Endocrine and Metabolic Disorders

Endocrine and metabolic disorders are among the most commonly encountered conditions in Australian general practice, accounting for a substantial proportion of chronic disease burden. The Australian Institute of Health and Welfare (AIHW) reports that endocrine, nutritional, and metabolic diseases rank in the top ten reasons for GP encounters nationally. These conditions span the hypothalamic–pituitary–thyroid, hypothalamic–pituitary–adrenal, hypothalamic–pituitary–gonadal, and calcium–phosphate axes, as well as the emerging field of metabolic syndrome and its components.

In Australia, autoimmune thyroid disease is the most prevalent endocrine condition, affecting approximately 5–10% of the population. The Busselton Health Study and subsequent Australian cohorts have demonstrated a female-to-male ratio of approximately 5:1 for autoimmune thyroiditis. Graves disease accounts for 75–80% of thyrotoxicosis cases in iodine-replete areas. Following the voluntary iodine fortification of bread in 2009 (Australia New Zealand Food Standards Code — Standard 2.1.1), iodine deficiency has decreased, though mild deficiency persists in certain populations, particularly in Tasmania and among pregnant women.

Primary adrenal insufficiency (Addison disease) affects approximately 1 per 10,000 population in Australia, while exogenous glucocorticoid-induced adrenal suppression is considerably more common. Cushing syndrome is rare (incidence 2–3 per million per year) but has significant morbidity if unrecognised. Pituitary adenomas have an estimated prevalence of 77–94 per 100,000 population, with prolactinomas being the most common functioning subtype.

Electrolyte disorders, particularly hyponatraemia and hypercalcaemia, are frequent incidental findings and clinical presentations across all healthcare settings. Polycystic ovary syndrome (PCOS) affects 8–13% of women of reproductive age and is a leading cause of anovulatory infertility and metabolic dysfunction.

This guideline covers the major thyroid, adrenal, pituitary, and metabolic disorders encountered in Australian primary and secondary care, with emphasis on evidence-based investigation, management aligned with Therapeutic Guidelines (eTG), PBS-listed pharmacotherapy, and culturally safe care for Aboriginal and Torres Strait Islander populations.

Hypothyroidism

Hypothyroidism is defined as insufficient thyroid hormone production to meet metabolic needs. In Australia, autoimmune thyroiditis (Hashimoto disease) is the most common aetiology in iodine-sufficient populations, followed by post-ablative (radioiodine or surgery) and drug-induced causes (lithium, amiodarone, immune checkpoint inhibitors).

Diagnosis: Elevated serum TSH (MBS 66710) with low free T4 (fT4, MBS 66719) confirms overt hypothyroidism. Subclinical hypothyroidism is defined as elevated TSH with normal fT4. TPO antibodies (MBS 66802) confirm autoimmune aetiology. The reference range for TSH in most Australian laboratories is 0.4–4.0 mIU/L, though trimester-specific ranges apply in pregnancy.

Monitoring: Recheck TSH 6–8 weeks after dose initiation or adjustment. Once stable, monitor annually. Target TSH 0.5–2.5 mIU/L for most adults; relaxed target TSH 4–6 mIU/L acceptable in patients aged >70 years to avoid iatrogenic thyrotoxicosis.

Drug interactions: Separate levothyroxine from calcium supplements, iron, proton-pump inhibitors, and antacids by ≥4 hours. Cholestyramine and sucralfate reduce absorption. Phenytoin, carbamazepine, and rifampicin increase T4 clearance.

Hashimoto Thyroiditis

Hashimoto thyroiditis (chronic lymphocytic thyroiditis) is the most common autoimmune thyroid disorder and the leading cause of hypothyroidism in Australia. It is characterised by lymphocytic infiltration of the thyroid gland with progressive fibrosis and glandular destruction.

Diagnosis: Elevated TSH ± low fT4, with positive anti-TPO antibodies (sensitivity 90–95%) and/or anti-thyroglobulin antibodies. Ultrasound typically shows a diffusely heterogeneous, hypoechoic gland with increased vascularity. FNA is not routinely required unless a discrete nodule is present.

Associated conditions: Hashimoto thyroiditis co-occurs with other autoimmune conditions at higher rates — coeliac disease (AIHW: 3–5%), type 1 diabetes, Addison disease (Schmidt syndrome), pernicious anaemia, and vitiligo. Screen for these comorbidities as clinically indicated.

Management is identical to hypothyroidism (levothyroxine replacement). In the euthyroid phase with positive antibodies, monitor TSH every 6–12 months as progression to overt hypothyroidism occurs at a rate of approximately 5% per year.

Hyperthyroidism

Hyperthyroidism (thyrotoxicosis) results from excessive thyroid hormone production or release. In Australia, Graves disease accounts for approximately 75% of cases, followed by toxic multinodular goitre (more common in older patients and in areas of historical iodine deficiency) and toxic adenoma.

Diagnosis: Suppressed TSH with elevated fT4 and/or free T3 (fT3, MBS 66719). TSH receptor antibodies (TRAb, MBS 66802) are positive in Graves disease (sensitivity ~95%, specificity ~99%). Radioactive iodine uptake (RAIU) scan differentiates Graves (diffuse uptake) from toxic nodular disease (focal uptake).

Graves Disease

Graves disease is an autoimmune condition caused by thyroid-stimulating immunoglobulins (TSI) that activate the TSH receptor, leading to unregulated thyroid hormone synthesis and gland hypertrophy. It is the most common cause of hyperthyroidism in Australia, with a peak incidence in women aged 20–50 years.

Extra-thyroidal features: Graves ophthalmopathy (proptosis, lid retraction, diplopia — occurs in 25–50%), pretibial myxoedema (dermopathy), and thyroid acropachy (digital clubbing). Smoking significantly worsens ophthalmopathy — all patients must be counselled on smoking cessation.

Treatment options in Australia:

1. Antithyroid drugs (ATDs): Carbimazole (preferred) or PTU — 12–18 months, remission rate ~50%. Titration regimen preferred over block-and-replace to minimise side-effects.
2. Radioactive iodine (I-131): Definitive therapy; administered by nuclear medicine physicians (MBS 13300 series). Most patients become hypothyroid and require lifelong levothyroxine. Contraindicated in pregnancy and severe Graves ophthalmopathy without concurrent steroid cover.
3. Total thyroidectomy: Indicated for large goitres, suspected malignancy, failed medical therapy, or patient preference. Requires lifelong levothyroxine and monitoring for hypoparathyroidism and recurrent laryngeal nerve injury.

Thyroid Nodules

Thyroid nodules are extremely common, detected in up to 50% of adults on high-resolution ultrasound. The clinical significance lies in excluding malignancy, which occurs in 5–10% of biopsied nodules.

Evaluation pathway:

1. TSH (MBS 66710) — if suppressed, proceed to radionuclide scan to assess for autonomously functioning (hot) nodule (very low malignancy risk, FNA not required).
2. Thyroid ultrasound with ACR TI-RADS scoring to determine need for FNA:
   • TI-RADS 1 (benign): No FNA required
   • TI-RADS 2 (not suspicious): FNA if ≥2.5 cm
   • TI-RADS 3 (mildly suspicious): FNA if ≥1.5 cm
   • TI-RADS 4 (moderately suspicious): FNA if ≥1.0 cm
   • TI-RADS 5 (highly suspicious): FNA if ≥0.5 cm
3. FNA cytology classified using Bethesda System (6 categories). Bethesda III–VI require multidisciplinary thyroid MDT discussion.
4. Thyroglobulin and calcitonin (medullary thyroid carcinoma marker) in selected cases.

Addison Disease (Primary Adrenal Insufficiency)

Addison disease results from destruction of the adrenal cortex, leading to deficiency of cortisol, aldosterone, and adrenal androgens. In Australia, autoimmune adrenalitis accounts for ~80% of cases, followed by bilateral adrenal haemorrhage, infection (tuberculosis, fungal), infiltrative disease, and metastatic malignancy. Autoimmune adrenalitis may occur in isolation or as part of autoimmune polyendocrine syndromes (APS type 1 or 2).

Diagnosis:

1. Morning serum cortisol (MBS 66577): <100 nmol/L is highly suggestive; >500 nmol/L essentially excludes the diagnosis.
2. Short Synacthen (ACTH stimulation) test: Measure cortisol at 0, 30, and 60 minutes after 250 µg synthetic ACTH (tetracosactide) IV/IM. Peak cortisol <500 nmol/L confirms adrenal insufficiency. Available in most Australian hospitals and endocrine clinics.
3. Plasma ACTH (MBS 66564): Elevated (>2× upper limit) in primary adrenal insufficiency (distinguishes primary from secondary/tertiary).
4. Serum aldosterone and plasma renin activity: Low aldosterone with high renin confirms mineralocorticoid deficiency.
5. Adrenal antibodies (21-hydroxylase antibodies): Confirm autoimmune aetiology in ~85% of cases.

Patient education (essential):

• Never cease glucocorticoid replacement — lifelong therapy required.
• Wear medical alert bracelet/necklace at all times.
• Carry Solu-Cortef Act-O-Vial emergency injection kit and know how to self-inject IM.
• Sick-day rules: double oral hydrocortisone dose for febrile illness, vomiting (if unable to take oral, administer IM injection and present to ED).
• Ensure adequate dietary salt intake (especially in hot climates or with exercise).
• Annual screening for associated autoimmune conditions: thyroid function, B12, coeliac serology, type 1 diabetes antibodies.

Cushing Syndrome

Cushing syndrome results from chronic exposure to excess glucocorticoids. In Australia, the most common cause is exogenous (iatrogenic) glucocorticoid use. Endogenous Cushing syndrome is rare and divided into ACTH-dependent (pituitary Cushing disease ~70%, ectopic ACTH ~10%) and ACTH-independent (adrenal adenoma/carcinoma ~20%) causes.

Clinical features: Central obesity, moon face, dorsal fat pad ("buffalo hump"), purple striae (>1 cm width), proximal myopathy, easy bruising, skin thinning, hirsutism, menstrual irregularity, hypertension, glucose intolerance/diabetes, osteoporosis, psychiatric disturbances, and immunosuppression.

Biochemical confirmation (stepwise):

1. Screening tests (at least 2 required):
   • 24-hour urinary free cortisol (MBS 66577): ≥3× upper limit of normal is highly suggestive. Collect 2 specimens.
   • Late-night salivary cortisol (MBS 66577): Elevated result on 2 specimens (collected at 2300h).
   • Low-dose dexamethasone suppression test (LDDST): 1 mg dexamethasone PO at 2300h, serum cortisol at 0900h next day. Cortisol >50 nmol/L = failure to suppress.
2. Distinguish cause:
   • Plasma ACTH (MBS 66564): Suppressed (<5 pmol/L) = ACTH-independent (adrenal); Elevated = ACTH-dependent (pituitary vs ectopic).
   • High-dose dexamethasone suppression test (8 mg overnight or 2 mg QID × 48h): Suppression suggests pituitary source; no suppression suggests ectopic.
   • Pituitary MRI ± inferior petrosal sinus sampling (IPSS) for ACTH-dependent cases.
   • Adrenal CT for ACTH-independent cases.

Treatment: Depends on cause. Transsphenoidal surgery for Cushing disease (pituitary microadenoma); adrenalectomy for adrenal tumours; treatment of underlying ectopic source. Medical therapy (ketoconazole, metyrapone, osilodrostat) as bridging therapy or when surgery is not feasible. Referral to a specialist endocrine centre is mandatory.

Pituitary Adenomas — Overview

Pituitary adenomas are the most common sellar masses, with an estimated prevalence of 77–94 per 100,000 in population-based autopsy and imaging studies. They are classified by size (microadenoma <10 mm, macroadenoma ≥10 mm) and functional status. Prolactinomas are the most common functioning subtype (~40%), followed by non-functioning pituitary adenomas (NFPA, ~30%), GH-secreting adenomas (acromegaly, ~15%), and ACTH-secreting adenomas (Cushing disease, ~10%).

Mass effect symptoms: Headache, visual field defects (classically bitemporal hemianopia from chiasmal compression), cranial nerve palsies (CN III, IV, VI — cavernous sinus invasion), and hypopituitarism (compression of normal pituitary tissue).

Investigation of pituitary function:

Prolactinoma

Prolactinomas are the most common secretory pituitary adenomas. Clinical features include galactorrhoea, menstrual irregularity/amenorrhoea, infertility, and decreased libido in women; erectile dysfunction, gynaecomastia, and infertility in men. Men often present later with macroadenomas due to delayed recognition.

Important: Mildly elevated prolactin (up to ~2000 mIU/L in women, ~1500 mIU/L in men) can be caused by medications (metoclopramide, domperidone, risperidone, SSRIs, verapamil), hypothyroidism, renal impairment, pregnancy, and chest-wall irritation. Stalk effect from any pituitary mass can also cause mild hyperprolactinaemia (typically <2000 mIU/L). Always exclude these before attributing elevation to a prolactinoma.

Monitoring and discontinuation: After ≥2 years of dopamine agonist therapy with normal prolactin and ≥50% tumour shrinkage, a trial of dose reduction/discontinuation may be considered under specialist guidance. Recurrence rate is approximately 30–40% for microprolactinomas.

Hypopituitarism

Hypopituitarism may result from pituitary tumours, surgery, radiotherapy, Sheehan syndrome (postpartum pituitary necrosis), traumatic brain injury, infiltrative diseases, or infections. The order of hormone loss typically follows: GH → LH/FSH → TSH → ACTH → prolactin (compression order). Acute hypopituitarism (pituitary apoplexy) presents with sudden headache, visual loss, ophthalmoplegia, and cardiovascular collapse — an emergency requiring immediate glucocorticoid administration and neurosurgical assessment.

Replacement therapy: Hydrocortisone (as for adrenal insufficiency — must be started BEFORE levothyroxine), levothyroxine, sex steroid replacement (testosterone in men, HRT or OCP in premenopausal women), GH (recombinant somatotropin — PBS Authority Required), and desmopressin for central diabetes insipidus.

Calcium Disorders

Hypercalcaemia

Hypercalcaemia (corrected calcium >2.60 mmol/L) is most commonly caused by primary hyperparathyroidism (PHPT, ~60% of outpatients) and malignancy (~30% of inpatients). Other causes include vitamin D excess, thiazide diuretics, sarcoidosis and other granulomatous diseases, familial hypocalciuric hypercalcaemia (FHH), milk-alkali syndrome, and thyrotoxicosis.

Initial workup:

Primary hyperparathyroidism (PHPT) management:

• Surgery (parathyroidectomy) — indicated for: symptomatic PHPT, serum calcium >0.25 mmol/L above normal, age <50, eGFR <60 mL/min, osteoporosis (T-score ≤−2.5), vertebral fracture. Refer to endocrine surgery. Pre-operative localisation with sestamibi scan (MBS 61327) and/or 4D-CT.
• Conservative/monitoring — for asymptomatic patients not meeting surgical criteria: annual calcium, creatinine, eGFR; bone mineral density (DEXA) every 1–2 years; 24-hour urine calcium. Encourage adequate hydration, avoid thiazides and lithium if possible.

Acute severe hypercalcaemia (corrected calcium >3.0 mmol/L or symptomatic): IV normal saline rehydration (200–300 mL/h initially), IV zoledronic acid 4 mg over 15 minutes (once eGFR confirmed >35 mL/min), calcitonin (rapid but tachyphylaxis at 48h). Consider denosumab if zoledronic acid contraindicated. Treat underlying cause. Involve endocrinology and/or oncology.

Hypocalcaemia

Common causes: hypoparathyroidism (post-surgical most common), vitamin D deficiency, chronic kidney disease, magnesium deficiency, acute pancreatitis, rhabdomyolysis, and citrated blood product transfusion.

Symptomatic hypocalcaemia (perioral tingling, carpopedal spasm, tetany, seizures, QTc prolongation): IV calcium gluconate 10% — 10–20 mL (1–2 g) over 10–20 minutes with cardiac monitoring. Repeat as needed. Correct hypomagnesaemia concurrently.

Chronic management: Oral calcium carbonate 1–3 g/day in divided doses (with meals for absorption) + calcitriol (active vitamin D) 0.25–1 µg/day for hypoparathyroidism. Monitor serum calcium, phosphate, 24-hour urine calcium (aim to avoid hypercalciuria and nephrocalcinosis). Recombinant PTH (teriparatide) available for refractory cases under specialist supervision.

Sodium Disorders

Hyponatraemia

Hyponatraemia (serum Na <135 mmol/L) is the most common electrolyte disorder in hospitalised patients in Australia, affecting up to 30% of acute admissions. Accurate classification by volume status is critical to guide treatment.

Classification by volume status:

Hypernatraemia

Hypernatraemia (serum Na >145 mmol/L) almost always reflects a water deficit relative to sodium. Common causes include inadequate water intake (elderly, cognitively impaired), diabetes insipidus (central or nephrogenic), osmotic diuresis (hyperglycaemia), and excessive hypertonic saline or sodium bicarbonate administration.

Treatment: Replace free water deficit gradually — correct at a rate of ≤0.5 mmol/L/h (≤12 mmol/L/day) to avoid cerebral oedema. Use 5% dextrose or oral water. In hypovolaemic hypernatraemia, restore intravascular volume with 0.9% NaCl first, then switch to 5% dextrose for free water replacement.

Polycystic Ovary Syndrome (PCOS)

PCOS is the most common endocrine disorder in women of reproductive age, affecting 8–13% of Australian women (up to 21% using broader diagnostic criteria). It is a leading cause of anovulatory infertility and has significant long-term metabolic implications including increased risk of type 2 diabetes, metabolic syndrome, obstructive sleep apnoea, non-alcoholic fatty liver disease, and endometrial cancer.

Diagnosis (Rotterdam criteria — require ≥2 of 3):

1. Oligo-anovulation: Menstrual cycles >35 days apart, <8 cycles per year, or amenorrhoea.
2. Clinical and/or biochemical hyperandrogenism: Hirsutism (modified Ferriman–Gallwey score ≥6), acne, alopecia; elevated serum testosterone (MBS 66655) or free androgen index (FAI).
3. Polycystic ovaries on ultrasound: ≥12 follicles (2–9 mm) per ovary or ovarian volume >10 mL (note: ultrasound criteria updated by international PCOS guidelines 2023 — threshold raised to ≥20 follicles per ovary on modern high-resolution transducers to reduce over-diagnosis).

Metabolic screening in PCOS:

• Fasting glucose and insulin, or 75 g OGTT (preferred in Australia for PCOS metabolic screening — AIHW recommendation)
• Lipid profile (total cholesterol, LDL, HDL, triglycerides)
• Blood pressure
• BMI and waist circumference
• Liver function tests (NAFLD screening)
• Repeat metabolic screening every 1–3 years

Management — tiered approach:

Tier 1 — Lifestyle (ALL patients): Weight loss of 5–10% body weight significantly improves ovulatory function, insulin resistance, and androgen levels. Australian dietary guidelines and physical activity guidelines (≥150 min/week moderate intensity). Referral to accredited practising dietitian (Medicare-rebatable with GP Management Plan — MBS 721).

Tier 2 — Pharmacotherapy:

Tier 3 — Fertility management: Letrozole (2.5–7.5 mg/day, days 2–6 of cycle) is now first-line for ovulation induction in PCOS (superior to clomiphene citrate per the NEJM 2014 PPCOS II trial). Letrozole is available in Australia but requires Authority PBS approval for ovulation induction, or may be accessed through private prescription or IVF clinic compounding. Clomiphene citrate (Clomid®) remains PBS-listed for anovulatory infertility. Referral to reproductive endocrinology/IVF specialist if >6 cycles of ovulation induction fail, or if tubal/male factor identified.

The following table summarises key investigations for endocrine and metabolic disorders commonly ordered in Australian primary care, including relevant MBS item numbers for Medicare rebates.

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