Testosterone and 5-Alpha-Dihydrotestosterone

Testosterone is the main circulating androgen in men. Its principal source is the testicular Leydig cells, whose activity is regulated by luteinizing hormone (LH). The hypothalamus, pituitary and gonads are connected through feedback mechanisms. In women, testosterone is produced in the ovaries and adrenal glands and through peripheral conversion of precursors.

Androgens contribute to sexual development, hair growth, sex drive, and maintenance of muscle and bone. In men, testosterone is important for reproductive-organ development and, together with other hormones, maintenance of spermatogenesis. Erections and sexual behavior also depend on vascular, neurological and psychological factors and are not determined by testosterone alone.

In women, androgen excess may be accompanied by hirsutism, acne, ovulatory dysfunction and menstrual irregularities. Marked virilization is possible but does not accompany every elevation. Testosterone and other hormone tests are ordered for clinical indications, including suspected hyperandrogenism; they are not mandatory for every cause of infertility.

Total and Free Testosterone

Most circulating testosterone is bound to sex hormone-binding globulin (SHBG) and albumin; a small fraction is free. The loosely albumin-bound fraction may also be available to tissues. The claim that free testosterone is always less than 1% is incorrect: its proportion depends on SHBG and other conditions.

Concentrations vary during the day and between days and depend on age, illness, nutrition and medicines. Age-related decline differs between people. A universal range of 2.6–11 µg/L for every man aged 20–40, or an inevitable 30–50% fall after 60, should not be applied; validated reference values appropriate to the assay and patient are used.

Dihydrotestosterone Formation and Action

The enzyme 5-alpha-reductase converts testosterone to 5-alpha-dihydrotestosterone (DHT) in tissues including the prostate, skin and hair follicles. DHT binds the androgen receptor more strongly, but its action cannot be explained by an allegedly inevitably higher blood concentration. Local production, receptor sensitivity and metabolism matter.

DHT plays a major role in the formation of male external genitalia and the prostate. In adulthood, it contributes to androgen-dependent processes in the prostate, skin and hair. Androgen mechanisms are important in benign prostatic hyperplasia and androgenetic alopecia, but elevated blood DHT alone neither diagnoses these conditions nor predicts prostate cancer.

DHT levels depend on precursor availability, enzyme activity, medicines and clearance. It is incorrect to consider DHT entirely independent of hormonal feedback or dependent only on 5-alpha-hydroxylase: the correct enzyme name is 5-alpha-reductase.

Enzyme Deficiency and Androgen Insensitivity

Type 2 5-alpha-reductase deficiency is associated with pathogenic variants in both copies of SRD5A2 and may affect external genital development in people with a 46,XY karyotype. It is a distinct autosomal recessive condition. Androgen insensitivity syndrome involves impaired androgen receptor function, usually due to AR variants; these conditions must not be confused.

Low DHT with normal or elevated testosterone is not unequivocal proof of a genetic defect. Age, developmental stage, medicines and assay quality must be considered. When suspicion is justified, a specialist may request additional hormonal, functional and molecular genetic investigations.

Choosing Tests

In men, diagnosing hypogonadism requires relevant symptoms and consistently low testosterone concentrations. A low total testosterone result is confirmed with a repeat fasting morning sample on another day. Free testosterone is assessed when indicated, particularly with borderline total levels or altered SHBG, using a reliable method or a validated calculation from total testosterone, SHBG and albumin. DHT is not required in every evaluation for hypogonadism.

Diagen Plus Laboratory offers the following serum tests:

• TESTtot: total testosterone.
• TESTfree: free testosterone.
• DH-TEST: 5-alpha-dihydrotestosterone.

Test selection, preparation and interpretation should be agreed with the clinician. Ordering all three together does not necessarily improve information in every clinical situation.