Endocrinology & Neurosurgery & Family Medicine
Gigantism and acromegaly
Gigantism is a syndrome characterized by excess secretion of growth hormone (GH) before epiphyseal growth cartilage fusion, resulting in excessive statural growth. When GH hypersecretion occurs after cartilage fusion - i.e. in adults - we speak of acromegaly, characterized by growth of the extremities (hands, feet, jaw) and progressive visceral changes. These two entities represent the two clinical expressions of the same pathophysiological process: chronic hypersecretion of GH, responsible for sustained elevation of IGF-1 (insulin-like growth factor 1 - somatomedin C), the principal mediator of GH's anabolic and growth-promoting effects. In over 95 % of cases, the cause is a somatotropic (benign) pituitary adenoma - microadenoma (10 mm). Pediatric forms of gigantism are particularly rare (incidence estimated at 5-10 cases per million children) and may be associated with genetic forms (multiple endocrine neoplasia type 1 - NEM1, Carney complex, XLAG syndrome - X-linked acrogigantism linked to duplications of the GPR101 gene). Left untreated, gigantism leads to significantly increased adult height (often >2.0-2.5 m) and severe metabolic and cardiovascular complications, significantly reducing life expectancy. Acromegaly, which is more common (prevalence 40-70/million), is often diagnosed late (average delay of 7-10 years between first symptoms and diagnosis) due to the insidious evolution of morphological changes.
Aetiologies, clinical presentation and biological diagnosis
- Aetiologies and genetic forms of gigantism and acromegaly : sporadic pituitary somatotropic adenoma (>95 % of cases): microadenoma (<10 mm — plus fréquent dans l'acromégalie) ou macroadénome (>10 mm - more frequent in pediatric gigantism) - autonomous GH secretion by somatotropic tumor cells - somatic GNAS mutation (Gs alpha protein - constitutive activation of adenylate cyclase) : present in 40 % of sporadic somatotropic adenomas (gs-alpha+ adenomas) - smaller tumors + better response to somatostatin analogues; genetic forms and associated syndromes (10-15 % of GH adenomas): NEM1 (multiple endocrine neoplasia type 1 - MENIN mutation - 11q13) : pituitary adenomas (GH + prolactin + corticotropins) + parathyroid adenomas + pancreatic endocrine tumors (insulinomas + gastrinomas) → systematic screening for NEM1 in any young patient with pituitary GH adenoma; Carney complex (PRKAR1A mutation - 17q24): GH pituitary adenomas + cardiac myxomas + cutaneous lentiginosis + pigmented adrenal nodules (PPNAD); XLAG syndrome (X-linked acrogigantism): duplication of the GPR101 gene on the X chromosome (Xq26.3) → pediatric gigantism with very early onset (before 2-4 years) + mixed GH/prolactin pituitary macroadenoma → adult height often >2 m; AIP (aryl hydrocarbon receptor interacting protein - 11q13): germline mutations of AIP in 20 % of familial somatotropic adenomas (FIPA - familial isolated pituitary adenoma) - invasive adenomas with young onset - poor response to somatostatin analogues; rare causes of ectopic hypersecretion of GH or GHRH: carcinoid tumors (lung + pancreas) secreting GHRH (growth hormone releasing hormone) → pituitary stimulation → somatotropic cell hyperplasia → very rare (<1 % of acromegalia)
- Clinical presentation of gigantism (children) and acromegaly (adults): gigantism (GH hypersecretion before cartilage fusion) : accelerated statural growth (growth rate >3 DS for age) + progressive tall stature (often >97th percentile from childhood + potential adult height >2.0 m if untreated) + increased size of hands and feet + progressive coarse facial features (rounded forehead + prognathism) + macroglossia + deep voice + hyperhidrosis + headache + signs of pituitary tumor compression if macroadenoma (bitemporal hemianopsia + oculomotor paralysis) + puberty: delayed or early puberty depending on mass effect on pituitary + fatigue + early joint pain; acromegaly (GH hypersecretion after cartilage fusion - adult): hand signs (ring sign - increased ring size + rings needing to be enlarged) + increased shoe size + macroglossia + prognathism + dental diastema (tooth spacing) + bulging forehead (frontal humps) + thickening of facial features + hyperhidrosis + carpal tunnel syndrome (median nerve compression - present in 40-50 % of acromegals) + arthropathies + headaches (30-50 % - mechanism not exclusively related to tumor size) + visual field disorder if macroadenoma with chiasmatic compression + snoring + obstructive sleep apnea syndrome (OSA - macroglossia + pharyngeal soft tissue hypertrophy - present in 60-80 %) + arterial hypertension + cardiomegaly + cardiomyopathy + diabetes or glucose intolerance (insulin resistance induced by excess GH) + brown-skin discoloration (melanotrophy) + acanthosis nigricans if marked insulin resistance; delay in diagnosis of acromegaly : 7-10 years on average (progressive morphological changes little noticed by close relatives) - often discovered during a workup for hypertension + diabetes + OSA + polyarthropathy + bilateral carpal + or during brain imaging performed for another reason
- Biological diagnosis and pituitary imaging : IGF-1 assay (IGF-1 - insulin-like growth factor 1 - somatomedin C) : examination of 1st intention - high if chronic GH excess - interpretation according to age and sex (normal values vary with age - physiological peak at puberty + progressive decline with age) - a high IGF-1 for age and sex is the best screening test for acromegaly/gigantism - high PPV + a normal IGF-1 practically excludes the diagnosis apart from cases of exclusive pulsatile secretion ; test for GH inhibition by oral glucose load (HGPO 75 g - diagnostic gold standard): in normal subjects, glucose loading suppresses GH at <0,4 ng/mL (nadir GH) — dans l'acromégalie/gigantisme : absence de suppression de la GH (nadir >1 ng/mL according to old criteria + nadir >0.4 ng/mL according to current Endocrine Society 2014 criteria) or paradoxically elevated GH after glucose (paradoxical response - present in 10-20 % of acromegals) - GH sampling at T0 + T30 + T60 + T90 + T120 min after glucose ingestion; random basal GH : not very useful on its own (pulsatile secretion) - useful if very high (>20-30 ng/mL) to rapidly orient the diagnosis; pituitary MRI with gadolinium: reference morphological examination - sequences T1 + T2 + FLAIR + dynamic sequence after gadolinium injection - microadenoma : late contrast compared with normal pituitary tissue + hypointense T1 signal - macroadenoma: mass >10 mm + suprasellar extension + chiasmatic compression + invasion of cavernous sinus (Knosp grades I-IV) - fundus + visual field by automated perimetry : mandatory if macroadenoma + suprasellar extension → bitemporal hemianopsia if optic chiasm compression; full pituitary workup (assessment of associated hypopituitarism - common with macroadenomas): cortisol + ACTH + Synacthen test (adrenal insufficiency) + TSH + T4L (central hypothyroidism) + FSH + LH + testosterone or estradiol (hypogonadism) + prolactin (hyperprolactinemia by rod effect or GH/PRL co-secretion)
Treatment of gigantism and acromegaly
| Therapeutic modality | Technique, dosage and mechanism | Results, complications and follow-up |
|---|---|---|
| Transsphenoidal surgery 1st line - endoscopy - tumor resection |
Transsphenoidal surgery (TSS) is the 1st-line treatment for gigantism and acromegaly in the vast majority of cases - it offers the possibility of immediate cure if resection is complete; surgical technique: endoscopic endonasal approach (current reference technique in most centers - gradually replacing microscopic microsurgery): access to the sphenoid sinus via the nasal cavity → opening of the anterior wall of the sella turcica → tumor resection under direct endoscopic vision (4K high definition) + neuronavigation assisted by preoperative MRI → closure of the sella (abdominal fat + biological glue + mucosal graft) - advantages vs microscopic route: better visualization of blind spots + reduced complications (rhinorrhea + olfactory disorders) + better control of lateral extensions; post-operative biochemical cure criteria (assessed at 3 months): GH nadir <0.4 ng/mL on glucose braking test + IGF-1 normalized for age and gender - cure rate according to tumor size: microadenoma: 70-85 % biochemical cure in first-line setting - macroadenoma without cavernous sinus invasion (Knosp 0-2): 50-65 % - invasive macroadenoma (Knosp 3-4 - invasion of cavernous sinus): 10-30 % (total resection virtually impossible if cavernous invasion → complementary medical treatment mandatory); preoperative preparation: somatostatin analogues preoperatively (3-6 months): used if bulky macroadenoma + high anesthetic risk (severe OSA + cardiomyopathy) → reduction in tumor size (10-20 % on average) + improvement in cardiovascular comorbidities + improvement in OSA → no demonstrated benefit on surgical cure rate in meta-analyses → not routinely recommended preoperatively in all patients | Complications of transsphenoidal surgery: transient diabetes insipidus (10-15 % - ADH deficiency → massive polyuria + polydipsia → desmopressin treatment - resolution in a few days to weeks - permanent in <1 %) + cerebrospinal rhinorrhea (CSF leakage through the sphenoidal sinus - 1-3 % - risk of meningitis → repeat surgery if persistent) + postoperative hypopituitarismhypopituitarism (5-15 % - normal pituitary damage intraoperatively → adrenal insufficiency + hypothyroidism + hypogonadism → full pituitary workup at 3 months postoperation) + bacterial meningitis (rare - <1 % - IV antibiotic therapy) + intrasellar haemorrhage + vascular lesion (internal carotid - exceptional) + visual disturbances (worsening or appearance of hemianopia by traction on the chiasma - rare if careful technique) ; immediate post-operative follow-up: pituitary MRI at 72h post-op (assessment of resection) + 3 months post-op (post-op reference MRI - before resorption of filling fat) + hormonal check-up at D3 (morning cortisol) + at 3 months (complete pituitary check-up + IGF-1 + HGPO-GH) + systematic corticosteroid replacement therapy (hydrocortisone) in the first few days post-op (prevention of acute adrenal insufficiency); persistence or recurrence after surgery: tumor recurrence: annual MRI × 5 years then every 2-3 years if stable - biochemical recurrence: IGF-1 and HGPO-GH annually × 10 years → medical treatment (ASS) or radiosurgery if documented recurrence |
| Somatostatin analogues (SSA) Octreotide - lanreotide - pasireotide |
Somatostatin analogues (SSAs) are the 1st-line medical treatment for acromegaly and gigantism - they bind somatostatin receptors (SSTRs - especially SSTR2 and SSTR5) expressed by somatotropic tumor cells → inhibition of GH secretion + reduction in tumor volume in 30-50 % of cases; octreotide LP (Sandostatin LAR - Novartis): sustained-release formulation - 10-40 mg IM deep (buttock) every 4 weeks - initial dose: 20 mg/4 weeks → adjustment according to IGF-1 and GH - available in Canada + reimbursed by RAMQ with exception criteria for acromegaly; lanreotide autogel (Somatuline Depot - Ipsen): pre-filled syringe in hydrogel formulation - 60-120 mg deep SC every 4 weeks (or every 6-8 weeks in well-controlled patients - dosing flexibility) - self-injection possible by patient or home nurse - non-inferiority vs octreotide demonstrated - available in Canada + reimbursed by RAMQ; pasireotide LAR (Signifor LAR - Recordati): 2nd-generation analog - affinity for SSTR1 + SSTR2 + SSTR3 + SSTR5 (broader profile than octreotide and lanreotide, which mainly target SSTR2) → more effective on adenomas with little or no SSTR2 expression - 40-60 mg IM every 4 weeks - PAOLA trial (Lacroix 2018): biochemical control (IGF-1 + GH normalized) in 15-20 % of octreotide/lanreotide-resistant cases - adverse effects: hyperglycemia ++ (present in 57-73 % of patients - mechanism: inhibition of insulin secretion by pancreatic SSTR5) → close glycemic monitoring + metformin or other hypoglycemic agents if diabetes induced; side effects common to SSA: digestive intolerance (nausea + cramps + diarrhea - transient at start of treatment) + vesicular lithiasis (25-30 % of patients treated - mechanism: inhibition of vesicular motility → biliary stasis) → annual vesicular ultrasonography | SSA efficacy in acromegaly: biochemical control (normal IGF-1 + GH 1.3 × ULN (upper limit of normal) after 3-6 months of treatment at maximum dose → options: dose escalation + switch to pasireotide LAR + addition of cabergoline + switch to pegvisomant; follow-up on ASS: IGF-1 + GH every 3 months (adjustment phase) → every 6 months (stable phase) + annual pituitary MRI (monitoring residual tumor growth) + annual biliary ultrasound + fasting blood glucose + HbA1c (pasireotide); ASS in pediatric gigantism: limited data (small pediatric populations) - used after surgery if tumor residue + uncontrolled GH/IGF-1 - effects on growth rate: reduction but not arrest of growth if cartilage still open - association with GnRH analogues (to delay bone maturation) discussed in some pediatric protocols |
| Pegvisomant and GH receptor antagonists Somavert - resistance to SSA |
Pegvisomant (Somavert - Pfizer) is a GH receptor antagonist - it binds to the GH receptor (GHR) without activating it → blocks GH signaling → reduction in hepatic IGF-1 production → normalization of IGF-1; unique mechanism of action (distinct from SSAs) : pegvisomant does not act on the pituitary tumor itself - it blocks the peripheral effects of GH → IGF-1 decreases → serum GH may paradoxically increase under pegvisomant (absence of IGF-1's negative feedback control on the pituitary) → do not use GH as a follow-up marker under pegvisomant (use IGF-1 exclusively); dosage: loading dose 80 mg SC then 10-30 mg SC/d - dose adjusted according to IGF-1 (target: IGF-1 within the norm for age and sex); efficacy: normalization of IGF-1 in 97 % of patients treated at optimal doses (ACROSTUDY studies - international registry) - pegvisomant is the most effective treatment for normalizing IGF-1 in acromegaly - indications: resistance or intolerance to 1st and 2nd generation ASS + association with ASS (combined treatment ASS + pegvisomant): allows reduction of the dose of pegvisomant (cost + frequency of injections) + improves control in patients partially controlled on ASS alone - combined treatment ASS + pegvisomant: positive data (meta-analysis Franck-Raue 2017 + ACROSTUDY registry); adverse effects of pegvisomant: injection site reactions + transaminase elevation (5-10 % - liver workup monitored monthly for first 6 months then every 6 months - stopped if ALAT >5× N) + tumor growth possible (MRI monitoring - absence of IGF-1 negative feedback may lift tumor growth inhibition in some cases - annual MRI monitoring mandatory) + lipodystrophy at injection site (site rotation recommended); reimbursement in Canada: pegvisomant reimbursed by most private insurance plans (high cost: 15,000-30,000 CAD/year depending on dose) + Pfizer Canada special access program if coverage insufficient | Combined treatment with pegvisomant + ASS - Quebec clinical practice: indications for combined treatment: acromegaly partially controlled under SSA alone (IGF-1 between 1.0 and 2.0 × ULN) - residual voluminous macroadenoma requiring tumor control (SSA) + optimal biochemical control (pegvisomant) - cost of combination lower than full-dose pegvisomant alone (reduction of daily dose of pegvisomant by 30-50 %); comparison of medical strategies in residual post-surgical acromegaly: octreotide/lanreotide alone: 55-60 % biochemical control + pasireotide LAR: 15-20 % additional control in 1st-generation ASS resistant patients + pegvisomant alone: 97 % IGF-1 normalization + combined ASS + pegvisomant: 90-95 % IGF-1 control at reduced doses - decision individualized according to: side-effect profile (diabetes → avoid pasireotide) + cost + compliance (daily pegvisomant injection vs. monthly ASS) + presence of tumor residue (ASS for tumor control); cabergoline (dopaminergic agonist - Dostinex): 3rd line in acromegaly - effective especially if GH + prolactin co-secretion or if tumor expresses D2R - IGF-1 normalization in 20-35 % (results of meta-analyses) - dosage: 0.5-3.5 mg/week PO - well tolerated + low cost - interesting option in mild to moderate acromegaly or in combination with ASS |
| Radiotherapy and stereotactic radiosurgery Gamma Knife - CyberKnife - adjuvant treatment |
Radiotherapy and stereotactic radiosurgery are 3rd-line treatment options for acromegaly and gigantism - they are reserved for patients with post-surgical tumor residue uncontrolled by medical treatment, or unable to benefit from further surgery; stereotactic radiosurgery (Gamma Knife - Leksell Gamma Knife + CyberKnife - Accuray): delivery of a high focused dose in a single session (Gamma Knife) or in several fractions (CyberKnife - stereotactic fractionation) - principle : ablative dose on tumor residue + maximum protection of adjacent structures (optic chiasma - dose limit 8 Gy + cranial nerves of cavernous sinus) - condition: minimum distance of 3-5 mm between residual tumor and optic chiasma (otherwise conventional fractionated radiotherapy) - efficacy: biochemical control (normalization IGF-1) in 40-60 % of cases at 5-10 years - time to efficacy: 2-10 years (slow - requires relay medical treatment during the waiting period); fractionated conformal radiotherapy (IMRT - intensity-modulated radiation therapy): delivered in 25-30 fractions over 5-6 weeks (total dose 45-54 Gy) - indication if tumor residue close to the chiasma or infiltrating surrounding structures → 2nd-line treatment compared with stereotactic radiosurgery - efficacy: biochemical control 50-60 % at 10 years (Minniti 2011 meta-analysis); proton therapy: available in a few centers in Canada (TRIUMF Vancouver) → irradiation with protons (Bragg peak → precise dose deposition) → reduction of surrounding irradiated structures + data on acromegaly similar to stereotactic radiosurgery; main complication of pituitary radiotherapy: radiation hypopituitarism: adrenal insufficiency + hypothyroidism + hypogonadism → delay: 2-15 years after irradiation → cumulative incidence: 50-80 % at 10 years → annual hormone monitoring for life post-irradiation. | Indications for stereotactic radiosurgery in acromegaly in Quebec: post-surgical tumor residue visible on MRI + not controlled by medical treatment (ASS + pegvisomant) + chiasma-tumor distance ≥3 mm (otherwise fractionated radiotherapy) + patient refusing or unable to benefit from 2nd surgery + residual invasive macroadenoma of the cavernous sinus (Knosp 3-4) after surgery + medical treatment not reimbursed or intolerable; Quebec centers for stereotactic radiosurgery: CHUM (CyberKnife + Gamma Knife) + Montreal General Hospital (MUHC - Gamma Knife) + CHUS Sherbrooke + Hôtel-Dieu de Québec (CHU de Québec); post-radiosurgery follow-up: IGF-1 + complete pituitary workup every 6 months × 5 years + annual pituitary MRI × 5 years then every 2 years - medical treatments (ASS + pegvisomant) must be maintained until biochemical proof of post-radiosurgery cure (often 3-7 years after irradiation) → risk of rebound if ASS stopped prematurely; criteria for biochemical cure after radiosurgery: IGF-1 normal for age and sex + nadir GH <0.4 ng/mL on OGTT (2 successive checks 6 months apart) → medical treatment can be stopped if these criteria met + monitoring maintained for life (late recurrences documented up to 15-20 years post-irradiation) |
| Systemic complications and multidisciplinary follow-up Cardiovascular - metabolic - quality of life |
Untreated or inadequately treated acromegaly and gigantism are associated with multiple systemic complications that significantly reduce life expectancy (mortality × 2-3 vs general population in uncontrolled acromegaly) - their detection and management are an integral part of multidisciplinary follow-up; cardiovascular complications (leading cause of death in acromegaly): arterial hypertension (30-40 % - mechanism: sodium retention + RAAS activation + functional hyperaldosteronism) → standard antihypertensive treatment → target BP <130/80 mmHg + cardiomegaly (acromegalic cardiomyopathy): septal thickening + posterior wall (concentric hypertrophy) → diastolic dysfunction → heart failure → TTE (transthoracic echocardiogram) at initiation of follow-up + every 2-3 years + arrhythmias (atrial fibrillation + ventricular tachycardias) + annual ECG; metabolic complications: diabetes mellitus or glucose intolerance (30-50 % of acromegals - insulin resistance induced by GH antagonism on insulin sensitivity + inhibition of insulin secretion by pasireotide) → fasting blood glucose + HbA1c every 6 months + HOMA-IR → metformin ± insulin depending on degree; obstructive sleep apnea syndrome (OSAS): 60-80 % of acromegals - mechanism: macroglossia + pharyngeal soft tissue hypertrophy + craniofacial deformity → polysomnography if snoring + daytime somnolence + CPAP if confirmed SAOS → partial improvement under medical treatment (reduction of macroglossia); colorectal cancer: increased risk × 2-3 (frequent adenomatous polyposis under hypersecretion of IGF-1 → colonocyte growth factor) → colonoscopy on announcement of diagnosis + every 5 years if active acromegaly + every 10 years if controlled; acromegalic arthropathies: thickened articular cartilage + ligament laxity + early osteoarthritis (knees + hips + spine) → physiotherapy + NSAIDs + analgesics → joint prosthesis if severe disabling osteoarthritis. | Multidisciplinary management of acromegaly and gigantism in Quebec: multidisciplinary team: endocrinologist (coordination + medical treatment) + pituitary neurosurgeon (transsphenoidal surgery) + neuroradiologist (high-resolution pituitary MRI) + radiation oncologist (stereotactic radiosurgery) + ophthalmologist (visual field (visual field + fundus) + cardiologist (ETT + cardiovascular monitoring) + pneumologist/sleep specialist (SAOS + polysomnography) + gastroenterologist (colonoscopy) + rheumatologist (arthropathies) + ENT (macroglossia + snoring) + maxillosurgeon (severe prognathism - orthognathic surgery if acromegaly controlled) + psychologist (psychosocial impact + quality of life) + nurse coordinator ; Quebec reference centers : CHUM pituitary neuroendocrinology center (pituitary tumors) + CHU Sainte-Justine (pediatric gigantism) + CHUS Sherbrooke + CHU de Québec; patient association: Acromegaly Quebec + Acromegaly Community (international) + Cushing's Support and Research Foundation (for pituitary tumors); quality of life in acromegaly : even in biochemical remission, many patients report an altered quality of life (chronic fatigue + joint pain + cognitive disorders + depression + morphological sequelae) → psychological management + physical rehabilitation + validated questionnaires (AcroQoL - Acromegaly Quality of Life Questionnaire) at the announcement + at annual follow-up → adaptation of the therapeutic project according to functional impact |
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Pediatric gigantism - XLAG syndrome and early diagnosis : XLAG (X-linked acrogigantism) syndrome, linked to a duplication of the GPR101 gene on the X chromosome, is the best-characterized genetic cause of very early-onset gigantism (before 2-4 years of age). These children present with explosive statural growth, macrocephaly and a mixed GH/prolactin pituitary macroadenoma that is often large at diagnosis. In any child presenting an abnormal statural acceleration with a growth rate exceeding +3 DS for age, an IGF-1 assay and pituitary MRI should be carried out without delay. Early diagnosis is crucial: every year of delay in diagnosis translates into several centimetres of irreversible excessive statural growth.
Situations requiring urgent medical assessment
Sudden visual deficit (hemianopia) + intense headache in a patient with known or suspected acromegaly → pituitary apoplexy (intratumoral hemorrhage) → emergency brain MRI + neurosurgery + IV corticosteroids (acute corticotropic insufficiency).
Child with statural growth rate >+3 DS + acromegaly (large hands + feet) + headaches → gigantism on pituitary adenoma → IGF-1 urgent + pituitary MRI + pediatric endocrinology + neurosurgery opinion.
Post-operative transsphenoidal surgery: polyuria >3 L/24h + polydipsia + very dilute urine → postoperative central diabetes insipidus → desmopressin (DDAVP) SC or nasal + ionogram + urinary and plasma osmolality + endocrinology.
Known acromegaly + decompensated heart failure + severe OSA + uncontrolled hypertension → severe cardiovascular complications of uncontrolled acromegaly → hospitalization + cardioprotection + optimization of anti-GH therapy + polysomnography + CPAP.
Consult at Clinique Omicron
Clinique Omicron's physicians assess patients presenting signs suggestive of gigantism or acromegaly (increased hand or foot size in adults, changes in facial features, prognathism, bilateral carpal tunnel syndrome, persistent headaches), prescribe IGF-1 assays and refer them to the appropriate pituitary neuroendocrinology center. Co-morbidities (hypertension, diabetes, sleep apnea) are monitored in coordination with specialized teams at several points of service in Quebec. To book an appointment, visit cliniqueomicron.ca.
The content of this page is provided for information purposes only and does not replace the advice of an endocrinologist or neurosurgeon specializing in pituitary tumors. The management of gigantism and acromegaly requires an experienced multidisciplinary team.
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