Is there such thing as needing to take a "break" from steroids or TRT: Androgen Receptor Downregulation?

Hey guys, so something I see online from time to time is the idea that androgen receptors are down-regulated or “burnt out” after a long period of time on AAS or TRT. I’ve even heard a doctor mention that it’s good to “take time off TRT” to allow the receptors to “have a break”.

Basically, the theory is that using AAS or TRT will somehow de-sensitise your androgen receptors and lead to less growth overall if “breaks” are not taken.

I think this idea may come from the fact that thermogenic drugs like clen do lead to receptor downregulation: as a beta-2 adrenergic receptor agonist, long-term use of clenbuterol can lead to de-sensitisation and down-regulation of these receptors. In this study (below), administration of a B2AR agonist (black dots) significantly reduced the number of B2-adrenergic receptors after 20 hours:

However, there is no such evidence that androgen receptors act in the same way and will be down-regulated to such an extent.

In fact, looking at both Testosterone and Oxandrolone (Anavar) across multiple studies, if there was evidence that androgen receptors become fully saturated and de-sensitised, then increasing doses of anabolic compounds wouldn’t stimulate further muscle growth.

And yet, in the research the exact opposite occurs.

And, looking at studies across both testosterone and oxandrolone (which are both commonly studied) provides some valuable insights into this theory.

Testosterone Studies:

• A study conducted by Sinha-Hikim et al. involved varying doses of testosterone enanthate: 125 mg, 300 mg, and 600 mg administered weekly for 20 weeks. As you can see below, it was found that higher doses led to significant increases in muscle fibre growth, indicating a dose-dependent relationship between testosterone and AR content as well as muscle growth.

• Another randomised clinical trial examined the impact of testosterone on muscle AR content and muscle hypertrophy. Men received 200 mg of testosterone enanthate weekly and showed enhanced muscle AR protein and total RNA content compared to the placebo group, resulting in a significant increase in muscle mass. If the “downregulation” theory is to be believed, androgen receptor expression should have decreased, but as you can see, in the group receiving 200 mg T per week, androgen receptor expression was significantly higher (white bar = Testosterone 200 mg/wk group):

Oxandrolone (Anavar) Studies:

• A short-term study involving 6 healthy men used a daily dose of 15 mg of oxandrolone for 5 days. As seen below, AR expression (first chart) increased again in skeletal muscle and muscle protein synthesis (second graph) also increased significantly as a result:

• In a more extended study by Grunfeld et al., different doses of oxandrolone (20, 40, and 80 mg/day) were tested over a 12-week period on men with HIV-associated weight loss. The study found dose-dependent increases in body weight and body cell mass, particularly significant in the 40 mg and 80 mg daily groups - the opposite of what would be expected if the “downregulation” theory was true:

So in short, no, androgen receptors don’t become de-sensitised or down-regulated in any way on TRT or cycle.

Thanks for reading as always.