Endocrine Feedback Axes

Axis

Lesion

Dots flow at a rate proportional to each hormone’s level. Gauges are on a log scale from 0.1× to 30× normal; the green box is the normal band. With exogenous hormone the gauge shows total activity and the hollow marker the gland’s own output. Amber dashed arcs are negative feedback, thicker when the brake is pressed harder.

Lab pattern

TSH normal, FT4 normal

Euthyroid

lownormalhighnegative feedback

Steady state Normal

Levels are multiples of normal from a small feedback model, not real concentrations.

Dynamic testing

Stimulate deficiency, suppress excess

A single level is hard to read when secretion pulses and follows the clock. Push the axis instead: stimulate it when you suspect deficiency, try to suppress it when you suspect excess. An intact loop responds; a diseased one does not.

Curves are illustrative responses, not patient data.

Dynamic and screening tests

Test	Protocol	Normal response or cut-off	Use and pitfalls
Short Synacthen test	Tetracosactide 250 µg IV or IM; cortisol at 0 and 30 (± 60) min	Peak cortisol ≥ ~430–500 nmol/L, depending on assay	Adrenal reserve. Can pass in early secondary insufficiency (first 4–6 weeks after a pituitary insult) because the adrenals have not yet atrophied. Oral oestrogen raises CBG and total cortisol.
Insulin tolerance test	Soluble insulin 0.1–0.15 U/kg IV; glucose, cortisol and GH to 120 min	Needs glucose < 2.2 mmol/L. Cortisol peak above the assay cut-off (~450–500 nmol/L); GH peak > 3 µg/L	Gold standard for ACTH and GH reserve. Contraindicated in ischaemic heart disease and seizures; avoid if 09:00 cortisol < 100 nmol/L. Specialist unit only.
Glucagon stimulation test	Glucagon 1 mg IM (1.5 mg if > 90 kg); GH and cortisol to 240 min	GH peak > 3 µg/L (> 1 µg/L if BMI > 30)	GH (and ACTH) reserve when the ITT is contraindicated. Nausea; late hypoglycaemia. Cortisol response less reliable.
Overnight 1 mg dexamethasone suppression	Dexamethasone 1 mg at 23:00–24:00; cortisol 08:00–09:00	Cortisol < 50 nmol/L makes Cushing’s syndrome unlikely	Screen for excess. False positives with oral oestrogen, enzyme inducers (carbamazepine, phenytoin, rifampicin), malabsorption or a missed dose.
Late-night salivary cortisol	Saliva at 23:00–24:00 on two nights	Below the laboratory’s upper limit	Tests loss of the nadir. Unreliable in shift workers; contamination by topical hydrocortisone, liquorice, smoking, bleeding gums.
24 h urinary free cortisol	At least two complete collections	Below the assay’s upper limit	Screen for excess. High fluid intake raises it; incomplete collection and renal impairment lower it.
Low-dose dexamethasone (48 h)	0.5 mg 6-hourly for 48 h; cortisol at 48 h	Cortisol < 50 nmol/L	Confirms excess; also useful where the overnight test is equivocal.
GH suppression on 75 g OGTT	75 g oral glucose; GH at 0, 30, 60, 90, 120 min	GH nadir < 1 µg/L (< 0.4 µg/L with ultrasensitive assays)	Confirms acromegaly when IGF-1 is high. Unreliable in diabetes, liver or renal failure, puberty and anorexia.
IGF-1	Single random sample	Within the age- and sex-specific range	Screening and monitoring of acromegaly. Low in malnutrition, liver disease, poorly controlled diabetes, hypothyroidism and with oral oestrogen. A normal IGF-1 does not exclude adult GH deficiency.

Cortisol in nmol/L, GH in µg/L. Cut-offs depend on the assay; modern immunoassays and LC-MS/MS read lower than older assays, so use your laboratory’s values.

Circadian rhythm

The cortisol day

Cortisol peaks 30–45 minutes after waking and falls to a nadir around midnight. Test for deficiency at the peak and for excess at the nadir.

Illustrative serum cortisol in nmol/L for someone waking at 07:00. Dashed grey is the normal day for comparison.

09:00 Cortisol ≈ 420 nmol/L

Time of day09:00

Deficiency: test the peak

A 09:00 cortisol below 100 nmol/L strongly suggests adrenal insufficiency; above about 450 nmol/L makes it unlikely. Values between need a Synacthen test. Cut-offs are assay-dependent, and shift work or oral oestrogen (raised cortisol-binding globulin) distort them.

Excess: test the nadir

The earliest and most consistent change in Cushing’s syndrome is loss of the late-night nadir; morning cortisol is often normal. Screen with late-night salivary cortisol, the overnight 1 mg dexamethasone test or 24 h urinary free cortisol, and confirm with a second test.

Glucocorticoids and sick-day rules

Prednisolone 5 mg daily or equivalent for 4 weeks or more, by any route, can suppress the axis: give a steroid emergency card and taper rather than stop.
Fever or illness needing bed rest or antibiotics: double the usual daily glucocorticoid dose.
Vomiting or unable to take tablets: hydrocortisone 100 mg IM and urgent assessment.
Adrenal crisis: hydrocortisone 100 mg IV or IM, then 200 mg over 24 h, with IV fluids.

Bedside

Reading the pattern

Choose the axis and enter each result as low, normal or high against your laboratory’s range. The interpreter places the lesion from the direction of the trophic and effector hormones, then suggests the next test.

Illustrative patterns, not real patients.

Thyroid

Primary hypothyroidism

Reference

The five axes at a glance

Axis	Hypothalamus	Pituitary	Gland	Effector	Main feedback	Classic deficiency	Classic excess	First-line test
Thyroid	TRH	TSH	Thyroid follicular cells	T4 (prohormone), T3	T4 and T3 on TRH and TSH; T4 is converted to T3 inside the thyrotroph	Hashimoto’s thyroiditis; central hypothyroidism	Graves’ disease, toxic nodules, thyroiditis; TSH-secreting adenoma (rare)	TSH, with FT4; FT4 if pituitary disease is known or suspected
Adrenal	CRH (with AVP)	ACTH	Adrenal cortex, zona fasciculata	Cortisol	Cortisol on CRH and ACTH	Addison’s disease; secondary from exogenous glucocorticoids or pituitary disease	Cushing’s syndrome: exogenous, pituitary, adrenal, ectopic ACTH	Deficiency: 09:00 cortisol with ACTH, then Synacthen. Excess: 1 mg DST, late-night salivary cortisol, 24 h UFC
Gonadal, male	GnRH (pulsatile)	LH, FSH	Testis: Leydig cells (LH), Sertoli cells (FSH)	Testosterone; inhibin B	Testosterone on GnRH and LH; inhibin B on FSH	Klinefelter syndrome; Kallmann syndrome; functional (opioids, obesity, illness)	Exogenous androgens; testosterone-secreting tumours (rare)	Morning fasting testosterone on two occasions, with LH and FSH
Growth	GHRH (+), somatostatin (−)	GH	Liver	IGF-1	IGF-1 on GH and GHRH, and stimulates somatostatin	Adult GH deficiency (pituitary disease, cranial irradiation)	Acromegaly; gigantism before epiphyseal closure	Excess: IGF-1, then GH on OGTT. Deficiency: ITT or glucagon test
Prolactin	Dopamine (−); TRH (+)	Prolactin	Breast	None (lactation)	Short loop: prolactin raises hypothalamic dopamine	Sheehan’s syndrome (failure of lactation)	Prolactinoma; drugs; stalk effect; primary hypothyroidism	Rested prolactin; macroprolactin screen if raised

Opposite directions of trophic and effector hormone: primary (gland) disease. Same direction: pituitary or hypothalamic disease, hormone resistance, or exogenous hormone with assay cross-reactivity. Prolactin: 1 µg/L ≈ 21.2 mU/L.