and testosterone decline, supported by studies showing that Accutane increases oxidative stress and damages testicular tissue. Accutane elevates ROS, which damages DNA and leads to cell death in testicular tissue, contributing to lower testosterone production.
- Omega-3 supplementation: An animal study group receiving omega-3 supplements showed less testosterone suppression and healthier testicular tissue compared to the Accutane-only group, indicating omega-3’s protective role against oxidative stress.
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References
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[1] https://www.medicaljournals.se/acta/content/html/10.2340/00015555-1013
[2] https://www.proquest.com/openview/3eca022f8b56176ab84e6957dfe0cab7/1?pq-origsite=gscholar&cbl=105601
[3] https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/abs/10.1002/cbf.2830
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