Endocrine dysfunction in homozygous beta-thalassemia: An underrecognized and undertreated consequence of prolonged survival

Table 1 Endocrine dysfunction in homozygous beta-thalassemia

Endocrine axis	Prevalence key data	Pathophysiology	Clinical features	Diagnostic considerations	Management recommendations
Thyroid dysfunction	15%-30% (primary and central)	Iron-induced thyroid damage; pituitary hemosiderosis	Subclinical or overt hypothyroidism	Low-normal T4 and low/inappropriate TSH; ferritin > 2500 ng/mL	Annual screening; early detection protocols
AI	Pooled 25.6%; up to 51% in adults	Hypothalamic dysfunction (tertiary AI); pituitary iron deposition	Fatigue, hypotension, adrenal crisis risk	Dynamic testing (low-dose ACTH, glucagon > serum cortisol); males more affected (92%)	Annual testing in adults or symptomatic patients
Hypogonadotropic hypogonadism	Up to 80% in adults; common in adolescents	Pituitary iron overload leads to lower LH/FSH	Delayed puberty, amenorrhea, infertility, low libido	MRI pituitary R2× inverse correlation with function	Individualized HRT; monitor bone/cardiac/hepatic status
Hypoparathyroidism	4%-6%	Parathyroid iron toxicity; exacerbated by vitamin D deficiency and renal dysfunction	Hypocalcemia, tetany, perioral numbness, seizures	Low PTH; latent hypocalcemia despite chelation	Calcium-phosphate balance, vitamin D, PTH analogs
Bone disease (osteopenia/osteoporosis)	> 50%	Multifactorial: Anemia, hypogonadism, iron toxicity	Fragility fractures, bone pain	DXA scan; poor chelation linked to severity	Early DXA screening, bisphosphonates, endocrine optimization
GH axis dysfunction	Not well quantified; low IGF-1 with normal GH response to stimulation testing	Hypothalamic iron overload leads to neurosecretory dysfunction; GH insensitivity	Growth failure (children), low IGF-1	24 hours GH profile, MRI of hypothalamus-pituitary	Evaluate somatotropic axis; MRI for early changes
Contributing factors	Adherence to chelation therapy	Variability: 57%-98% adherence	Influences all endocrine outcomes	Fragmented care post-transition	Multidisciplinary annual assessment: Endocrine, hematology, reproductive care

AI: Adrenal insufficiency; TSH: Thyroid stimulating hormone; ACTH: Adrenocorticotropic hormone; LH: Luteinizing hormone; FSH: Follicular stimulating hormone; MRI: Magnetic resonance imaging; HRT: Hormone replacement therapy; PTH: Parathormone; DXA: Dual-energy X-ray absorptiometry; IGF-1: Insulin-like growth factor-1; GH: Growth hormone.