Androgens and Antiandrogens

• Testosterone replacement treats confirmed hypogonadism. Exogenous androgen suppresses LH and FSH by negative feedback, which shrinks the testes and impairs spermatogenesis — so it is the wrong drug for a man seeking fertility, a favourite exam point. Other concerns include erythrocytosis, acne, sleep apnoea and worsening of an existing prostate cancer.
• 5-alpha reductase inhibitors (finasteride, dutasteride) block conversion of testosterone to dihydrotestosterone, treating benign prostatic hyperplasia and androgenetic alopecia. They lower PSA by roughly half, which must be accounted for in screening interpretation. Adverse effects include reduced libido and gynaecomastia.
• Androgen receptor antagonists: flutamide, bicalutamide, nilutamide in prostate cancer (flutamide is hepatotoxic); spironolactone, an aldosterone antagonist with antiandrogen activity used in hirsutism and acne, causing gynaecomastia in men; cyproterone.
• GnRH agonists (leuprolide) stimulate the axis when given in pulses but suppress it when given continuously, which is how they treat prostate cancer, endometriosis and fibroids. The initial surge can cause a testosterone flare, so an antiandrogen is given first in advanced prostate cancer. GnRH antagonists (degarelix) avoid the flare.
• Ketoconazole inhibits steroid synthesis at high doses.

Androgen deficiency — primary (testicular, high LH/FSH)

• Klinefelter syndrome (47,XXY): the most common congenital cause; small firm testes with hyalinised tubules, so FSH rises earliest.
• Acquired testicular injury: mumps orchitis, torsion, trauma, alkylating chemotherapy, pelvic radiation, cryptorchidism.

Androgen deficiency — secondary (hypothalamic/pituitary, low or inappropriately normal LH/FSH)

• Structural: pituitary macroadenoma, prolactinoma (prolactin suppresses GnRH pulsatility), craniopharyngioma, hemochromatosis, infiltrative disease.
• Functional and largely modifiable: chronic opioids, high-dose glucocorticoids, obesity, obstructive sleep apnoea, alcohol, systemic illness — examiners plant the chronic-pain patient on long-acting opioids.
• Congenital: Kallmann syndrome (GnRH neuron migration failure with anosmia).
• Exogenous androgen or anabolic steroid use is the classic reversible cause: the stem is a young weightlifter with high muscle mass, small testes and infertility.

Androgen excess in women

• PCOS: by far the most common; insulin resistance drives ovarian theca-cell androgen output and lowers SHBG.
• Non-classic 21-hydroxylase deficiency: precursor shunting into the androgen pathway.
• Androgen-secreting ovarian or adrenal tumour: suggested by rapid onset and frank virilisation rather than slow hirsutism.

Conditions treated with antiandrogens

• Benign prostatic hyperplasia and androgenetic alopecia: DHT-dependent; risk rises with age and family history.
• Prostate cancer: androgen-driven; age, Black race, family history and germline BRCA2 are the non-modifiable risks.

• Pulsatile GnRH is the master switch: hypothalamic GnRH pulses drive pituitary LH and FSH. LH stimulates Leydig cells to convert cholesterol to testosterone; FSH acts on Sertoli cells to support spermatogenesis. Testosterone and its aromatised product estradiol close the loop by negative feedback at both hypothalamus and pituitary.
• Spermatogenesis depends on intratesticular testosterone, which is orders of magnitude higher than serum levels. Exogenous testosterone raises serum levels but suppresses LH, so intratesticular concentrations collapse — hence testicular atrophy and oligo-/azoospermia despite a normal or high serum testosterone. This is why testosterone is the wrong drug for a man who wants fertility, and why hCG (an LH analogue) or clomiphene is used instead.
• Peripheral conversion determines the phenotype:
• 5-alpha reductase → dihydrotestosterone binds the androgen receptor with higher affinity and slower dissociation. DHT drives external genital development in utero, prostate growth, sebum, terminal beard hair and scalp follicle miniaturisation. Congenital 5-alpha reductase type 2 deficiency therefore gives a 46,XY infant with normal internal wolffian structures (testosterone-dependent) but undervirilised external genitalia that masculinise at puberty.
• Aromatase → estradiol mediates epiphyseal closure, bone density maintenance and feedback; excess conversion in supraphysiologic androgen users produces gynaecomastia.
• Androgen receptor: a cytosolic nuclear-receptor-family protein; ligand binding displaces heat-shock proteins, allowing dimerisation and DNA binding at androgen response elements. Receptor blockade (flutamide, bicalutamide) leaves testosterone circulating but transcriptionally inert.
• The GnRH paradox: continuous receptor occupancy by leuprolide first triggers a gonadotropin surge and testosterone flare over roughly the first one to two weeks, then downregulates and desensitises the GnRH receptor, producing castrate testosterone. Antagonists (degarelix) block the receptor competitively and drop testosterone without a flare.

Male androgen deficiency (the stem: a middle-aged or older man, often obese or on chronic opioids)

• Specific symptoms: reduced morning erections, low libido, erectile dysfunction — these track most closely with a truly low testosterone.
• Non-specific symptoms: fatigue, depressed mood, poor concentration, reduced exercise tolerance.
• Signs from loss of androgen action on target tissues: decreased muscle mass and strength, increased visceral fat, reduced body and facial hair, gynaecomastia (unopposed estrogen effect), small soft testes, low bone density.
• Pre-pubertal onset gives eunuchoid proportions (arm span exceeding height because epiphyses stay open), high-pitched voice and absent adrenarche-independent virilisation; with anosmia, think Kallmann.

Anabolic steroid user (young man, gym or competitive sport exposure)

• Rapid muscle gain with acne, striae, male-pattern balding, testicular atrophy and infertility (suppressed LH/FSH), gynaecomastia from aromatisation, irritability and aggression, hypertension.

Androgen excess in a woman

• Hirsutism in androgen-dependent areas (upper lip, chin, chest, linea alba), acne, oily skin, and with higher levels virilisation: clitoromegaly, voice deepening, temporal balding, increased muscle bulk. Rapid onset over months points to a tumour; slow onset with oligomenorrhoea and obesity points to PCOS.

DHT-dependent disease

• BPH: lower urinary tract symptoms — hesitancy, weak stream, incomplete emptying, nocturia — with a smooth enlarged prostate on rectal exam.
• Androgenetic alopecia: bitemporal recession and vertex thinning.

On androgen deprivation therapy

• Hot flushes, fatigue, loss of libido, gynaecomastia, sarcopenia with central weight gain, and mood change. A man newly started on leuprolide for metastatic disease who develops worsening bone pain, retention or leg weakness is having a flare.

Suspected male hypogonadism — the Endocrine Society sequence

• Initial test: total testosterone drawn in the early morning, fasting, because levels peak near waking and fall after meals. A single low value is never enough — confirm with a second morning measurement on a separate day, ideally by liquid chromatography–tandem mass spectrometry.
• Correct for binding protein: obesity, nephrotic syndrome and insulin resistance lower SHBG (falsely low total testosterone); ageing, cirrhosis, hyperthyroidism and HIV raise it. When SHBG is deranged, measure free testosterone by equilibrium dialysis.
• Localise with LH and FSH: high gonadotropins = primary testicular failure → karyotype (Klinefelter); low or inappropriately normal gonadotropins = secondary → prolactin, iron studies/ferritin and transferrin saturation, other pituitary hormones, and pituitary MRI for markedly low testosterone, hyperprolactinaemia or visual field loss.
• Semen analysis if fertility is the concern. Suppressed LH/FSH with a high testosterone in a muscular young man is exogenous androgen use, not disease.

Hirsutism/androgen excess in women

• Quantify hair growth with the modified Ferriman–Gallwey score; measure early-morning total testosterone and DHEAS, plus follicular-phase 17-hydroxyprogesterone to screen for non-classic 21-hydroxylase deficiency. Markedly elevated testosterone with rapid virilisation prompts ovarian imaging; markedly elevated DHEAS prompts adrenal imaging.

Prostate evaluation

• PSA and digital rectal exam, with transrectal ultrasound-guided (increasingly MRI-targeted) biopsy for confirmation and Gleason grade group assignment. Symptom burden in BPH is scored with the AUA Symptom Index/IPSS.
• Critical interpretive point: after roughly 6–12 months of finasteride or dutasteride, PSA falls by about half — double the measured value before comparing with age-based thresholds, and treat any rise above the on-drug nadir as suspicious.

• First line: testosterone replacement — intramuscular esters (testosterone cypionate/enanthate), transdermal gel or patch, subcutaneous pellets, or oral/nasal formulations. Gels carry an FDA boxed warning for virilising transfer to women and children.
• If fertility is desired, testosterone is the wrong drug. Use hCG (LH analogue) to maintain intratesticular testosterone, with FSH added if needed; clomiphene or an aromatase inhibitor raises endogenous gonadotropins. Pulsatile GnRH is an option in hypothalamic disease.
• Contraindications: breast cancer, untreated prostate cancer, elevated haematocrit, severe untreated sleep apnoea, untreated severe LUTS, uncontrolled heart failure, recent MI or stroke, and desire for near-term fertility.

Of testosterone therapy

• Erythrocytosis: androgens stimulate erythropoiesis and suppress hepcidin; rising haematocrit raises viscosity and thrombotic risk. The Endocrine Society advises monitoring haematocrit and holding or reducing therapy when it exceeds roughly 54%. Check at baseline, then at intervals during the first year.
• Infertility and testicular atrophy from gonadotropin suppression — often only partly reversible after prolonged use.
• Gynaecomastia from aromatisation; acne; worsening obstructive sleep apnoea; acceleration of an existing prostate cancer (testosterone does not cause the cancer but can feed one already present).
• 17-alpha-alkylated oral anabolic steroids specifically cause cholestatic jaundice, peliosis hepatis and hepatic adenoma; illicit use also produces low HDL, hypertension, left ventricular hypertrophy and mood disturbance.

Of 5-alpha reductase inhibitors

• Decreased libido, erectile dysfunction, ejaculatory dysfunction, gynaecomastia; PSA halving that can mask a cancer if uncorrected. Teratogenic — a pregnant woman must not handle crushed or broken tablets because DHT blockade disrupts male external genital development.

Of androgen deprivation therapy

• Tumour flare with a GnRH agonist is the emergency: in men with vertebral metastases or bulky pelvic disease it can precipitate spinal cord compression or acute urinary retention within the first weeks — new back pain with neurologic deficit demands urgent MRI and steroids.
• Osteoporosis and fragility fracture, sarcopenia, insulin resistance and dyslipidaemia, hot flushes, anaemia, and QT prolongation. Abiraterone causes mineralocorticoid excess (hypertension, hypokalaemia, oedema) and hepatotoxicity; enzalutamide lowers the seizure threshold.
• Flutamide: fulminant hepatic necrosis — monitor transaminases.

• Muscular young man with small testes and infertility: exogenous anabolic steroid use. The tell is a high testosterone with suppressed LH and FSH — endogenous disease never does that.
• Best next step when a man with low testosterone wants children: stop or never start testosterone and use hCG (± FSH) or clomiphene. Replacement testosterone is contraceptive, not fertility-restoring.
• A single low testosterone is not a diagnosis. Repeat an early-morning, fasting total testosterone on a second day, then use LH/FSH to separate primary from secondary disease.
• Finasteride halves PSA. Double the on-drug value before interpreting it, and treat any rise above the nadir as suspicious rather than reassuring.
• 5-alpha reductase type 2 deficiency: 46,XY with undervirilised external genitalia but normal internal wolffian ducts, then dramatic virilisation at puberty as testosterone surges — "penis at twelve." Contrast with complete androgen insensitivity, where the receptor itself is defective and there is no pubertal virilisation.
• Leuprolide given continuously suppresses; given in pulses it stimulates. Give bicalutamide first in advanced prostate cancer, or use degarelix to sidestep the flare altogether. New back pain with leg weakness after the first leuprolide dose is cord compression until proven otherwise.
• Antiandrogen side-effect matching: flutamide → hepatotoxicity; spironolactone → hyperkalaemia and gynaecomastia; abiraterone → mineralocorticoid excess, hence co-administered prednisone; enzalutamide → seizures; ketoconazole → adrenal insufficiency and hepatotoxicity.
• Common distractor: attributing new prostate cancer to testosterone therapy. Androgens can accelerate an existing tumour and are contraindicated in untreated prostate cancer, but the exam-safe framing is worsening, not causing. A second distractor is checking a testosterone level in the afternoon.