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DHT: a primary cause of hair loss in men

Written by
XYON Medical Team
Clinically reviewed by
Dr. C. Han, MD, FRCPC
Dr. V. Hasson, MD
Dr. S. Pimstone, MD, PhD, FRCPC

5-alpha reductase (5-AR) is an enzyme synthesized at various sites in the body. It facilitates a number of important chemical reactions, breaking down or catalyzing certain androgens to yield entirely different molecules called metabolites.

Dihydrotestosterone (DHT) is one 5-AR metabolite that’s synthesized from testosterone. DHT plays a key role in male sexual development until puberty, and a large amount of the hormone is necessary during periods of rapid growth. After puberty, elevated DHT has been tied to medical conditions including male pattern hair loss (androgenetic alopecia) and prostate enlargement (benign prostatic hyperplasia).

In this article, we really delve into the science behind DHT production, focusing on the 5-AR enzyme and how it can influence your hair loss. Learn what this enzyme is, what it does and how it can alter your hair health.

How is DHT made?

Testosterone – likely a more familiar hormone – is the starting point of the chemical reaction that yields DHT. Normally, about 10% of circulating testosterone is converted into DHT, and the amount of DHT in circulation should remain proportional to the amount of testosterone (Nassar and Leslie 2021).

Testosterone binds to the 5-AR enzyme at a location called the active site. The hormone is reduced, meaning it gains hydrogen (H) atoms. The byproduct of this chemical reaction, DHT, has a slightly different chemical structure as a result:

The chemical formula for testosterone is C19H28O2

The chemical formula for dihydrotestosterone is C19H30O2

While these two molecules may seem identical, the structural difference means that DHT is a more potent or bioactive androgen. The 5-AR metabolite has a higher affinity for androgen receptors than testosterone – it’s more likely to bind to them (Asada et al. 2001).

Among other sites throughout the body, androgen receptors can be found within hair follicles rooted in your scalp. When DHT becomes attached to androgen receptors within hair follicles, it can stunt hair growth and signal premature termination of the hair growth cycle. The effects of DHT on your locks can range from mild thinning or slight loss of volume to more noticeable hair loss over time.

Beyond DHT: 5-AR metabolites

The 5-AR enzyme plays a part in several steroid hormone reactions in addition to DHT synthesis.

Corticosteroids such as aldosterone, cortisone and cortisol are also produced by 5-AR, typically within the adrenal glands (Davey and Grossman 2016). These metabolites influence energy metabolism, stress response, electrolyte balance, mood, behaviour and immune function (Nixon et al. 2012).

Sex hormones including estrogens, progestrogens and certain androgens – like testosterone – are primarily sythesized by 5-AR within male and female sex organs. Their metabolites contribute to sexual growth and development in different ways (Bremer and Miller 2014).

Note: Medications such as finasteride target hair loss by reducing 5-AR enzyme activity and lowering DHT at the scalp. While rare, some individuals have noted sexual and other side effects as a result of treatment.

It’s thought that some of these side effects are tied to the unintentional inhibition of other chemical reactions synthesized by 5-AR. Select topical finasteride formulations may be able to reduce the drug’s side effect profile by effectively targeting treatment and minimizing widespread, systemic drug action.

5-alpha reductase (5-AR)

The 5-AR enzyme has three known structural variants called isozymes. Each one facilitates a similar set of chemical reactions at different sites throughout the body: 5-AR I, 5-AR II and 5-AR III.

5-AR I and hair loss

Coding gene: SRD5A1

Location of coding gene: chromosome 5p15 (Azzouni et al. 2011)

Primary site(s) of gene expression: liver, skin, prostate gland (Qin et al. 2010)

5-AR I expression has been confirmed within the scalp skin, with SRD5A1 gene expression identified within hair follicles (Sanchez et al. 2018). While it’s thought to contribute to local DHT synthesis, additional research is needed to confirm this isozyme’s clinical significance to hair loss (Bremer and Miller 2014).

5-AR II and hair loss

Coding gene: SRD5A2

Location of coding gene: chromosome 2p23 (Azzouni et al. 2011)

Primary site(s) of gene expression: prostate gland, hair follicles (Asada et al. 2001)

This 5-AR isozyme has the highest clinical significance to the development of AGA and rate of hair loss in individuals with AGA.

Of the 5-AR isoenzymes, 5-AR II appears to be most active within the scalp skin and in hair follicles (Thomas et al. 2008). Mutations in the SRD5A2 gene increase 5-AR II activity within the scalp skin and hair follicles in particular, elevating the concentration of DHT at these specific sites and directly contributing to androgenetic hair loss (Asada et al. 2001).

5-AR III and hair loss

Coding gene: SRD5A3

Location of coding gene: chromosome 4q12 (Azzouni et al. 2011)

Primary site(s) of gene expression: connective tissue, skin

5-AR III doesn’t appear to directly impact DHT levels at the scalp to the same extent as 5-AR I and II, although it has been confirmed within hair follicles (Sanchez et al. 2018). The clinical significance of the 5-AR isozyme in the development of AGA has yet to be determined.

Local DHT concentrations

Local DHT concentrations are tied to the 5-AR isozyme found within surrounding tissue, which we know ultimately boils down to site-specific gene expression (Azzouni et al. 2011).

The concentration of DHT at different sites in the body varies. A greater baseline concentration is typical within reproductive organs, the liver and the skin, corresponding to greater enzyme activity at these sites (Yamana et al. 2010).

The rate of local DHT synthesis by 5-AR also fluctuates. Factors such as biological age and circulating testosterone levels influence site-specific 5-AR expression. In fetal and pubertal males, for example, DHT is synthesized locally at a higher rate than normal (Feldman et al. 2012). Greater 5-AR enzyme action within the sex organs increases the concentration of DHT during these periods of growth (Azzouni et al. 2011).

The genetic factor

Your genetic profile can greatly affect local rates of DHT synthesis throughout the body. Heritable genetic mutations of SRD5A1, SRD5A2 and SRD5A3 can affect the expression of 5-AR isozymes and the production of DHT at various sites throughout the body (Thomas et al. 2008).

Mutations of the SRD5A2 gene are particularly relevant to hair loss, as they impact 5-AR II expression and are most likely to affect DHT levels within the scalp. A genetic condition known as congenital 5-AR II deficiency results from a heritable mutation in the SRD5A2 gene that limits or prevents expression of 5-AR II.

Excess 5-AR II activity can result from overexpression of the SRD5A2 gene. While you can inherit this type of genetic mutation from one of your parents, gene expression can also be influenced by epigenetic factors such as diet, stress, sleep and exercise. Increased 5-AR II enzyme activity in particular has been linked to hair loss in men.

The take-home

5-AR enzyme activity largely determines local concentrations of DHT, a hormone closely tied to pattern hair loss in men. A variety of factors including local gene expression, genetic variation and developmental stage all influence site-specific enzyme activity and ultimately, DHT production.

References

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Azzouni, Faris, et al. The 5 Alpha-Reductase Isozyme Family: A Review of Basic Biology and Their Role in Human Diseases. Advances in Urology, vol. 2012, Dec. 2011, p. e530121, doi:10.1155/2012/530121

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