Andrology

Priapism

Priapism is a persistent erection (>4 hours) unrelated to stimulation. The critical first step is distinguishing ischemic (low-flow, painful — a compartment-syndrome emergency) from non-ischemic (high-flow, traumatic, not an emergency); corporal blood gas settles indeterminate cases. Ischemic priapism risks permanent erectile dysfunction, and the chance of recovery falls steeply with duration.

Classification

Feature	Ischemic (low-flow, veno-occlusive)	Non-ischemic (high-flow, arterial)
Frequency	Most common	Rare
Pain	Painful, rigid, tender corpora	Painless, tumescent but not fully rigid
Cavernous blood gas	Hypoxic, hypercarbic, acidotic (dark)	Normal (bright red)
Cause	Non-traumatic (drugs, SCD, malignancy)	Traumatic — cavernous-artery laceration (straddle injury)
Urgency	Emergency	Not emergent

Recurrent ("stuttering") ischemic priapism is repeated ischemic episodes (± the 4-hour criterion), strongly associated with sickle cell disease — the commonest cause of priapism in children.

Recovery of Erectile Tissue

Recovery of erectile function after an ischemic episode depends on time to reversal: ~100% if <12 h, ~75% at 12–24 h, ~50% at 24–36 h, and 0% beyond 36 h (erectile tissue is likely irreversible by ~48 h).

Risk Factors

Medications (α-blockers, trazodone and antipsychotics, anticoagulants, antihypertensives, ADHD stimulants, hormones, intracavernosal vasoactive agents), recreational drugs (cocaine, alcohol, marijuana), genitourinary trauma, thrombophilia, and haematologic disease — above all sickle cell disease (priapism in 23–89% of males by age 18). Other causes include malignant infiltration (prostate, bladder, urethra), neurogenic causes (spinal-cord injury), and metabolic disease (Fabry, amyloidosis).

Diagnosis

History and examination usually distinguish the subtypes (the corpora cavernosa are affected; the glans and spongiosum are spared). Corporal blood gas is the key test when in doubt:

Source	PO₂	PCO₂	pH
Normal arterial	>90	<40	7.40
Normal venous	40	50	7.35
Ischemic priapism	<30	>60	<7.25

CBC, haemoglobin electrophoresis, and toxicology are selective. Penile colour-Doppler ultrasound differentiates indeterminate cases (ischemic — absent cavernosal flow; non-ischemic — high systolic velocities or a fistula) but is not part of the first-line ED workup.

Ischemic Priapism — Management

An emergency — counsel about the risk of ED and penile shortening. Conservative measures (observation, oral agents, cold packs) are not recommended, and cold compresses are contraindicated in SCD.

• First-line: intracavernosal phenylephrine + corporal aspiration ± saline irrigation. Phenylephrine (α1-selective, fewest systemic effects) is diluted to 100–500 mcg/mL and injected laterally (3/9 o'clock), typically 100–200 mcg per dose given ≥5 min apart for up to 1 hour to a maximum of ~1000 mcg (1 mg); aspirate before injecting. Monitor BP and heart rate (adverse effects: hypertension, reflex bradycardia, headache); a cumulative dose of ~2 mg has caused hypertensive stroke.
• Surgical shunting if refractory after phenylephrine + aspiration/irrigation (consider for episodes ≤72 h; generally forego beyond 72 h). A distal corporoglanular shunt ± tunnelling is first choice (percutaneous Winter, Ebbehoj, T-shunt; open Al-Ghorab); proximal shunts (Quackles, Grayhack, Barry) are largely historical. Shunt complications: oedema, haematoma, infection, urethral fistula, penile necrosis, PE.
• >36 hours or refractory: options are observation, distal shunting, or early penile prosthesis (within 2 weeks) — giving detumescence, pain relief, and preserved length, with infection <10% (higher if delayed).
• Role of MRI in prolonged ischemic priapism (>36–48 h): gadolinium-enhanced MRI (or corporal biopsy) assesses cavernosal smooth-muscle viability — non-enhancement indicates smooth-muscle necrosis / non-viable tissue, which predicts irreversible ED and supports proceeding to early penile prosthesis rather than further shunting. MRI also helps confirm the priapism subtype and detect any underlying malignant corporal infiltration.

Recurrent (Stuttering) Priapism

Abort acute episodes (phenylephrine + aspiration), then prevent recurrence. Pharmacologic prophylaxis (usually at bedtime): ketoconazole + prednisone (highest success — monitor LFTs), pseudoephedrine, PDE5 inhibitors, dutasteride, baclofen, and anti-androgens/GnRH agents (which impair fertility and sexual function). In SCD, add hydroxyurea and chronic exchange transfusion.

Prevention of recurrent ischemic priapism falls into three practical categories:

• Self-injectable phenylephrine — patient-administered intracavernosal α-agonist to abort a developing episode at home before it becomes established.
• GnRH agonists (and anti-androgens) — suppress androgen-driven nocturnal erections; reserve and counsel carefully, as they impair fertility, libido, and sexual function.
• Penile prosthesis — a definitive option for frequent, refractory stuttering priapism; earlier placement is technically easier, before recurrent ischemia causes dense corporal fibrosis.

Non-Ischemic Priapism

Not an emergency, and aspiration is only diagnostic. First-line is observation (resolves spontaneously in up to 62%; reasonable for ~4 weeks), with penile Doppler to locate the fistula. Second-line is percutaneous arterial embolization (detumescence ~85%, ~80% retain erectile function; recurrence ~30%, so repeat if it fails — bilateral embolization raises ED risk). Surgical fistula ligation (transcorporal) is reserved for embolization failure.

Peyronie's Disease

Peyronie's disease is an acquired fibrosis of the tunica albuginea producing penile curvature, deformity, pain, and often erectile dysfunction and distress. It follows abnormal wound healing after (often unrecalled) microtrauma, and management is staged — support and intralesional/traction therapy in the active phase, surgery once the deformity is stable.

Pathophysiology

An inflammatory disorder of the tunica in which a scar fails to remodel (TGF-β1 is central).

The tunica's outer longitudinal layer is thinnest at 3/9 o'clock and absent ventrally (5–7 o'clock) — the commonest site of prosthesis extrusion, and the reason most plaques (60–70%) and curvature are dorsal. The penis deviates toward the plaque (the opposite of a penile fracture, which deviates away from the injury); a circumferential plaque causes an hourglass deformity.

Risk Factors

Risk factors (mnemonic IT DRAG A Crooked Wand): Infection, Trauma, Diabetes, Radical prostatectomy (11–16%), increasing Age, Genetic predisposition, Autoimmunity, Collagen disorders (Dupuytren contracture, Ledderhose disease, tympanosclerosis), and aberrant Wound healing. Hypogonadism worsens severity; PDE5 inhibitors are not associated.

Natural History

• Active (acute) disease — changing symptoms with pain (the defining feature), lasting up to 18 months.
• Stable (chronic) disease — clinically unchanged for ≥3 months.

Pain resolves spontaneously in ~90%, but curvature improves in only 12–13% (worsens ~45%, stable ~42%) — so deformity rarely self-corrects. The differential includes congenital curvature, a thrombosed dorsal vein, penile fracture, and (rarely) penile cancer.

Diagnosis

History and examination are mandatory; examine the penis on stretch and record a baseline stretched penile length. Before any invasive treatment, document the erect deformity objectively — the intracavernosal-injection (ICI) test ± duplex Doppler ultrasound is the gold standard (home photographs are an alternative). Ultrasound also identifies plaque calcification (extensive calcification predicts a poor response to non-surgical therapy). Routine labs and MRI are not needed.

Non-Surgical Treatment

• Active phase: NSAIDs for pain. (ESWT is a conditional option for pain only — it does not reduce curvature and may worsen it.)
• Stable phase:
  • Penile traction — the first-line non-invasive option (wear ≥3 h/day); reduces curvature and increases stretched length and girth.
  • Intralesional injection with modelling — collagenase (Clostridium histolyticum, Xiaflex) degrades collagen I/III for curvature 30–90° with intact erections and a single non-calcified dorsal/lateral plaque (IMPRESS I/II: ~17° vs 9° improvement); it does not treat pain or ED, can rarely cause corporal rupture, and was withdrawn in Canada/Europe in 2020. Collagenase should not be given for ventral plaques, hourglass deformity, or penile curvature >90°. Verapamil (weak evidence) and interferon-α2b (modest; flu-like effects) are alternatives; corticosteroids are not recommended, and PRP/stem-cell therapy lacks efficacy data.
  • Oral agents (CUA may consider; AUA does not endorse): colchicine, CoQ10, potassium para-aminobenzoate, pentoxifylline. Vitamin E and tamoxifen are not recommended.

Surgical Treatment

For stable disease (≥1 year from onset, ≥3–6 months stable) with deformity compromising intercourse, or after failed/declined non-surgical therapy. Counsel about residual/recurrent curvature, penile shortening, reduced rigidity, and transient sensory change; the goal is a functionally straight penis (<30° residual).

Procedure	Best for	Trade-offs
Plication (tunical shortening — Nesbit, Yachia, 16-dot)	Simple curvature <60°, adequate length	Shorter and simpler, preserves rigidity; causes penile shortening; recurrence ~10%
Plaque incision/excision + grafting (tunical lengthening — pericardial or porcine SIS grafts, never synthetic)	Complex curvature >60°, large plaque, hourglass	Restores length but higher risk of reduced rigidity; needs strong pre-op erections (poor for ventral curves)
Penile prosthesis (inflatable, ± manual modelling/grafting)	Refractory ED with deformity, or profound instability	Gold standard when ED coexists; commonest complaint is length loss; modelling's main risk is urethral injury

Erectile Dysfunction

Erectile dysfunction — the inability to attain or maintain an erection sufficient for satisfactory sex — affects ~40% of men in their 40s and rises ~10% per decade. Most organic ED is vascular, and erection depends on a nitric-oxide → cGMP cascade that PDE5 inhibitors exploit. Management climbs a ladder from PDE5 inhibitors through injection/vacuum/intraurethral therapy to a penile prosthesis.

Erectile Physiology

• Innervation — parasympathetic (S2–S4) drives erection (via the cavernous nerves), sympathetic (T10–L2) drives detumescence, and the somatic pudendal nerve (S2–S4, Onuf's nucleus) carries sensation and powers the ischiocavernosus (rigid-erection phase). Nerve-sparing prostatectomy aims to protect the cavernous nerves.
• Neurochemistry — nitric oxide is the principal pro-erectile transmitter (from NANC nerves and endothelium); nNOS initiates and eNOS maintains the erection. NO → cGMP (via guanylate cyclase) → smooth-muscle relaxation, and PDE5 degrades cGMP (the drug target). Norepinephrine maintains flaccidity.
• Haemodynamics — erection = sinusoidal relaxation + arterial inflow + venous compression against the tunica (intracavernous pressure ~100 mmHg). The corpus spongiosum/glans reaches only ⅓–½ that pressure (it lacks the outer longitudinal tunica layer).
• Erection types — psychogenic (T11–L2), reflexogenic (S2–S4; preserved in 95% of upper-cord but only ~25% of lower-cord injuries), and nocturnal (REM sleep).

Causes

Organic ED is classified "ED VAN" — Endocrine, Drug-induced, Vascular, Anatomic, Neurogenic — plus psychogenic and mixed. Aging is the single most important contributor, and arteriogenic disease is the commonest organic mechanism (ED is a sentinel marker for cardiovascular disease).

• Endocrine — hypogonadism, thyroid disease, diabetes, and hyperprolactinaemia (low libido, ED, galactorrhoea, gynaecomastia, infertility). The testosterone threshold for nocturnal erections is ~200 ng/dL.
• Drugs — associated: thiazides, spironolactone, central α2-agonists (clonidine, methyldopa), and non-selective β-blockers; not associated: ACE inhibitors, ARBs, calcium-channel blockers, α1-blockers (but they cause retrograde ejaculation), and β1-selective blockers. SSRIs cause anorgasmia; bupropion does not cause ED. 5-ARIs and anti-androgens reduce function.
• Vascular (arteriogenic and veno-occlusive), anatomic (pelvic surgery — RP 43–100%; pelvic fracture), neurogenic (spinal-cord injury, neuropathy), and psychogenic (performance anxiety, with nocturnal/situational erections preserved).

Diagnosis

• Work-up — AUA mandates history/exam, a diabetes screen, and morning total testosterone. Repeat a low testosterone with LH and prolactin; image the pituitary if testosterone <150 ng/dL or pituitary disease is suspected.
• Questionnaires — the IIEF (15 items, 5 domains: desire, erectile function, intercourse satisfaction, orgasmic function, overall satisfaction), SHIM, and the Erection Hardness Scale.
• Specialised testing (only if it changes management) — NPTR, the ICI test, and penile duplex ultrasound (the vascular gold standard: peak systolic velocity <25–30 cm/s indicates arterial insufficiency, end-diastolic velocity >5 cm/s indicates veno-occlusive dysfunction).

Treatment

The ladder is PDE5 inhibitors → vacuum / intraurethral / intracavernosal therapy → surgery, alongside psychosexual counselling, medication review, and lifestyle change (aerobic exercise improves IIEF).

PDE5 inhibitors (first-line) raise cGMP and augment but do not induce erection (sexual stimulation is still required); they are metabolised by CYP3A4 and succeed in ~70%. Non-response is usually incorrect use (56–81%).

Agent	Onset	Duration (T½)	Food effect
Sildenafil	30–60 min	~12 h (4 h)	High-fat meal reduces efficacy
Vardenafil	30–60 min	~10 h (4 h)	High-fat meal reduces efficacy
Tadalafil	60–120 min	~36 h (17.5 h)	None (the only one licensed for daily dosing)
Avanafil	15–30 min	~6 h (5 h)	None

• Contraindications — absolute: nitrates (precipitous hypotension) and hypersensitivity; relative: severe cardiac disease (avoid for 6 months post-MI), non-selective α-blockers, and — for vardenafil — class IA/III antiarrhythmics or congenital long-QT. Adverse effects: headache, dyspepsia, flushing, nasal congestion, myalgia (more with tadalafil), visual disturbance (more with sildenafil/vardenafil, via PDE6 cross-reactivity), and rare NAION.
• Dose reduction — use a lower PDE5i dose with concurrent α-blockers, hepatic or renal impairment, and HIV/antiretroviral (CYP3A4-inhibiting) therapy.
• PDE5i with α-blockers — current guidance is to start only when the patient is haemodynamically stable (no episodes of hypotension) and to begin at the lowest possible dose. With tamsulosin, sildenafil 25 mg needs no time separation; if the sildenafil dose is increased, separate the two drugs by ~4 hours. With doxazosin, reduce the PDE5i dose.
• Second-line — a vacuum erection device (constriction ring ≤30 min), intraurethral alprostadil (MUSE; inferior to PDE5i/ICI), and intracavernosal injection (alprostadil alone, trimix = alprostadil + papaverine + phentolamine, or bimix = papaverine + phentolamine; inject at 3/9 o'clock, limit to ~10/month to avoid fibrosis). The most serious ICI complication is priapism — more frequent with bimix (no alprostadil), whereas trimix (which contains alprostadil) causes more penile pain.
• Surgery (third-line) — the inflatable penile prosthesis (see the Penile Prosthesis tab) is effective and high-satisfaction but irreversible (other therapies rarely work after explant); infection (within 3 months) usually mandates removal, and ~50% of devices still function at 20 years. Penile arterial reconstruction suits young men with focal traumatic arterial occlusion; venous ligation is not recommended.

Low-intensity shockwave, stem-cell, and PRP therapies are investigational. Because ED is a cardiovascular risk marker (as strong as smoking), men who are not clearly low-risk warrant cardiology evaluation before treatment.

Special Scenarios

After radical prostatectomy, erectile recovery occurs over 12–24 months (up to 36), better with bilateral nerve-sparing (~60% vs ~47% unilateral); after radiotherapy, ED is delayed (24–36 months). Penile rehabilitation is ideally started before (or at the time of) RP, though its overall benefit remains unclear: the evidence for scheduled PDE5i is weak, and a vacuum erection device does not improve erectile recovery but may help prevent penile shortening. Testosterone monotherapy is not recommended for ED, but PDE5i + testosterone can salvage hypogonadal PDE5i failures.

Penile Prosthesis

A penile prosthesis is the definitive surgical treatment for erectile dysfunction refractory to or unsuitable for medical therapy, and for ED coexisting with Peyronie's deformity. It is irreversible — native erectile capacity is lost — but satisfaction is high, and the inflatable three-piece device is the most popular.

Indications and Contraindications

Indicated for ED that has failed or is unsuitable for conservative therapy, irreversible organic ED, refractory psychogenic ED, Peyronie's disease with coexisting ED and deformity, penile fibrosis, and phalloplasty. The absolute contraindications are active systemic, cutaneous, or urinary infection (relative: poorly controlled diabetes, immunosuppression, and limited motivation or unrealistic expectations).

Device Types

Type	Features	Notes
Non-inflatable (semirigid rod) — malleable or positional	Paired solid cylinders, bent up/down	Cheap, easy to implant/use, low failure; but a constant erection (hard to conceal) and no girth change. Best for limited manual dexterity (~10% of implants)
2-piece inflatable	Cylinders + scrotal pump (reservoir within the cylinders)	Avoids a separate reservoir — useful when the space of Retzius is hostile (colostomy, transplant, prior pelvic surgery); small/hard pump, less natural feel (~20%)
3-piece inflatable	Cylinders + scrotal pump + separate reservoir	Most natural function (girth + length); the most popular (~70%)

Pre-operative Evaluation and Technique

Counsel that the procedure is irreversible and that the stretched penile length is the maximum achievable length (warn about shortening and glans softening). Evaluate with ICI and penile Doppler. The device is placed through a scrotal or infrapubic incision (~1 inch): the corpora are dilated with Hegar dilators (avoid force — perforation risk), sized, and the cylinders placed; the reservoir sits in the space of Retzius (use submuscular placement after prior pelvic surgery, and empty the bladder first). Keep the device fully deflated (reservoir full) postoperatively to prevent auto-inflation, give perioperative antibiotics, and teach device use at ~4 weeks.

Complications

• Intraoperative
  • Corporal perforation is most likely at the septum during dilation; prevent crossover with counter-traction and dilators/scissors angled away from the midline.
  • Crossover (a cylinder crosses the septum into the contralateral corpus) does not require abandoning the implant: leave a dilator in the contralateral corpus while the ipsilateral corpus is re-dilated, then insert the first prosthesis cylinder while the contralateral dilator remains in place.
  • Distal perforation — if the contralateral corpus has not yet been dilated, abandon prosthesis placement; if the contralateral corpus is already dilated, place a malleable prosthesis in the contralateral corpus.
  • Proximal perforation — proceed with placement and secure the cylinder by suturing the rear-tip extender to the proximal tunica albuginea.
  • Urethral perforation — insert a urethral catheter; abandon device placement on that side (remove an inflatable device entirely) and allow healing before re-attempting.
• Infection — 1–3% after a primary implant but 7–18% after revision; usually skin flora (S. epidermidis, S. aureus, Candida). Antibiotic-coated devices cut infection by 50–70%. Persistent pain or tethering at 3–4 weeks suggests infection; management is systemic antibiotic therapy plus removal of all prosthesis components, and a salvage washout-and-immediate-replacement preserves length but is contraindicated with Enterococcus, tissue necrosis, sepsis, DKA, or urethral erosion.
• Device malfunction (tubing cracks, leaks, pump failure) — replace the faulty component if early, but do a complete replacement after >2 years; ~50% of devices still function at 20 years.
• Erosion — remove all components and allow 8–12 weeks to heal. Pain only on inflation suggests oversized, buckling cylinders (confirm on an inflated MRI) → downsize.
• Postoperative deformities
  • S-shaped deformity — caused by cylinders that are too long.
  • SST deformity (glans bowing / drooping glans) — caused by cylinders that are too short or a hypermobile glans; corrected by replacing with appropriately longer cylinders or anchoring the glans to the tunica (glansplasty).

Disorders of Ejaculation and Orgasm

Ejaculation has three phases — emission (sympathetic, T10–L2), ejection/expulsion (somatic pudendal, S2–S4), and orgasm (central) — and disorders arise when any is disrupted. Premature ejaculation is the commonest male sexual dysfunction; delayed, retrograde, and absent ejaculation usually follow surgery, medication, or neuropathy.

Normal Ejaculation

• Emission — sympathetic (T10–L2) contraction of the vas, seminal vesicles, and prostate deposits semen in the prostatic urethra, with α-sympathetic bladder-neck closure. Damage to these fibres (e.g. RPLND) causes retrograde ejaculation.
• Ejection — bulbar-urethral distension triggers the somatic pudendal nerve (S2–S4) → rhythmic bulbocavernosus contractions with external-sphincter relaxation → antegrade expulsion.
• Neurochemistry — dopamine (D2) promotes and serotonin inhibits ejaculation; PE is linked to 5-HT2C hyposensitivity / 5-HT1A hypersensitivity.

Distinguish retrograde ejaculation from failure of emission with a post-orgasm urinalysis (sperm in the urine = retrograde). In spinal-cord injury, ejaculatory ability improves with more caudal lesions (the opposite of erectile recovery).

Premature Ejaculation

The commonest male sexual dysfunction. The ISSM definition is ejaculation within ~1 minute (lifelong) or a bothersome fall to ~3 minutes (acquired), with an inability to delay and negative personal consequences. Subtypes are lifelong, acquired, variable, and subjective. Acquired PE is often driven by erectile dysfunction (treat the ED first), performance anxiety, prostatitis/CPPS, or hyperthyroidism.

Management is staged:

• First-line — psychosexual therapy (squeeze and stop-start techniques).
• Second-line — pharmacotherapy (mnemonic PASTA): PDE5 inhibitors (only with comorbid ED), topical Anaesthetic (lidocaine/prilocaine 20–30 min before, then wiped off), SSRIs (paroxetine has the strongest effect, ~8.8× IELT; daily or on-demand dapoxetine), Tramadol, and Alpha-blockers — all off-label.

Delayed Ejaculation and Anejaculation

Latency >25–30 minutes with distress, or absent ejaculation (lifelong in ~25%, acquired in ~75%). Causes:

• Neurogenic / surgical — radical prostatectomy (anejaculation but orgasm preserved), RPLND (anejaculation in non-nerve-sparing; antegrade preserved in 80–100% with nerve-sparing), proctocolectomy, and spinal-cord injury.
• Endocrine — diabetes, hypogonadism, hypothyroidism (strongly associated), and hyperprolactinaemia.
• Drugs — SSRIs, antipsychotics, tricyclics, α-methyldopa, and alcohol.

Management: psychosexual therapy, lifestyle change, and pharmacotherapy (pseudoephedrine, cabergoline, and others — generally low efficacy). For spinal-cord injury, vibratory stimulation and electroejaculation retrieve semen but risk autonomic dysreflexia.

Retrograde Ejaculation

Follows bladder-neck disruption — classically TURP — and diabetes. Diagnose with a post-ejaculate urine showing sperm. Treat with α-agonists (pseudoephedrine, ephedrine, midodrine) or imipramine to restore bladder-neck closure.

Painful Ejaculation and POIS

Painful ejaculation reflects an underlying cause (urethritis, BPH, prostatitis/CPPS, ejaculatory-duct obstruction) and is treated accordingly. Post-orgasmic illness syndrome (POIS) is a flu-like illness with myalgia and fatigue beginning within 30 minutes of orgasm — proposed to be a type 1 hypersensitivity reaction, sometimes treated with autologous-semen hyposensitisation.

Testosterone Deficiency

The terms androgen deficiency (AD) or testosterone deficiency are preferred over "hypogonadism." Unlike female menopause — a universal, age-related process — the rate of testosterone decline and the symptoms it produces are highly variable between men.

Terminology and Epidemiology

The true prevalence of AD in adult males is unknown because the literature uses inconsistent definitions; population-based studies suggest a prevalence of 2–39%.

Classification and Causes

AD is classified by the site of the defect. Primary (hypergonadotropic) disease reflects testicular failure; secondary (hypogonadotropic) disease reflects disruption of the hypothalamic–pituitary–gonadal (HPG) axis.

Feature	Primary (hypergonadotropic)	Secondary (hypogonadotropic)
Site of defect	Testis	HPG axis (hypothalamus/pituitary)
LH	High	Low or low/normal
Mechanism	Testicular failure	Reduced central gonadotropin drive

Primary causes — congenital causes follow the mnemonic DUNKY XX: Down syndrome, Undescended testis, Noonan's syndrome, Klinefelter syndrome, Y-microdeletions, and XX-male. Acquired primary causes are iatrogenic (bilateral orchiectomy, testicular radiation, chemotherapy), testicular trauma, infection (orchitis), and autoimmune disease.

Secondary causes:

• Congenital — e.g. Kallmann syndrome (congenital GnRH deficiency).
• Pituitary or suprasellar tumours.
• Pituitary infiltrative disorders — haemochromatosis, tuberculosis, sarcoidosis, histiocytosis.
• Pituitary apoplexy.
• Medications — chronic opioid exposure.
• Hyperprolactinaemia.
• Severe chronic illness.

Systemic illnesses associated with AD: diabetes, obesity, HIV, myocardial infarction, stroke, COPD and other respiratory illness, cancer, sepsis, chronic liver disease, chronic kidney disease (renal transplantation appears to reverse the hormonal abnormalities of ESRD), rheumatoid arthritis, burn injury, traumatic brain injury, and surgical stress.

Diagnosis

The clinical diagnosis of testosterone deficiency requires BOTH:

• Low testosterone — total morning testosterone <300 ng/dL on 2 separate occasions, AND
• Symptoms or signs associated with low serum total testosterone.

A patient is considered testosterone deficient and a candidate for therapy only when he meets both criteria. The recommended workup is a history and physical exam plus laboratory confirmation. Validated questionnaires are not recommended for diagnosis.

History and Physical Exam

Symptoms fall into three categories:

• Physical — loss of body hair, reduced lean muscle mass, gynecomastia, fatigue; visual-field changes (bitemporal hemianopsia) and anosmia point to a pituitary/central cause.
• Cognitive — depression, poor concentration and memory, irritability.
• Sexual — erectile dysfunction, decreased libido, infertility/difficulty conceiving.

Many symptoms (e.g. fatigue) are non-specific and may reflect conditions other than low testosterone. The history should also capture risk factors for AD, past medical and surgical history, and medications.

On examination, assess body habitus (BMI/waist circumference), virilisation (androgen-dependent hair pattern), gynecomastia, testicular size and consistency, and the presence of a varicocele.

• Gynecomastia is benign enlargement of male breast tissue occurring when the testosterone/estradiol (E2) ratio shifts (infancy, adolescence, old age) and may signal low testosterone. Causes are pharmacological (risperidone, anti-androgens, marijuana, clomiphene), physiological (neonatal, puberty), or pathological (testicular tumours, Klinefelter syndrome, cirrhosis). With any male breast enlargement, consider carcinoma.
• Varicocele — there is no definitive evidence that a varicocele causes low testosterone, though varicocele ligation may increase serum testosterone.

Laboratory Confirmation

• A morning total testosterone <300 ng/dL is considered low. Measure it by liquid chromatography/tandem mass spectrometry (LC-MS/MS, preferred), radioimmunoassay, or immunometric assay. Assays vary significantly between techniques and laboratories, so use the same laboratory and method for serial measurements.
• Free testosterone is not recommended as the primary diagnostic test. Although the free fraction is the most biologically active, direct measurement is unreliable and labour-intensive, and calculation-derived values are confounded by albumin/SHBG variation. Free testosterone has a role only in highly symptomatic men with low/normal or equivocal total testosterone.
• Some men with total testosterone >300 ng/dL are highly symptomatic and still improve with therapy.
• Diagnose only after 2 early-morning measurements on separate occasions — testosterone peaks in the morning and varies with circadian and circannual rhythm. There is no defined optimal interval between tests. If the first is <300 ng/dL but the second is normal, use clinical judgment about a third confirmatory test. Fasting is not required.

Even without symptoms, consider checking total testosterone in men with any of these 11 associations: diabetes; obesity (BMI ≥30) or increased waist circumference (>40 inches); HIV/AIDS; male infertility; chemotherapy exposure; testicular radiation; chronic narcotic use; chronic corticosteroid use; pituitary dysfunction; unexplained anaemia; bone-density loss.

Validated questionnaires (ADAM, quantitative ADAM, Aging Male Survey, MMAS, ANDROTEST) are not recommended to select candidates or monitor response — they are highly sensitive (≈80%) but not specific (<50%).

Adjunctive Testing

The initial adjunct is LH; the remaining tests are obtained before initiating treatment.

• Luteinising hormone (LH) — measure in all men with low testosterone to determine etiology. Low or low/normal LH indicates a secondary (central) defect; high LH indicates a primary testicular defect. When the cause is not obvious, a karyotype may establish Klinefelter syndrome (47,XXY) — characterised by very high LH and FSH with low testosterone, managed with exogenous testosterone for symptoms. With ageing, LH does not decline (testosterone falls from testicular hypofunction rather than central change), and Leydig-cell number remains stable.
• Prolactin — measure when low testosterone is paired with low or low/normal LH to screen for hyperprolactinaemia.
• Hematocrit — in all patients (polycythaemia risk; see below).
• Estradiol — in men with breast symptoms or gynecomastia. E2 commonly rises on therapy (aromatase converts testosterone to E2); refer men with breast symptoms and E2 >40 pg/mL to endocrinology. Symptomatic gynecomastia is an uncommon side effect.
• Reproductive health (testicular exam + FSH) — in men interested in fertility. Reduced testicular volume often accompanies impaired sperm production. Elevated FSH (which targets Sertoli cells) signals impaired spermatogenesis — pursue semen analysis. Elevated FSH with azoospermia or severe oligospermia (<5 million/mL) warrants reproductive genetics (karyotype + Y-chromosome microdeletion analysis); the 2015 CUA azoospermia guidelines recommend the same in testicular failure.
• PSA — measure in men >40, younger men with prostate-cancer risk factors, or any history of prostate cancer. PSA rise on therapy depends on baseline testosterone (lower baseline → greater rise). If baseline PSA is elevated, repeat it; two suspicious values warrant formal evaluation (4K, phi, MRI ± biopsy) before starting therapy.

Hyperprolactinaemia

Prolactin is secreted by the pituitary and is a cause of secondary testosterone deficiency, producing infertility, decreased libido, sexual dysfunction, and gynecomastia (via inhibition of dopaminergic activity in the medial preoptic area, lowering testosterone, plus a direct contractile effect on cavernous smooth muscle).

Causes:

• Medications — dopamine antagonists (most common), antipsychotics, SSRIs, PPIs, calcium-channel blockers, anti-emetics, opiates.
• Chronic conditions — hypothyroidism, renal failure, cirrhosis.
• Stress.
• Tumours — pituitary prolactinomas (benign, managed with bromocriptine or cabergoline), non-lactotroph adenomas (GH, ACTH, chromophobe), cystic adenomas, lesions near the hypothalamus/pituitary that disrupt dopamine delivery (e.g. craniopharyngioma), infiltrative disease (sarcoidosis, haemochromatosis, TB), and metastases.
• Other — elevated estrogen, chest-wall injury.

Evaluation: if prolactin is only mildly elevated (≤1.5× upper limit of normal), repeat a fasting level to exclude a spurious/stress-related result. Persistent elevation without an exogenous cause warrants MRI. Any man with total testosterone <150 ng/dL and low/low-normal LH should have a pituitary MRI regardless of prolactin (non-secreting adenomas). Refer to endocrinology if no etiology is found.

Management depends on the cause. A prolactinoma is treated with dopamine agonists (first-line), reserving transsphenoidal surgery for treatment failure or patient preference over lifelong therapy. Otherwise, treat the underlying driver (e.g. hypothyroidism, offending medication).

Pre-Treatment Bloods

Check hemoglobin/hematocrit before starting and counsel about polycythaemia — the most frequent adverse event of testosterone therapy (androgens stimulate erythropoiesis).

• Polycythaemia (erythrocytosis) = Hct >52%. Injectable testosterone produces the greatest rise. Hb/Hct generally climbs for the first 6 months, then plateaus. Increased viscosity can aggravate coronary, cerebrovascular, or peripheral vascular disease, especially in the elderly.
• If baseline Hct >50%, consider withholding therapy until the cause is explained.
• On therapy, a Hct ≥54% warrants intervention. In men with elevated Hct and:
  • High on-treatment testosterone → dose reduction is first-line.
  • Low/normal on-treatment testosterone → measure SHBG and free testosterone: if free T is high with low SHBG, consider dose adjustment; if free T is low/normal, refer to haematology for evaluation and possible phlebotomy.

Management

Lifestyle Modification (First-Line)

Weight loss and increased physical activity may raise total testosterone and reduce symptoms, but counsel that gains may not be clinically meaningful — significant testosterone improvement requires losing 5–10% of body weight. Pursue lifestyle change primarily for overall health.

Testosterone Therapy (Second-Line)

"Testosterone therapy" is the preferred term (over "replacement" or "supplementation") and includes exogenous testosterone as well as alternatives such as SERMs (clomiphene citrate), hCG, and aromatase inhibitors.

Indications (Campbell's): hypopituitarism; testicular dysgenesis with AD; delayed puberty (idiopathic, Kallmann syndrome); Klinefelter syndrome with AD; adult men with signs and symptoms of AD; sexual dysfunction with low testosterone; low bone density with AD.

Contraindications (Campbell's — CHEAPS BLUTS):

• Very high risk — metastatic prostate cancer, breast cancer.
• Moderate–high risk — poorly controlled congestive heart failure, hematocrit >50%, elevated PSA, abnormal DRE, unevaluated sleep apnea, severe BPH-associated LUTS (IPSS >19).
• Do not initiate within 3–6 months of a cardiovascular event.

Counselling — potential benefits (7): erectile function, libido, depressive symptoms, anaemia, bone mineral density, lean body mass, and mitigating the cardiovascular risk of low testosterone.

Testosterone therapy for ED — the role of testosterone monotherapy for ED is unclear. When a PDE5 inhibitor already restores erection, adding testosterone gives no further benefit; in PDE5i-refractory ED, testosterone helps only in men with biochemical AD (<300 ng/dL). In young men with symptomatic AD, testosterone is first-line (with PDE5i added if needed); in elderly men with ED, PDE5i is first-line with comorbidity optimisation, reserving testosterone for non-responders with biochemically confirmed AD.

Potential harms (5):

• Polycythaemia.
• Increased prostate size — prostate volume rises in the first 6 months but does not translate into worsening LUTS.
• Sleep apnea.
• Gynecomastia (rare).
• Infertility — do not prescribe exogenous testosterone to men currently trying to conceive; it suppresses spermatogenesis to severely oligospermic/azoospermic states. Most healthy men recover, but data in testosterone-deficient/infertile men are lacking. Stop testosterone before attempting conception: ~two-thirds recover ejaculated sperm within 6 months and 10% not until the second year, and some never recover.

Inconclusive areas:

• Cardiovascular events — low testosterone is itself a risk factor for cardiovascular disease (MI, stroke, possibly cardiovascular mortality), but it cannot be stated whether testosterone therapy raises or lowers cardiovascular risk. In TRAVERSE (Lincoff, 2023), 5,246 men aged 45–80 with established or high cardiovascular risk plus hypogonadal symptoms and two fasting testosterone levels <300 ng/dL were randomised to transdermal testosterone or placebo; over a mean 27-month treatment and 33-month follow-up there was no significant difference in the primary or secondary cardiovascular composite, though the testosterone group had more atrial fibrillation, acute kidney injury, and pulmonary embolism. There is no definitive link to venothrombotic events.
• Evidence is also inconclusive for cognition, energy, fatigue, diabetes measures, lipids, and quality of life — counsel patients about possible improvement nonetheless.
• Prostate cancer — no definitive link. The FDA warning persists, but evidence increasingly argues against a causal link. In men with a prostate-cancer history the risk–benefit ratio cannot be quantified; therapy can be considered after radical prostatectomy with favourable pathology (negative margins, seminal vesicles, and nodes) and undetectable PSA. Post-radiation patients (± prior ADT) do not appear to recur, but allow time for endogenous testosterone recovery first. Evaluate PSA recurrence as in untreated men, and discuss that stopping therapy may lower PSA. Data in active-surveillance candidates are limited.

Administration — available formulations (5): topical gel/patch (counsel about transference), buccal patch, nasal gel, subcutaneous pellets, intramuscular injections (3 types: two short-acting, one long-acting), and subcutaneous injections.

• Oral testosterone should not be prescribed — methyltestosterone is rapidly hepatically metabolised (inconsistent levels, liver toxicity), and oral testosterone undecanoate (absorbed via intestinal lymphatics, avoiding first-pass) is approved in some countries but not the US. Esterification of native testosterone yields the analogues with usable bioavailability.
• Prefer commercially manufactured products over compounded testosterone.
• Use the minimal dose to reach a total testosterone of 450–600 ng/dL (middle tertile of normal). Treatment success = therapeutic testosterone of 450–600 ng/dL plus symptom/sign improvement.

Alternatives for Men Desiring Fertility

Exogenous testosterone suppresses intratesticular testosterone, which is essential for spermatogenesis. To preserve fertility, use agents that promote endogenous production (alone or combined):

• SERMs (clomiphene citrate, tamoxifen) — block estrogen negative feedback on LH at the hypothalamus and pituitary.
• Aromatase inhibitors (anastrozole) — inhibit conversion of testosterone to estrogen.
• Human chorionic gonadotropin (hCG) — acts as an LH agonist, stimulating Leydig-cell testosterone.

Only hCG is FDA-approved in males (for hypogonadotropic hypogonadism); the overall evidence for these agents is limited.

Monitoring and Follow-Up

• Initial on-treatment testosterone, timed to the formulation: gels/patches/intranasal at 2–4 weeks; short-acting IM/SQ after several cycles (once equilibrated). The Endocrine Society advises measuring midway between injections for enanthate/cypionate and at the end of the interval before the next undecanoate dose, targeting the low–mid physiologic range (350–600 ng/dL; 12.1–20.8 nmol/L). Wait longer before checking after anastrozole, clomiphene, or hCG.
• Re-evaluate symptoms within 3 months — most improvement occurs in the first 3 months. If a man remains testosterone deficient despite symptom improvement, stop therapy. If on-treatment testosterone is below target but symptoms are partially relieved, up-titrate; if symptoms fully resolve, no titration is needed. If testosterone normalises but symptoms do not improve, discuss stopping at 3–6 months — unless there is documented bone-density loss or anaemia that improves on therapy.
• Total testosterone every 6–12 months.
• Hematocrit/hemoglobin every 6–12 months (or sooner) to keep Hct <54%.
• PSA — in men without prostate-cancer history, use shared decision-making per the AUA Early Detection of Prostate Cancer guideline; men with prostate cancer follow the same schedule (clinicians may test more often).
• DEXA — if baseline shows bone loss, repeat at 1–2 years (sooner after any low-trauma fracture); if normalised, image again at 2–5 years.