Male Hypogonadism

• Primary (hypergonadotropic): the testis fails and LH/FSH rise. Causes include Klinefelter syndrome (47,XXY), cryptorchidism, mumps orchitis, trauma, torsion, chemotherapy or radiation, and alcohol.
• Secondary (hypogonadotropic): the hypothalamus or pituitary fails and LH/FSH are low or inappropriately normal. Causes include Kallmann syndrome, pituitary adenoma including prolactinoma, haemochromatosis, opioids, anabolic steroid use, obesity and systemic illness.
• Presentation depends on timing: prepubertal deficiency gives eunuchoid proportions, absent secondary sexual characteristics and small testes; postpubertal deficiency gives low libido, erectile dysfunction, fatigue, reduced muscle mass, gynaecomastia and osteoporosis.
• Diagnosis rests on a morning total testosterone, repeated to confirm, since levels are diurnal and a single low value is not sufficient.

Primary (testicular) — non-modifiable

• Klinefelter syndrome (47,XXY): meiotic nondisjunction; the most common congenital cause of primary hypogonadism and the single most common cause of male infertility from a chromosomal defect.
• Cryptorchidism: intra-abdominal temperature damages germinal epithelium; risk persists even after orchiopexy.
• Congenital anorchia, myotonic dystrophy, and 46,XX/other disorders of sex development.

Primary — acquired/modifiable or exposure-related

• Mumps orchitis (postpubertal), testicular torsion, and trauma: direct destruction of seminiferous tubules and Leydig cells.
• Gonadotoxic therapy: alkylating agents (cyclophosphamide) and testicular/pelvic radiation; germ cells are more radiosensitive than Leydig cells, so FSH rises before testosterone falls.
• Alcohol use disorder and cirrhosis: direct Leydig cell toxicity plus increased SHBG and peripheral aromatization.

Secondary (hypothalamic–pituitary) — non-modifiable

• Kallmann syndrome: failed GnRH neuron migration, with anosmia; ANOS1/KAL1 (X-linked) and FGFR1 forms.
• Normosmic idiopathic hypogonadotropic hypogonadism, pituitary adenoma (mass effect or prolactin excess), craniopharyngioma, infiltrative disease (haemochromatosis, sarcoidosis), and prior cranial irradiation.

Secondary — modifiable, the ones examiners plant in the stem

• Exogenous anabolic-androgenic steroids: negative feedback suppresses LH/FSH; the classic young bodybuilder with large muscles and small soft testes.
• Chronic opioid therapy and high-dose glucocorticoids: suppress hypothalamic GnRH pulsatility.
• Obesity and metabolic syndrome: adipose aromatase converts testosterone to estradiol, which feeds back centrally; also lowers SHBG.
• Systemic illness, malnutrition, extreme exercise, obstructive sleep apnoea, and hyperprolactinaemia (including antipsychotic-induced).

• The axis: hypothalamic GnRH is released in pulses → pituitary LH and FSH → LH drives Leydig cell testosterone synthesis, FSH drives Sertoli cell support of spermatogenesis and inhibin B secretion. Testosterone and estradiol feed back on LH; inhibin B selectively suppresses FSH.
• Primary failure: loss of Leydig and Sertoli cells removes both testosterone and inhibin B feedback, so LH and FSH rise. Because inhibin B is the dedicated FSH brake, FSH typically rises more than LH when tubules are damaged — the pattern in Klinefelter and post-chemotherapy testes.
• Secondary failure: absent or non-pulsatile GnRH, or pituitary destruction, leaves gonadotropins low or inappropriately normal in the face of a low testosterone. The testis is intrinsically healthy, which is why fertility is often salvageable with gonadotropin therapy while primary failure is usually irreversible.
• Why continuous stimulation fails: GnRH receptors downregulate with non-pulsatile exposure — the same principle that makes leuprolide a chemical castrator and mandates pulsatile GnRH pumps for induction of fertility.
• Timing determines phenotype: androgens close epiphyses. Prepubertal deficiency leaves growth plates open, so long bones keep growing — the eunuchoid habitus with arm span exceeding height and lower segment exceeding upper segment. Postpubertal deficiency cannot undo virilisation already achieved, so the presentation is functional: low libido, reduced lean mass, fatigue.
• Gynaecomastia arises when the androgen-to-oestrogen ratio falls. In Klinefelter and in obesity, aromatase activity is preserved or increased while testosterone falls, so breast tissue proliferates.
• Bone: testosterone (largely after aromatisation to estradiol) restrains osteoclast activity; deficiency accelerates resorption and produces low bone density.
• Erythropoiesis: testosterone stimulates erythropoietin and suppresses hepcidin, so deficiency causes a normocytic anaemia and replacement can cause erythrocytosis.

Specific (androgen-deficiency) symptoms

• Reduced libido and erectile dysfunction: loss of central androgen drive and of nitric-oxide–mediated cavernosal responsiveness.
• Loss of morning erections, reduced spontaneous erections — an early and relatively specific marker.
• Small testes: <4 mL by Prader orchidometer or <3.5 cm long axis. Small firm testes suggest tubular hyalinisation (Klinefelter); small soft testes suggest gonadotropin withdrawal (exogenous androgens, opioids, pituitary disease).
• Gynaecomastia: falling androgen-to-oestrogen ratio; tender subareolar disc.
• Decreased beard and axillary/pubic hair, fine facial wrinkling, decreased shaving frequency — slow to appear.

Prepubertal-onset findings

• Eunuchoid proportions: arm span > height by several centimetres, lower segment > upper segment, from delayed epiphyseal closure.
• Micropenis, absent voice deepening, high-pitched voice, sparse body hair, and absent pubertal growth spurt.

The demographics the stem names

• Tall adolescent or young man with long limbs, gynaecomastia, small firm testes, learning or language difficulties, and infertility → Klinefelter syndrome.
• Teenage boy with absent puberty who cannot smell the coffee/his food → Kallmann syndrome; look for cryptorchidism, cleft lip/palate, unilateral renal agenesis, and mirror movements (synkinesia).
• Middle-aged man with fatigue, arthralgias, bronze skin, diabetes and low libido → haemochromatosis with pituitary iron deposition.
• Man on chronic opioids or anabolic steroids, or with headache, bitemporal hemianopia and galactorrhoea → pituitary/prolactinoma.

Step 1 — confirm biochemical deficiency

• Morning (before 10 AM), fasting total testosterone is the initial test; testosterone has a diurnal peak in the early morning and is suppressed by food and by acute illness. The Endocrine Society requires two separate low morning values on a reliable assay before diagnosing hypogonadism, and both they and the AUA emphasise pairing low levels with consistent signs/symptoms.
• The AUA uses total testosterone below 300 ng/dL as the diagnostic threshold; the Endocrine Society defers to the assay's lower limit of normal.
• Free or bioavailable testosterone (equilibrium dialysis, or calculated) when SHBG is altered — obesity, nephrotic syndrome, glucocorticoids and insulin resistance lower SHBG; ageing, cirrhosis, hyperthyroidism, HIV and anticonvulsants raise it. A borderline total testosterone in an obese man is the classic trap.
• Do not test during acute illness or hospitalisation; transient central suppression is expected.

Step 2 — localise with LH and FSH

• High LH/FSH → primary. Next step is a karyotype if the picture fits Klinefelter (47,XXY; may be mosaic 46,XY/47,XXY).
• Low or inappropriately normal LH/FSH → secondary. Obtain prolactin, TSH/free T4, morning cortisol or ACTH-stimulation, IGF-1, and transferrin saturation/ferritin for haemochromatosis, plus a medication review for opioids and androgens.
• Pituitary MRI for secondary hypogonadism that is severe, panhypopituitary, hyperprolactinaemic, or accompanied by headache or visual field loss.

Adjuncts

• Semen analysis if fertility is a concern — azoospermia in Klinefelter, low count with low FSH centrally.
• DXA for bone density in confirmed androgen deficiency.
• Anosmia testing (formal smell identification) distinguishes Kallmann from normosmic idiopathic hypogonadotropic hypogonadism.
• Screening asymptomatic men with testosterone is not recommended.

First-line, fertility not desired

• Testosterone replacement, per the Endocrine Society and AUA, for men with unequivocally low levels plus symptoms. Representative agents: injectable testosterone cypionate or enanthate (IM, every 1–2 weeks; peak-and-trough mood/energy swings), transdermal 1% gel (steady levels; counsel on skin-to-skin transfer causing virilisation of women and children), testosterone undecanoate (long-acting IM, with a pulmonary oil microembolism risk requiring post-injection observation), subcutaneous pellets, and oral undecanoate. Methyltestosterone and other 17-alpha-alkylated oral androgens are avoided — hepatotoxicity/peliosis hepatis.

• Secondary hypogonadism: hCG (LH analogue) to restart Leydig cell function, adding FSH (or hMG) if sperm do not appear; pulsatile GnRH is an option in hypothalamic disease with an intact pituitary. Off-label clomiphene or aromatase inhibitors (anastrozole) raise endogenous LH/FSH.
• Primary hypogonadism/Klinefelter: gonadotropins do not work; microdissection testicular sperm extraction with ICSI is the definitive fertility option.

Of untreated hypogonadism

• Osteoporosis and fragility fracture: loss of testosterone-derived estradiol disinhibits osteoclasts; signalled by low DXA T-score or a vertebral compression fracture in a young or middle-aged man.
• Infertility/azoospermia: absent FSH-driven spermatogenesis or destroyed germinal epithelium.
• Normocytic anaemia: testosterone normally stimulates erythropoiesis and suppresses hepcidin.
• Sarcopenia, increased visceral adiposity, insulin resistance and depressed mood, with reduced quality of life.
• Cause-specific: Klinefelter carries an increased risk of breast cancer, extragonadal (mediastinal) germ cell tumours, autoimmune disease, venous thromboembolism and metabolic syndrome. A pituitary macroadenoma can cause bitemporal hemianopia, panhypopituitarism, and apoplexy — an emergency.

Of testosterone therapy

• Erythrocytosis — the most common adverse effect; excess erythropoietic drive raises haematocrit and viscosity, risking thrombosis and stroke. Check haematocrit at baseline, 3–6 months, then annually.
• Suppressed spermatogenesis and testicular atrophy: exogenous androgen shuts off LH/FSH, dropping intratesticular testosterone. Often reversible but may take many months; counsel every man of reproductive age.
• Gynaecomastia and acne: peripheral aromatisation to estradiol and sebaceous stimulation.
• Worsening obstructive sleep apnoea and fluid retention precipitating heart failure decompensation.
• Prostate effects: rising PSA and worsened lower urinary tract symptoms; testosterone does not appear to cause prostate cancer, but it is contraindicated in known prostate cancer.
• Formulation-specific: transdermal gel transfer causing virilisation in a female partner or child (the classic precocious puberty in a toddler vignette); injection-site pain; hepatotoxicity with 17-alpha-alkylated oral androgens; pulmonary oil microembolism and anaphylaxis with long-acting undecanoate — an acute emergency.

• The single best next step for suspected hypogonadism is a repeat early-morning fasting total testosterone, not an MRI, not a karyotype, and not empiric testosterone. LH and FSH come next and localise the lesion.
• Tall man, long limbs, gynaecomastia, small FIRM testes, azoospermia = Klinefelter (47,XXY) — confirm with karyotype. FSH is disproportionately elevated because loss of Sertoli-cell inhibin B removes the selective FSH brake. Remember the increased breast cancer risk.
• Absent puberty plus anosmia = Kallmann — failed migration of GnRH neurons from the olfactory placode. Low LH/FSH, low testosterone; associations include cryptorchidism, unilateral renal agenesis, cleft palate and mirror movements.
• Small SOFT testes with low LH/FSH in a muscular young man = exogenous anabolic steroid use. The distractor is to call it primary failure; gonadotropin suppression makes it secondary and potentially reversible.
• Never give testosterone to a man who wants children. Use hCG ± FSH (or pulsatile GnRH) for secondary hypogonadism; testosterone suppresses intratesticular androgen and worsens azoospermia.
• Check prolactin in every man with secondary hypogonadism — a prolactinoma is treated medically with a dopamine agonist (cabergoline), not surgically, as first line.
• The complication to monitor on therapy is erythrocytosis — recheck haematocrit at 3–6 months and yearly; hold therapy if it climbs too high.
• Obesity is the great confounder: it lowers SHBG, so total testosterone can look low while free testosterone is normal. Order free testosterone by equilibrium dialysis when SHBG is likely altered.
• Do not test during acute illness — transient central suppression produces false-positive results.