How Finasteride Changes The Androgen Receptor
Introduction
Whilst many people will be familiar with steroid hormones such as testosterone and estrogen, fewer people know of the targets of these hormones – the steroid hormone receptors. You can think of the hormones circulating through the blood as keys which need to be bound the receptor sites such as the Androgen Receptor, to unlock their effects.
Without these binding sites, hormones like testosterone, simply cannot have an effect on the body. Whilst there has been an increasing recognition of the importance of testosterone in popular culture, with countless online guides on maximising testosterone levels, and even services to replace natural production entirely with TRT (Testostorone Replacement Therapy) – the significance of the Androgen Receptor still remains largely ignored.
Even for professional bodybuilders who attempt to hack their own biology by administering exogenous androgens (such as testosterone and anabolic steroids), their individual response will still largely depend on the availability of these receptor sites. Like hormones, androgen receptor sensitivity is not fixed over time. While genetics significantly influence the body’s sensitivity to androgens, factors such as medications, supplements, and even training can also affect receptor responsiveness. In this article, I’ll explore the mechanisms behind androgen receptor function and present evidence on how Finasteride impacts its activity.
The Androgen Receptor
The androgen receptor can be broken down into different domains, that are key to understanding how ligands (such as testosterone) exert an effect on the body:
Ligand Binding Domain (LBD): This is the region of the androgen receptor that directly binds to hormones such as Testosterone and DHT. When these hormones bind to the LBD, the receptor undergoes physical changes to become active.
The N-terminal domain (NTD): This region of the androgen receptor doesn’t directly bind to hormones such as testosterone. Instead, it provides a binding surface for around 150 different co-activators and co-repressors, through the AF-1 (activation function-1) region. These co-activators can boost the response of androgen receptor to hormones binding the LBD.
Whilst the LBD is the region of the androgen receptor that androgens bind to, the role of the NTD shouldn’t be minimised. In fact, the availability of co-activators to the androgen receptor can dramatically enhance gene transcription even in response to relatively weak androgens. One of these cofactors is a key growth signalling protein called β-catenin, which is one of the downstream effectors of IGF-1 (insulin-like growth factor-1). β-catenin binds to the N-terminal domain of the androgen receptor to give a greatly enhanced transcriptional response to the comparatively weak androgen androstenedione. [1] This effect is so potent that DHEA can have the same effect as dihydrotestosterone (DHT), the most potent androgen naturally produced by the body!
The profound influence of these co-activators, through the N-terminal domain, can cause significant complications in treating prostate cancer. This because even when undergoing androgen deprivation therapy (blocking the effects of androgens), patients with high androgen receptor sensitivity can still experience strong androgen signalling through these otherwise weak peripheral androgens such as DHEA. [2]
Androgen receptor sensitivity
Clearly the NBD is highly relevant in understanding how the body responds to androgens. An important feature of the NBD is that highly dependent on individual genetics, with different people possessing varying degrees of androgen sensitivity based on their genetic make up. The sensitivity depends on the length of the polyglutamine tract on the NTD. This length of this tract determined by the number of CAG repeats. CAG refers to a sequence of cytosine-adenine-guanine in the DNA, and the number of these trinucleotide repeats can have implications for a variety of genetic disorders.
Shorter tracts polyglutamine tracts fewer CAG repeats, resulting in increased androgen receptor sensitivity. The shorter tract length means that the receptor can more effectively recruit co-activators and facilitate gene transcription. Conversely, longer polyglutamine tracts result in worse recruitment of co-activators and a lower androgen receptor sensitivity.
The typical number of CAG repeats is between 10 and 26, however some people may have many more, resulting in Androgen Receptor Insensitivity syndrome. [3][4] On the other hand, Men with fewer CAG repeats are more pre-disposed to aggression and violence. [5] A study on Taiwanese criminals even found that those involved in violent crime had far fewer CAG repeats against controls. [6]
PFS patients have abnormal AR sensitivity
Given the fundamental importance of androgen receptor sensitivity, researchers have investigated its possible connection to Post Finasteride Syndrome (PFS). Cecchin et al. (2014) examined the genomes of 69 patients purporting to have PFS, as well as 91 control patients with androgenic alopecia controls and 76 controls without balding. They found a slightly increased prevalence of extremely long polyglutamine tracts in the PFS cohort. [7]
6% of the PFS group had more that 24 CAG repeats against only 1% in controls – however the median number of repeats didn’t vary across the groups. In fact, patients with abnormally few CAG were also overrepresented in the PFS group, with 19% versus 9% in the controls with androgenic alopecia (and 3% in controls without androgenic alopecia). This study would indicate that both abnormally high and low AR sensitivity are possible risk factors for developing PFS.
Another study that compared the severity of PFS symptoms against the number of CAG repeats found similar results. Those with lower AR sensitivity (CAG repeats more than 25) experienced increased fatigue. However, those with fewer CAG repeats reported more severe loss in libido and sexual desire compared to more CAG repeats. [8] The researchers concluded that worse symptoms were experienced by those on the extremes, both abnormally few repeats and abnormally many CAG repeats, compared to those closer to the average.
Does Finasteride Treatment upregulate the Androgen receptor?
The expression of the androgen receptor can vary in response to androgen stimulation. This is an area of research that has received a lot of attention as it has great importance in effectively treating prostate cancer, which is driven by androgens such as DHT. Attempts to treat prostate cancer with anti-androgen therapies, including Finasteride, is often undermined by a compensatory mechanism that upregulates androgen receptor expression. [9]
A similar effect has been found in biopsies of penile tissue in patients with post finasteride syndrome. Androgen receptor expression was significantly elevated in PFS patients versus controls (9.961 vs. 9.494). [10] It’s also the case that exposure to strong androgens such as DHT can trigger a reduction in AR gene expression. This part of a negative feedback mechanism to prevent overstimulation. AR mRNA is decreased in prostate tissues in response to DHT. [11]
Kennedy Syndrome
Gerraton et al. (2016) present two case studies of PFS, along with an interesting hypothesis centred on the elevation of AR expression in Finasteride treated tissue. As previously outlined, increased CAG repeats on the androgen receptor results in lower AR sensitivity. In an attempt to maintain androgen signalling, the androgen receptor becomes overexpressed. This increase in AR protein isn’t sufficient to counteract the loss in sensitivity, and in fact may even further hamper androgen signalling. [12]
Abnormally high CAG repeats (>40) can manifest in a condition called Kennedy Syndrome. In this case the Androgen Receptor becomes so overexpressed that the AR protein over accumulates and blocks the translocation of AR into the nucleus. The aggregated AR proteins also interfere with the availability of co-factors.
For patients with Kennedy Syndrome, this results in all the typical symptoms one would associate with androgen deprivation, including muscle wasting, sexual dysfunction, and cognitive decline. The Gerraton study draws the obvious comparison to Post Finasteride Syndrome, suggesting that the drop in DHT as a result of Finasteride treatment is sufficient to upregulate AR expression to this same degree of dysfunctional aggregation.
Conclusion
In a previous article I present the convincing evidence that the 5-alpha-reductase can be downregulated through epigenetic mechanisms that persist well after discontinuation of Finasteride (read more). This is likely because DHT can stimulate 5-alpha-reductase in a feedforward loop.
Strong androgens such as DHT destabilise Androgen Receptor mRNA, so it’s possible that this negative feedback loop becomes broken as a result the previously outlined epigenetic repression of 5-alpha-reductase. As a result, the Androgen Receptor protein would remain elevated, and potentially continue to hamper normal androgen signalling.
However, it’s important to recognise that the negative feedback effect of androgens on AR mRNA isn’t universal across all tissues. Studies have also found that in the hippocampus androgens instead up-regulate AR mRNA.[13] Similarly, AR can be upregulated in response to DHT in certain prostate tissue cell types. [14] Although this particular finding deviates from many other similar experiments, which has led to some questioning over the experimental techniques used. [15]
One of the findings that was consistent across the studies on PFS patients was that both abnormally few and abnormally many CAG were both overrepresented against controls. Furthermore, these extremes were both correlated with increased severity of symptoms. This does suggest the AR is likely playing a role. For those with more CAG repeats, the mechanism of AR overexpression observed in Kennedy Syndrome is a plausible contributing factor in the development of PFS. [12] However, how higher AR sensitivity is also a risk to AR protein aggregation is less obvious.
Article Summary
Steroid Hormone Receptors: Hormones like testosterone exert effects by binding to specific receptors (e.g., Androgen Receptor). Without these receptors, the hormones cannot affect the body, even if present in large quantities.
Androgen Receptor Structure: Ligand Binding Domain (LBD) Binds directly to hormones like testosterone, activating the receptor. N-terminal Domain (NTD) Binds co-activators and co-repressors, enhancing the receptor’s response to hormones.
Androgen Sensitivity: Co-activators, like β-catenin, enhance the effect of weak androgens by interacting with the LBD, boosting hormone responses. Variations in androgen receptor sensitivity are linked to the number of CAG repeats (polyglutamine tracts) in the NTD.
Genetic Variability and Sensitivity: Shorter CAG repeats result in higher androgen receptor sensitivity, while longer tracts lead to reduced sensitivity. Fewer CAG repeats are associated with aggression and violent behaviour.
Androgen Receptor Sensitivity and Disease: High androgen receptor sensitivity can complicate prostate cancer treatment due to the continued signalling of weak androgens. Variations in CAG repeats are linked to Post-Finasteride Syndrome (PFS), where both abnormally high and low AR sensitivity contribute to symptoms.
Post-Finasteride Syndrome (PFS): Studies suggest a connection between abnormal CAG repeats and PFS, with both extremes (high or low repeats) associated with increased severity of symptoms. Androgen receptor expression is elevated in PFS patients, potentially contributing to the disorder through a compensatory mechanism.
Kennedy Syndrome: Excessive CAG repeats lead to Androgen Receptor aggregation, interfering with receptor function and causing symptoms like muscle wasting and sexual dysfunction.
Negative Feedback Mechanism: Androgens can downregulate AR mRNA, but this effect is tissue-specific. Overexpression of AR protein in some tissues may contribute to conditions like PFS and may remain elevated even after discontinuing treatments like Finasteride.