EndocrinologyTier 2Disease (DEADMAN)

Gonadal system - male hypogonadism

Description

Failure of the testis to produce testosterone, sperm, or both
Testosterone from Leydig cells under LH drive alone; spermatogenesis needs FSH + high intratesticular testosterone from Sertoli cell support
- Which is why exogenous testosterone suppresses LH/FSH -> intratesticular testosterone collapses -> azoospermia. The commonest iatrogenic cause of male infertility

	Primary (hypergonadotropic)	Secondary (hypogonadotropic)
Lesion	Testis	Pituitary/hypothalamus
LH/FSH	HIGH	Low or inappropriately normal
Testis size	Small, firm	Small, soft
Fertility	Usually irrecoverable	Recoverable with gonadotrophins
Gynaecomastia	Common (inc LH -> inc aromatisation)	Less common

Clinical

Pre-pubertal onset: eunuchoid proportions (arm span > height by >5 cm, lower segment > upper), no voice break, sparse body hair, small testes and phallus, failure of epiphyseal fusion -> tall stature
Post-pubertal onset: dec libido, erectile dysfunction, fatigue, dec muscle mass and strength, inc fat mass, low bone density, normocytic anaemia, hot flushes, dec shaving frequency, poor concentration and low mood, infertility
*Loss of morning erections and hot flushes are the most specific symptoms; fatigue and low mood are the least*

Epidemiology

Klinefelter syndrome (47,XXY) - prevalence ~1:500-660 males - the commonest cause of primary hypogonadism, and the commonest chromosomal cause of male infertility
- Fewer than half are ever diagnosed
Symptomatic androgen deficiency in ~2-6% of middle-aged and older men
Testosterone falls ~1%/yr from age 40 while SHBG rises - free testosterone falls faster than total
Kallmann syndrome ~1:8,000 males (M>F 4:1)

Aetiopathogenesis

Primary (testicular)

Klinefelter syndrome (47,XXY)
- Puberty often starts normally, then testicular growth arrests - LH/FSH rise, testosterone falls
- Small firm testes (usually <4 mL), gynaecomastia, tall stature with long legs, azoospermia
- Learning and executive function difficulties, often diagnosed only when fertility is sought
- Diagnosis is by karyotype
Cryptorchidism, testicular torsion, orchitis (mumps), trauma, castration
Chemotherapy (alkylating agents), radiotherapy - germ cells more sensitive than Leydig cells, so FSH rises before testosterone falls
Drugs - ketoconazole, spironolactone, cyproterone, GnRH agonists, chronic opioids, alcohol, anabolic steroid abuse (with subsequent HPG suppression)
Systemic - haemochromatosis, cirrhosis, CKD, HIV, sickle cell disease, myotonic dystrophy
Noonan syndrome (RASopathy - short stature, pulmonary stenosis, webbed neck, cryptorchidism)

Secondary (central)

Functional and reversible - always look for these first
- Obesity (inc aromatisation -> oestrogen feedback; also dec SHBG lowers total testosterone with normal free)
- Opioids - a very common and under-recognised cause
- Glucocorticoids, anabolic steroid use, hyperprolactinaemia
- Acute or chronic illness, OSA, T2DM, alcohol
Structural - pituitary adenoma, craniopharyngioma, apoplexy, infiltration (haemochromatosis, sarcoid, hypophysitis), surgery, radiotherapy, TBI
Congenital isolated hypogonadotropic hypogonadism
- *Kallmann syndrome - the commonest form - anosmia or hyposmia from failed co-migration of GnRH and olfactory neurons (ANOS1/KAL1* X-linked, FGFR1, PROKR2, CHD7)
  - Associated with renal agenesis, synkinesia (mirror movements), cleft lip/palate, dental agenesis**
- Normosmic forms: GNRHR, KISS1R, TAC3
- Prader-Willi, CHARGE, Laurence-Moon-Bardet-Biedl

Diagnosis

Confirm the biochemistry before doing anything else

*Total testosterone on two separate mornings (07:00-11:00), fasting, when not acutely unwell*
- Testosterone has a marked diurnal rhythm, falls with food, and falls with any acute illness. A single low afternoon level in a sick inpatient means nothing
SHBG + calculated free testosterone where total is borderline or SHBG is likely abnormal
- SHBG low: obesity, T2DM, nephrotic syndrome, hypothyroidism, glucocorticoids, androgens
- SHBG high: ageing, cirrhosis, hyperthyroidism, oestrogen, anticonvulsants, HIV
LH and FSH - this is what splits primary from secondary

Then find the cause

Primary (high LH/FSH) -> karyotype (mandatory - Klinefelter is common and frequently missed), testicular examination and ultrasound
Secondary (low/normal LH/FSH) -> prolactin, ferritin/transferrin saturation, iron studies, full pituitary panel, pituitary MRI
- MRI indicated if: testosterone very low, hyperprolactinaemia, headache/visual symptoms, other pituitary deficits, or panhypopituitarism
- Review the drug chart for opioids and glucocorticoids before ordering an MRI
Semen analysis if fertility is a concern; Y-chromosome microdeletion and CFTR testing in azoospermia
DEXA - androgen deficiency is a treatable cause of osteoporosis in men
Haematocrit, PSA (age-appropriate), lipids

Management

Treat the reversible causes first

Weight loss, opioid reduction or cessation, treat OSA, stop anabolic steroids, treat hyperprolactinaemia, replace iron overload management
Obesity-related functional hypogonadism improves substantially with weight loss and with GLP-1 therapy - it does not need testosterone

Testosterone replacement - who

*Only for men with consistent symptoms AND unequivocally, repeatedly low morning testosterone*
- Not for symptoms alone, not for ageing alone, not for a single borderline result
Absolute contraindications: desire for fertility now or soon, prostate or breast cancer, haematocrit >54%, untreated severe OSA, uncontrolled heart failure, recent MI or stroke, palpable prostate nodule or PSA above threshold without urological assessment, planned or current pregnancy in the partner (gel transfer)

Formulations

	Notes
Transdermal gel	Daily; transfer to partners and children - wash hands, cover the site
IM testosterone undecanoate (Reandron) 1000 mg 10-14 weekly	Convenient; risk of pulmonary oil microembolism/POME
IM esters (enantate) 2-3 weekly	Peaks and troughs
Oral testosterone undecanoate	Erratic absorption

AU: PBS authority requires two morning testosterone levels below threshold with a raised LH/FSH, or a pituitary cause, and specialist endorsement in men over 40

Monitoring

Testosterone (aim mid-normal), haematocrit, PSA and digital rectal examination, symptoms at 3, 6 and 12 months then annually
Haematocrit >54% -> reduce dose, lengthen interval, or stop (venesection if needed)
DEXA at 1-2 years if osteoporosis present at baseline

What the evidence actually shows

TRAVERSE (men with hypogonadism and high cardiovascular risk): testosterone non-inferior to placebo for MACE
- But more pulmonary embolism, more AF, more acute kidney injury, and more clinical fractures (4.0% vs 2.8%) - it does not protect bone in the way once assumed
Benefits are real but modest: sexual function, mood, lean mass, bone density. No proven benefit for cognition, depression or cardiovascular outcome

Fertility - a completely different problem

*Testosterone does not restore fertility. It abolishes it.*
Secondary hypogonadism wanting fertility
- hCG (LH analogue) to drive intratesticular testosterone, then add FSH (hMG or recombinant FSH) if azoospermia persists after 3-6 months
- Or pulsatile GnRH by pump where the lesion is hypothalamic
- Testosterone alone restores libido and secondary sexual characteristics but does NOT increase testicular volume or produce sperm
Primary hypogonadism: gonadotrophins do not work
- Klinefelter: micro-TESE recovers sperm in ~40-50%, best in adolescence/young adulthood -> ICSI. Refer early
Pubertal induction in adolescents: low-dose testosterone escalated over 2-3 years, or hCG +/- FSH to also grow the testes

Associations

Klinefelter - breast cancer (~20-50x male baseline), extragonadal germ cell tumours, osteoporosis, T2DM and metabolic syndrome, autoimmune disease (SLE, Sjogren), VTE, learning and language difficulties
Kallmann - anosmia, renal agenesis, mirror movements, cleft palate, dental agenesis
Haemochromatosis - hypogonadotropic hypogonadism is often the first endocrine manifestation
Chronic opioid therapy - hypogonadism in up to 50%
Noonan syndrome - cryptorchidism, delayed puberty, impaired spermatogenesis; GH for stature and androgen or gonadotrophin replacement
Myotonic dystrophy, cirrhosis, CKD, HIV, sickle cell disease
Osteoporosis in men - check testosterone in every man with a minimal-trauma fracture

Natural history & complications

Klinefelter: puberty begins normally, then testicular growth arrests and gonadotrophins climb; testes progressively hyalinise
- Azoospermia in >90%; fertility potential declines through adolescence, which is why testicular sperm retrieval is offered early
- Life expectancy reduced ~2 years; morbidity is metabolic, skeletal and psychosocial
Congenital hypogonadotropic hypogonadism: ~10-20% show spontaneous reversal in adulthood - withdraw therapy periodically to test for it
Untreated androgen deficiency -> progressive osteoporosis, sarcopenia, anaemia, metabolic syndrome, low mood
Testosterone replacement: sexual function improves in weeks, body composition and bone over 6-24 months; the benefit stops when the drug stops
Anabolic-steroid-induced hypogonadism can take 12 months or longer to recover, and sometimes never does

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