Endocrine Related Myopathy

• Hypothyroid Myopathy
• Hyperthyroid Myopathy
• Hypoparathyroid Myopathy
• Hyperparathyroid Myopathy
• Addison`s Disease-Related Myopathy
• Cushing`s Syndrome-Related Myopathy
• Diabetic Myopathy
• Acromegaly Related Myopathy
• GH Deficiency Related Myopathy

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Hypothyroid Myopathy

Introduction

Hypothyroid myopathy refers to a group of muscle manifestations resulting from thyroid hormone deficiency. It is one of the most common endocrine myopathies and can range from mild muscle complaints to significant muscle weakness and even pseudohypertrophy. The myopathy can precede or accompany other systemic signs of hypothyroidism, making awareness of its features important for early diagnosis and treatment.

Epidemiology

Hypothyroid myopathy occurs in a significant proportion of individuals with overt hypothyroidism. Estimates suggest that up to 80% of patients with untreated hypothyroidism may have some form of muscle involvement, although only a subset experience clinically significant symptoms. It is more prevalent in women and typically presents in middle age, reflecting the demographics of autoimmune thyroid disorders such as Hashimoto’s thyroiditis. Subclinical hypothyroidism may also be associated with mild muscle symptoms, though less commonly.

Pathophysiology

Thyroid hormones are essential for muscle metabolism, regulating mitochondrial function, energy production, and muscle repair. In hypothyroidism, mitochondrial oxidative capacity is reduced, impairing ATP synthesis and muscle fatigue. Altered calcium handling slows muscle contraction and relaxation, while glycosaminoglycan accumulation contributes to stiffness and pseudohypertrophy. Additionally, muscle fibers may shift from fast- to slow-twitch types, and autoimmune mechanisms can play a role, particularly in autoimmune thyroiditis.

Clinical Manifestations

Hypothyroid myopathy presents various symptoms, most commonly proximal muscle weakness affecting the shoulders and hips, along with muscle stiffness, cramps, fatigue, and myalgia. Slowed deep tendon reflexes, especially in the relaxation phase, are a classic finding. Some patients experience exercise intolerance and delayed muscle recovery, and in rare cases, muscle pseudohypertrophy, such as calf enlargement, may occur. Serum creatine kinase (CK) levels are often mildly elevated but can be markedly increased in some individuals.

Diagnosis

• Serum TSH: Elevated (primary hypothyroidism).
• Free T4: Decreased.
• Creatine kinase (CK): Elevated in 30–90% of patients.
• Electromyography (EMG): May show myopathic changes or be normal.
• Muscle biopsy: Rarely needed; may show fiber atrophy, lipid accumulation, and other nonspecific changes.
• Differential diagnoses include other endocrine myopathies, inflammatory myopathies, and muscular dystrophies.

Treatment

• Normalization of thyroid function leads to gradual resolution of muscle symptoms.
• CK levels often normalize within weeks to months.
• In cases with severe weakness, physical therapy may support recovery.

Prognosis

The prognosis of hypothyroid myopathy is generally excellent with adequate thyroid hormone replacement. Most patients experience complete resolution of muscle symptoms. Recovery may take several weeks to months, depending on the duration and severity of hypothyroidism. Delayed treatment or long-standing disease may lead to incomplete recovery or residual weakness in some cases.

Hyperthyroid Myopathy 

Introduction

Hyperthyroid myopathy refers to muscle dysfunction associated with excess thyroid hormone levels. It is a relatively common manifestation of hyperthyroidism and can range from mild muscle fatigue to significant proximal weakness and, in rare cases, acute paralysis. Muscle symptoms may precede, accompany, or follow other classic signs of hyperthyroidism.

Epidemiology

Muscle involvement is reported in up to 60–80% of patients with untreated hyperthyroidism, though the severity varies. It is more frequently seen in older adults and individuals with more prolonged or severe thyrotoxicosis. Hyperthyroid myopathy is commonly associated with Graves’ disease but can also occur in toxic multinodular goiter or thyroiditis. A distinct and rare form, thyrotoxic periodic paralysis, is more common in men of Asian or Hispanic descent.

Pathophysiology

Excess thyroid hormones affect skeletal muscle through multiple mechanisms. Increased basal metabolic rate and protein turnover lead to catabolic muscle wasting, especially of fast-twitch (type II) fibers. There is also impaired neuromuscular transmission and increased oxidative stress. In thyrotoxic periodic paralysis, increased Na⁺/K⁺-ATPase activity drives potassium into cells, resulting in hypokalemia and transient muscle paralysis. Unlike hypothyroid myopathy, CK levels are typically normal or only mildly elevated.

Clinical manifestations 

The most common feature is painless proximal muscle weakness, particularly in the thighs and shoulders, which can make climbing stairs or lifting objects difficult. Muscle atrophy may be visible in chronic cases. Fatigue, tremor, and heat intolerance are common coexisting symptoms. In thyrotoxic periodic paralysis, episodes of flaccid paralysis occur suddenly, often at night or after heavy carbohydrate intake or exercise. Reflexes are often brisk due to the underlying hyperthyroid state.

Diagnosis

• TSH: Suppressed or undetectable
• Free T4 and/or T3: Elevated
• CK: Typically normal or mildly increased
• EMG: May show non-specific myopathic changes
• Potassium levels: Often decreased during attacks of thyrotoxic periodic paralysis
• Differential diagnoses include steroid myopathy, inflammatory myopathies, and other causes of periodic paralysis. 

Treatment

• Antithyroid drugs (e.g., methimazole or propylthiouracil)
• Radioiodine therapy or thyroidectomy in selected cases
• Muscle symptoms usually improve gradually as thyroid function normalizes.
• In thyrotoxic periodic paralysis, potassium supplementation and beta-blockers (e.g., propranolol) are used acutely, with prevention dependent on achieving euthyroidism. 

Prognosis

The prognosis is generally good with appropriate treatment of the thyroid disorder: Muscle strength typically returns to normal over weeks to months. In periodic paralysis, recurrence is preventable once euthyroidism is achieved. Chronic, untreated hyperthyroidism can lead to persistent muscle atrophy and weakness.

Thyrotoxic periodic paralysis (TPP) is a rare complication of hyperthyroidism characterized by sudden, transient episodes of muscle weakness or paralysis. It occurs most commonly in young Asian or Hispanic males, despite hyperthyroidism being more prevalent in females. The condition is caused by an intracellular potassium shift driven by increased Na⁺/K⁺-ATPase activity stimulated by excess thyroid hormones and adrenergic tone. Attacks are often triggered by high-carbohydrate meals, rest after strenuous exercise or stress, and typically occur at night or early morning. During episodes, patients exhibit flaccid paralysis, most often affecting the lower limbs, with preserved consciousness and sometimes life-threatening hypokalemia. Treatment includes acute potassium supplementation and non-selective beta-blockers, while long-term prevention depends on achieving and maintaining euthyroid status.

Hypoparathyroid Myopathy 

Introduction

Hypoparathyroid myopathy refers to muscle dysfunction associated with low parathyroid hormone (PTH) levels, typically due to autoimmune disease, postsurgical hypoparathyroidism, or genetic causes. This condition is mainly related to calcium and phosphate metabolism disturbances, which affect neuromuscular excitability.

Epidemiology

Hypoparathyroidism is relatively rare, and myopathy is not as frequently recognized compared to hyperparathyroid myopathy. It can affect individuals of all ages but is most often seen after thyroid or parathyroid surgery. Symptoms may be subtle or misinterpreted as neurological or musculoskeletal disorders.

Pathophysiology

Deficiency of PTH leads to hypocalcemia and hyperphosphatemia, which increase neuromuscular excitability and may impair muscle contraction and relaxation. Low calcium affects the nerve and muscle activation threshold, contributing to cramps and spasms. Chronic hypocalcemia may also affect mitochondrial function and energy metabolism in muscles.

Clinical manifestations 

Symptoms include muscle cramps, tetany, stiffness, and painful spasms, often in the hands and feet. Proximal muscle weakness can also occur, though it is less prominent. Signs of neuromuscular irritability, such as Chvostek’s and Trousseau’s signs, may be present. In some cases, muscle symptoms may mimic other forms of neuromuscular disease.

Diagnosis

• Low serum calcium
• High serum phosphate
• Low or inappropriately normal PTH
• CK levels may be normal or mildly elevated.
• EMG may show myotonic or nonspecific changes.
• Muscle biopsy, if performed, is usually nonspecific.

Treatment

• Calcium supplementation
• Active vitamin D analogs (e.g., calcitriol)
• Thiazide diuretics may be used to reduce urinary calcium loss.
• In rare cases, recombinant PTH therapy is considered.

Prognosis

The prognosis is generally good, with adequate calcium and vitamin D replacement. Muscle symptoms often improve with the normalization of serum calcium. However, long-standing hypocalcemia may result in persistent symptoms or complications, such as calcifications in soft tissue or basal ganglia.

Hyperparathyroid Myopathy 

Introduction

Hyperparathyroid myopathy refers to muscle dysfunction associated with elevated parathyroid hormone (PTH) levels, typically due to primary or secondary hyperparathyroidism. It is a relatively uncommon but well-documented complication that presents with muscular symptoms, particularly proximal muscle weakness and fatigue.

Epidemiology

This myopathy is more commonly seen in individuals with primary hyperparathyroidism, particularly in older adults and postmenopausal women. It can also occur in patients with secondary hyperparathyroidism, especially those with chronic kidney disease. The prevalence of muscle symptoms in hyperparathyroidism is variable but can significantly impact quality of life. 

Pathophysiology

Excess PTH leads to hypercalcemia and hypophosphatemia, which impair muscle cell excitability and contractility. Chronic PTH elevation also contributes to muscle protein catabolism and mitochondrial dysfunction. In secondary hyperparathyroidism, uremic toxins and metabolic derangements further exacerbate muscle weakness.

Clinical manifestations 

The most common symptom is proximal muscle weakness, especially in the pelvic and shoulder girdles, which may make climbing stairs or lifting arms difficult. Fatigue, muscle pain, and cramps are also reported. In severe cases, patients may have impaired mobility or even present with features mimicking inflammatory myopathies.

Diagnosis

• Hypercalcemia (in primary hyperparathyroidism)
• Hypophosphatemia
• Normal or mildly elevated CK levels
• EMG may show nonspecific myopathic features.
• Differential diagnoses include other metabolic or endocrine myopathies and primary muscle disorders.

Treatment

• Parathyroidectomy in symptomatic primary hyperparathyroidism
• Phosphate binders
• vitamin D analogs
• calcimimetics in secondary hyperparathyroidism.
• Improvement in muscle strength is usually observed following normalization of PTH and calcium levels.

Prognosis

The prognosis is generally good with effective treatment of the hormonal imbalance. Muscle symptoms typically resolve or improve within weeks to months, although chronic disease may lead to delayed or incomplete recovery in some individuals.

Addison's Disease-Related Myopathy 

Introduction

Addison's disease, also known as primary adrenal insufficiency, is a condition where the adrenal glands fail to produce sufficient cortisol and aldosterone. Myopathy is a recognized but relatively uncommon feature of Addison's disease, primarily affecting muscle strength and endurance. The condition is usually associated with generalized weakness, fatigue, and muscle pain, significantly impacting quality of life.

Epidemiology

Addison's disease is a rare condition, with an estimated prevalence of 1 in 100,000 individuals. Myopathy occurs in a subset of patients with Addison's disease and is more commonly seen when there is severe cortisol deficiency. It can affect individuals of all ages but is most commonly diagnosed in young adults, with a higher prevalence in women.

Pathophysiology

The primary cause of Addison's disease is the destruction or dysfunction of the adrenal glands, which leads to deficient production of cortisol and aldosterone. Low cortisol levels result in muscle weakness, likely due to impaired carbohydrate and protein metabolism. At the same time, aldosterone deficiency contributes to electrolyte imbalances (e.g., hyponatremia and hyperkalemia) that affect muscle cell function. These metabolic disturbances result in muscle fatigue, cramps, and reduced muscle endurance. Chronic cortisol deficiency also impairs the body's ability to repair muscle tissue after exercise.

Clinical manifestations 

In Addison's disease, myopathy typically presents as generalized muscle weakness, which may affect proximal and distal muscles. Patients often experience muscle fatigue, cramps, and pain after physical exertion. Muscle wasting may also occur over time if cortisol deficiency is not adequately treated. Additionally, orthostatic hypotension and gastrointestinal symptoms (such as nausea, vomiting, and weight loss) are common and may exacerbate the weakness.

Diagnosis

• Low cortisol levels
• Elevated ACTH (adrenocorticotropic hormone)
• Hyponatremia and hyperkalemia due to aldosterone deficiency
• Electromyography (EMG) may show nonspecific myopathic changes
• Muscle biopsy can reveal nonspecific changes such as muscle fiber atrophy.
• Differential diagnoses include other metabolic myopathies and neuromuscular disorders.

Treatment

• Glucocorticoid replacement (e.g., hydrocortisone or prednisone) to correct cortisol deficiency
• Mineralocorticoid replacement (e.g., fludrocortisone) to replace aldosterone
• Electrolyte management for sodium and potassium imbalances.
• Physical therapy may also improve muscle strength and function, especially in patients with significant muscle weakness.

Prognosis

With appropriate treatment, the prognosis of Addison's disease myopathy is generally favorable. Muscle strength typically improves with the normalization of cortisol and aldosterone levels. However, recovery can be slow and may take several months, especially in individuals with longstanding adrenal insufficiency or untreated disease. In severe or chronic cases, residual muscle weakness or wasting may persist despite treatment.

Cushing's Syndrome-Related Myopathy

Introduction

Cushing's syndrome is a condition characterized by prolonged exposure to high levels of cortisol, either due to endogenous overproduction or exogenous corticosteroid therapy. Myopathy is a recognized complication of Cushing's syndrome, primarily affecting skeletal muscles, particularly those of the proximal limbs. The muscle weakness can be significant and debilitating, often manifesting in a gradual or sudden onset of symptoms.

Epidemiology

Cushing's syndrome is relatively rare, with an estimated incidence of 2 to 3 cases per million people per year. Myopathy is present in about 40-60% of patients with Cushing's syndrome and is more commonly seen in those with long-term or severe cortisol excess. The condition affects both men and women, although women are more frequently diagnosed due to the higher prevalence of conditions such as Cushing's disease (pituitary adenomas). Myopathy often occurs in conjunction with other signs of cortisol excess, such as obesity, hyperglycemia, and hypertension.

Pathophysiology

The pathophysiology of Cushing's syndrome-related myopathy involves the toxic effects of excess cortisol on muscle tissue. Cortisol leads to muscle protein breakdown (catabolism), inhibits protein synthesis, and impairs muscle repair. It also alters the neuromuscular junction and muscle cell function, contributing to muscle weakness and atrophy. Furthermore, cortisol dysregulates insulin, leading to insulin resistance and an imbalance in glucose metabolism, which may further impair muscle function and promote muscle wasting.

Clinical manifestations 

Myopathy in Cushing's syndrome often presents as proximal muscle weakness, particularly affecting the upper legs, shoulders, and hips. Patients may experience difficulty standing up from a seated position, climbing stairs, and lifting objects. The weakness tends to worsen with prolonged steroid use or untreated Cushing's syndrome. Other common features of Cushing's syndrome, such as central obesity, striae, hypertension, and easy bruising, may also be present and contribute to the clinical picture.

Diagnosis

• Elevated cortisol levels (either through blood, urine, or saliva testing)
• Increased ACTH levels in cases of pituitary Cushing's disease
• Electromyography (EMG) can show myopathic changes
• Muscle biopsy may demonstrate type 2 muscle fiber atrophy.
• Differential diagnoses include other causes of proximal muscle weakness, such as steroid-induced myopathy and myopathies related to other endocrine disorders.

Treatment

• Surgical removal of tumors (e.g., pituitary adenomas, adrenal tumors)
• Medical treatment (e.g., ketoconazole, metyrapone) to inhibit cortisol production
• Gradual reduction or discontinuation of corticosteroids if they are the cause
• Physical therapy is important to improve muscle strength and function, especially in patients with significant muscle weakness.
• In some cases, insulin-sensitizing agents and anabolic steroids may help counteract muscle wasting.

Prognosis

The prognosis of Cushing's syndrome-related myopathy is generally favorable with proper treatment of the underlying cortisol excess. Muscle weakness often improves as cortisol levels are normalized, but recovery can be slow, and some residual weakness may persist, particularly in patients with prolonged exposure to high cortisol levels. The earlier the diagnosis and treatment of Cushing's syndrome, the better the long-term muscle function.

Diabetic Myopathy 

Introduction

Diabetic myopathy refers to a spectrum of muscle disorders associated with diabetes mellitus. It encompasses chronic muscle weakness, muscle wasting, and, in rare cases, acute muscle infarction. These muscle complications may result from long-standing hyperglycemia and its metabolic and vascular consequences, and they can significantly impact mobility and quality of life in affected individuals.

Epidemiology

Diabetic myopathy is a relatively common but under-recognized complication of diabetes, particularly in patients with poor glycemic control or long-standing disease. It affects both type 1 and type 2 diabetes, although more frequently seen in type 2 due to its higher prevalence. Risk increases with the duration of diabetes, the presence of other complications (e.g., neuropathy, nephropathy), and a sedentary lifestyle. Diabetic amyotrophy, a painful proximal neuropathic myopathy, is more common in older men with type 2 diabetes.

Pathophysiology

The pathogenesis of diabetic myopathy is multifactorial. Chronic hyperglycemia leads to non-enzymatic glycation of proteins, oxidative stress, and inflammation, damaging muscle fibers. Microvascular dysfunction impairs muscle perfusion and oxygen delivery. Insulin resistance decreases muscle protein synthesis and promotes atrophy, especially in type 2 diabetes. Diabetic neuropathy may contribute to secondary denervation and disuse-related atrophy. In some cases, immune-mediated mechanisms or vascular occlusion can lead to muscle infarction.

Clinical manifestations 

Patients may present with proximal muscle weakness, fatigue, muscle cramps, and reduced exercise tolerance.  Muscle wasting becomes evident in advanced cases, particularly in the thighs and shoulders. Diabetic amyotrophy manifests with asymmetric, painful thigh weakness and weight loss. Rarely, patients may develop diabetic muscle infarction, presenting with sudden pain, swelling, and tenderness in a muscle group, often in the thigh or calf. Reflexes are typically preserved unless neuropathy is present.

Diagnosis

• Elevated HbA1c reflects poor long-term glycemic control
• Normal to mildly elevated CK (higher in acute infarction)
• EMG may show myopathic or neurogenic changes
• MRI is useful for detecting edema or infarction in muscles
• Muscle biopsy (if needed) may reveal muscle fiber atrophy, lipid accumulation, or necrosis in infarcted areas.
• Differential diagnoses include inflammatory myopathies, statin-induced myopathy, and neuropathic causes.

Treatment

• Optimizing glycemic control with insulin or oral hypoglycemics
• Physical therapy to maintain muscle strength and mobility
• Pain management in cases of amyotrophy or infarction
• Rest and supportive care for muscle infarction (surgical intervention is rarely needed)
• In cases of immune-mediated components, immunosuppressive therapy may be considered.
• Correction of vitamin D deficiency and management of comorbidities (e.g., neuropathy) are also important.

Prognosis

The prognosis of diabetic myopathy depends on the underlying type and severity. With good glycemic control and rehabilitation, many patients show improvement in muscle strength and function. However, in diabetic amyotrophy or muscle infarction, recovery may be slow, and residual weakness or atrophy can persist. Early recognition and intervention improve outcomes and reduce the risk of long-term disability.

Acromegaly-Related Myopathy

Introduction

Acromegaly-related myopathy is muscle dysfunction caused by excess growth hormone (GH) and insulin-like growth factor-1 (IGF-1), typically due to a pituitary adenoma. It is a frequent but often overlooked manifestation of acromegaly and can contribute to fatigue, weakness, and impaired physical performance. The condition may persist even after biochemical control of acromegaly, underscoring its clinical relevance.

Epidemiology

Myopathy affects up to 50–75% of individuals with acromegaly, although its severity varies. It may be one of the earliest symptoms and can precede diagnosis by years. Both men and women are affected, usually during middle age, when acromegaly is most commonly diagnosed. The degree of muscle involvement often correlates with the GH/IGF-1 excess duration.

Pathophysiology

The pathogenesis involves several mechanisms. Chronic exposure to elevated GH and IGF-1 leads to muscle fiber hypertrophy but paradoxically impairs muscle function, particularly type II (fast-twitch) fibers. This results in a shift toward type I (slow-twitch) fibers, reduced muscle strength, and increased fatigue. Neuromuscular transmission may also be affected, and fibrosis and fatty infiltration can occur in long-standing cases. Joint abnormalities and skeletal changes in acromegaly may further limit mobility and exacerbate symptoms.

Clinical manifestations 

Patients typically present with proximal muscle weakness, most commonly affecting the hips and shoulders. Fatigue, stiffness, and exercise intolerance are common. Symptoms often progress slowly and may go unrecognized or attributed to aging or joint disease. Unlike inflammatory myopathies, pain is less prominent, and reflexes are usually normal. Muscle bulk may appear preserved or even increased, despite functional weakness.

Diagnosis

• Serum IGF-1: Elevated
• GH suppression test (e.g., oral glucose tolerance test)
• CK level is usually normal or mildly elevated.
• EMG may show mild myopathic changes.
• Muscle biopsy (rarely required) may reveal fiber-type grouping, hypertrophy of type I fibers, and type II fiber atrophy.
• Differential diagnosis includes other endocrine myopathies, metabolic causes, and neuromuscular disorders.

Treatment

• Control of GH and IGF-1 levels through surgery
• Medical therapy (e.g., somatostatin analogs)
• Radiotherapy
• Physical therapy is essential to maintain strength, flexibility, and function.
• In patients with persistent symptoms despite hormonal control, rehabilitation, and supportive measures remain important.
• Analgesia or other treatments may be needed for concurrent joint or skeletal symptoms. 

Prognosis

With effective treatment of acromegaly, many patients experience a gradual improvement in muscle function. However, full recovery may be limited, especially in those with long-standing disease or structural muscle changes. Persistent myopathy can contribute to reduced quality of life even after biochemical remission, emphasizing the need for early diagnosis and a multidisciplinary management approach.

GH Deficiency–Related Myopathy

Introduction

Growth hormone (GH) deficiency-related myopathy is a muscle disorder arising from insufficient GH levels in childhood or adulthood. GH plays a critical role in maintaining muscle mass, strength, and metabolism through its anabolic effects and insulin-like growth factor-1 (IGF-1) stimulation. In adults, GH deficiency reduces physical capacity, muscle weakness, and diminished quality of life.

Epidemiology

GH deficiency can occur as part of congenital hypopituitarism, acquired pituitary disease, or isolated GH deficiency. Myopathic symptoms are more common in adults with long-standing deficiencies, and prevalence increases with the presence of multiple pituitary hormone deficiencies. The condition is under-recognized due to nonspecific symptoms and overlapping features with aging or other endocrine disorders.

Pathophysiology

GH and IGF-1 regulate muscle protein synthesis, mitochondrial function, and fat metabolism. GH deficiency leads to: Decreased lean muscle mass and increased fat deposition, Reduced mitochondrial oxidative capacity and ATP production, Impaired muscle regeneration and exercise tolerance, Muscle fiber atrophy, especially of type II (fast-twitch) fibers. Overall, there is a shift toward reduced muscle performance and endurance.

Clinical manifestations 

Patients typically report muscle weakness, fatigue, decreased exercise tolerance, and sometimes muscle cramps. The weakness is usually generalized or proximal, affecting activities like climbing stairs or lifting. Muscle atrophy may be present in chronic cases, and functional impairment can significantly impact daily living.

Diagnosis

• Low IGF-1 levels support the diagnosis.
• GH stimulation tests (e.g., insulin tolerance or GHRH-arginine) confirm deficiency.
• CK levels: Usually normal.
• EMG may show mild myopathic changes or be normal.
• Body composition analysis (e.g., DEXA) may show reduced lean mass.

Treatment

• GH replacement therapy improves muscle mass, strength, and quality of life in adults with confirmed deficiency.
• Physical exercise programs enhance the effects of GH therapy.
• Nutritional support and managing other hormone deficiencies (e.g., thyroid, cortisol) are important for optimal recovery.
• Monitoring for side effects of GH therapy (e.g., edema, arthralgia) is essential.

Prognosis

Most patients experience improvements in muscle strength, exercise capacity, and body composition with GH replacement and rehabilitation. The response may vary depending on age, duration of deficiency, and comorbidities. Early diagnosis and treatment improve outcomes and help restore functional independence.