Testis
One organ doing two jobs with two different cells — Leydig cells make the hormone, Sertoli cells make the sperm — both driven by a feedback loop with the brain, and almost every disease and every drug on this page either breaks that loop or hijacks it.
What it normally does
Leydig cells sit in the spaces between the tubules and make testosterone when luteinising hormone (LH) from the pituitary tells them to. Testosterone, and the oestradiol made from it, then travel back and turn the signal down at both the hypothalamus and the pituitary (the hypothalamic-pituitary-gonadal axis, a classic negative feedback loop). Testosterone is released in pulses and is highest in the early morning, which is why a level taken at 4 pm can be low in a perfectly normal man and cannot be used to diagnose anything.
Every case of low testosterone splits on this loop. Measure LH and FSH at the same time and the answer falls out: the gonadotrophins are high when the testis has failed, and low or inappropriately normal when the problem is above it. It also explains why anything that raises androgen from outside switches the whole axis off.
Sertoli cells line the seminiferous tubules and nurse the developing sperm from spermatogonium to spermatozoon, a process that takes about 70 days. They need two things: FSH from the pituitary, and testosterone at roughly 50 to 100 times the blood concentration right there inside the tubule, supplied locally by the neighbouring Leydig cells. Sertoli cells and the peritubular myoid cells around the tubule carry androgen receptors, and it is their response to that huge local testosterone concentration that drives spermatogenesis. Sertoli cells send back inhibin B, which brakes FSH specifically, and their tight junctions wall the developing sperm off from the bloodstream (blood-testis barrier).
Explains why testosterone rubbed on the arm relieves a man's androgen-deficiency symptoms while sterilising him: the blood level rises, but LH is suppressed, the Leydig cells stop making the local supply, and the intratubular concentration collapses. It also explains why FSH is the gonadotrophin that rises first when the tubules are damaged (inhibin B falls first), and why testicular volume — which is mostly tubule — is a bedside readout of spermatogenesis.
The testis hangs outside the abdomen on the spermatic cord, held about 2 to 3 °C below core temperature by the scrotal skin and by a countercurrent heat exchange between the testicular artery and the surrounding venous plexus (pampiniform plexus). Spermatogenesis fails at body temperature. The price of that arrangement is that everything the testis depends on — testicular artery, pampiniform veins and the vas deferens — runs through one narrow, mobile stalk.
Explains why a dilated vein bag (varicocele) or a testis that never descended wrecks sperm counts while leaving testosterone roughly intact, and why the cord can twist and strangle the organ within hours (torsion).
Testosterone is half prohormone. 5-alpha-reductase converts it to the more potent dihydrotestosterone (DHT) in prostate, genital skin, beard and scalp; aromatase converts it to oestradiol in fat, brain, bone and breast (and, in smaller amounts, in the testis itself). In men, bone mineral density and the closure of the growth plates are oestradiol's job, not testosterone's, and oestradiol is a major part of the feedback signal to the pituitary.
Explains why pushing androgens sky-high grows breast tissue, why hypogonadal men lose bone, and why the last two drugs on this page work on the oestrogen arm — one blocking the receptor centrally, one blocking the enzyme — rather than touching androgen directly.
What goes wrong
- Primary hypogonadism — the testis itself has failed← from “Leydig cells sit in the spaces between the tub…”
The gonad is damaged or was never fully built. Leydig cells make less testosterone and Sertoli cells make less inhibin B, so both brakes come off the pituitary and LH and FSH climb (physiology 0). In Klinefelter syndrome (47,XXY) the tubules progressively fibrose through and after puberty, so testosterone is often adequate in early adolescence and then drifts down while the testes stay tiny and firm. Acquired causes do the same thing faster: mumps orchitis, torsion, chemotherapy (alkylating agents especially), radiation and trauma. Haemochromatosis can deposit iron in the gonad, but the hypogonadism it causes is usually secondary rather than primary, because the pituitary gonadotroph is the more vulnerable target — so check the gonadotrophins rather than assuming.
Low testosterone plus HIGH LH and FSH means the problem is in the testis. Confirm with two morning levels, then karyotype a young man with small firm testes. Testosterone replacement here treats symptoms and protects bone; it does not restore fertility, and it is honest to say so — though sperm can sometimes still be retrieved surgically from a Klinefelter testis, so refer before assuming there is nothing there.
You would find: Low morning total testosterone with HIGH LH and FSH. Small firm testes — often under 4 to 5 mL in Klinefelter against a normal 15 to 25 mL — sparse body and facial hair, gynaecomastia, low muscle bulk, and in Klinefelter a tall build with long limbs and learning or language difficulties. Klinefelter occurs in roughly 1 in 500 to 1000 male births and most cases are never diagnosed. Mumps orchitis is the acquired version to know in Australia: the outbreaks from 2015 onwards in the Kimberley, the Top End and remote Queensland fell heavily on Aboriginal and Torres Strait Islander communities, where waning two-dose immunity left older children and young adults exposed.
- Secondary (hypogonadotrophic) hypogonadism — nobody is telling the testis to work← from “Leydig cells sit in the spaces between the tub…”
The gonad is intact but the drive is missing. Without LH the Leydig cell idles and testosterone falls, and because the fault is upstream the gonadotrophins do not rise to compensate (physiology 0). The causes you actually meet are functional rather than structural: obesity and type 2 diabetes (fat aromatises testosterone to oestradiol, which strengthens the feedback brake, and inflammation blunts GnRH pulses), long-term opioids, high-dose glucocorticoids, and any severe systemic illness. Structural causes are a prolactinoma (prolactin suppresses GnRH pulses), a non-functioning pituitary macroadenoma compressing the gonadotrophs, haemochromatosis loading iron into the pituitary, and congenital GnRH deficiency (Kallmann syndrome, with anosmia and no puberty).
Low testosterone plus low or normal LH/FSH means look above the testis. In Australian practice the commonest driver by far is obesity with type 2 diabetes — both markedly more prevalent in Aboriginal and Torres Strait Islander communities — and weight loss and glycaemic control genuinely reverse it, which is why they come before any script. Exclude a prolactinoma before treating.
You would find: Low testosterone with LOW or 'normal' LH and FSH — a normal gonadotrophin is the wrong answer when testosterone is low, and that inappropriateness is the finding. Testes are normal-sized but soft. Next tests: prolactin, iron studies, thyroid, and a pituitary MRI if prolactin is high, the testosterone is very low, or there are headaches or bitemporal field loss. Galactorrhoea points straight at prolactin.
- Anabolic-androgenic steroid use — axis shutdown, small testes, no sperm← from “Sertoli cells line the seminiferous tubules an…”
Supraphysiological androgen slams the feedback loop shut (physiology 0). LH and FSH disappear, the Leydig cells stop working, and the intratubular testosterone that Sertoli cells need at 50 to 100 times blood level collapses (physiology 1). Spermatogenesis halts and the testes shrink, even while the blood testosterone is far above normal. At the same time the excess androgen is aromatised in fat to oestradiol (physiology 3), so glandular breast tissue grows. Androgen also drives erythropoiesis — chiefly by stimulating renal erythropoietin and suppressing hepatic hepcidin, which frees up iron for the marrow — so the haematocrit climbs.
High testosterone in the blood, none in the tubule. That one sentence explains steroid-induced infertility, testicular atrophy, and why prescribed testosterone behaves as a male contraceptive. Recovery of the axis after stopping takes months to over a year and is sometimes incomplete.
You would find: A muscular young man with small soft testes, acne across the shoulders and back, tender breast tissue under the nipple, and azoospermia or severe oligospermia on semen analysis. LH, FSH and SHBG are all suppressed; haematocrit and haemoglobin are high; HDL is low. Ask directly and without judgement, including about injecting equipment and needle-sharing. Use is rising among young Australian men, and people using performance and image enhancing drugs now make up a substantial share of needle and syringe program clients; these agents are prescription-only (Schedule 4) and possession without a prescription is an offence in most states.
The pampiniform plexus refluxes and dilates, almost always on the left, where the testicular vein drains at a right angle into the renal vein rather than obliquely into the inferior vena cava. Warm pooled venous blood defeats the countercurrent cooling that keeps the testis a few degrees below core temperature (physiology 2), and the raised scrotal temperature plus local hypoxia progressively damages spermatogenesis. Tubular function suffers first, so the semen analysis deteriorates while testosterone stays roughly normal.
The commonest surgically correctable cause of male infertility. Diagnosis is clinical, with the man standing; treatment is ligation or embolisation, not a drug — no medication on this page fixes it.
You would find: A soft 'bag of worms' felt above and behind the testis, more prominent on standing and with Valsalva, and collapsing when the man lies flat. The affected testis may be smaller. Present in about 15% of all men but in roughly 40% of men presenting with infertility. A right-sided varicocele appearing suddenly, or one that does NOT decompress lying down, means a retroperitoneal mass obstructing venous drainage until imaging says otherwise.
- Testicular torsion← from “The testis hangs outside the abdomen on the sp…”
The testis hangs on a mobile cord (physiology 2). If the tunica vaginalis inserts too high the testis swings free inside it (bell clapper deformity) and the cord can twist. The low-pressure veins occlude first, so the testis engorges and swells, which then shuts off arterial inflow and the organ becomes ischaemic. Salvage rates are near 90 to 100% within 6 hours, fall steeply after 12, and approach zero beyond 24. The contralateral testis usually shares the anatomical anomaly.
A clinical diagnosis and a surgical emergency. Ultrasound that delays theatre costs the testis; if the story fits, explore. Both sides are fixed at the same operation (bilateral orchidopexy) because the anatomy is bilateral.
You would find: Sudden severe unilateral scrotal pain, often waking the patient at night, with nausea and vomiting and sometimes referred lower abdominal pain — always examine the scrotum in a boy with abdominal pain. The testis sits high and lies transversely, the cremasteric reflex is absent, and lifting the scrotum does not relieve the pain (relief on elevation suggests epididymo-orchitis instead). Two peaks: the first year of life and ages 12 to 18.
What we give, and how it works
Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.
- Binds
- The intracellular androgen receptor, a nuclear hormone receptor. In prostate, skin and scalp the active ligand is dihydrotestosterone after conversion by 5-alpha-reductase; in bone and brain a large part of the effect is via oestradiol after aromatisation.
- Which does
- The hormone diffuses into the cell, binds the receptor, sheds its chaperone (heat-shock) proteins, and the complex dimerises, moves to the nucleus and binds androgen response elements on DNA, switching transcription of muscle, marrow and bone genes on. The effect is genomic, so it builds over weeks, not hours.
- So you see
- Libido and spontaneous erections return within a few weeks, energy and mood improve, lean muscle mass rises and fat mass falls over months, bone mineral density improves over a year or more, haemoglobin rises, and beard growth and body hair return.
- And the same mechanism causes
- The same molecule feeds straight back onto the hypothalamus and pituitary. LH and FSH switch off, the Leydig cells stop producing the enormous local testosterone concentration the Sertoli cells depend on, spermatogenesis stops and the testes shrink. The drug for low testosterone is also a male contraceptive — it should not be started in a man who wants to father a child now, and every man started on it needs to be told this.
- Handling
- Androgen stimulates erythropoiesis, so haematocrit climbs predictably — it is checked before starting and periodically after, and the dose is reduced or stopped if it rises too far, because hyperviscosity raises thrombotic risk. Testosterone also aromatises to oestradiol, which is why some men on replacement grow breast tissue. Where fertility is the goal, the fertility-sparing options are hCG or clomifene under specialist care rather than testosterone.
Catches people out: In Australia testosterone is Schedule 4 and PBS-subsidised only for established androgen deficiency, which requires two low early-morning total testosterone levels together with LH and FSH, plus a specialist or specialist-consultation requirement that varies with the man's age and the cause. Tiredness and low mood alone are not androgen deficiency. Transdermal preparations transfer to a partner or child on skin contact — cover the site.
- Binds
- The LH/hCG receptor, a Gs-protein-coupled receptor on the Leydig cell. hCG shares the alpha subunit of LH, and its beta subunit carries a C-terminal extension that gives it a far longer half-life, so it acts as a long-lasting LH.
- Which does
- Gs raises intracellular cAMP, protein kinase A phosphorylates and upregulates StAR protein, cholesterol is shuttled into the mitochondrion, and the steroidogenic enzyme chain runs it through to testosterone.
- So you see
- The testis makes its own testosterone again. Blood levels rise — but crucially so does the intratesticular concentration, so testicular volume is preserved and sperm production is maintained or comes back. This is the difference between hCG and a testosterone gel.
- And the same mechanism causes
- Driving the Leydig cell hard raises everything downstream of it. The surplus testosterone is aromatised in fat to oestradiol, so oestradiol rises out of proportion and the man gets breast tenderness, gynaecomastia and fluid retention with weight gain — the same mechanism as in the steroid user, arrived at therapeutically.
- Handling
- Given by subcutaneous or intramuscular injection two or three times a week. It will produce a positive result on a urine pregnancy test, which is worth knowing before someone is confused by one.
Catches people out: Useless if there is no functioning Leydig cell to stimulate. In primary testicular failure, where LH is already maximally high, adding more LH signal achieves nothing — check the gonadotrophins before reaching for it. Restarting spermatogenesis takes 3 to 6 months and sometimes needs FSH added, because hCG replaces LH only.
- Binds
- Oestrogen receptor alpha, at which it behaves as an antagonist in the hypothalamus and pituitary (and as a partial agonist in some other tissues, which is what 'selective' means).
- Which does
- Blocking the receptor makes the hypothalamus and pituitary read oestradiol as absent, so it removes the negative feedback: GnRH pulse frequency rises, and the pituitary releases more LH and FSH.
- So you see
- The man's own Leydig cells are driven, so testosterone rises from the inside. Intratesticular concentration and testicular volume are preserved and sperm counts hold up or improve — the whole reason to choose it over testosterone in a man who wants children. It is taken orally rather than injected.
- And the same mechanism causes
- Antagonising oestrogen receptors centrally is felt as mood swings and irritability. Visual disturbance — blurring, light sensitivity and persistent afterimages — is the recognised class effect and the signal to stop the drug; the exact mechanism is not established, so do not learn it as settled receptor pharmacology, learn it as the symptom that ends the prescription. Note what does NOT follow: because clomifene blocks the receptor centrally rather than blocking aromatase, the extra testosterone is still aromatised and serum oestradiol usually RISES on treatment, so this is not an oestrogen-deficient state. Long-term bone outcomes in men on clomifene are simply not well studied.
- Handling
- Visual symptoms that persist are a reason to stop, not to push through.
Catches people out: Off-label in men in Australia — the TGA registration is for anovulatory infertility in women. It cannot work if the pituitary itself is destroyed by a macroadenoma or surgery, and it will not undo established fibrous gynaecomastia. In an androgen user the actual treatment is stopping the androgen; drugs only support the recovery.
- Binds
- Aromatase (CYP19A1), inhibited competitively and reversibly by the non-steroidal agents anastrozole and letrozole (the steroidal agent exemestane is instead an irreversible inactivator).
- Which does
- Androgens can no longer be converted to oestrogens, so circulating and local tissue oestradiol falls while the androgen substrate accumulates.
- So you see
- Breast tenderness settles and early glandular tissue can regress. Because oestradiol carries much of the feedback signal to the pituitary, removing it also lifts the brake: LH rises and the man's own testosterone rises with it.
- And the same mechanism causes
- Oestradiol, not testosterone, maintains male bone. Strip it out and bone mineral density falls, and the patient gets the arthralgia and stiffness familiar from women on the same drugs for breast cancer. In a boy or young man whose epiphyses have not fused, removing oestradiol keeps the growth plates open. The lesson is the physiology: a man needs oestrogen.
- Handling
- Reserved for a demonstrably high oestradiol, with bone density considered if it is used for more than a short course.
Catches people out: Off-label in men in Australia, and the evidence in men is thin — in obesity-related hypogonadism, weight loss and treating the diabetes are the interventions with real evidence, and an aromatase inhibitor is a specialist decision, not a substitute. It does nothing for established gynaecomastia that has become fibrous — that needs surgery — and it does not treat the underlying steroid use. It should not be used in an adolescent without specialist input, because oestradiol is what closes the growth plates.
Low testosterone? The next test is LH and FSH on the same early-morning sample, and it splits the entire problem in two. High LH and FSH means the testis has failed — small firm testes, karyotype the young ones, replace the hormone for symptoms and bone, and be honest that fertility is unlikely to return. Low or inappropriately normal LH and FSH means look above the testis — check prolactin, iron studies and weight, and remember this is the man whose gonad still works, so hCG or clomifene can restart him while testosterone would sterilise him. The trap to avoid is thinking testosterone spares the tubule because the tubule lacks androgen receptors: it has them, and that is exactly why it needs the enormous local concentration that exogenous testosterone destroys. Then two things that are not endocrine at all: sudden severe scrotal pain with a high transverse testis and no cremasteric reflex goes to theatre, not to ultrasound; and a bag of worms that does not decompress when he lies down means imaging the retroperitoneum.
Now test whether it stuck
Reading this through is not the same as being able to reconstruct it. Every question in the bank is free, with a full debrief on each option.