1. Introduction
2. androgen sensitivity
3. Accutane causes reduced AR binding
4. Is β-catenin suppression the culprit?
5. Restoring the Androgen Receptor with Carnitine
6. Article Summary
7. Related Articles
8. References

Introduction

Androgen signalling plays a crucial role in the development of acne, influenced not just by hormonal levels but also variations in the androgen receptor (AR) gene. Androgens like Testosterone and DHT plainly exacerbate acne, and while isotretinoin has been shown to alter serum hormone levels, this effect is typically minor and transient.

However, this doesn’t mean that Androgenic signalling isn’t involved in Accutane’s therapeutic effects. The AR’s influence on androgenic effects in the body is just as significant as that of the hormones themselves. Hormones circulating in the bloodstream can be thought of as keys that need to bind to specific receptor sites, such as the Androgen Receptor, to unlock their effects.

Without these receptor sites, hormones like testosterone, regardless of abundance, cannot influence the body. For example, bodybuilders may attempt to manipulate their biology by using exogenous androgens (such as testosterone or synthetic derivatives), but their individual response largely depends on the availability of these receptor sites.

androgen sensitivity

Individual variations in sensitivity to androgens are linked to differences in the N-terminal domain of the androgen receptor (AR), particularly the length of the polyglutamine tract (CAG repeats). This length is strongly associated with the degree of virilization and androgen signalling, with shorter tracts (fewer CAG repeats) leading to greater androgen sensitivity.

In contrast to the C-terminal domain, which binds directly to ligands like testosterone and DHT, the N-terminal domain serves as a binding surface for around 150 co-regulators and co-repressors. These co-regulators modulate the androgen receptor’s response when it is activated by androgens like DHT.

The length of the polyglutamine tract is significant enough that extreme variations can result in conditions such as complete androgen insensitivity. Interestingly, a study on individuals reporting post-Finasteride syndrome found a higher number of CAG repeats in their AR genes, indicative of lower androgen sensitivity compared to controls. [1]

Additionally, the androgen receptor plays a role in the anti-acne effects of isotretinoin (Accutane), which may also relate to the development of post-Accutane syndrome (PAS). Patients with shorter polyglutamine tracts (fewer than 20 CAG repeats) in the AR are observed to have higher relapse rates and require higher doses of isotretinoin. This suggests that the androgen receptor may influence treatment outcomes beyond the retinoic acid receptor (RAR)-mediated mechanism of cell apoptosis typically associated with isotretinoin.

Another clue that androgenic mechanisms may be relevant to understanding how Accutane works, is the incidence of ‘Dry Eyes’ (also called Meibomian Gland Dysfunction) caused by the treatment. The Meibomian gland secretes lipids prevent the eye from drying out. Up to 27% of patients undergoing Isotretinoin treatment experience some degree of meibomian gland dysfunction.

Notably, the meibomian gland, is highly sensitive to androgens, with these hormones impacting the expression of around 3000 genes. Individuals with complete androgen insensitivity syndrome (CAIS) are twice as likely to experience MGD compared to the general population.[2]

In a remarkable study, researchers successfully mitigated MGD caused by isotretinoin using the topical application of DHEA, an androgen precursor. [3] This finding suggests that isotretinoin impacts androgenic signalling pathways. Such insights could also be relevant in understanding MGD associated with the use of finasteride, another medication known to interact with androgen pathways (read more). [4]

Accutane causes reduced AR binding

Research has demonstrated a direct impact of isotretinoin on the androgen receptor (AR). A specific study observed a significant decrease in AR-positive cells in male skin biopsies after a 12-week isotretinoin treatment, dropping from 26.6% to 20.6%.[5]

Furthermore, the researchers identified a minor yet statistically insignificant alteration in AR binding affinity (from 0.44 to 0.32 nmol/L), coupled with a more substantial 2.6-fold reduction in binding capacity.[6] Binding capacity, in this context, refers to the concentration of receptors in the cytosol. These studies also noted a decrease in dihydrotestosterone (DHT) and its metabolite, 5-alpha-androstane-3beta-17beta-diol.

Interestingly, parallels were drawn with cases of androgen insensitivity syndrome (AIS), where genetic polymorphisms result in normal AR binding affinity but reduced binding capacity, leading to the AIS phenotype. [7] This comparison suggests that isotretinoin’s effect on AR could have broader implications for understanding androgen signalling pathways and related disorders.

Is β-catenin suppression the culprit?

The Wnt/β-catenin pathway regulates growth and cell proliferation, as well as immunity via the T-cell factor (TCF). One of the mechanisms of Accutane is the suppression of β-catenin signalling by enhancing the destruction-complex that binds β-catenin in the nucleus in a variety of tissues throughout the body. It does this through disruption of the PI3K/Akt pathway which upregulates GSK3 (one of the kinases that composes the destruction complex).

β-Catenin is an important co-regulator of the androgen receptor. Its cytoplasmic levels are elevated in response to Wnt signaling, which inactivates GSK3 within the destruction complex. In this role, β-catenin interacts with the ligand-binding domain (LBD) of the AR and influences the transcriptional activities the AR’s N-terminal domain (NTD). [8][9]

It’s important to note that β-catenin binds to the AR only in the presence of ligand agonists, but not antagonists. The interaction of β-catenin with the AR LBD leads to an increase in transcriptional activity following ligand binding. The Wnt/β-catenin pathway is suppression during Accutane treatment, potentially through epigenetic mechanisms that continue beyond drug cessation. [10]

Restoring the Androgen Receptor with Carnitine

Researchers have discovered that it may be possible to increase androgen receptor sensitivity by supplementing a particular compound often found in meat called carnitine. A study of 10 resistance-trained men were supplemented with L-carnitine in the form L-carnitine L-tartrate (LCLT) for 3 weeks before taking muscle biopsies. [11] The researchers were aiming to investigate how supplementing L-carnitine may modulate the response to exercise in the short period after training has been completed.

It’s known that the androgen receptor is influenced by training alone, since AR mRNA (although not protein) is elevated 48 hours after training. [12] However there is a relevant lack of research on the impact of resistance training on androgen receptors immediately after training. It’s been hypothesised that L-carnitine supplementation could preserve androgen receptors in muscle tissue that been broken down during training, and thereby improve recovery.

The test group consumed a total of 2g of L-carnitine evenly split across breakfast and lunch each day. The morning training regimen consisted of a typical compound movement routine including bench press, squat, bent-over row, and shoulder press. The biopsies from the quadricep leg muscles revealed a dramatic increase in AR content versus control. Additionally, feeding after the training further enhanced AR content compared to pre-training values. The researchers also found that there was also a greater cellular uptake in testosterone as compared to control.

The impact of carnitine supplementation on androgen signalling is so profound that it’s even been found analogous to testosterone replacement therapy. A study of 120 patients given either testosterone undecanoate, carnitine (2g of propionyl-l-carnitine per day with acetyl-l-carnitine 2g per day) or placebo, found that both testosterone and carnitine significantly improved erectile function and reduced fatigue. [13]

In fact, the carnitine protocol proved to be significantly more effective at improving nocturnal erections than testosterone. Acetyl-l-carnitine (ALCAR) might have an advantage in being better at crossing the blood brain barrier than other preparations. [14] In other articles I’ve highlighted the beneficial role of ALCAR is restoring ALDH activity, perhaps mediated through an increase in β-catenin signalling (read more).

Article Summary

• Androgens and acne: Androgen signalling, especially through Testosterone and DHT, exacerbates acne. Variations in the androgen receptor (AR) gene, particularly in the N-terminal domain, influence sensitivity to androgens.
• Role of AR gene in androgen sensitivity: Shorter polyglutamine tracts (fewer CAG repeats) in the AR gene lead to greater androgen sensitivity and more pronounced androgenic effects.
• AR and acne treatment: Isotretinoin (Accutane) affects androgen signalling, influencing acne treatment outcomes. AR’s role is significant, as patients with fewer than 20 CAG repeats tend to relapse more frequently and require higher doses of isotretinoin.
• Androgen receptor and meibomian gland dysfunction (MGD): Isotretinoin may cause MGD (dry eyes) due to its impact on androgen signalling in the meibomian glands, which are highly sensitive to androgens.
• Isotretinoin’s impact on AR: Studies show isotretinoin reduces AR-positive cells and AR binding capacity in the skin, suggesting that isotretinoin affects androgen receptor pathways.
• β-catenin and AR interaction: The Wnt/β-catenin pathway influences AR activity by interacting with its ligand-binding domain, modulating transcriptional activities. Isotretinoin suppresses this pathway, potentially influencing androgen signalling and cell proliferation.

Related Articles

How Finasteride Changes The Androgen Receptor

How Accutane Changes Your Hormones

References