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.

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

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.

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.

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

Random Serum GH Levels

• Elevated levels are suggestive but not diagnostic due to physiological variability.
• Random GH measurements are generally discouraged.

GH-Releasing Hormone (GHRH)

• Elevated in cases of ectopic GHRH secretion from neuroendocrine tumors.

Plasma Cortisol

• Assessed to evaluate hypothalamic-pituitary-adrenal axis dysfunction.
• May be reduced in cases of pituitary adenoma-related hypopituitarism.

Prolactin

• Often elevated due to co-secretion by the adenoma or stalk compression.

Thyroid-Stimulating Hormone (TSH) and Free Thyroxine (T4)

• Secondary hypothyroidism may be present in cases of pituitary tumor-induced dysfunction.

Sex Hormones (Estradiol or Testosterone)

• Hypogonadism, present in up to 50% of men, and reduced estradiol in women can occur.

Visual Field Testing

• Detects deficits (e.g., bitemporal hemianopia) from optic chiasm compression.

Investigations for Ectopic GH or GHRH Sources

Chest and Abdominal CT

• Localises tumors secreting ectopic GH or GHRH.

Somatostatin Receptor Scintigraphy (Octreoscan)

• Identifies somatostatin receptor-positive neuroendocrine tumors.

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

Familial Tall Stature

• Normal familial growth patterns without pathological hormonal changes.

Exogenous Obesity

• Increased growth due to higher insulin levels but lacking other features of GH excess.

Cerebral Gigantism (Sotos Syndrome)

• Caused by NSD1 gene mutations.
• Features include macrocephaly, developmental delay, and tall stature.

Weaver Syndrome

• A genetic overgrowth syndrome with advanced bone age and intellectual disability.

Oestrogen Receptor Mutation

• Delayed epiphyseal closure, leading to prolonged growth.

Syndromic Conditions Associated with Acromegaly or Gigantism

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.

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

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.

Pachydermoperiostosis Syndrome

• Rare condition characterised by:
  • Clubbing of fingers, extremity enlargement, hypertrophic skin changes, and periosteal bone formation.

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

Beckwith-Wiedemann Syndrome

• Overgrowth disorder associated with organomegaly and increased tumor risk.

Congenital Adrenal Hyperplasia

• Adrenal hormone imbalances affecting growth and puberty.

Fragile X Syndrome

• Genetic syndrome with intellectual disability and physical overgrowth features.

Marfan Syndrome

• Connective tissue disorder characterised by tall stature, joint hypermobility, and cardiovascular issues.

Hyperinsulinism

• Associated with increased growth due to elevated insulin levels.

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

Surgical Management

• 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%).

Medical Therapy

• 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.

Radiotherapy

• 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

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.

Imaging

• MRI to evaluate for residual or recurrent tumors after surgery or during medical therapy.

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

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.

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).

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.

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.

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

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.

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.

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.

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

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.

Respiratory

• Sleep apnea (obstructive and central), airway narrowing, and dyspnea are significant causes of morbidity.

Neuromuscular

• Carpal tunnel syndrome, spinal stenosis, and radiculopathy can persist despite treatment.

Bone and Metabolic

• Disorders such as hypercalciuria, hyperphosphatemia, and osteoporosis can result from chronic GH excess.

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.

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