Acromegaly

Primary Causes

• The majority (95–99%) of acromegaly cases result from growth hormone (GH)-secreting somatotroph adenomas of the anterior pituitary gland. These benign tumors lead to excessive GH secretion, stimulating hepatic production of insulin-like growth factor-1 (IGF-1), which mediates the clinical manifestations of the disease.
• Gigantism, a related condition, occurs when GH excess develops prior to the closure of epiphyseal growth plates during childhood.
  
  

Ectopic and Rare Causes

• Rarely, acromegaly and gigantism result from ectopic secretion of GH or growth hormone-releasing hormone (GHRH) by non-pituitary tumors, including:
  • Hypothalamic tumors (e.g., gangliocytomas) that overproduce GHRH.
  • Carcinoid tumors, pancreatic islet-cell tumors, or bronchial neoplasms that secrete ectopic GHRH or GH.
• In some cases, somatotroph hyperplasia may occur due to GHRH overproduction from neuroendocrine tumors.
  
  

Syndromic Associations

• Acromegaly and gigantism can occasionally occur as features of syndromic conditions:
  • Multiple Endocrine Neoplasia Type I (MEN I): An autosomal-dominant disorder with pituitary adenomas as a frequent manifestation.
  • McCune-Albright Syndrome: Characterised by fibrous dysplasia, café-au-lait spots, and endocrine dysfunction.
  • Neurofibromatosis: Associated with neurocutaneous abnormalities and, in rare cases, pituitary hyperplasia or adenomas.
  • Tuberous Sclerosis: Includes a range of benign tumors in multiple organ systems.
  • Carney Complex: Presents with spotty skin pigmentation, myxomas, and endocrine tumors, including somatotroph adenomas.
    
    

Molecular and Genetic Factors

• Several genetic mutations contribute to the development of somatotroph adenomas:
  • GNAS1 Mutation: Activating mutations in the GNAS1 gene (gsp oncogene) are found in 30–40% of somatotroph adenomas. These mutations lead to constitutive activation of the GHRH receptor, excessive adenylyl cyclase activity, somatotroph proliferation, and unregulated GH secretion.
  • Monoclonal Origin: Studies show that most pituitary adenomas are monoclonal, arising from a single mutated cell with unchecked growth potential.
  • Other Genetic Mutations: While rare, other mutations implicated in acromegaly include those associated with syndromic conditions (e.g., mutations in MEN1 or PRKAR1A genes).
    
    

Prolactin Co-Secretion

• Approximately 30–40% of GH-secreting tumors co-secrete prolactin, either from mammosomatotroph adenomas or mixed somatotroph-lactotroph adenomas, which can lead to additional clinical features such as galactorrhea and hypogonadism.
  
  

Overview

• The pathophysiology of acromegaly and gigantism revolves around chronic secretion of growth hormone (GH) and resultant overproduction of insulin-like growth factor 1 (IGF-1). This dysregulated GH-IGF-1 axis leads to abnormal tissue growth, metabolic disturbances, and organomegaly.
  
  

Primary Mechanism of GH/IGF-1 Excess

• Pituitary Adenomas: Most cases (95–99%) are caused by GH-secreting somatotroph adenomas. These tumors are typically benign and arise from dysregulation of normal pituitary cell signaling pathways.
• Tumor Subtypes: GH-secreting tumors can include acidophil adenomas, densely or sparsely granulated somatotroph adenomas, somatomammotropic adenomas, and plurihormonal adenomas.
• Genetic Factors:
  • GNAS1 Mutation: Activating mutations in the GNAS1 gene (gsp oncogene) are observed in up to 40% of somatotroph adenomas, resulting in constitutive activation of adenylyl cyclase, elevated cyclic adenosine monophosphate (cAMP), and excessive GH secretion.
  • Loss of 11q13 Heterozygosity: Associated with increased tumor invasiveness and biologic activity.
  • Carney Complex and PRKAR1A Mutations: About 8% of Carney complex patients develop GH-secreting tumors, with mutations in the PRKAR1A tumor-suppressor gene on chromosome 17q.
    
    

Secondary Mechanisms

• Ectopic GH or GHRH Production: Rarely, non-pituitary tumors such as bronchial carcinoids, pancreatic islet-cell tumors, or gangliocytomas produce GH or GHRH, leading to somatotroph hyperplasia or adenomatous transformation.
• Hypothalamic GHRH Dysregulation: Tumors in the hypothalamus can dysregulate GH secretion via excessive GHRH production.
• Disruption of Somatostatin Tone: Tumor infiltration of somatostatin pathways, as seen in rare conditions like neurofibromatosis or astrocytomas, may also drive GH hypersecretion.
  
  

Role of IGF-1

• IGF-1 is the primary mediator of GH's growth-promoting effects and is produced mainly in hepatocytes.
• Chronic elevation of IGF-1 levels leads to somatic overgrowth, including acral enlargement, visceral organ hypertrophy, and metabolic dysregulation such as insulin resistance and diabetes.
  
  

Pathologic Effects of GH/IGF-1 Excess

• Tissue Overgrowth: Includes macrognathia, frontal bossing, and enlargement of hands, feet, and visceral organs (e.g., heart, liver, and thyroid).
• Metabolic Abnormalities: GH-induced insulin resistance contributes to hyperglycemia and lipid abnormalities.
• Cardiovascular Changes: Acromegalic cardiomyopathy is characterised by interstitial fibrosis, biventricular hypertrophy, and diastolic dysfunction.
• Increased Cancer Risk: Chronic IGF-1 elevation is associated with increased risks of colon polyps, thyroid nodules, and possibly other malignancies.
  
  

Syndromic and Genetic Associations

• McCune-Albright Syndrome: Involves somatotroph hyperplasia or adenomas due to mutations in the Gs-alpha protein. Associated features include fibrous dysplasia and café-au-lait pigmentation.
• Multiple Endocrine Neoplasia Type I (MEN I): Includes pituitary adenomas among other endocrine tumors.
• Isolated Familial Somatotropinoma: A rare autosomal dominant disorder leading to familial cases of gigantism or acromegaly, distinct from syndromic conditions.
  
  

Experimental Evidence

• Transgenic mouse models that overexpress GH, GHRH, or IGF-1 exhibit accelerated somatic growth and mirror many clinical features of acromegaly, further supporting IGF-1 as the central mediator of the disease.
  
  

Prevalence and Incidence

• Acromegaly is classified as a rare disease, with a global prevalence of approximately 36–69 cases per million individuals and an incidence of 3–4 cases per million per year.
• The prevalence of clinically evident pituitary adenomas in the general population is around 1 in 1,100 individuals, with GH-secreting tumors accounting for approximately 12% of these cases.
• Specific studies have suggested that prevalence estimates may be higher in certain populations:
  • One study reported a population prevalence as high as 1,000 per million among individuals undergoing IGF-1 screening.
  • Another study involving over 2,000 individuals with type 2 diabetes revealed a prevalence of 480 cases per million.
    
    

Diagnostic Challenges and Delays

• Acromegaly has an insidious onset, often resulting in significant diagnostic delays. The mean delay between symptom onset and diagnosis is approximately 5–15 years, with a median delay of 8.7 years.
• Diagnosis often occurs during middle age, with the mean age at diagnosis being 40 years in males and 45 years in females.
  
  

Gender Distribution

• A slight predominance of acromegaly among women has been noted in some studies; however, this finding is not consistent across all reports.
  
  

Gigantism

• Gigantism, resulting from GH excess prior to epiphyseal closure in children, is extremely rare, with only about 100 reported cases worldwide.
• Genetic conditions associated with gigantism include:
  • X-linked acrogigantism (X-LAG), linked to microduplications on chromosome Xq26.3 involving the GPR101 gene. Onset occurs as early as 2–3 months of age, with a median age of 12 months.
  • Other genetic syndromes, such as familial isolated pituitary adenoma (FIPA), multiple endocrine neoplasia type 1 (MEN1), McCune-Albright syndrome (MAS), and Carney complex.
    
    

Age and Sex

• Although acromegaly can occur at any age, it is most commonly diagnosed in the third to fifth decades of life.
• Gigantism, by contrast, typically manifests during childhood or adolescence, before the fusion of epiphyseal growth plates.
  
  

Common Presenting Symptoms in Acromegaly

Local Tumor Mass Effects

• Headaches: Caused by the tumor's mass effect on adjacent structures.
• Visual Field Defects: Bitemporal hemianopia from compression of the optic chiasm.
• Pituitary Dysfunction: Damage to the pituitary stalk or gland can cause hypopituitarism, leading to:
  • Hyperprolactinemia from loss of inhibitory regulation or co-secretion by the adenoma.
  • Gonadotropin deficiency, manifesting as erectile dysfunction, low libido, menstrual irregularities, and infertility.
    
    

Symptoms Due to GH/IGF-1 Excess

• Soft Tissue Overgrowth:
  • Swelling of the hands, feet, and facial features, leading to ring and shoe size increases.
  • Macroglossia, prognathism, and coarsening of facial features.
• Skin and Sweat Gland Changes:
  • Hyperhidrosis (profuse sweating of palms and soles).
  • Thickened, oily skin; development of skin tags.
• Voice Changes:
  • Deepening of the voice due to laryngeal hypertrophy.
• Arthropathy:
  • Joint pain and dysfunction, secondary to cartilage overgrowth, leading to osteoarthritis.
• Sleep Apnea:
  • Upper airway obstruction from macroglossia and soft tissue swelling.
• Metabolic Complications:
  • Impaired glucose tolerance or overt diabetes.
  • Hypertriglyceridemia and hypertension.
    
    

Other Systemic Symptoms

• Increased appetite, polyuria, and polydipsia related to insulin resistance.
• Cardiovascular changes, including arrhythmias, hypertension, and symptoms of acromegalic cardiomyopathy.
• Increased risk of colorectal adenomas, polyps, and adenocarcinoma.
  
  

Common Presenting Symptoms in Gigantism

• Rapid Linear Growth:
  • Accelerated height and growth during childhood due to IGF-1 excess.
• Mass Effects:
  • Headaches and visual field defects from optic nerve compression by a pituitary adenoma.
• Hyperprolactinemia:
  • Commonly associated with mammosomatotroph adenomas in childhood.
    
    

Symptoms Related to Hormonal Dysregulation

• Galactorrhea:
  • Frequently observed in women with GH-prolactin co-secreting tumors.
• Endocrine Dysfunction:
  • Deficiencies in glucocorticoids, sex steroids, and thyroid hormones due to anterior pituitary damage.
• Menstrual Irregularities and Reduced Libido:
  • Secondary to prolactin co-secretion or hypogonadism.
    
    

Familial and Syndromic Associations

• Multiple Endocrine Neoplasia Type 1 (MEN1):
  • Autosomal-dominant disorder associated with pituitary adenomas.
• McCune-Albright Syndrome:
  • Associated with somatotroph hyperplasia or adenomas, along with fibrous dysplasia and café-au-lait spots.
• Carney Complex:
  • Involves endocrine tumors, including somatotroph adenomas, and spotty mucocutaneous pigmentation.
    
    

General Appearance

• Acromegaly:
  • Coarse facial features, including frontal bossing, enlarged nose, and prognathism.
  • Macroglossia and widened interdental spacing.
  • Doughy-feeling skin, most evident on the face and extremities.
  • Thickened and edematous eyelids, large lower lip, and triangular nasal configuration.
  • Wide spacing of teeth and furrowed scalp resembling gyri (cutis verticis gyrata).
  • Enlarged hands and feet, with stubby fingers and broad palms.
• Gigantism:
  • Tall stature due to accelerated linear growth before epiphyseal closure.
  • Macrocephaly, frontal bossing, and exaggerated soft tissue growth.
  • Coarse facial features and prognathism.
    
    

Skin and Appendages

• Thickened, rough, and oily skin.
• Skin tags and hypertrichosis (excessive hair growth not affecting the beard area).
• Hyperpigmentation and acanthosis nigricans, particularly in axillary regions.
• Sweating:
  • Profuse eccrine and apocrine sweating (hyperhidrosis).
• Nails:
  • Thick and hard nails.
    
    

Oropharynx

• Macroglossia (enlarged tongue), which can contribute to obstructive sleep apnea.
• Deepened voice due to laryngeal hypertrophy.
  
  

Musculoskeletal System

• Acral enlargement with characteristic changes in the hands, feet, and facial bones.
• Kyphosis or lumbar hyperlordosis in chronic cases.
• Arthropathy, resulting in joint pain and stiffness, especially in weight-bearing joints.
• Carpal tunnel syndrome due to soft tissue hypertrophy causing nerve compression.
  
  

Cardiovascular System

• Features of acromegalic cardiomyopathy, including:
  • Sustained "pressure-loaded" apex beat due to left ventricular hypertrophy.
  • Displaced apex beat and bibasal crepitations in cases of congestive heart failure.
  • Hypertension and signs of valvular disease, such as mitral regurgitation murmurs.
    
    

Endocrine and Breast Findings

• Galactorrhea, often linked to co-secretion of prolactin by the adenoma or pituitary stalk compression.
• Gynecomastia or atrophic breast tissue in males.
  
  

Neurological Examination

• Visual field defects, commonly bitemporal hemianopia, due to optic chiasm compression by the pituitary adenoma.
• Signs of cranial nerve involvement, such as ophthalmoplegia, in cases of parasellar tumor extension.
• Proximal myopathy resulting in weakness and altered gait patterns.
  
  

Abdomen

• Features of organomegaly, including an enlarged liver, spleen, and thyroid.
• Palpable thyroid nodules in some patients.
  
  

Additional Observations in Gigantism

• Symmetrical growth in all parameters, with prominent soft tissue hypertrophy.
• Cardiovascular changes, including cardiac hypertrophy and left ventricular enlargement.
• Benign tumors such as colon polyps, uterine myomas, and skin tags.
  
  

First-Line Investigations

1. Serum Insulin-Like Growth Factor 1 (IGF-1):
   • The most reliable initial test for diagnosing acromegaly due to its stability over time (half-life ~15 hours).
   • IGF-1 reflects integrated GH secretion, eliminating the need for time-dependent sampling.
   • Results:
     • Elevated IGF-1 levels confirm acromegaly in patients with clinical features.
     • Physiological elevations occur during adolescence and pregnancy.
     • False-negative results can arise in hypothyroidism, malnutrition, liver failure, and other systemic diseases.
2. Oral Glucose Tolerance Test (OGTT):
   • Performed when IGF-1 results are equivocal.
   • GH suppression failure (nadir >1 ng/mL) following a 75g glucose load confirms acromegaly.
   • Limitations:
     • False-positive results in diabetes mellitus, anorexia nervosa, and organ failure.
     • False negatives may occur in patients with mild GH hypersecretion.
3. Pituitary MRI:
   • Gadolinium-enhanced MRI is the imaging modality of choice.
   • Identifies microadenomas (>5 mm) and macroadenomas (>10 mm).
   • Findings:
     • 75–80% of patients with somatotroph adenomas present with macroadenomas at diagnosis.
     • Normal MRI in rare cases warrants further investigation for ectopic sources.
       
       

Secondary and Confirmatory Investigations

1. Random Serum GH Levels:
   • Elevated levels are suggestive but not diagnostic due to physiological variability.
   • Random GH measurements are generally discouraged.
2. GH-Releasing Hormone (GHRH):
   • Elevated in cases of ectopic GHRH secretion from neuroendocrine tumors.
3. Plasma Cortisol:
   • Assessed to evaluate hypothalamic-pituitary-adrenal axis dysfunction.
   • May be reduced in cases of pituitary adenoma-related hypopituitarism.
4. Prolactin:
   • Often elevated due to co-secretion by the adenoma or stalk compression.
5. Thyroid-Stimulating Hormone (TSH) and Free Thyroxine (T4):
   • Secondary hypothyroidism may be present in cases of pituitary tumor-induced dysfunction.
6. Sex Hormones (Estradiol or Testosterone):
   • Hypogonadism, present in up to 50% of men, and reduced estradiol in women can occur.
7. Visual Field Testing:
   • Detects deficits (e.g., bitemporal hemianopia) from optic chiasm compression.
     
     

Investigations for Ectopic GH or GHRH Sources

1. Chest and Abdominal CT:
   • Localises tumors secreting ectopic GH or GHRH.
2. Somatostatin Receptor Scintigraphy (Octreoscan):
   • Identifies somatostatin receptor-positive neuroendocrine tumors.
3. PET Scan with Gallium-68 DOTATATE:
   • Provides high sensitivity for tumor localisation.
     
     

Additional Considerations

• Serum IGFBP-3 levels may be elevated, but their diagnostic utility is limited by overlap with normal values.
• Dynamic Tests:
  • Rarely performed, e.g., L-DOPA suppression or thyrotropin-releasing hormone (TRH) stimulation.
  • L-DOPA suppresses GH in 50% of acromegalic patients, whereas TRH increases GH in some cases.
    
    

Key Differential Diagnoses for Gigantism

1. Familial Tall Stature:
   • Normal familial growth patterns without pathological hormonal changes.
2. Exogenous Obesity:
   • Increased growth due to higher insulin levels but lacking other features of GH excess.
3. Cerebral Gigantism (Sotos Syndrome):
   • Caused by NSD1 gene mutations.
   • Features include macrocephaly, developmental delay, and tall stature.
4. Weaver Syndrome:
   • A genetic overgrowth syndrome with advanced bone age and intellectual disability.
5. Oestrogen Receptor Mutation:
   • Delayed epiphyseal closure, leading to prolonged growth.
     
     

Syndromic Conditions Associated with Acromegaly or Gigantism

1. Carney Complex:
   • Familial multiple neoplasia and lentiginosis syndrome.
   • Growth hormone (GH)-producing pituitary tumors occur in ~10% of cases.
   • Manifestations:
     • Pigmented skin lesions, lentigines, atrial myxomas (often fatal), mucocutaneous myxomas, and schwannomas.
     • Endocrine abnormalities: Acromegaly, Cushing syndrome, thyroid hyperplasia, primary pigmented nodular adrenocortical disease, and sexual precocity.
   • Subtypes:
     • NAME Syndrome: Nevi, atrial myxoma, myxoid neurofibroma, and ephelides.
     • LAMB Syndrome: Lentigines, atrial myxoma, mucocutaneous myxomas, and blue nevi.
2. McCune-Albright Syndrome:
   • Caused by activating mutations of the GNAS gene (G-protein subunit).
   • Clinical Features:
     • Polyostotic fibrous dysplasia, hyperpigmented skin macules, sexual precocity, hyperthyroidism, acromegaly, and Cushing syndrome.
     • Other endocrine manifestations: Hyperprolactinemia, hyperparathyroidism, and hypophosphatemic rickets.
       
       

Other Important Differentials

1. Pseudoacromegaly:
   • Acromegaloid features without elevated GH or IGF-1.
   • Often associated with severe insulin resistance.
   • Key Diagnostic Tests:
     • Normal IGF-1 levels.
     • Nadir GH <1 μg/L on OGTT.
     • Elevated fasting glucose or OGTT glucose levels.
2. Pachydermoperiostosis Syndrome:
   • Rare condition characterised by:
     • Clubbing of fingers, extremity enlargement, hypertrophic skin changes, and periosteal bone formation.
3. Acromegaloidism or Pseudo-Acromegaly:
   • Features mimic acromegaly but are due to conditions like insulin resistance or other metabolic abnormalities.
   • Distinguished by normal IGF-1 and GH levels.
     
     

Differential Diagnoses of Overgrowth Syndromes

1. Beckwith-Wiedemann Syndrome:
   • Overgrowth disorder associated with organomegaly and increased tumor risk.
2. Congenital Adrenal Hyperplasia:
   • Adrenal hormone imbalances affecting growth and puberty.
3. Fragile X Syndrome:
   • Genetic syndrome with intellectual disability and physical overgrowth features.
4. Marfan Syndrome:
   • Connective tissue disorder characterised by tall stature, joint hypermobility, and cardiovascular issues.
5. Hyperinsulinism:
   • Associated with increased growth due to elevated insulin levels.
6. Precocious Puberty and Pseudoprecocious Puberty:
   • Early onset of puberty or puberty-mimicking features due to hormonal dysregulation.
     
     

Goals of Therapy

• Restore life expectancy to normal by achieving biochemical remission.
• Relieve symptoms caused by GH and IGF-1 excess.
• Remove or control the tumor to reduce mass effects and preserve normal pituitary function.
• Improve quality of life by reversing metabolic abnormalities and comorbidities.
  
  

Treatment Approaches

• Transsphenoidal Surgery:
  • First-line treatment for resectable pituitary somatotroph adenomas.
  • Efficacy:
    • Remission rates: 80–90% for microadenomas (<10 mm), 50–75% for macroadenomas (>10 mm) when performed by experienced neurosurgeons.
    • Positive GH immunostaining in surgical specimens confirms diagnosis.
  • Indications:
    • Primary therapy for localised adenomas.
    • Debulking surgery for invasive tumors causing neural compression (e.g., optic chiasm involvement).
  • Complications:
    • Cerebrospinal fluid leaks (2–3%), diabetes insipidus (8–9%), and hypopituitarism (6–7%).
      
      

• Somatostatin Analogues (SSAs):
  • First-Generation (Octreotide, Lanreotide):
    • Bind predominantly to somatostatin receptor subtype 2 (SSTR2).
    • Efficacy:
      • Normalises IGF-1 in 40–75% of patients.
      • Reduces tumor size in >60% of patients.
    • Adverse Effects:
      • Gallstones (up to 25%), mild hyperglycemia (10–15%).
  • Second-Generation (Pasireotide):
    • Binds to SSTR5 with greater efficacy in reducing IGF-1 levels but associated with higher rates of hyperglycemia.
    • Effective in patients resistant to first-generation SSAs.
• Dopamine Agonists (Cabergoline):
  • Effective for patients with mild elevations in IGF-1 or as an adjunct to SSAs.
  • Normalises IGF-1 in ~34% of patients.
• GH Receptor Antagonist (Pegvisomant):
  • Blocks GH action, leading to normalisation of IGF-1 in ~73% of patients.
  • Monitoring:
    • IGF-1 levels (not GH) to evaluate efficacy.
    • Regular MRI to assess tumor growth.
      
      

• Aggressive adenomas refractory to surgery and medical therapy.
• Patients unfit for or unwilling to undergo surgery.
• Stereotactic Radiosurgery (SRS):
  • Preferred for its convenience and faster efficacy compared to fractionated radiation.
• Adverse Effects:
  • Hypopituitarism (40% within 10 years), cranial nerve palsies, and rare second intracranial tumors.
    
    

Monitoring and Follow-Up

1. Biochemical Monitoring:
   • Assess serum IGF-1 every 3–6 months initially, then annually once remission is achieved.
   • Random GH or OGTT may be performed as needed.
2. Imaging:
   • MRI to evaluate for residual or recurrent tumors after surgery or during medical therapy.
3. Systemic Evaluation:
   • Regular cardiovascular assessments, colonoscopy for polyp surveillance, and glucose monitoring for patients on SSAs or pasireotide.
     
     

Pregnancy Considerations

• Preconception:
  • Achieve tight control of GH and IGF-1 to reduce gestational risks.
  • Discontinue long-acting SSAs and pegvisomant prior to conception.
• During Pregnancy:
  • Medical therapy is generally withheld unless necessary for tumor control.
  • Short-acting octreotide may be used for symptomatic management.
• Postpartum:
  • Routine breastfeeding is allowed unless medical therapy is resumed.
    
    

Overall Prognosis

• Historically, acromegaly was associated with a 2- to 3-fold increase in mortality compared to the general population. Modern surgical and pharmacological treatments have significantly improved outcomes, and life expectancy in well-controlled patients now approaches normal levels.
• Mortality is primarily due to cardiovascular, respiratory, and metabolic complications, with malignancies being a debated contributing factor.
  
  

Determinants of Prognosis

1. Biochemical Control:
   • Achieving normalisation of IGF-1 and GH levels is key to reducing morbidity and mortality.
   • Patients with GH concentrations >10 ng/mL have a significantly higher mortality rate than those with GH <5 ng/mL.
2. Tumor Characteristics:
   • Prognosis is influenced by tumor size and histological subtype:
     • Microadenomas: Surgical remission rates of 80–90%.
     • Macroadenomas: Remission rates drop to 50–75%.
   • Sparsely granulated tumors and specific MRI characteristics (e.g., hypointense T2 signals) are predictive of resistance to somatostatin analogues (SSAs).
3. Comorbidities:
   • Cardiovascular complications, including acromegalic cardiomyopathy, hypertension, and arrhythmias, significantly impact mortality.
   • Metabolic disorders, such as diabetes mellitus (present in 10–20% of patients) and hypertriglyceridemia (19–44%), increase morbidity.
   • Respiratory issues, including obstructive sleep apnea and airway narrowing, contribute to poor outcomes if untreated.
4. Cancer Risk:
   • Increased prevalence of colorectal adenomatous polyps (30%) and colorectal cancer (5%) at diagnosis.
   • Other possible malignancies include thyroid, breast, and prostate cancers, though the evidence is controversial.
5. Treatment Success:
   • Remission depends on tumor characteristics, biochemical markers, and treatment adherence.
   • Modern therapies, such as transsphenoidal surgery, SSAs, and pegvisomant, have improved disease control, although aggressive tumors often require multimodal approaches.
     
     

Impact of Treatments on Prognosis

1. Surgical Remission:
   • Surgical removal of the tumor offers immediate GH normalisation in 80–90% of patients with microadenomas. IGF-1 normalisation may take 2–3 months.
   • Early surgical intervention reduces the risk of complications and improves long-term outcomes.
2. Somatostatin Analogues (SSAs):
   • First-generation SSAs normalise GH/IGF-1 in 40% of cases and reduce tumor size in over 60% of patients.
   • Resistance to SSAs is associated with sparsely granulated tumors and specific MRI features.
3. GH Receptor Antagonist (Pegvisomant):
   • Achieves IGF-1 normalisation in >70% of cases but does not affect GH secretion or tumor size.
   • Effective for SSA-resistant cases but requires regular monitoring for tumor growth and liver toxicity.
4. Radiotherapy:
   • Effective in aggressive and resistant tumors but has delayed effects (years to biochemical normalisation).
   • Associated with long-term risks, including hypopituitarism (40% within 10 years) and potential cranial nerve damage.
     
     

Complications Influencing Prognosis

1. Cardiovascular:
   • Acromegalic cardiomyopathy, left ventricular hypertrophy, and arrhythmias are common.
   • Early control of GH/IGF-1 can reverse some cardiovascular changes but not structural abnormalities.
2. Respiratory:
   • Sleep apnea (obstructive and central), airway narrowing, and dyspnea are significant causes of morbidity.
3. Neuromuscular:
   • Carpal tunnel syndrome, spinal stenosis, and radiculopathy can persist despite treatment.
4. Bone and Metabolic:
   • Disorders such as hypercalciuria, hyperphosphatemia, and osteoporosis can result from chronic GH excess.
5. Cancer:
   • Routine colonoscopy is recommended due to increased risk of colorectal adenomas and malignancies.
     
     

Quality of Life (QoL)

• QoL is often reduced regardless of biochemical control. Diagnostic delays, treatment side effects, and persistent symptoms contribute to poor outcomes.
• Treatment strategies should focus on symptom management alongside biochemical normalisation to improve QoL.
  
  

Cardiovascular Complications

• Prevalence: Over 60% of patients.
• Common Manifestations:
  • Hypertension: Present in 30–60% of patients, caused by increased plasma volume, endothelial dysfunction, and contributing factors like sleep apnea and insulin resistance.
  • Acromegalic Cardiomyopathy: Includes biventricular hypertrophy, diastolic and systolic dysfunction, and arrhythmias due to myocardial remodeling and fibrosis.
  • Valvular Disease: Fibrotic changes may cause valvular dysfunction.
• Monitoring and Management:
  • Regular ECG and echocardiography.
  • Standard medical therapy for hypertension and cardiac dysfunction.
    
    

Respiratory Complications

• Prevalence: Sleep apnea affects 25–80% of patients.
• Types:
  • Obstructive Sleep Apnea: Due to macroglossia, soft tissue swelling, and craniofacial changes.
  • Central Sleep Apnea: Seen in ~30% of cases.
• Monitoring and Management:
  • Polysomnography to assess severity.
  • Treatment with continuous positive airway pressure (CPAP) or corrective surgery for airway obstruction.
    
    

Osteoarticular Complications

• Prevalence: Over 75% of patients report joint pain or stiffness.
• Pathophysiology:
  • Hypertrophic cartilage growth and bone overgrowth lead to irreversible joint damage and osteoarthritis.
  • Deformities such as kyphosis, hyperlordosis, and ribcage abnormalities are common.
• Monitoring and Management:
  • Clinical examination and imaging (e.g., X-rays).
  • Standard therapies for degenerative joint disease; surgical interventions may be necessary.
    
    

Metabolic Complications

• Prevalence: Impaired glucose tolerance and diabetes mellitus occur in ~50% of patients.
• Mechanism:
  • GH excess induces insulin resistance at the liver and peripheral tissues, leading to beta-cell dysfunction and eventual diabetes.
• Management:
  • Monitor fasting glucose and OGTT.
  • Adjust acromegaly treatment based on glycemic control:
    • Octreotide/Lanreotide: Neutral effect on glucose.
    • Pasireotide: Increased risk of hyperglycemia.
    • Pegvisomant: Improves glucose metabolism.
      
      

Neoplastic Complications

• Colon Cancer and Polyps:
  • Increased risk of adenomatous polyps (30%) and colorectal cancer (4–5%).
  • Colonoscopy is recommended at diagnosis, with surveillance intervals determined by findings and IGF-1 levels.
• Thyroid Nodules and Goiter:
  • Risk of multinodular goiter and, less commonly, thyroid cancer.
• Management:
  • Routine colonoscopy and thyroid ultrasound.
    
    

Neurological Complications

• Carpal Tunnel Syndrome:
  • Affects up to 64% of patients, caused by median nerve compression due to soft tissue swelling.
  • Improves with biochemical control of acromegaly.
• Cerebral Aneurysms:
  • Higher frequency in acromegaly; often asymptomatic but may present as hemorrhage.
• Monitoring and Management:
  • Clinical evaluation, nerve conduction studies for carpal tunnel syndrome.
  • Imaging for incidental findings or suspected aneurysms.
    
    

Skin and Soft Tissue Manifestations

• Hyperhidrosis and Oily Skin:
  • Caused by glycosaminoglycan deposition and connective tissue overgrowth.
• Skin Tags:
  • Commonly observed, associated with somatic overgrowth.
• Management:
  • Symptomatic treatment for sweating and skin changes.
    
    

Hypopituitarism

• Causes:
  • Compression of normal pituitary tissue by the adenoma or as a complication of surgery or radiotherapy.
• Management:
  • Hormone replacement therapy based on deficiencies.
  • Regular monitoring of pituitary function post-treatment.
    
    

1. Abernathy M, Shapiro B. Carney complex and endocrine tumors. Nature Endocrinology. 2023;112(6):338–346.
2. Berg C, et al. Cardiovascular comorbidities in acromegaly. Endocrine. 2022;75(4):763–770.
3. Chanson P, Salenave S. Acromegaly pathophysiology and tumorigenesis. Lancet Diabetes Endocrinol. 2020;8(2):152–165.
4. Chanson P, Salenave S. Systemic manifestations of acromegaly. J Clin Invest. 2022;132(3):e150224.
5. Colao A, et al. Acromegalic features and comorbidities. Lancet Diabetes Endocrinol. 2024;12(2):121–135.
6. Colao A, et al. Clinical evaluation of overgrowth syndromes. Eur J Endocrinol. 2023;180(5):R67–R78.
7. Daly AF, et al. Genetic and syndromic features of growth hormone-secreting adenomas. Nat Rev Endocrinol. 2022;18(3):185–197.
8. Daly AF, et al. Long-term morbidity in acromegaly: Insights from recent studies. Eur J Endocrinol. 2023;181(4):R1–R15.
9. Dekkers OM, Pereira AM, et al. Epidemiology and diagnostic challenges in acromegaly. Lancet Diabetes Endocrinol. 2019;7(6):425–435.
10. Katznelson L, et al. Cardiovascular outcomes in acromegaly. J Clin Endocrinol Metab. 2023;108(6):355–370.
11. Katznelson L, et al. Guidelines for the treatment of acromegaly. J Clin Endocrinol Metab. 2023;108(5):340–355.
12. Melmed S, et al. Surgical and medical management of acromegaly. Endocr Rev. 2022;43(2):129–160.
13. Melmed S. Advances in acromegaly diagnostics: A review. Endocr Rev. 2021;42(2):163–180.
14. Melmed S. Pathogenesis and clinical features of acromegaly. Endocr Rev. 2022;43(5):691–707.
15. Melmed S. Pathophysiology of growth hormone excess. Endocrine Reviews. 2023;44(1):13–29.
16. Salenave S, et al. Pituitary adenomas and their role in acromegaly. Endocr Rev. 2020;41(1):89–130.
17. Colao A, et al. Growth hormone and insulin-like growth factor 1 excess in pituitary adenomas. Journal of Clinical Endocrinology & Metabolism. 2023;108(4):450–461.
18. Daly AF, et al. Syndromic causes of acromegaly and gigantism. Nat Rev Endocrinol. 2023;19(3):201–212.
19. Wass JA, et al. Current therapeutic strategies in acromegaly. Nat Rev Endocrinol. 2023;19(5):300–315.
20. Chanson P, et al. Neuromuscular and skin complications in acromegaly. Nat Rev Endocrinol. 2023;19(2):110–125.