Testosterone is often called the "strength hormone," but it doesn't build anything by itself. All the work is done by the androgen receptor, a protein that reads the hormonal signal and turns on the necessary genes. The editors explain how this receptor is arranged, how the signal travels from the blood to the cell nucleus, and which popular ideas about it do not stand up to scrutiny.
What is androgen receptor
Androgen receptor (AR) is a protein that "recognizes" male sex hormones and converts their signal into a change in gene activity. It belongs to a large family of nuclear receptors that also includes estrogen, progesterone, glucocorticoid, and vitamin D receptors (Mangelsdorf et al., 1995).
The AR gene is on the X chromosome. In most people with an XY karyotype there is one copy, so a function-altering variant can have substantial effects. Androgen insensitivity ranges from partial to complete; complete androgen insensitivity can lead to typical female external genital development despite an XY karyotype and testicular androgen production.
This illustrates the importance of a functioning androgen receptor for direct androgen signaling. It is not a claim that every effect of testosterone uses AR: conversion to estradiol and signaling through estrogen receptors also matter.
Androgen receptors are found in many tissues: skeletal muscles, bones, skin, hair follicles, prostate, testicles, liver, heart, brain. It is because of such a wide presence that androgens simultaneously affect strength, mood, lipids, hematopoiesis and skin condition.
Receptor structure
The receptor molecule consists of several functional areas - domains. Each of them is responsible for a separate step in signal transduction, and understanding this structure helps explain why different substances act in different ways (Davey, Grossmann, 2016).
| Domain | Function | Practical significance |
|---|---|---|
| N-terminal (NTD) | Activation of transcription, interaction with coregulators | Contains a polyglutamine (CAG) region of variable length |
| DNA binding (DBD) | Recognizes DNA regions — androgen response elements | Determines which genes will be "turned on" |
| Hinge region | Supports transport into the nucleus | Regulates the stability and mobility of the receptor |
| Ligand-binding (LBD) | Binds testosterone, DHT and other ligands | The affinity of different molecules depends on it |
The ligand-binding domain has a "pocket" into which the hormone enters. The shape of the molecule determines how tightly it fits there and how the conformation of the receptor changes. Dihydrotestosterone binds more strongly and detaches more slowly than testosterone, so the signal is stronger in the tissues where it is formed.
The N-terminal domain contains a glutamine amino acid repeat encoded by the CAG sequence. The length of this repetition varies from person to person. In studies, a shorter repeat is associated with slightly higher receptor activity, and a longer one with slightly lower, although the effect on an individual person is small and depends on many other factors.
So, the receptor is not a simple "switch", but a complex machine with several points of regulation. That is why different molecules that bind to the same receptor can produce a different set of effects in different tissues.
Signal pathway: from hormone to gene
The classical mechanism of action of androgens is described as genomic. It consists of several successive steps, each of which takes time, so the effects do not develop instantly, but over hours and days.
- The hormone passes through the cell membrane due to its fat solubility.
- In the cytoplasm, it binds to a receptor from which chaperone proteins (heat shock proteins) are released.
- The hormone–receptor complex changes shape, forms a pair (dimer) and moves into the nucleus.
- In the nucleus, the complex binds to androgen response DNA elements.
- It is joined by coregulators — proteins that increase or decrease transcription.
- Messenger RNA synthesis and, as a result, protein synthesis changes.
Coregulators deserve special attention. Dozens of them have been described, and the set of coregulators in different cells is not the same (Heinlein, Chang, 2002). This is one of the explanations why the same hormone in the muscle stimulates the growth of fibers, and in the hair follicle of the scalp, on the contrary, contributes to its miniaturization.
In addition to the genomic pathway, rapid non-genomic effects of androgens have been described, developing in seconds-minutes through signaling cascades near the membrane. Their practical significance in humans has been studied worse than the classical mechanism.
Receptors in muscles and other tissues
In skeletal muscles, the androgen receptor is present both in the muscle fibers themselves and in satellite cells — reserve cells that help recovery and growth. Activation of the receptor increases the synthesis of muscle protein and contributes to the inclusion of new nuclei in the fibers.
The classic study by Bhasin et al. (1996) showed that supraphysiological doses of testosterone increase muscle mass and strength even without training, and in combination with training, the effect is even greater. This result confirms that the amount of available hormone, not just the number of receptors, is important for the response.
In bones, androgens maintain mineral density partly directly, partly after conversion to estradiol. In the skin, the receptor stimulates the sebaceous glands, which explains the tendency to acne. In the bone marrow, androgens increase erythropoiesis, therefore, with their excess, the hematocrit increases.
In the brain, androgen receptors are involved in the regulation of libido, motivation, and behavior. They are also in the hypothalamus and pituitary gland, where they participate in a negative feedback mechanism that suppresses the production of hormones when they are received from the outside.
Common myths about receptors
Many simplistic ideas have formed around androgen receptors in the sports environment. The editors have collected some of the most common ones.
- "Receptors saturate, so large doses are useless." A dose-dependent increase in muscle mass in clinical trials was observed over a wide range of doses (Bhasin et al., 2001). At the same time, side effects increased along with the dose.
- "Receptors must be "rested", otherwise they "burn out". There are no convincing data on a clinically significant decrease in AR sensitivity in humans with the use of androgens; breaks are important primarily for the restoration of one's own hormonal axis and organ systems.
- "Stronger binding is always stronger anabolism." Receptor affinity is only one factor; tissue metabolism, binding with blood proteins, aromatization and other mechanisms.
Another common idea is that it is possible to "selectively" activate receptors only in muscles. It is on this idea that the development of SARMs is built, but real data shows that they also suppress your own testosterone and affect lipids. None of them are registered as medicinal products and all are banned by WADA.
Finally, the level of the hormone in the blood is not the only indicator of the activity of the androgenic system. The biological response depends on the free fraction of the hormone, local metabolism and the genetic characteristics of the receptor, so the same tests in two people do not guarantee the same effects.
Editorial conclusions
The androgen receptor is a nuclear signaling protein central to direct androgen effects. Its multiple functional domains help explain tissue-specific responses; testosterone can also act indirectly after conversion to other hormones.
The classical mechanism of action includes hormone binding, transfer to the nucleus, interaction with DNA and co-regulators. It is the tissue set of coregulators that partially determines whether the effect will be desirable or adverse.
The wide presence of receptors in the body means that any interference with the androgen system has systemic consequences — from muscles and bones to the heart, blood and psyche.
To continue the topic, we recommend editorial materials on 5-alpha-reductase and DHT, on the anabolic and androgenic index, and on the aromatization of testosterone.
References
- Mangelsdorf DJ, Thummel C, Beato M, et al. The nuclear receptor superfamily: the second decade. Cell. 1995;83(6):835–839.
- Davey RA, Grossmann M. Androgen receptor structure, function and biology: from bench to bedside. Clin Biochem Rev. 2016;37(1):3–15.
- Heinlein CA, Chang C. Androgen receptor (AR) coregulators: an overview. Endocr Rev. 2002;23(2):175–200.
- Bhasin S, Storer TW, Berman N, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med. 1996;335(1):1–7.
- Bhasin S, Woodhouse L, Casaburi R, et al. Testosterone dose-response relationships in healthy young men. Am J Physiol Endocrinol Metab. 2001;281(6):E1172–E1181.
- Kicman AT. Pharmacology of anabolic steroids. Br J Pharmacol. 2008;154(3):502–521.
- Pope HG Jr, Wood RI, Rogol A, et al. Adverse health consequences of performance-enhancing drugs: an Endocrine Society scientific statement. Endocr Rev. 2014;35(3):341–375.
