The Genetics of Testosterone: What Your DNA Says About Male Hormone Health

Testosterone is one of the most discussed hormones in men’s health, and also one of the most misunderstood. Conversations about it tend to focus narrowly on total testosterone levels — the number on a blood test — as though that single figure fully explains energy, libido, muscle mass, mood, and cognitive function. In reality, how testosterone affects a man’s body depends on a considerably more complex set of variables: how much is produced, how much is converted into other hormones, how much is bound to carrier proteins versus freely active, how sensitively the body’s tissues respond to the hormone’s signals, and how efficiently it is cleared.

Every one of those variables has a genetic dimension. Two men with identical testosterone readings on a standard blood panel can have meaningfully different functional testosterone status — and meaningfully different experiences of the symptoms associated with low or high testosterone — because the genetic architecture of their hormone systems differs. Understanding where those genetic variables sit, and what they actually influence, provides a more accurate framework for making sense of testosterone-related health than a single lab value ever can.

Testosterone is relevant to women’s health as well — women produce testosterone in smaller amounts and it plays roles in libido, energy, bone density, and mood across the female lifespan — but this article focuses primarily on male hormone health, where testosterone’s effects are most prominent and most studied.

How Testosterone Is Produced and Regulated

In men, testosterone is produced primarily by Leydig cells in the testes, with a smaller contribution from the adrenal glands. Like cortisol — which shares upstream biosynthetic machinery — testosterone production begins with cholesterol and proceeds through a series of enzymatic steps. Production is regulated by the hypothalamic-pituitary-gonadal (HPG) axis: the hypothalamus releases gonadotropin-releasing hormone (GnRH), which signals the pituitary to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn signal the testes to produce testosterone. Like cortisol’s negative feedback loop, rising testosterone levels signal back to the hypothalamus and pituitary to reduce stimulatory output — maintaining production within a regulated range.

Genetic variants influencing any step in this cascade — GnRH signaling, LH receptor sensitivity, the enzymatic steps of testosterone synthesis, or the feedback sensitivity of the hypothalamus and pituitary — can alter where an individual’s testosterone production settles. This is why there is a wide range of what constitutes normal testosterone across healthy men, and why two men with similar lifestyles and body compositions can have substantially different baseline hormone levels.

CYP17A1: A Key Enzymatic Step in Testosterone Synthesis

CYP17A1 encodes the enzyme 17α-hydroxylase/17,20-lyase, which catalyzes two critical steps in the production of both androgens and estrogens from cholesterol-derived precursors. In the adrenal glands and testes, CYP17A1 is responsible for converting pregnenolone and progesterone intermediates into DHEA and androstenedione — the immediate precursors to testosterone. Variants in CYP17A1 that affect enzyme activity alter androgen precursor production, which influences both testosterone levels and the substrate available for downstream hormonal conversions. This gene has been studied in relation to differences in sex hormone profiles across men, as well as prostate cancer risk, where androgen availability is a relevant biological factor.

LHCGR: How the Testes Respond to the Pituitary Signal

Luteinizing hormone receptor — encoded by LHCGR — is the receptor on Leydig cells that receives the LH signal from the pituitary and triggers testosterone production in response. Variants in LHCGR affect receptor sensitivity and signaling efficiency: men with more sensitive LHCGR variants produce more testosterone in response to a given LH signal, while those with less sensitive variants require stronger pituitary stimulation to achieve the same output. This means that two men with identical LH levels may have different testosterone levels if their LHCGR genotypes differ — a distinction that standard hormone panels measuring only testosterone and LH can miss entirely.

Testosterone Conversion: What Happens After It’s Made

Once produced, testosterone doesn’t act only as itself. It undergoes enzymatic conversion into other hormones — most notably dihydrotestosterone (DHT) and estradiol — that have distinct effects on different tissues. The balance between testosterone, DHT, and estradiol is a critical determinant of how the androgen system actually functions in any given man, and that balance is substantially controlled by genetics.

SRD5A2: Converting Testosterone to DHT

5α-reductase type 2 — encoded by SRD5A2 — converts testosterone into dihydrotestosterone (DHT) in the prostate, skin, hair follicles, and genital tissue. DHT is a significantly more potent androgen than testosterone — it binds to the androgen receptor with roughly five times the affinity of testosterone — and drives many of the androgenic effects most associated with male physiology: prostate development and growth, beard and body hair development, and the male pattern hair loss that affects a large proportion of men as they age.

Variants in SRD5A2 alter 5α-reductase activity, changing the rate of testosterone-to-DHT conversion. High-activity variants increase DHT production from a given testosterone level, which has implications for prostate health — DHT drives prostate cell proliferation and is central to the pathophysiology of benign prostatic hyperplasia (BPH) and prostate cancer. Medications called 5α-reductase inhibitors (finasteride, dutasteride) work by blocking SRD5A2 activity and are used clinically for both BPH treatment and male pattern hair loss. Genetic variants in SRD5A2 that influence baseline enzyme activity are one of the reasons men vary in their susceptibility to DHT-driven conditions and in their response to these medications.

CYP19A1: Converting Testosterone to Estradiol

Aromatase — encoded by CYP19A1, discussed in the context of female hormone health in the previous article — converts testosterone into estradiol in adipose tissue, the brain, bone, and other peripheral sites. This conversion is not merely a female hormone story: estradiol is essential for male bone density, cardiovascular health, libido, and cognitive function, and testosterone-derived estradiol is the primary estrogen source in men. Problems arise at both extremes — too little aromatization can impair bone density and libido; too much can reduce free testosterone availability and drive estrogen-related effects including gynecomastia (breast tissue development in men).

CYP19A1 variants that increase aromatase activity cause more testosterone to be converted to estradiol, reducing the testosterone available for androgenic effects while simultaneously increasing estrogenic signaling. This conversion is amplified by body fat, since adipose tissue is a major site of aromatase expression — which is one reason excess body fat tends to lower testosterone and raise estradiol in men, and why men with high-activity CYP19A1 variants are more sensitive to this effect than those with lower-activity variants at the same body composition.

How Your Tissues Respond to Testosterone: Receptor Genetics

Even when testosterone and DHT levels are measured and found to be within normal range, the tissues’ sensitivity to those hormones can vary substantially — and that sensitivity is genetically regulated through the androgen receptor.

AR: The Androgen Receptor Gene

The androgen receptor — encoded by the AR gene on the X chromosome — is the protein through which testosterone and DHT exert their effects inside cells. Testosterone or DHT binds to the androgen receptor, causing it to enter the cell nucleus and regulate the expression of genes involved in muscle protein synthesis, prostate cell growth, libido, red blood cell production, and numerous other androgen-responsive processes.

The AR gene contains a region with a variable number of CAG repeats — a sequence of three nucleotides repeated in tandem — within its coding sequence. The number of CAG repeats varies between men and has a direct, well-documented effect on androgen receptor sensitivity: fewer CAG repeats are associated with a more sensitive receptor that responds more strongly to a given testosterone or DHT level, while more CAG repeats produce a receptor with reduced sensitivity that requires higher hormone concentrations to generate equivalent biological effects.

This single genetic variable has broad implications. Men with shorter CAG repeat lengths — more sensitive receptors — experience stronger androgenic effects from the same testosterone level compared to men with longer repeat lengths. Research has linked shorter AR CAG repeats to higher rates of male pattern baldness, greater prostate cancer aggressiveness, and elevated muscle-building response to resistance training. Longer repeat lengths have been associated with lower androgenic drive at equivalent testosterone levels, reduced prostate cancer risk, and in some studies, a modest association with aspects of fertility. The practical implication is that a man with a high-sensitivity AR genotype may be functionally androgen-replete at a testosterone level that would leave a man with a low-sensitivity receptor feeling significantly symptomatic.

Free vs. Bound Testosterone: The SHBG Factor

Not all the testosterone circulating in the bloodstream is equally available to tissues. The majority — roughly 60 percent — is tightly bound to sex hormone-binding globulin (SHBG), a carrier protein produced by the liver that binds testosterone (and estradiol) with high affinity, rendering them biologically inactive while in that bound state. Most of the remainder is loosely bound to albumin and can be released relatively easily. Only a small fraction — typically 1 to 3 percent — is completely free and immediately available to bind androgen receptors in tissues.

SHBG levels are highly variable between men, and a significant portion of that variation is genetic. The SHBG gene contains promoter variants that affect how much SHBG the liver produces. Men with high SHBG production bind more testosterone, reducing free testosterone availability even when total testosterone measured by a standard blood test appears adequate. Men with low SHBG have more free testosterone available to tissues. This is one of the most common reasons why a man with total testosterone in the normal range experiences symptoms typically associated with low testosterone — his SHBG is high enough that free testosterone, the fraction that actually drives androgenic effects, is meaningfully reduced.

SHBG levels are also influenced by insulin sensitivity, thyroid function, liver health, and body composition — all of which interact with the underlying genetic setpoint. Men with SHBG-elevating gene variants who also have additional factors that raise SHBG — such as hyperthyroidism or very low body fat — can find their free testosterone substantially below what total testosterone suggests.

Testosterone Metabolism and Clearance

Testosterone is cleared from the body through conjugation reactions in the liver — primarily glucuronidation by UGT enzymes and sulfation by SULT enzymes — that make it water-soluble for renal excretion. Variants in UGT2B17 and UGT2B15, the primary UDP-glucuronosyltransferases responsible for testosterone glucuronidation, are among the most impactful in this context. UGT2B17 in particular carries a well-documented copy number variant — a gene deletion polymorphism where some men carry zero, one, or two functional copies. Men who are homozygous for the UGT2B17 deletion clear testosterone more slowly, resulting in higher testosterone and testosterone metabolite levels for a given production rate. This variant is actually detectable in anti-doping testing, since it produces a characteristic testosterone-to-epitestosterone ratio in urine that differs from the typical range.

Putting It Together: What Testosterone Genetics Means in Practice

The cumulative picture from testosterone genetics is that the hormone system involves at least four independent layers of genetic variation: production (CYP17A1, LHCGR), conversion (SRD5A2, CYP19A1), receptor sensitivity (AR CAG repeats), and availability/clearance (SHBG, UGT2B17). A man’s functional androgen status — how testosterone actually manifests in his experience and health — is the product of his specific combination of variants across all these layers, not the output of any single gene or the reading from a standard hormone panel.

This has concrete practical implications. For men experiencing symptoms associated with low testosterone — reduced energy, low libido, difficulty building muscle, mood changes, cognitive fogginess — standard testing that returns a normal total testosterone result does not fully address the question. Free testosterone, SHBG, estradiol, DHT, and the genetic factors shaping each of these should ideally be part of the picture. A man with a low-sensitivity AR genotype, high SHBG production, and high CYP19A1 aromatase activity may have a total testosterone number that looks entirely adequate while his tissue-level androgenic signaling is substantially lower than that number implies.

For men concerned about prostate health and DHT-driven conditions, SRD5A2 and AR CAG repeat length are particularly relevant variables. For men dealing with testosterone-to-estradiol balance issues — whether presenting as gynecomastia, mood disruption, or unexplained total testosterone decline with weight gain — CYP19A1 variants and their interaction with body composition deserve attention.

A DNA report analyzing the male hormones pathway maps out the specific variants across production, conversion, receptor, and clearance genes, translating the genetic complexity of the testosterone system into a coherent, personalized picture of how your hormonal biology is configured and where the most meaningful variables in your individual hormone health are likely to lie.

Frequently Asked Questions

If my total testosterone is normal on a blood test, why might I still feel symptoms of low testosterone?

Several genetic variables can produce low functional androgen status despite normal total testosterone. High SHBG due to SHBG gene variants reduces free testosterone below what total testosterone implies. A longer AR CAG repeat length means androgen receptors respond less sensitively to the testosterone that is present. High aromatase activity from CYP19A1 variants converts more testosterone to estradiol, reducing androgenic signaling while raising estrogenic signaling. Any of these — alone or in combination — can produce symptomatic low androgen status that standard total testosterone testing misses.

Does the AR CAG repeat length affect risk for prostate cancer?

Research has found associations between shorter AR CAG repeats — indicating more sensitive androgen receptors — and more aggressive prostate cancer behavior once it develops. The receptor’s heightened sensitivity to DHT may promote more vigorous cell proliferation in prostate tissue. This doesn’t mean shorter CAG repeats cause prostate cancer, but it does suggest that androgen receptor sensitivity is one genetic variable influencing how aggressively prostate cancer progresses if it occurs. Longer CAG repeats are associated with a somewhat more favorable prostate cancer risk profile in epidemiological studies.

Why does body fat lower testosterone in men?

Adipose tissue contains aromatase enzyme, which converts testosterone to estradiol. More body fat — particularly visceral fat — means more aromatase activity and more testosterone being diverted to estradiol conversion. The resulting higher estradiol also feeds back to the hypothalamus and pituitary, suppressing LH release and thereby reducing the signal driving testicular testosterone production. Men with high-activity CYP19A1 variants are more sensitive to this effect, meaning the same amount of excess body fat produces a larger reduction in their testosterone-to-estradiol ratio than it does in men with lower-activity aromatase genetics.

What is DHT, and is it good or bad?

DHT is dihydrotestosterone — a more potent androgen than testosterone itself, produced from testosterone by 5α-reductase enzymes in certain tissues. It drives androgenic effects in the prostate, skin, and hair follicles more powerfully than testosterone does. Whether DHT is “good or bad” depends entirely on context: it is essential for normal male development, contributes to libido and sexual function, and supports certain androgenic tissue effects. At the same time, excess DHT activity in the prostate contributes to benign prostatic hyperplasia, and DHT’s effect on hair follicles drives male pattern hair loss in genetically susceptible men. The balance matters more than the absolute level.

Can genetics explain why some men respond better to testosterone therapy than others?

Yes, significantly. AR CAG repeat length influences how sensitively tissues respond to administered testosterone — men with shorter repeats may achieve greater clinical benefit from a given dose, while those with longer repeats may need higher levels to achieve comparable effects. SHBG genetics determines how much administered testosterone is bound versus free. CYP19A1 variants influence how much is aromatized to estradiol, which affects both the ratio of androgenic to estrogenic effects and the need for aromatase inhibitor use alongside therapy. Understanding these genetic factors before initiating testosterone therapy provides a more personalized basis for dosing and monitoring decisions.