Endocrine abnormalities have varied presentations secondary to imbalances of normal hormonal homeostasis. Abnormalities covered in this section that are associated with the musculoskeletal system include hypogonadism, hypopituitarism/growth hormone insufficiency, hypothyroidism/hyperthyroidism, and hyperadrenalism/hypoadrenalism. Other endocrine topics covered in other sections of “Knowledge Now” include diabetes, metabolic bone disease, sarcopenia, pregnancy, female athlete triad, and menopausal changes in older women.
Growth hormone (GH)
- Overproduction: Acromegaly/Gigantism
- Pituitary adenoma
- Occurs after epiphyseal plate closure
- Under-secretion: Adult Growth Hormone Deficiency (AGHD)
- Intrinsic pituitary dysfunction (tumor, resection, radiation, panhypopituitarism)
- may be secondary to treatment of acromegaly
- Prolonged stress
- Peripheral insensitivity to GH1
Androgen deficiency syndrome
- Low circulating testosterone
- Congenital or acquired
- Primary (disorder of the testes)
- Secondary (disorders of the hypothalamus and pituitary)
- Autoimmune (Grave’s Disease)
- Toxic adenomas
- Subacute thyroiditis
- Exogenous thyroid replacement
- Hashimoto’s thyroiditis
- Iodine deficiency (leading cause in the world)2
- 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.3,4
- 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
Adult Growth Hormone Deficiency (AGHD)
- Rare Disease2,7
- 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 1:10,000 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.7
- Associated with pituitary dysfunction after traumatic brain injury (TBI)8
- 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 ejection fraction, stroke volume, and atherogenic lipid profile).9–11
- 3x increase in cerebrovascular-related mortality.1,9–11
- 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.12
- Rare (incidence 11 per 1,000,000 person years)13
- Left untreated, it is associated with near 100% prevalence of joint problems.1,14
- With better detection and treatment, 50%
- Decline in testosterone levels, often age-related, but also seen in response to stress state15
- However, a study of 325 males, published in a 2012, found that serum concentrations of testosterone, dihydrotestosterone (DHT), estradiol (E2) did not differ significantly with increased age among men over 40 years of age who self-report very good or excellent health.16
- Low normative total testosterone levels in 20% and low free testosterone in 35% of 60-69-year-old men.
- The estimated prevalence of symptomatic androgen deficiency in men 30 and 79 years of age is 5.6% and increases substantially with advanced age.15
- Total testosterone decline of 0.8% per year of life, with free and bioavailable testosterone declines at 2% per year of life.17
- Can predict future diabetes mellitus type 2, metabolic syndrome, cardiovascular events, mobility limitations, and mortality.
- Risk factors: stress, poor sleep hygiene, history of TBI, Bisphenol A (BPA) plastic exposure
- Studies have demonstrated a clear increase in risk for developing hypopituitarism and chronic pituitary related morbidity following blast related TBI.18–21
- Risk factors: Iodine deficiency, overtraining, genetics (autoimmune disorder)4
- Overall US prevalence: 4.6%22
- Risk factors: genetics (autoimmune disorder), changes in iodine intake4
- Overall US prevalence: 1.3%22
- CS incidence 10-15 people per million23
- No U.S. population-based studies reporting the prevalence of aldosteronoma, hypercortisolism, AI, or adrenal mass.22
- Risk factors: stress, poor sleep hygiene, chronic disease, excessive glucocorticoids
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.1,24 There is an association between fibromyalgia and GH deficiency, attributed to alpha-delta sleep anomalies.21,25,26 In acromegaly, early musculoskeletal complaints include enlarged cartilage and joint capsules with hypermobility and instability.11 Schwann cell hypertrophy can lead to peripheral neuropathy, and flexor tendon hyperplasia may lead to Carpal Tunnel Syndrome (CTS).1
Low testosterone in hypogonadism is associated with lower lean body tissue and muscle mass and increased abdominal fat, as seen in spinal cord injury patients when compared to able-bodied controls. It is also associated with increased musculoskeletal pain, as well as decreased mobility, endurance, tissue healing, and bone density.27
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. Hyperthyroidism may increase calcium uptake by the sarcoplasmic reticulum. Within physiologic norms, it has been shown to increase the shortening velocity of skeletal muscle, which may be related to greater efficiency of exercising muscles.28–30
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.31–36 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.37 Hypothyroidism has also been highly associated with neuropathies, most commonly CT. However, the effects of thyroid hormones on peripheral nerves remains unclear.38
CS is associated with various catabolic effects. Selective atrophy of fast-twitch (type 2) myofibers has been implicated in proximal myopathy. 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. Hyperaldosteronism can cause weakness and neuropathy from hypokalemia due to renal potassium wasting.
In AI, negative feedback from exogenous glucocorticoids inhibits adrenocorticotropic hormone (ACTH) output, resulting in hyperkalemia, hyponatremia, volume depletion, and hypotension.39
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.1,4,17,23,24,38–47
Essentials of Assessment
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
- 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.48 When associated with concomitant reductions in ACTH, anorexia and weight loss can also manifest clinically.
- 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
- Decreased muscle mass, increased body fat, gynecomastia, body hair loss, loss of height
- 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
- Fluid retention, mucinous non-pitting edema, bradycardia, slow reflexes, constipation, and cold intolerance
- Tachycardia, hypertension, muscle weakness4
- Central obesity, “buffalo hump,” “moon facies,” hirsutism, skin striae
- Clinical manifestations are the same in primary and secondary disease: Weakness, fatigue, weight loss, hyperpigmentation of the skin and mucosa, vitiligo.43,50
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.
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 following:
- TSH, T4/Free T4
- Anti-thyroid peroxidase autoantibody
CS can be measured with 24-hour urine free cortisol, ACTH levels, and urine 17-hydroxycorticoid. Aldosterone and renin are measured for hyperaldosteronism.
- 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 in endocrine disease states. For example, both severe steroid myopathy and polymyositis have normal nerve conduction studies and low-amplitude short-duration motor unit action potentials. However, the absence of spontaneous activity can be used to differentiate it from polymyositis. Electrodiagnostics can also be helpful in diagnosing conditions such as carpal tunnel syndrome in acromegaly or hypothyroidism.
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.
Psychosocial and physical stressors impact endocrine homeostasis, therefore proper sleep hygiene, physical activity and exercise should be emphasized. Avoiding Bisphenol A (BPA) plastics can help to improve testosterone levels, as elevated serum BPA levels are associated with decreased free testosterone, androstenedione and increased sex hormone-binding globulin levels.51
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.
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.52 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.
- Removal of the tumor is critical.53 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
- octreotide acetate
- octreotide LAR
- lanreotide acetate
- pasireotide diaspartate
- Dopamine agonists – often used in conjunction with somatostatin analogs
- GH receptor antagonists
- Somatostatin analogs
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, and decreasing metabolic syndrome, and low bone mass.54–56
- Short-acting growth hormone
- Compliance is an issue
- 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
- GH replacement for longer than 12 months is associated with an increase in bone mass as noted in the lumbar spine and femoral neck.56
- 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
- Men have a more significant increase in bone density than women
- Risks of GH: new onset diabetes, headache, arthralgias, and nasopharyngitis
- Short-acting growth hormone
- 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.57
- 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
- short-acting- weekly or every other week
- longer-acting- every 10 weeks
- 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
- mood fluctuations including anger, skin reactions with topicals
- Thyroid replacement with levothyroxine is the mainstay of treatment.58
- 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.
- Risk of thyroid supplementation: cardiac arrhythmias and osteoporosis.
- The primary musculoskeletal manifestation of hyperthyroidism is decreased bone mass density, but also includes adhesive capsulitis and myalgias.59,60
- Treatment is based on the etiology of hyperthyroidism.61
- Beta-blockers for those with tachycardia
- Radioactive iodine (RAI)
- Antithyroid drugs (ATD)
- methimazole (MMI)
- propylthiouracil (PTU
- Surgical: thyroidectomy
- Musculoskeletal risks of treatment: myopathy and symptoms associated with resultant hypothyroidism.61,62
Cushing Syndrome (myopathy, muscle weakness, osteoporosis)
- Preservation or restoration of muscle function is critical.63
- 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.53
- 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.
- mitotane-first line
- Steroids or other underlying causes should be addressed to treat CS.
- Monitor IGF levels- low levels have been associated with muscle dysfunction64
- Muscular pain associated with adrenal insufficiency usually resolves with treatment.65
- 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.
- 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
- Maintain homeostasis and monitor for symptoms of over treatment
- Monitor changes in body composition using anthropometric measurements and bone mineral density using DEXA.66
- 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.65 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.67
Sophisticated techniques have been developed to diagnose endocrine disorders.68 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.61,69 The 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.63
- IGF infusions, early and prophylactic, may reduce glucocorticoid-induced myopathy.64
- 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.70
- Vitamin E supplementation may protect mitochondria from oxidative damage in hyperthyroidism.71
- In adrenal insufficiency, rituximab, cosyntropin, and autologous stem cells have been shown to increase residual adrenocortical function.65 Other treatment innovations include modified-release and subcutaneous steroids.72
- Some studies have shown that treatment of subclinical hyperthyroidism may increase physical functioning, muscle mass, and strength in women.61
- Animal studies have shown that regenerative medicine may have a future role in endocrine disorders.72
- Women with hypopituitarism with severe androgen deficiency showed a positive effect on BMD and body composition.73 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.74
- Yoga has been shown to improve cholesterol, serum TSH, and reduce the amount of thyroxine medication required in women.75
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.61,65 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.25,26 However, currently there is no known endocrinology society that recognizes adrenal fatigue as a medical diagnosis and studies have conflicting results with limited validity.43
- Bennett R. Growth hormone in musculoskeletal pain states. Curr Pain Headache Rep. 2005;9(5):331-338.
- Fukuda I, Hizuka N, Muraoka T, Ichihara A. Adult growth hormone deficiency: current concepts. Neurol Med Chir . 2014;54(8):599-605.
- Hackney AC, Kallman A, Hosick KP, Rubin DA, Battaglini CL. Thyroid hormonal responses to intensive interval versus steady-state endurance exercise sessions. Hormones . 2012;11(1):54-60.
- Duhig TJ, McKeag D. Thyroid disorders in athletes. Curr Sports Med Rep. 2009;8(1):16-19.
- Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014;383(9935):2152-2167.
- Handelsman DJ. Chapter 24—Performance enhancing hormones in sports doping. Endocrinology: adult and pediatric, 7th edn, Philadelphia. Published online 2016:441-454.
- Monson JP, Brooke AM, Akker S. Adult Growth Hormone Deficiency. MDText.com, Inc.; 2015.
- Tanriverdi F, Schneider HJ, Aimaretti G, Masel BE, Casanueva FF, Kelestimur F. Pituitary dysfunction after traumatic brain injury: a clinical and pathophysiological approach. Endocr Rev. 2015;36(3):305-342.
- de Boer H, Blok GJ, Van der Veen EA. Clinical aspects of growth hormone deficiency in adults. Endocr Rev. 1995;16(1):63-86.
- Sherlock M, Ayuk J, Tomlinson JW, et al. Mortality in patients with pituitary disease. Endocr Rev. 2010;31(3):301-342.
- Giovannini L, Tirabassi G, Muscogiuri G, Somma CD, Colao A, Balercia G. Impact of adult growth hormone deficiency on metabolic profile and cardiovascular risk [Review]. Endocr J. 2015;62(12):1037-1048.
- Melmed S, Larry Jameson J, De Groot LJ. Endocrinology Adult and Pediatric: Neuroendocrinology and The Pituitary Gland E-Book. Elsevier Health Sciences; 2013.
- Broder MS, Chang E, Cherepanov D, Neary MP, Ludlam WH. INCIDENCE AND PREVALENCE OF ACROMEGALY IN THE UNITED STATES: A CLAIMS-BASED ANALYSIS. Endocr Pract. 2016;22(11):1327-1335.
- Killinger Z, Payer J, Lazúrová I, et al. Arthropathy in acromegaly. Rheum Dis Clin North Am. 2010;36(4):713-720.
- Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab. 2007;92(11):4241-4247.
- Sartorius G, Spasevska S, Idan A, et al. Serum testosterone, dihydrotestosterone and estradiol concentrations in older men self-reporting very good health: the healthy man study. Clin Endocrinol . 2012;77(5):755-763.
- Cunningham GR, Toma SM. Why Is Androgen Replacement in Males Controversial? J Clin Endocrinol Metab. 2011;96(1):38-52.
- Baxter D, Sharp DJ, Feeney C, et al. Pituitary dysfunction after blast traumatic brain injury: The UK BIOSAP study. Ann Neurol. 2013;74(4):527-536.
- Wilkinson CW, Pagulayan KF, Petrie EC, et al. High prevalence of chronic pituitary and target-organ hormone abnormalities after blast-related mild traumatic brain injury. Front Neurol. 2012;3:11.
- Agha A, Rogers B, Sherlock M, et al. Anterior pituitary dysfunction in survivors of traumatic brain injury. J Clin Endocrinol Metab. 2004;89(10):4929-4936.
- Jones KD, Deodhar P, Lorentzen A, Bennett RM, Deodhar AA. Growth hormone perturbations in fibromyalgia: a review. Semin Arthritis Rheum. 2007;36(6):357-379.
- Golden SH, Robinson KA, Saldanha I, Anton B, Ladenson PW. Prevalence and Incidence of Endocrine and Metabolic Disorders in the United States: A Comprehensive Review. J Clin Endocrinol Metab. 2009;94(6):1853-1878.
- Guaraldi F, Salvatori R. Cushing syndrome: maybe not so uncommon of an endocrine disease. J Am Board Fam Med. 2012;25(2):199-208.
- Ohlsson C, Bengtsson BA, Isaksson OG, Andreassen TT, Slootweg MC. Growth hormone and bone. Endocr Rev. 1998;19(1):55-79.
- Jacobsen S, Main K, Danneskiold-Samsøe B, Skakkebaek NE. A controlled study on serum insulin-like growth factor-I and urinary excretion of growth hormone in fibromyalgia. J Rheumatol. 1995;22(6):1138-1140.
- Cuatrecasas G, Gonzalez MJ, Alegre C, et al. High prevalence of growth hormone deficiency in severe fibromyalgia syndromes. J Clin Endocrinol Metab. 2010;95(9):4331-4337.
- Bauman WA, Spungen AM, Adkins RH, Kemp BJ. Metabolic and endocrine changes in persons aging with spinal cord injury. Assist Technol. 1999;11(2):88-96.
- Caiozzo VJ, Herrick RE, Baldwin KM. Influence of hyperthyroidism on maximal shortening velocity and myosin isoform distribution in skeletal muscles. Am J Physiol. 1991;261(2 Pt 1):C285-C295.
- Chan EK, Sepkovic DW, Yoo Bowne HJ, Yu GP, Schantz SP. A hormonal association between estrogen metabolism and proliferative thyroid disease. Otolaryngol Head Neck Surg. 2006;134(6):893-900.
- Ciloglu F, Peker I, Pehlivan A, et al. Exercise intensity and its effects on thyroid hormones. Neuro Endocrinol Lett. 2005;26(6):830-834.
- Staykova ND, Geneva-Popova MG, Troev DD, Kuzmanova SI, Alimanska SA, Murdzheva MA. Immune profile and thyroid function in patients with rheumatoid arthritis. Folia Med . 2000;42(4):30-33.
- Atzeni F, Doria A, Ghirardello A, et al. Anti-thyroid antibodies and thyroid dysfunction in rheumatoid arthritis: prevalence and clinical value. Autoimmunity. 2008;41(1):111-115.
- Hellevik AI, Johnsen MB, Langhammer A, et al. Incidence of total hip or knee replacement due to osteoarthritis in relation to thyroid function: a prospective cohort study (The Nord-Trøndelag Health Study). BMC Musculoskelet Disord. 2017;18(1):201.
- Waung JA, Bassett JHD, Williams GR. Adult mice lacking the type 2 iodothyronine deiodinase have increased subchondral bone but normal articular cartilage. Thyroid. 2015;25(3):269-277.
- Bos SD, Bovée JVMG, Duijnisveld BJ, et al. Increased type II deiodinase protein in OA-affected cartilage and allelic imbalance of OA risk polymorphism rs225014 at DIO2 in human OA joint tissues. Ann Rheum Dis. 2012;71(7):1254-1258.
- Waung JA, Bassett JHD, Williams GR. Thyroid hormone metabolism in skeletal development and adult bone maintenance. Trends Endocrinol Metab. 2012;23(4):155-162.
- Tagoe CE, Zezon A, Khattri S. Rheumatic manifestations of autoimmune thyroid disease: the other autoimmune disease. J Rheumatol. 2012;39(6):1125-1129.
- Palumbo CF, Szabo RM, Olmsted SL. The effects of hypothyroidism and thyroid replacement on the development of carpal tunnel syndrome. J Hand Surg Am. 2000;25(4):734-739.
- Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease. Elsevier Science Health Science Division; 2014.
- Krasnoff JB, Basaria S, Pencina MJ, et al. Free testosterone levels are associated with mobility limitation and physical performance in community-dwelling men: the Framingham Offspring Study. J Clin Endocrinol Metab. 2010;95(6):2790-2799.
- Sattler FR, Castaneda-Sceppa C, Binder EF, et al. Testosterone and growth hormone improve body composition and muscle performance in older men. J Clin Endocrinol Metab. 2009;94(6):1991-2001.
- Mor F, Green P, Wysenbeek AJ. Myopathy in Addison’s disease. Ann Rheum Dis. 1987;46(1):81-83.
- Kersey RD, Elliot DL, Goldberg L, et al. National Athletic Trainers’ Association Position Statement: Anabolic-Androgenic Steroids. J Athl Train. 2012;47(5):567-588.
- Cranney A, Welch V, Adachi J, et al. Calcitonin for preventing and treating corticosteroid‐induced osteoporosis. Cochrane Database Syst Rev. 2000;(1). doi:10.1002/14651858.CD001983
- Kimberly RP. Mechanisms of action, dosage schedules, and side effects of steroid therapy. Curr Opin Rheumatol. 1991;3(3):373-379.
- Kaganov Y, Gattas N, Rimon D. Fibromyalgia-Like Syndrome Secondary to Addison’s Disease. J Clin Rheumatol. 2000;6(1):27-29.
- Lippi G, Banfi G. Doping and thrombosis in sports. Semin Thromb Hemost. 2011;37(8):918-928.
- Burt MG, Ho KKY. Hypopituitarism and Growth Hormone Deficiency. In: Endocrinology: Adult and Pediatric. Elsevier; 2016:188-208.e5.
- Allan CA, McLachlan RI. Androgen deficiency disorders. In: Endocrinology: Adult & Pediatric. Saunders; 2016:2394-2420.
- Barthel A, Willenberg HS, Gruber M, Bornstein SR. Adrenal insufficiency. In: Endocrinology: Adult and Pediatric. Elsevier Inc.; 2015:1763-1774.
- Zhou Q, Miao M, Ran M, et al. Serum bisphenol-A concentration and sex hormone levels in men. Fertil Steril. 2013;100(2):478-482.
- The Prohibited List. World Anti-Doping Agency. Accessed January 31, 2022. https://www.wada-ama.org/en/prohibited-list
- Javorsky BR, Aron DC, Findling JW, Tyrrell JB. Chapter 4: Hypothalamus and Pituitary Gland. In: Gardner DG, Shoback-Gardner D, eds. Greenspan’s Basic & Clinical Endocrinology. 10th ed. McGraw Hill; 2017.
- Dutta D, Mahajan K, Kumar M, Sharma M. Efficacy and safety of long-acting growth hormone in adult growth hormone deficiency: A systematic review and meta-analysis. Diabetes Metab Syndr. 2022;16(2):102421.
- Yuen KCJ, Miller BS, Boguszewski CL, Hoffman AR. Usefulness and Potential Pitfalls of Long-Acting Growth Hormone Analogs. Front Endocrinol . 2021;12:637209.
- Tritos NA, Klibanski A. Effects of Growth Hormone on Bone. Prog Mol Biol Transl Sci. 2016;138:193-211.
- Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(5):1715-1744.
- Wilson SA, Stem LA, Bruehlman RD. Hypothyroidism: Diagnosis and Treatment. Am Fam Physician. 2021;103(10):605-613.
- Huang SW, Lin JW, Wang WT, Wu CW, Liou TH, Lin HW. Hyperthyroidism is a risk factor for developing adhesive capsulitis of the shoulder: a nationwide longitudinal population-based study. Sci Rep. 2014;4:4183.
- Jordan B, Uer O, Buchholz T, Spens A, Zierz S. Physical fatigability and muscle pain in patients with Hashimoto thyroiditis. J Neurol. 2021;268(7):2441-2449.
- Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016;26(10):1343-1421.
- Lu R, Wang H, Hong T, Gao H. Myopathy after rapid correction of hyperthyroidism: A case report and review of literature. Medicine . 2020;99(3):e18878.
- Reincke M. Cushing syndrome associated myopathy: It is time for a change. Endocrinol Metab (Seoul). 2021;36(3):564-571.
- Vogel F, Braun L, Rubinstein G, et al. Patients with low IGF-I after curative surgery for Cushing’s syndrome have an adverse long-term outcome of hypercortisolism-induced myopathy. Eur J Endocrinol. 2021;184(6):813-821.
- Husebye ES, Pearce SH, Krone NP, Kämpe O. Adrenal insufficiency. Lancet. 2021;397(10274):613-629.
- Boguszewski CL. Growth Hormone Deficiency (GHD) in Adults: To Treat or Not To Treat? Rev Argent Endocrinol Metab. 2010;47(3):30-38.
- Sonino N, Fava GA. Improving the concept of recovery in endocrine disease by consideration of psychosocial issues. J Clin Endocrinol Metab. 2012;97(8):2614-2616.
- Asa SL, Mete O. Endocrine pathology: past, present and future. Pathology. 2018;50(1):111-118.
- Ruggeri RM, Trimarchi F, Biondi B. MANAGEMENT OF ENDOCRINE DISEASE: l-Thyroxine replacement therapy in the frail elderly: a challenge in clinical practice. Eur J Endocrinol. 2017;177(4):R199-R217.
- Zhou J, Gauthier K, Ho JP, et al. Thyroid Hormone Receptor α Regulates Autophagy, Mitochondrial Biogenesis, and Fatty Acid Use in Skeletal Muscle. Endocrinology. 2021;162(8). doi:10.1210/endocr/bqab112
- Napolitano G, Fasciolo G, Di Meo S, Venditti P. Vitamin E Supplementation and Mitochondria in Experimental and Functional Hyperthyroidism: A Mini-Review. Nutrients. 2019;11(12). doi:10.3390/nu11122900
- Gan EH, Pearce SH. MANAGEMENT OF ENDOCRINE DISEASE: Regenerative therapies in autoimmune Addison’s disease. Eur J Endocrinol. 2017;176(3):R123-R135.
- Miller KK, Biller BMK, Beauregard C, et al. Effects of testosterone replacement in androgen-deficient women with hypopituitarism: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2006;91(5):1683-1690.
- Rahimzadeh P, Imani F, Faiz SHR, et al. Adding Intra-Articular Growth Hormone to Platelet Rich Plasma under Ultrasound Guidance in Knee Osteoarthritis: A Comparative Double-Blind Clinical Trial. Anesth Pain Med. 2016;6(6):e41719.
- Clinical roundup: Selected treatment options for migraine—part 2. Altern Complement Ther. 2017;23(3):115-118.
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
Nothing to Disclose
Richard G. Chang, MD, MPH
Nothing to Disclose