Endocrine Abnormalities Affecting the Musculoskeletal System

Disease/Disorder

Definition

Endocrine abnormalities cause a wide variety of end-organ changes secondary to imbalances of normal hormonal homeostasis. Endocrine disease affecting the musculoskeletal system that will be covered in this section includes hypogonadism, hypopituitarism/growth hormone insufficiency, hypothyroidism/hyperthyroidism, and hyperadrenalism/hypoadrenalism.

Additional endocrine related topics are covered in other sections of PM&R KnowledgeNOW and include Diabetic Neuropathy, Osteoporosis in Rehabilitation, Geriatric Frailty, Spine and Musculoskeletal Disorders and Complications in Pregnancy and Female Athlete Triad.

Etiology

Abnormalities of each hormone can either result in overproduction or underproduction of the hormone. Etiology of either overproduction or underproduction is typically different.

Most common causes and presentations are presented below.

Growth hormone (GH)

• Overproduction: Acromegaly/Gigantism
  • Pituitary adenoma
  • Occurs after epiphyseal plate closure
• Adult Growth Hormone Deficiency (AGHD)^1,2
  • Under-secretion: intrinsic pituitary dysfunction (commonly tumor, resection, radiation, panhypopituitarism; less commonly traumatic brain injury, cerebrovascular accidents, hypophysitis)
  • Secondary to acromegaly treatment
  • Chronically increased levels of glucocorticoids (Cushing’s disease, exogenous steroid use)³

Androgen deficiency syndrome

• Low circulating testosterone
  • Congenital or acquired
  • Primary (disorder of the testes)
  • Secondary (disorders of the hypothalamus and pituitary)

Hyperthyroidism

• Autoimmune (Grave’s Disease)
• Toxic adenomas
• Subacute thyroiditis
• Exogenous thyroid replacement

Hypothyroidism

• Autoimmune
  • Hashimoto’s thyroiditis
• Iodine deficiency (leading cause in the world)⁴
• Thyroid removal
• In athletes, overtraining has been associated with a hypothyroid state, likely a transient one, that is potentially related to increased conversion from T4 to reverse T3 (rT3), a less biologically active form.⁵

Adrenal cortex

• Hypercortisolism or Cushing Syndrome (CS): increased glucocorticoids⁵
  • Excessive exogenous glucocorticoids (e.g., ingesting oral prednisone)
  • 70-80% of endogenous CS from increased hypothalamic-pituitary ACTH secretion
• Hyperaldosteronism: increased mineralocorticoids
  • Primary due to neoplasm or hyperplasia
  • Secondary due to increased activation of the renin-angiotensin system, such as in pregnancy⁵
• Adrenal insufficiency (AI) or Addison’s Disease
  • Extensive exogenous glucocorticoids causes a negative feedback loop⁵
  • >90% autoimmune adrenalitis, tuberculosis, AIDS, or malignancies
• Anabolic-androgenic steroids (AAS):
  • Exogenous androgens
  • Often clinically useful for males with low normative testosterone (“low T”) or post-menopausal females
  • Commonly used for “doping” in sports and/or exercise to act as a performance enhancing substance or to aid in healing and recovery from injuries⁶ 

Epidemiology including risk factors and primary prevention

Acromegaly

• Majority of cases (~95%) are due to excessive secretion of GH by a pituitary adenoma. Acromegaly can also occur as part of the familial syndromes (McCune-Albright syndrome or MEN-I). Rarely, acromegaly can be due to excessive ectopic GHRH or GH secretion from extra-pituitary sources.⁶
• Rare (incidence 5.9 per 1,000,000 person years)⁷
• More than 75% of patients experience joint pain (hip and spine most common)
• Acromegalic arthropathy secondary to increased growth hormone and IGF-1 affect cartilage and bone remodeling, leading to a generalized arthropathy process, which differs from primary osteoarthritis
• Spinal changes similar to DISH (diffuse idiopathic skeletal hyperostosis)
• Muscular pain and decreased endurance secondary to muscle structural changes
• Increased fracture risk despite “normal” bone mineral density (3-8x increased vertebral fracture risk)⁷ secondary to abnormal calcium homeostasis
• Peripheral neuropathy in 19-64% ⁷ including very frequent carpal tunnel syndrome

Adult Growth Hormone Deficiency (AGHD)

Adult growth hormone deficiency reduced muscle mass and strength, decreases bone density, and increases body fat. Muscle pain and decreased recovery or adaptation to training are common.

• Rare Disease⁸
  • The true prevalence of adult-onset GH deficiency is difficult to estimate with certainty, but a reasonable estimate may be obtained from prevalence data for pituitary macroadenoma, which approximates to 1-2:10,000 population.
  • Addition of cases of childhood-onset GHD persisting into adult life gives an overall prevalence of between 2 and 3 per 10,000 population.
• Associated with pituitary dysfunction after traumatic brain injury (TBI)^2,9
• Risk increases with age, malnutrition states, chronic inflammatory diseases, and renal and liver disease.9,10
• 2x increase in cardiovascular-related mortality (reduced left ventricular wall mass, cardiac output, and atherogenic lipid profile).⁸
• 3x increase in cerebrovascular disease.¹⁰

Androgen deficiency syndrome

• Congenital/genetic causes are rare (Klinefelter syndrome is the most common at 9-22 out of 10,000 births, myotonic dystrophy, Kallmann syndrome, Prader-Willi)¹¹
• Most acquired causes are also rare (bilateral testicular trauma, testicular torsion, orchidectomy, infectious orchitis), with TBI being the most common
• Decline in testosterone levels is often age-related and potentially linked to uncontrolled metabolic disorders,
• Low serum total testosterone levels in 10% of 50-59-year-old men, 20% in 60-69-year-old men, and 70% in 70-80-year-old men
• Symptomatic androgen deficiency in men between 40 and 79 years of age is only 2.1%, but similarly increases with age (up to 5.1% at 70-79-years-old)
• Can predict future diabetes mellitus type 2, metabolic syndrome, cardiovascular events, mobility limitations, and mortality.
• Potential causal association with frailty in older men¹²
• Risk factors: stress, poor sleep hygiene, history of TBI, Bisphenol A (BPA) plastic exposure, chronic opioid use¹³
• After moderate to severe TBI, chronic pituitary dysfunction leading to secondary hypogonadism occurs at rates around 30%. Minor TBI more often causes transient hypogonadism.¹¹

Hypothyroidism

• Risk factors: Iodine deficiency, overtraining, genetics autoimmune disorder), neck radiation⁴
• Overall US prevalence: 0.3-3.7%⁴
• Proximal muscle myopathy in 25-79% of patients; Dupuytren contracture in 21.7%; carpal tunnel in 30.4%
• Increased risk of hip and vertebral fractures (hazard ratios 1.36, 1.51 respectively), with lower TSH associated with higher fracture risk¹⁴
• Increased risk of sarcopenia ¹⁵

Hyperthyroidism

• Risk factors: genetics (autoimmune disorder), changes in iodine intake
• Overall US prevalence: 0.7%⁴
• Myopathy present in up to 67%, increased risk of sarcopenia¹⁵
• Radiographically evident bone change in 3-50%, with increased risk of insufficiency fractures due to low BMD¹⁶
• Thyroid acropachy (soft tissue swelling with digital clubbing, periosteal new bone formation in hand and feet) is seen in only 0.5% of patients with Graves disease¹⁶

Adrenal cortex

• US Cushing Syndrome (CS) incidence 49 people per million¹⁷
• No U.S. population-based studies reporting the prevalence of aldosteronoma, hypercortisolism, AI, or adrenal mass.¹⁸
• Risk factors: stress, poor sleep hygiene, chronic disease, excessive glucocorticoids
• Increased risk of osteopenia/osteoporosis leading to insufficiency fractures and osteonecrosis¹⁶

Patho-anatomy/physiology

Dysregulation of hormones affects the musculoskeletal system in various ways.

Growth Hormone (GH) deficiency can lead to decreased muscle mass and strength, increased abdominal fat, and poor bone quality and density, as GH and insulin-like growth factor (IGF)-1 directly stimulate osteoblasts and modulate osteoclast turnover.^19,20There is an association between fibromyalgia and GH deficiency, attributed to alpha-delta sleep anomalies.^21,22

In acromegaly, chondrocyte hypertrophy and osteophytosis lead to degenerative joint disease most commonly affecting the hip and spine.⁷ Schwann cell hypertrophy can lead to peripheral neuropathy, and flexor tendon hyperplasia may lead to Carpal Tunnel Syndrome (CTS).^7,20

Low testosterone in hypogonadism is associated with lower lean body tissue and muscle mass and increased abdominal fat, as well as frailty.²³ Low serum testosterone has also been inconsistently linked to osteoarthritis prevalence and outcomes, as well as number of pain sites in chronic musculoskeletal pain.²⁴

Thyroid hormones regulate gene transcription in skeletal muscle. Specific examples in coding include Type I myosin heavy chain (MHC), the sarcoplasmic reticulum (SR), Ca21, ATPase pump, and actin. In hyperthyroidism, smoothelin-like protein 1 inhibits myosin phosphatase and may act to produce myopathy and muscle weakness.^25,26,28-30 Thyroid hormones also regulate chondrocytes, osteoblasts, and osteoclasts, affecting bone remodeling in older individuals and skeletal maturation and growth in children; pathologic fractures occur due to over-mineralization in hypothyroidism and osteoporosis in hyperthyroidism.¹⁴

Based mostly on promising basic and translational research with mixed observations among human subjects, hypothyroid and euthyroid individuals with antithyroid antibodies have theoretically higher associations with certain musculoskeletal diseases such as osteoarthritis (OA) and inflammatory arthritis.^27-30 It is theorized to be related to a thyroid stimulating hormone (TSH)-dependent increase in hyaluronic acid and proteoglycan synthesis. Studies have also found a strong relationship between autoimmune thyroid disease and fibromyalgia, although the underlying pathophysiology is unclear. Ongoing symptoms after hormone replacement may have to do with hormone resistance.³¹ Hypothyroidism has also been highly associated with neuropathies, most commonly CT, with recent research suggesting peripheral nerve hyperexcitability as a potential mechanism.³²  Hypothyroid myopathy is theorized to be cause by impaired glycogen breakdown leading to muscle fiber atrophy and low muscle carnitine.¹⁴

CS is associated with various catabolic effects. Selective atrophy of fast-twitch (type 2) myofibers has been implicated in proximal myopathy.³⁴ Loss of collagen can cause fragile skin and poor wound healing. Decreased bone resorption can cause osteoporosis with secondary back pain and susceptibility to fractures, more commonly affecting trabecular bone of the axial skeleton. Hyperaldosteronism can cause weakness and neuropathy from hypokalemia due to renal potassium wasting.³⁵

In AI, negative feedback from exogenous glucocorticoids inhibits adrenocorticotropic hormone (ACTH) output, resulting in hyperkalemia, hyponatremia, volume depletion, and hypotension.³⁶

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Musculoskeletal manifestations may occur at various stages of each endocrine disease process. Due to the diversity of the musculoskeletal complications, it is beyond the scope of this discussion to include the disease progression of each disorder.

Specific secondary or associated conditions and complications

The endocrine disorders discussed in this section have various overlapping secondary manifestations including myopathy/muscle weakness, neuropathy/paresthesia, CTS, fatigue/poor endurance, osteoporosis, avascular necrosis, fibromyalgia, heat illness, and cardiovascular manifestations.^{5,7,20,35,37,38}

Essentials of Assessment

History

Consider endocrine dysfunction in patients that are refractory to conventional treatments, patients treated with oral or injectable steroids, and patient populations susceptible to dysfunctions of homeostasis. Traumatic brain injury (TBI) or stroke, pituitary injury, and environmental stress can also negatively affect hormonal balance. Review of systems should include

• Constitutional: fatigue, weight changes, cold/heat intolerance, decreased athletic performance, insomnia
• Cardiology/vascular: palpitations, leg swelling
• Psychiatric: depression, anxiety
• Genitourinary: amenorrhea, decreased libido
• Musculoskeletal: myalgias/arthralgias, weakness
• Neurological: paresthesias, neuropathy
• Integumentary: rashes/hyperpigmentation, loss of body hair

Physical examination

AGHD

• Increased abdominal fat, reduced muscle mass/strength, thin/dry skin.
• On history, can be associated with lethargy, fatigue, disinterest, weight gain, low mood, and declining libido.^19,39 When associated with concomitant reductions in ACTH, anorexia and weight loss can also manifest clinically.

Acromegaly⁴⁰

• CNS: Palpable peripheral nerves, CTS, symmetric sensorimotor polyneuropathy on electrodiagnostics
• CVS/MSK: cardiomegaly, enlarged distal structures (hands, feet), arthritis with hypermobility, sleep apnea
• Headaches, bitemporal hemianopsia, and cranial nerve palsies can result from somatotroph adenoma/macroadenomas

Androgen deficiency⁴¹

• Decreased muscle mass, increased body fat, gynecomastia, body hair loss, loss of height

Testosterone replacement

• Most commonly presents with reversal of prior signs of low testosterone (e.g., decreased vigor, decreased muscle bulk, systemic fatigue)
• Acne, oily skin, male pattern baldness, increased muscle mass, leg edema/worsening of heart failure.
• Note: “Roid rage,” while commonly described, is not part of the typical presentation, and is more consistent with high-dose abuse rather than therapeutic usage

Hypothyroidism

• Fluid retention, mucinous non-pitting edema, bradycardia, slow reflexes, constipation, and cold intolerance

Hyperthyroidism

• Tachycardia, hypertension, muscle weakness⁵

Cushing Syndrome

• Central obesity, “buffalo hump,” “moon facies,” hirsutism, skin striae

Adrenal insufficiency

• Clinical manifestations are the same in primary and secondary disease: Weakness, fatigue, weight loss, vitiligo, hypoglycemia, hypotension. Skin hyperpigmentation occurs in primary adrenal insufficiency.⁴²

Laboratory studies

Growth hormone is secreted in a pulsatile fashion, and levels are highest within 1 hour of onset of sleep and are therefore difficult to measure. IGF-1 acts as an indirect measurement and can be used to evaluate possible AGHD or acromegaly, however stimulation tests with macimorelin or GHRH may be used as confirmatory tests instead of insulin tolerance test nowadays^8,43

Androgen deficiency can be detected by early morning fasting total and free testosterone levels (normal 250-400ug/ml).

Thyroid function may be measured with the following⁴

• TSH, T4/Free T4
• Anti-thyroid peroxidase autoantibody
• Anti-thyroglobulin
• Serum CK is often elevated (up to 10 times normal)³⁵

CS can be measured with 24-hour urine free cortisol, ACTH levels, and urine 17-hydroxycorticoid.⁴⁴ Aldosterone and renin are measured for hyperaldosteronism.

Imaging

• Brain MRI or CT to evaluate hypothalamus or pituitary
• Neck MRI or ultrasound to evaluate the thyroid
• Abdomen/pelvis MRI, CT, or ultrasound to evaluate adrenals, pancreas, or gonads

Supplemental assessment tools

Electrodiagnostic studies can be useful for diagnosis of entrapment neuropathy such as carpal tunnel syndrome in acromegaly or hypothyroidism.

EMG can also be used to assess for certain myopathies. However, depending on the type of myopathy, EMG testing may appear normal. For example a typical steroid myopathy affects type IIb muscle fibers which are not able to be assessed with EMG. Myalgia due to effects of specific endocrine disorders listed above without myopathy may also appear normal on EMG sampling.

Electrocardiogram (EKG) can be used to detect cardiac abnormalities such as peaked P waves with hyperkalemia in hyperaldosteronism.

Early predictions of outcomes

The course of the musculoskeletal symptoms and prognosis is almost always linked to treatment of the underlying endocrine disorder. Early diagnosis and treatment of underlying endocrine abnormalities yields the best outcomes for treatment of the associated musculoskeletal conditions.

Environmental

Psychosocial and physical stressors impact endocrine homeostasis, therefore proper sleep hygiene, physical activity and exercise should be emphasized. Avoiding various endocrine-disrupting chemicals, especially during development, can prevent alteration of endocrine homeostasis. These include bisphenol A (BPA) plastics which can reduce testosterone levels, polybrominated diphenyl ethers associated with hypothyroidism.⁴⁵

Social role and social support system

Family and social support to help address and cope with underlying stressors can improve symptoms and function since psychosocial stress directly impacts homeostasis. Therefore, initial management of endocrine abnormalities should include addressing underlying stressors, including sleep disturbances, toxic relationships, and overwork syndromes.

Professional issues

Hormone supplementation costs should be considered. This can vary significantly due to differences in insurance coverage. Also, Food and Drug Administration (FDA) approval of supplementation varies. There is a potential for abuse of GH, exogenous thyroxine, and anabolic steroids in athletic and general populations for performance enhancement. Utilization of exogenous hormones is restricted in athletic competition.⁴⁶ Consideration of need for therapeutic use exemption (TUE) forms should be discussed with the patient. The potential side-effects of excessive treatment with oral and injectable glucocorticoids should be discussed.

Rehabilitation Management and Treatments

Available or current treatment guidelines

The most critical aspect of treatment for musculoskeletal manifestations of endocrine abnormalities is addressing the underlying cause.

Acromegaly/Gigantism

• Removal of the tumor is critical.⁷ These are usually an anterior pituitary tumor, but occasionally may be a growth hormone producing carcinoid, lung cancer, or pancreatic islet cell tumors.
• Face and skull enlargements do not change with treatment.
• Carpal tunnel syndrome and arthralgias may improve with treatment.
• If GH levels remain high after removal, medications are used.
  • Somatostatin analogs
    • Short-acting
      • octreotide acetate
    • Long acting
      • octreotide LAR
      • lanreotide acetate
      • pasireotide diaspartate
  • Dopamine agonists – often used in conjunction with somatostatin analogs
    • cabergoline
  • GH receptor antagonists
    • Pegvisomant
• Radiation therapy is third line, if there is persistent tumor growth or disease is refractory to maximum medical dosage.

Adult Growth Hormone Deficiency

• Growth hormone (GH) injections: have been shown to reverse many of the symptoms of AGHD including increasing lean muscle, decreasing abdominal fat deposits, decreasing metabolic syndrome, and improving bone density.^47,48
  • Short-acting growth hormone
    • Daily
    • Compliance is an issue
  • Long acting
    • Weekly to monthly
    • May decrease visceral adipose more than daily injections
  • IGF levels are monitored to help determine efficacy
  • Men are more sensitive to GH replacement than women
  • Optimal duration of GH replacement therapy is unclear
  • GH replacement associated with increase in bone mass as noted in the lumbar spine and femoral neck.^49-52
    • Men have a more significant increase in bone density than women
      • May be related to bone architecture or oral estrogen leading to GH resistance
    • Both men and women have decreased fracture risk with GH replacement
  • Risks of GH replacement: new onset diabetes, headache, arthralgias, and nasopharyngitis

Androgen deficiency

• Androgen deficiency should be treated with testosterone replacement in men with symptoms such as low libido, erectile dysfunction, mood and sleep changes, decreased lean muscle and increased adipose, and low bone mass density, as well as consistently low levels of serum total testosterone or free testosterone.⁵³
• Primary versus secondary androgen deficiency should be determined by luteinizing and follicle-stimulating hormone levels.
  • Primary-testicular levels
  • Secondary-hypothalamic/pituitary axis
• Causes of secondary androgen deficiency should be determined and corrected
• Formulations
  • Topical
    • Gel
    • Patch
    • Buccal
  • Injectables
    • short-acting- weekly or every other week
    • longer-acting- every 10 weeks
  • Implants
    • Pellets- 3-6 months
• After initiating therapy, monitor with serum testosterone and hematocrit levels at three to six months, at 12 months, and then annually
• If androgen deficiency was associated with osteoporosis, measure bone mass density one to two years after starting testosterone
• Testosterone replacement should be avoided in those men who plan to have children in the near future, those with a history of breast or prostate cancer or prostate nodule, elevated prostate-specific antigen (PSA), heart failure, myocardial infarction, or stroke.

Risks of testosterone replacement

• reduced fertility
• acne
• mood fluctuations including anger, skin reactions with topicals

Hypothyroidism

• Thyroid replacement with levothyroxine is the mainstay of treatment.⁵⁴
• Efficacy and dose changes are monitored with frequent serum thyroid stimulating hormone until levels normalize and then annually as well as symptom improvement such as a decrease in arthralgias, muscle cramps, myalgia, weakness, and fatigue.
• Patients who are refractory to treatment should have their medications evaluated since many can interfere with levothyroxine absorption, such as calcium, proton pump inhibitors, and selective serotonin reuptake inhibitors. A diet high in walnuts and grapefruit juice may also interfere with absorption.
• Clinical and subclinical hypothyroidism are associated with adhesive capsulitis.⁵⁵
• Risk of thyroid supplementation: cardiac arrhythmias and osteoporosis.

Hyperthyroidism (Thyrotoxicosis)

• The primary musculoskeletal manifestation of hyperthyroidism is decreased bone mass density, but also includes adhesive capsulitis, myalgias, and proximal muscle weakness.^16,56
• Treatment is based on the etiology of hyperthyroidism.⁵⁶
  • Beta-blockers for those with tachycardia
  • Radioactive iodine (RAI)
  • Antithyroid drugs (ATD)
    • methimazole (MMI)
    • propylthiouracil (PTU
    • carbimazole
  • Surgical: thyroidectomy
• Musculoskeletal risks of treatment: myopathy and symptoms associated with resultant hypothyroidism.⁵⁷ However, effective therapy improves body fat percentage and may improve muscle mass recovery in young patients.⁵⁸

Cushing Syndrome (myopathy, muscle weakness, osteoporosis)

• Preservation or restoration of muscle function is critical; muscle damage is influenced by glucocorticoid type and administration method.³⁴
• Endogenous
  • Surgical resection: The primary treatment for endogenous CS is surgical resection of the tumor. Most commonly an ACTH-secreting anterior pituitary tumor (the most common cause of Cushing disease), but increasingly found to be an adrenal tumor.⁵⁹
  • Prognosis is poor in cases with ACTH-producing lung carcinomas. If the cause is due to adrenal hyperplasia, bilateral adrenalectomy is the treatment of choice.
  • Medications:
    • mitotane-first line
    • ketoconazole
    • metyrapone
    • cabergoline
    • pasireotide
    • mifepristone
• Exogenous
  • Steroids or other underlying causes should be addressed to treat CS.
  • Monitor IGF levels- low levels have been associated with muscle dysfunction⁶⁰

Adrenal Insufficiency

• Muscular pain associated with adrenal insufficiency usually resolves with treatment.⁶¹
• Glucocorticoids⁶²
  • Hydrocortisone- taken multiple times per day
  • Modified-release hydrocortisone-once daily
  • Cortisone acetate
• Mineralocorticoids-combined with glucocorticoids for primary adrenal insufficiency
• Risks of treatment: osteoporosis

At different disease stages

• New onset/acute
  • Identify underlying endocrine dysfunction
  • Reduce or remove environmental causes (excessive exercise, stress)
  • Remove hormone secreting tumors with surgery and monitor response
  • Treat underlying issues with or without hormone replacement, ideally before or simultaneously with symptom management
  • Multidisciplinary approach with primary physician, endocrinologists, rheumatologists, mental health, and/or physical and occupational therapists.
  • Coordinate with oncology if cancer is suspected.
• Subacute
  • Monitor homeostasis, continue to adjust as needed. Patient should be monitored for over replacement
  • Symptom management ideally after hormonal homeostasis is attained
  • Multidisciplinary approach could add nutritionists and athletic trainers
• Chronic/stable
  • Maintain homeostasis and monitor for symptoms of over treatment
  • Monitor changes in body composition using anthropometric measurements and bone mineral density using DEXA.¹⁶
  • Continue multidisciplinary coordination
  • Adjunct complementary medicine as appropriate

Patient & family education

Education is important regarding prognosis, to understand management of symptoms such as pain, weakness and fatigue, and understand treatment strategies for underlying conditions^. Understanding of the relationship between the neuromusculoskeletal and endocrine system is important for patient compliance with treatments. Patients should also be educated regarding potential controversies. Psychosocial issues and support should be addressed to improve quality of life, regardless of endocrine etiology or treatment.⁶³

Emerging/unique interventions

Sophisticated techniques have been developed to diagnose endocrine disorders.⁶⁴ Treatment regimens continue to evolve as more studies are being conducted that evaluate long term outcomes. Furthermore, changes in medication formulation continue to improve, with dual-release oral medications that can better mimic normal physiological hormonal rhythm.^48,54The Brief Pain Inventory, Visual Analogue Scale (VAS), Functional Independence Measure (FIM) scores, the Oswestry Disability Index, or other similar outcomes scales can be used for assessment of pain and function.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

There should be a high index of suspicion to evaluate for possible underlying endocrine abnormalities in patients with musculoskeletal complaints who are refractory to traditional treatment. In addition, consider endocrine dysfunction in patient populations at higher risk (young female athletes, older males and females, TBI, stroke, SCI, obesity, and/or pre-existing metabolic syndrome).

Cutting Edge/Emerging and Unique Concepts and Practice

• Growth hormone may be beneficial in Cushing syndrome to help with muscle strength recovery.⁶⁵
• IGF infusions, early and prophylactic, may reduce glucocorticoid-induced myopathy.⁶⁰
• Persistent skeletal muscle weakness in hypothyroidism despite adequate thyroid replacement may be associated with loss of thyroid hormone receptor 𝝰, the predominant form found in skeletal muscle.⁶⁶
• Vitamin E supplementation may protect mitochondria from oxidative damage in hyperthyroidism.⁶⁷
• In adrenal insufficiency, rituximab, cosyntropin, and autologous stem cells have been shown to increase residual adrenocortical function.⁶⁸ Other treatment innovations include modified-release and subcutaneous steroids.⁶⁹
• Some studies have shown that treatment of subclinical hyperthyroidism may increase physical functioning, muscle mass, and strength in women.⁷⁰
• Animal studies have shown that regenerative medicine may have a future role in endocrine disorders.⁶⁹
• Women with hypopituitarism with severe androgen deficiency showed a positive effect on BMD and body composition.⁷¹ However, for postmenopausal women, a large clinical review demonstrated that only women with sexual arousal disorder should receive testosterone replacement. There was no significant improvement with anthropometric measures and bone density in postmenopausal women with testosterone therapy.
• Leptin, an adipose tissue hormone, has been shown as a regulator of chondrocyte metabolism and may play an important role in osteoarthritis and future therapeutic directions.⁷²
• Yoga has been shown to improve cholesterol, serum TSH, and reduce the amount of thyroxine medication required in women.⁷³
• Myokines are being described as cytokines mediating metabolism of lipids/glucose, bone formation, endothelial cell function, and more, and may become useful exercise biomarkers or therapeutic targets in patients with endocrine disease.⁷⁴

Gaps in the Evidence-Based Knowledge

There are many controversies regarding treatment of endocrine disorders and their musculoskeletal manifestations. Challenges still exist providing treatment that closely mimics the natural hormonal cycle.^68,70 Different responses to treatment by age and gender continue to be studied to provide optimal care. “Adrenal fatigue” in itself is a controversial term referring to non-specific symptoms from low-grade adrenal deficiency after extended hyperfunction due to exposure to mental, emotional, or physical stressors.^22,75 However, currently there is no known endocrinology society that recognizes adrenal fatigue as a medical diagnosis and studies have conflicting results with limited validity.⁷⁶

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Original Version of the Topic

Gary P. Chimes, MD, PhD, Shounuck I. Patel, DO, Libi Galmer, DO, Joslyn John, MD. Endocrine abnormalities affecting the musculoskeletal system. 9/20/2013

Previous Revision(s) of the Topic

Richard G. Chang, MD, Kameron Bazmi, MD, Andrew Beaufort, MD. Endocrine abnormalities affecting the musculoskeletal system. 2/14/2018

Deborah Pacik, MD, MPH, Richard G. Chang, MD, MPH. Endocrine Abnormalities Affecting the Musculoskeletal System. 4/27/2022

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Aleksandra Kostic, BSE
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Ziva Petrin, MD
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