Testosterone Physiology
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Direct answer
Leydig cells — the interstitial cells constituting roughly 5-20 per cent of testicular volume — produce about 5-7 mg of testosterone daily under luteinising hormone drive, with plasma levels in adult men of 300-1,000 ng/dL (10-35 nmol/L), peaking in the early morning and sampled clinically between 8 and 10 AM. The hormone circulates 60-70 per cent bound to sex hormone-binding globulin (high-affinity, inactive), 30-40 per cent loosely to albumin, and 1-2 per cent free — free plus albumin-bound forming the bioavailable fraction. Two peripheral conversions extend its reach: 5-alpha-reductase converts testosterone to dihydrotestosterone, two to three times more potent, which drives the prostate and external genitalia (the step finasteride blocks), and aromatase converts it to oestradiol, which protects male bone and brain. Feedback runs through GnRH pulse frequency and inhibin B from Sertoli cells suppressing FSH; intratesticular testosterone, some 100-fold plasma levels, sustains spermatogenesis — which is why exogenous anabolic steroids, suppressing LH, cause testicular atrophy and azoospermia.
What you must remember
- Synthesis chain: LH receptor (Gs, cAMP) on the Leydig cell, StAR protein moves cholesterol into mitochondria (the rate-limiting step), then the standard steroidogenic cascade to testosterone — the exam answer to "which cell, which second messenger, which rate-limiting protein".
- Levels and timing: 5-7 mg daily production; 300-1,000 ng/dL in men (women 15-70 ng/dL); diurnal rhythm with 8 AM peak — sample in the morning or falsely low results follow.
- Transport triad: SHBG-bound 60-70 per cent (inactive), albumin-bound 30-40 per cent, free 1-2 per cent; conditions raising SHBG (cirrhosis, hyperthyroidism, oestrogen therapy) lower free testosterone without changing total.
- DHT conversion: 5-alpha-reductase type 2 in prostate and genital skin yields DHT, two to three times more potent via higher receptor affinity; finasteride blocks type 2 (prostate, hair), dutasteride both isoenzymes.
- Aromatisation: aromatase in fat, liver, brain and bone yields oestradiol — the reason male bone maturation and epiphyseal closure are oestrogen-mediated; aromatase deficiency causes tall stature with unfused epiphyses.
- Control axis: GnRH pulses (rapid pulses favour LH, slower pulses FSH); testosterone and oestradiol feed back on hypothalamus and pituitary; inhibin B from Sertoli cells selectively suppresses FSH — a clean two-line answer.
- Actions timeline: prenatal masculinisation (internal ducts via testosterone, external genitalia via DHT, Mullerian regression via AMH), pubertal virilisation, adult spermatogenesis (needing the high intratesticular concentration achieved with androgen-binding protein), anabolic effects including erythropoiesis — men's higher haemoglobin (13-17 versus 12-16 g/dL).
- Clinical syndromes: 5-alpha-reductase deficiency — ambiguous genitalia at birth with virilisation at puberty (the Dominican guevedoces cohort); Klinefelter (XXY) — small testes, gynaecomastia, high gonadotrophins with low testosterone; anabolic steroid abuse — suppressed LH, atrophied testes, azoospermia, gynaecomastia from aromatisation.
A worked case in male infertility
A 30-year-old bodybuilder presents with infertility; his semen analysis shows azoospermia and his testes are soft and reduced in volume. The axis is inverted: exogenous androgens suppress GnRH and LH, Leydig cells go quiet, and intratesticular testosterone — the concentration spermatogenesis requires — collapses even though muscle is saturated. Recovery takes months because the spermatogenic cycle runs about 74 days.
Contrast Klinefelter syndrome: the primary failure is the testis — hyalinised tubules cannot support spermatogenesis or adequate androgen, so both LH and FSH rise in compensation. One case suppresses the axis from above, the other fails it from below — the gonadotrophin pattern reads the difference at a glance.
Where students slip
The recurring slip is attributing external genital masculinisation directly to testosterone; the external genitalia and prostate are DHT-dependent, the internal Wolffian ducts testosterone-dependent — the split that explains 5-alpha-reductase deficiency (female-appearing external genitalia with normal internal male ducts). The second is forgetting Mullerian regression is AMH's job, not testosterone's — a one-mark distinction asked every year. Third, students quote testosterone levels without timing: the 8 AM sampling rule is exam-relevant because afternoon levels can fall 20-30 per cent. Finally, remember oestrogen matters in men — gynaecomastia of puberty, cirrhosis and steroid abuse is an aromatase story, and male osteoporosis after aromatase deficiency proves the bone role.
Frequently asked questions
Where and under what control is testosterone synthesised?
Leydig cells of the testicular interstitium, stimulated by LH through cAMP signalling, with StAR-mediated cholesterol transport into mitochondria as the rate-limiting step; daily production is about 5-7 mg.
How does testosterone circulate in blood?
About 60-70 per cent bound to sex hormone-binding globulin (biologically inactive), 30-40 per cent to albumin, and 1-2 per cent free — the free and albumin-bound fractions together constituting bioavailable hormone.
What is the role of 5-alpha-reductase?
It converts testosterone to dihydrotestosterone, two to three times more potent, which drives prostate growth and male-pattern baldness; finasteride inhibits the type 2 isoenzyme to treat both.
Why do anabolic steroids cause testicular atrophy and infertility?
Exogenous androgens suppress GnRH and LH, shutting down Leydig cell production of the high intratesticular testosterone concentration spermatogenesis requires, leading to tubular atrophy and azoospermia.
Which endocrine pattern defines Klinefelter syndrome?
Primary testicular failure — low testosterone with compensatory elevation of LH and especially FSH, small firm testes, azoospermia and gynaecomastia in a 47,XXY male.