1. Introduction
2. Does Accutane impact your Pituitary Hormones?
3. DHT & 5-alpha Reductase
4. Conclusion
5. Article Summary
6. References
7. Related Articles

Introduction

As it currently stands, there are only two known ways to influence acne: interventions involving PPARs (a set of hormone receptors involved in fatty acid metabolism) and hormonal interventions. It’s no coincidence that acne occurrence is most frequent during the hormone-saturated years of adolescence. It, therefore, shouldn’t be surprising that Accutane treatment can cause radical changes in the hormonal profile, particularly affecting androgens. Androgens are typically male hormones, such as testosterone and dihydrotestosterone (DHT), but they are present in both men and women.

Androgens regulate the process of lipogenesis (sebum production) within the sebaceous glands, making antiandrogen treatments a viable option for acne. Antiandrogens can work in a variety of ways, such as directly blocking the androgen receptor (e.g., Flutamide) or inhibiting the conversion of androgens into more potent ones (e.g., Finasteride). Accutane, being a retinoid, is not typically considered an antiandrogen, yet it influences the androgen status of the patient in a variety of interesting and complex ways.

Does Accutane impact your Pituitary Hormones?

There’s evidence for Accutane directly affecting pituitary hormones, with measurable reduction in TSH (Thyroid Stimulating Hormone), and prolactin, LH (Luteinising Hormone), Testosterone and ACTH (Adrenocorticotropic hormone). [4]

A study involving 47 patients with acne vulgaris, with an average age of 21, found a reduction in Thyroid Stimulating Hormone (TSH), Luteinizing Hormone (LH), and total testosterone levels. Samples were collected three months after the patients completed a five-month course of Accutane, administered at doses between 0.5 and 0.75 mg/kg of body weight.

Acta Derm Venereol 2011; 91: 31–34 [1] This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

Notably, total testosterone levels dropped by 30%, which could be particularly concerning for young men, as testosterone is essential for the development of secondary sexual characteristics, such as body hair and muscle growth. This decrease was slightly less significant compared to the findings of a 2019 study by Nasrallah et al., which reported an average 40% reduction in total testosterone among 113 male patients after six months of treatment with a daily dose of 0.5 mg/kg. [17] Although other studies haven’t identified significant changes in Testosterone, LH, and cortisol. [5]

Luteinizing Hormone (LH), which is produced by the pituitary gland, stimulates testosterone synthesis in the testes. A decrease in LH levels could potentially explain the significant reduction in total testosterone by disrupting the Hypothalamic-Pituitary-Testicular Axis (HPTA), the complex feedback system that regulates hormone production to maintain balance in the body.

Interestingly, when the researchers analyzed the data by sex, they found that the decrease in LH levels among men was not statistically significant, which they attributed to a lack of statistical power. [4] Despite this, the findings raise the possibility that the reduction in total testosterone may instead be due to primary hypogonadism, suggesting that the dysfunction originates in the testes. You can read more about the possible impact of Accutane on the testes here.

Artoria2e5, CC BY 3.0 https://creativecommons.org/licenses/by/3.0, via Wikimedia Commons

Whilst Accutane treatment results in measurable changes to serum hormones, this isn’t the only way in which it exerts a hormonal effect. Of particular interest is the reduction in ACTH secretion. Accutane reduces the binding of transcription factors that control the POMC gene, which is the precursor to both ACTH and alpha-MSH. [6]

ACTH triggers the release of cortisol, which is the stress hormone that peaks in the morning to control the circadian rhythm and could partially explain the reports of fatigue experienced during treatment with the acne drug. Alpha-MSH plays a role in skin pigmentation, and interestingly also sexual behaviour.

In fact, alpha-MSH is so potent at inducing sexual desire that artificial analogues have been used to effectively treat hyposexual disorders in men. [7] This could go some way to explaining the reports of sexual dysfunction linked to Accutane treatment. [8]

DHT & 5-alpha Reductase

As previously stated, one of the ways of lowering the androgen status of the body is by blocking the conversion of androgens into more potent metabolites. The prototypical example of this approach is Finasteride, which inhibits an enzyme called 5-alpha-reductase, which converts testosterone in DHT.

Patients treated with this medication, usually to combat hair loss, will experience a modest increase in testosterone. [9] Despite the increase in testosterone, they will often suffer symptoms typical of androgen deprivation, such as erectile dysfunction. [10] This is because DHT is significantly more androgenic compared to testosterone (read more).

A similar change in androgen metabolism is also in response to Accutane treatment. Gene array analysis of patients treated with the acne drug determined an almost three-fold reduction in the 5-alpha-reductase (Type 1) enzyme after 8-weeks of treatment! [11]

This isn’t the only way DHT is suppressed, however, as Accutane also competitively inhibits an enzyme called RoHD-4 (Retinol Dehydrogenase 4). This enzyme shares some activity with 3-alpha-HSD by converting the weak androgen 3-alpha-androstanediol into DHT. [12] This combined effect on these two enzymes could significantly reduce the androgen load in the sebaceous glands, placing Accutane in a similar category to Finasteride.

Conclusion

Temporary changes in androgen status wouldn’t explain why acne doesn’t return for most patients treated with the acne drug. As it turns out, changes in enzymatic activity may not be so temporary. One of the biggest clues to Accutane’s lasting efficacy is the reports of permanent loss of night vision following treatment. [13]

The loss of night vision has been attributed to the suppression of an enzyme called 11-cis retinol dehydrogenase. [14] This enzyme plays a role in rhodopsin formation, the most abundant protein in the rod cells of the retina (read more). Similarly, retinoic acid treatment can trigger epigenetic suppression of ALDH enzymes, which also play a role in retinoid synthesis. [15]

It’s possible that similar lasting effects are imparted on the RoDH4 enzyme, leading to a long-term reduction in DHT synthesis. An androgenic hypothesis for Accutane’s efficacy is further supported by the fact that individuals with more sensitive androgen receptors have a higher incidence of relapse after treatment with Accutane. [16] I’ve written about the epigenetic mechanism that underlies these changes to enzymatic activity here.

Article Summary

• Accutane’s Hormonal Effects: Accutane causes significant hormonal changes, including reductions in testosterone, LH, TSH, and other pituitary hormones, affecting both men and women.
• Androgen Regulation: Androgens regulate sebum production in the sebaceous glands, and antiandrogen treatments, like Flutamide and Finasteride, are commonly used to manage acne. Accutane, while not a typical antiandrogen, affects androgen levels in complex ways.
• Testosterone Reduction: Studies have shown a 30-40% reduction in testosterone levels after Accutane treatment, which may impact young men’s sexual development and secondary sexual characteristics.
• Impact on the Hypothalamic-Pituitary-Testicular Axis (HPTA): Accutane disrupts the HPTA by lowering LH levels, though in some cases, the reduction is not statistically significant. This suggests testosterone decrease may be linked to primary hypogonadism.
• ACTH and Cortisol Reduction: Accutane lowers ACTH, impacting cortisol production and potentially contributing to fatigue during treatment. The reduction in alpha-MSH (involved in pigmentation and sexual behavior) could explain sexual dysfunction reports linked to Accutane.
• DHT and 5-alpha-Reductase Suppression: Accutane significantly reduces the enzyme 5-alpha-reductase (Type 1), lowering DHT production, similar to Finasteride, which is used for hair loss and androgen deprivation.
• Long-Term Effects: Accutane’s lasting effects, like permanent suppression of certain enzymes (e.g., RoDH4 and 11-cis retinol dehydrogenase), contribute to its long-term efficacy in preventing acne relapse. These changes may involve epigenetic mechanisms and could lead to lasting side effects.

References

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