Adult growth hormone deficiency

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Adult Growth Hormone Deficiency (AGHD)

Etiology & Pathophysiology

AGHD is usually caused by acquired hypothalamic or pituitary somatotrope damage. The most common etiology in adults is a pituitary adenoma (or its treatment). A well-recognized pattern governs the sequential loss of pituitary hormones:

GH → FSH/LH → TSH → ACTH

GH reserve is the first to be lost, making AGHD the earliest and most sensitive indicator of hypopituitarism.

Other causes include:

Pituitary/hypothalamic tumors (craniopharyngioma, germinoma, meningioma, Rathke cleft cyst, glioma)
Post-surgical disruption of the hypothalamic-pituitary axis
Cranial irradiation
Trauma
Infiltrative disorders (granulomas)
Patients with childhood-onset GHD (who must be retested as adults to confirm persistence)

— Harrison's Principles of Internal Medicine 22E, Goldman-Cecil Medicine

Clinical Features

AGHD produces a constellation of metabolic, cardiovascular, musculoskeletal, and neuropsychiatric findings:

Body Composition

Reduced lean body mass and muscle mass
Increased fat mass, with selective deposition of intra-abdominal visceral (omental) fat
Increased waist-to-hip ratio

Cardiovascular Risk

Left ventricular dysfunction and impaired cardiac structure
Hypertension
Dyslipidemia (elevated LDL, abnormal lipid profile)
Decreased fibrinolytic activity → increased plasma fibrinogen
Atherosclerosis
Adult hypopituitarism carries a ~threefold increase in cardiovascular mortality vs. age- and sex-matched controls

Musculoskeletal

Reduced exercise capacity and maximum O₂ uptake
Reduced bone mineral density → increased fracture risk

Quality of Life / Neuropsychiatric

Impaired quality of life
Decreased energy, drive, and concentration
Low self-esteem
Social isolation, depression
Difficulty maintaining gainful employment

— Harrison's Principles of Internal Medicine 22E

Diagnosis

Who to Test

Testing should be restricted to patients with well-defined predisposing factors:

Prior pituitary surgery
Pituitary or hypothalamic tumor or granulomas
History of cranial irradiation
Radiologic evidence of a pituitary lesion
Childhood GH replacement therapy (transition patients)

Shortcut: If a patient is deficient in ≥3 pituitary hormones AND has an IGF-1 below the lower limit of normal, provocative testing is not required — AGHD can be assumed.

Laboratory Findings

Test	Finding
Evoked GH (provocative test)	< 3 ng/mL is diagnostic
IGF-1	Low or normal (not sufficient alone)
IGFBP-3	Low or normal
LDL cholesterol	Elevated

Important caveat: Because GH is secreted episodically, a random GH level is not diagnostic. ~80% of GH values in normal individuals are below 1 ng/mL at any given time. Provocative testing is essential.

Provocative Tests

Test	Details
Insulin Tolerance Test (ITT)	Gold standard; GH must fail to rise >3–5 ng/mL when glucose <40 mg/dL. Requires physician supervision. Contraindicated in seizures, cardiac/cerebrovascular disease, diabetes, elderly
Glucagon Stimulation Test (GST)	Preferred alternative in the US (since GHRH is no longer commercially available). GH cut-off: <3 μg/L (or <1 μg/L in overweight/obese patients). Contraindicated in pheochromocytoma. Side effects: nausea, vomiting, delayed hypoglycemia
GHRH + Arginine	Previously preferred combination; GHRH no longer available in the US
IV Arginine alone (30 g)	Alternative
Ghrelin receptor agonist	Oral, 0.5 mg/kg

BMI adjustment: BMI significantly affects GH response to stimulation — BMI-based cut-offs should be used.

— Harrison's Principles of Internal Medicine 22E, Henry's Clinical Diagnosis and Management, Goldman-Cecil Medicine

Treatment

Indications & Contraindications

Treatment is indicated once AGHD is unequivocally established
Contraindications: active neoplasm, intracranial hypertension, uncontrolled diabetes with retinopathy

Dosing

Starting dose: 0.1–0.2 mg/day subcutaneously
Maximum dose: up to 1.25 mg/day
Target: IGF-1 in the mid-normal range for age- and sex-matched controls
Women require higher doses than men; elderly require lower doses
Long-acting GH preparations (weekly injections) are now approved for AGHD

Goldman-Cecil recommends: 2.0–5.0 μg/day SC (lower range), titrated to mid-normal IGF-1.

Benefits of Treatment

Increased lean body mass, decreased fat mass
Increased HDL cholesterol
Gradual improvement in lumbar spine bone mineral density (>1 year)
Significant improvement in quality of life
Long-term effect on mortality is under prospective investigation

Side Effects (~30–40% of patients)

Reversible fluid retention, joint pain, carpal tunnel syndrome (~30%)
Myalgias and paresthesias (~40%)
Headache, increased intracranial pressure, hypertension, tinnitus (rare)
Insulin resistance: GH is a potent counter-regulatory hormone — patients on insulin need careful dose monitoring. Patients with T2DM may develop initial worsening glycemia, but this typically improves with sustained visceral fat loss over the long term

— Harrison's Principles of Internal Medicine 22E, Goldman-Cecil Medicine

Key Points Summary

Feature	Detail
Most common adult cause	Pituitary adenoma (or treatment)
Hormone loss sequence	GH → FSH/LH → TSH → ACTH
Hallmark body composition change	↑ visceral fat, ↓ lean mass
Diagnostic gold standard	Insulin tolerance test (ITT)
US alternative	Glucagon stimulation test
GH cut-off (adults)	< 3 ng/mL on provocation
Treatment target	IGF-1 mid-normal for age/sex
Starting GH dose	0.1–0.2 mg/day SC
Cardiovascular risk	~3× increased mortality vs. controls

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