• Prevalence increases with age: approximately 2–4% of men aged > 40 have biochemically confirmed low testosterone with symptoms. By age 70–80, prevalence rises to 20–50% depending on the definition used.
• Klinefelter syndrome (47,XXY) is the most common congenital cause of primary hypogonadism in males: ~1 in 500–660 live male births.
• Late-onset hypogonadism (LOH) / "andropause" is increasingly recognised, though remains controversial as a distinct entity. The European Male Ageing Study (EMAS) found that only ~2% of men aged 40–79 meet strict criteria for LOH (low testosterone + ≥ 3 sexual symptoms).

• Premature menopause (age < 40) or early menopause (age 40–45) are recognised clinical risk factors for downstream sequelae such as osteoporosis ^[2].
• Primary ovarian insufficiency (POI) affects ~1% of women under 40.
• Turner syndrome (45,X) is the most common chromosomal cause of primary hypogonadism in females: ~1 in 2,000–2,500 live female births.
• Climacteric/menopausal hypogonadism is universal in women — average age of menopause in HK is ~51 years ^[3].

• High prevalence of chronic liver disease (hepatitis B carrier rate ~7–8% of HK population) — liver disease is a significant secondary cause of hypogonadism via ↑SHBG and direct gonadal toxicity ^[4].
• Use of traditional Chinese medicine and anabolic supplements may suppress the HPG axis — important to ask about in history.
• Klinefelter syndrome and Turner syndrome frequencies mirror global figures.

• GnRH (Gonadotropin-Releasing Hormone) is secreted in a pulsatile fashion from GnRH neurons in the arcuate nucleus and preoptic area.
• Pulsatility is critical: pulsatile GnRH stimulates gonadotropin release, whereas continuous GnRH (or GnRH agonists given continuously) paradoxically downregulates the GnRH receptor and suppresses LH/FSH — this is why GnRH agonists like leuprolide are used therapeutically to suppress sex hormones (e.g., in prostate cancer, precocious puberty) ^[5].
• GnRH pulse frequency determines the ratio of LH to FSH secreted:
  • Fast pulses → favour LH
  • Slow pulses → favour FSH

• LH (Luteinizing Hormone) and FSH (Follicle-Stimulating Hormone) are glycoprotein hormones secreted by gonadotroph cells.

Male (Testes):

• Leydig cells (interstitial): Produce testosterone under LH stimulation. Testosterone is the principal circulating androgen.
• Sertoli cells (within seminiferous tubules): Support spermatogenesis; produce inhibin B (which feeds back negatively on FSH specifically), anti-Müllerian hormone (AMH), and androgen-binding protein (ABP).
• Testosterone is converted peripherally to:
  • Dihydrotestosterone (DHT) via 5α-reductase — a more potent androgen (important for prostate, external genitalia, hair follicles)
  • Estradiol (E2) via aromatase — important for bone health, epiphyseal closure in males

Female (Ovaries):

• Theca cells: Produce androgens (androstenedione, testosterone) under LH stimulation.
• Granulosa cells: Convert androgens to estradiol via aromatase under FSH stimulation (the "two-cell, two-gonadotropin" model).
• Corpus luteum: Produces progesterone after ovulation.

• Negative feedback:
  • Testosterone/estradiol → inhibit GnRH (hypothalamus) and LH/FSH (pituitary)
  • Inhibin B → selectively inhibits FSH at the pituitary
  • Progesterone → inhibits GnRH pulsatility
• Positive feedback (unique to females): Rising estradiol in late follicular phase triggers the LH surge → ovulation. This does not occur in males.

• Most circulating testosterone is bound: ~60% to SHBG (tightly), ~38% to albumin (loosely), and only ~2% is free (biologically active).
• Free testosterone + albumin-bound testosterone = bioavailable testosterone.
• Conditions that ↑SHBG (ageing, liver cirrhosis, hyperthyroidism, estrogen therapy) → ↓free testosterone → can cause symptoms of hypogonadism even if total testosterone appears "normal."
• Conditions that ↓SHBG (obesity, hypothyroidism, insulin resistance, androgens, nephrotic syndrome) → ↑free testosterone relative to total testosterone.

Testosterone has a diurnal rhythm — levels are highest in the early morning and lowest in the late afternoon/evening. Therefore, blood for testosterone must be drawn in the early morning (before 10 AM) to ensure reproducibility. ^[6]

"So just because in the afternoon you take a spot testosterone test and it's low, doesn't mean it's hypogonadism → need to take first thing in the morning" ^[6]

This is the same principle as cortisol and ACTH, which also follow diurnal rhythms ^[6].

• Defect: At the level of the gonad itself
• Hormone pattern: ↓ sex steroids (testosterone / estradiol), ↑ LH and ↑ FSH (because loss of negative feedback → pituitary tries to compensate by ramping up gonadotropin secretion)
• The gonadotropins are "hyper" — hence "hypergonadotropic"
• Think of it as: the brain is shouting at the gonads to work, but the gonads cannot respond.

• Defect: At the level of the pituitary
• Hormone pattern: ↓ sex steroids, ↓ or inappropriately normal LH/FSH
• The gonadotropins are "hypo" or inappropriately normal — "hypogonadotropic"
• The pituitary is not sending the signal.

• Defect: At the level of the hypothalamus (↓ GnRH)
• Hormone pattern: Same as secondary — ↓ sex steroids, ↓ or normal LH/FSH
• Often grouped together with secondary hypogonadism as "central hypogonadism" because clinically it is difficult to distinguish pituitary from hypothalamic causes based on gonadotropin levels alone.
• Differentiation can sometimes be attempted with a GnRH stimulation test (exogenous GnRH → if LH/FSH rise, the pituitary is intact and the problem is hypothalamic; if they don't rise, the pituitary itself is defective).

• Combined primary and secondary: e.g., ageing, chronic systemic illness
• Androgen resistance syndromes: Gonads and pituitary work normally, but target tissues cannot respond (e.g., complete androgen insensitivity syndrome — 46,XY with female phenotype)

These causes are shared between males and females.

1. Chronic hepatitis B → cirrhosis → ↑SHBG, ↑aromatase, direct gonadal toxicity
2. Obesity (rising prevalence in HK) → functional hypogonadotropic hypogonadism
3. Prolactinoma — common pituitary tumour
4. Opioid use — increasingly recognised cause of secondary hypogonadism
5. Klinefelter syndrome — most common congenital cause in males
6. Premature menopause / POI — important cause in younger women
7. Drug-induced: antipsychotics (causing hyperprolactinaemia), steroids

This distinction is absolutely critical because it determines the clinical presentation:

Pre-pubertal onset (e.g., Klinefelter, Kallmann, Turner):

• Puberty does not occur or is incomplete
• Males: Small testes, penis and scrotum; ↓ hair (facial, pubic, axillary, body); high-pitched voice; ↓ muscle mass and strength ^[1]
• Eunuchoidism if no growth impairment (span > height, lower segment > upper segment) — this occurs because epiphyseal closure is driven by estradiol (aromatised from testosterone). Without testosterone → no estradiol → delayed epiphyseal closure → the long bones keep growing → patients are tall with disproportionately long limbs ^[1]
• Females: Primary amenorrhoea, impaired breast development ^[1]

Post-pubertal onset (e.g., acquired hypogonadism, menopause):

• Secondary sexual characteristics have already developed, so changes are more subtle
• Males: ↓ libido; impotence; ↓ morning erection; infertility; ↓ hair; failure of scalp hair to recede; testes soft, size normal or mildly decreased; normal external genitalia ^[1]
• Females: Secondary amenorrhoea, vasomotor symptoms, vaginal dryness, bone loss

• Unlike menopause (which is universal and abrupt), the decline in testosterone in ageing males is gradual (~1–2% per year after age 30).
• LOH is defined as the combination of biochemically low testosterone + at least 3 sexual symptoms (↓ libido, ↓ morning erections, ED).
• Many "low testosterone" cases in older men are due to functional causes (obesity, type 2 DM, opioids, chronic illness) rather than true gonadal failure.
• Treatment is controversial — testosterone replacement therapy (TRT) in older men has benefits (bone density, muscle mass, mood, sexual function) but potential risks (CVD, prostate, polycythaemia) — current guidelines recommend a personalised risk-benefit discussion.

Obesity is a major cause of functional hypogonadotropic hypogonadism in males ^[10]

The mechanism is bidirectional:

1. Obesity → ↓ testosterone: ↑ aromatase in adipose tissue converts testosterone → estradiol → negative feedback on HPG axis; ↑ insulin resistance → ↓ SHBG → ↓ total testosterone; adipokines (leptin resistance) impair GnRH pulsatility
2. ↓ Testosterone → ↑ obesity: loss of testosterone's lipolytic effects → further fat accumulation → a vicious cycle

Weight loss is the most effective intervention for obesity-related hypogonadism and should be first-line before considering testosterone replacement ^[10].

Erectile dysfunction (ED) is multifactorial ^[11]

While hypogonadism is an important cause of ED, most ED in clinical practice is vascular (atherosclerotic) or neurogenic (diabetes). Hypogonadism accounts for only ~5% of ED cases. However, testosterone modulates the NO/cGMP pathway in cavernosal smooth muscle, so hypogonadal men may have a blunted response to PDE5 inhibitors (e.g., sildenafil). Correcting testosterone deficiency can improve PDE5i responsiveness.

1. Sexual history: libido, erectile function, morning erections, ejaculatory function (males); menstrual history, menopausal symptoms (females)
2. Pubertal history: age of puberty, progression of secondary sexual characteristics
3. Fertility history: previous pregnancies, time trying to conceive
4. Constitutional symptoms: weight changes, fatigue, mood
5. Anosmia/hyposmia — screening for Kallmann
6. Drug history — opioids, steroids, antipsychotics, chemotherapy
7. Past medical history — chronic illness, autoimmune diseases, head injury, pituitary surgery/radiation
8. Family history — delayed puberty, infertility, chromosomal disorders
9. Social history — alcohol, recreational drugs, exercise pattern, diet (anorexia)
10. Visual symptoms — headache, visual field defects (pituitary lesion)

1. General: body habitus (eunuchoid proportions?), BMI, body hair distribution
2. Head: visual fields by confrontation, anosmia testing, gynecomastia inspection
3. Genitalia (male): testicular volume (orchidometer — normal > 4 mL; adult average 15–25 mL), consistency (soft = post-pubertal atrophy; small/firm = Klinefelter), penile size, phallus, scrotal development
4. Breast exam: gynaecomastia (glandular vs adipose), galactorrhoea
5. Skin: acne (or lack thereof), hair pattern, pallor
6. Musculoskeletal: muscle bulk, proximal weakness
7. Signs of underlying cause: hepatomegaly/stigmata of CLD, signs of Cushing's, thyroid exam

Constitutional delay of puberty accounts for 14% of primary amenorrhoea and is also the most common cause of delayed puberty in boys ^[18].

Approach to amenorrhoea differentials include: Gonadal dysgenesis (Turner, Swyer — 43%), Müllerian agenesis (15%), Constitutional delay (14%), PCOS (7%), Transverse vaginal septum (3%), Weight loss/anorexia (2%), Hypopituitarism (2%) ^[18]

Physiological causes of secondary amenorrhoea: pregnancy, menopause, breastfeeding ^[18]

Gynaecomastia can be the presenting feature of hypogonadism, but has a broad differential:

Gynaecomastia aetiology: Physiological (newborn, adolescence) vs Pathological (change in oestrogen:androgen activity ratio) — ↑Oestrogen: liver disease, drugs (e.g. spironolactone); ↓Androgen: hypogonadism, testicular tumour; Defect in AR: androgen insensitivity syndrome ^[7]

Investigations for gynaecomastia: Bloods (LFT, sex hormone profile) + Testis (testicular USG, AFP, βHCG) ^[7]

The diagnosis of hypogonadism rests on three pillars:

1. Consistent symptoms and/or signs of sex hormone deficiency (as detailed in Part 1)
2. Unequivocally low sex hormone levels on at least two separate morning samples
3. Exclusion of reversible/functional causes before labelling as permanent hypogonadism

For the majority of endocrine disorders, they are classified as "primary" or "secondary". Disorders along the HPG axis use a different nomenclature — hyper vs. hypogonadotropic [6, 22]

— Hypergonadotropic hypogonadism → issue within the ovaries/testes, primary issue — low estrogen/testosterone, but high levels of FSH/LH

— Hypogonadotropic hypogonadism → issue in pituitary, secondary issue — low estrogen/testosterone, as a consequence of a low level of FSH/LH ^[22]

Female hypogonadism is diagnosed somewhat differently depending on the clinical context:

Diagnosis of Klinefelter syndrome requires karyotyping to identify 47,XXY or other variants, usually performed on peripheral leukocytes. Consider complementary FISH to detect mosaicism if karyotyping is normal but clinical suspicion remains high ^[14]

In primary hypogonadism, the gonads themselves are failing — gonadotropin therapy cannot help because the target organ is damaged. Options are limited:

In primary ovarian failure (POI, Turner), the ovaries have no or very few functional follicles. Options:

Management approach for Klinefelter includes: testosterone replacement for hypogonadism + screen and manage complications ^[14]

Management of Turner syndrome: GH replacement for short stature + estrogen replacement for gonadal insufficiency + screening for cardiac, renal, and hearing anomalies + genetic counselling ^[17]

Management of delayed puberty: Identify and treat underlying pathology → Reassure for constitutional delay → ± puberty induction [24a]

Indications for puberty induction: Males > 14 years or females > 12 years (in some centres > 13) with no or few signs of puberty; severe psychosocial concern that cannot be resolved by reassurance [24a, 25]

Aims: Induction of growth spurt without inducing premature epiphyseal closure; induction of age-appropriate secondary sexual characteristics ^[25]

When multiple pituitary hormones are deficient, the order of replacement matters:

Monitoring in thalassaemia includes Q6 months: serum Ca/PO4, BG/fructosamine/HbA1c, TFT, infection screening; Q1 yearly: endocrine assessment, cardiac assessment (MUGA, ECG, CXR, cMRI T2), serum zinc* ^[24]

Pathophysiology (Male):

• Testosterone has multiple metabolic effects: it promotes lean muscle mass (the largest glucose-disposal organ), inhibits lipoprotein lipase in visceral adipose (reducing fat accumulation), and improves insulin sensitivity.
• Testosterone deficiency → ↓ muscle mass → ↓ glucose uptake → insulin resistance.
• Testosterone deficiency → ↑ visceral fat accumulation → further insulin resistance → hyperinsulinaemia → ↓ SHBG → ↓ total testosterone → a vicious cycle.
• Hypogonadism in males and growth hormone deficiency preferentially cause an increase in abdominal and visceral fat ^[10].

Pathophysiology (Female — post-menopause):

• Estrogen loss → redistribution of fat from gynoid (hips/thighs) to android (central) pattern → insulin resistance.
• Loss of estrogen's beneficial effects on lipid profile (↑ LDL, ↓ HDL) → atherogenic dyslipidaemia.

Clinical consequence:

• Metabolic syndrome (central obesity, hypertension, dyslipidaemia, impaired fasting glucose).
• DM — screen with fasting glucose / OGTT ^[14].
• Complications arising from obesity: CVS diseases (atherosclerosis), diabetes mellitus, obstructive sleep apnoea ^[27].

Monitoring: Fasting glucose, HbA1c, lipid profile — at diagnosis and annually on treatment.

• Testosterone deficiency → ↑ total cholesterol, ↑ LDL, ↑ triglycerides, ↓ HDL.
• Estrogen deficiency (post-menopause) → ↑ LDL (estrogen normally upregulates hepatic LDL receptors), ↓ HDL.
• Contributes to accelerated atherosclerosis and cardiovascular risk.

Pathophysiology:

• Male: Spermatogenesis requires both FSH (stimulating Sertoli cells) and very high intratesticular testosterone concentrations (~100× serum levels, maintained by LH-driven Leydig cell production). Hypogonadism → ↓ intratesticular testosterone → impaired or absent spermatogenesis → oligozoospermia or azoospermia.
• Klinefelter syndrome: infertility (most common presentation) — oligo/azoospermia ^[13].
• Men with history of undescended testes have an increased incidence of lower sperm counts, sperm of poorer quality and lower fertility rates ^[8].
• Female: Ovarian failure or hypothalamic/pituitary dysfunction → anovulation → infertility. In POI, the follicular pool is depleted or dysfunctional.

Clinical consequence:

• Infertility is often the presenting complaint of hypogonadism, particularly in Klinefelter syndrome.
• Important to counsel about fertility preservation before initiating gonadotoxic treatments (chemotherapy, radiation) or TRT (which itself suppresses spermatogenesis).

• Male: ↓ Libido, impotence (erectile dysfunction), ↓ morning erections ^[1]. Testosterone modulates the NO/cGMP pathway in cavernosal smooth muscle and drives central libido pathways.
• Female: ↓ Libido, vaginal dryness, dyspareunia (painful intercourse due to vaginal atrophy from estrogen deficiency).
• Sexual dysfunction occurs early in the development of the condition in both eating disorders (functional hypogonadism) ^[19] and structural hypogonadism.

Transfusion haemosiderosis → iron accumulation within: Liver → liver fibrosis and HCC; Endocrine organs → diabetes mellitus, growth retardation and hypogonadism; Heart → heart failure ^[15]

Monitoring: Q6 months: serum Ca/PO4, BG/fructosamine/HbA1c, TFT, infection screening. Q1 yearly: endocrine assessment, cardiac assessment (MUGA, ECG, CXR, cMRI T2), serum zinc* ^[24].

Late complications of HSCT include: endocrine dysfunction — T2DM (3× risk post-allogeneic HSCT), hypothyroidism, hypogonadism (due to active cGVHD and conditioning), infertility, osteoporosis and AVN (due to steroid use) ^[28]

• Conditioning regimens (high-dose alkylating agents, total body irradiation) are directly gonadotoxic.
• Chronic graft-versus-host disease and its treatment (long-term steroids) further suppress the HPG axis.
• Endocrine dysfunction and infertility are listed among the late/long-term effects of HSCT [28, 29].

Side effects of androgen replacement: acne, fluid retention, aggressiveness, BPH, OSA ^[26]

Disadvantages of HRT: endometrial cancer (if uterus intact without progesterone), slight ↑ risk of breast cancer, venous thromboembolism ^[2]