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, and female athlete triad.
Growth hormone (GH)
- Overproduction: Acromegaly
- Pituitary adenoma
- Occurs after epiphyseal plate closure
- Under-secretion: Adult Growth Hormone Deficiency (AGHD)
- Intrinsic pituitary dysfunction (tumor, resection, radiation, panhypopituitarism)
- 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)52
- 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 rT3, a less biologically active form 2, 50
- Hypercortisolism or Cushing Syndrome (CS): increased glucocorticoids 51
- Excessive exogenous glucocorticoids (e.g., ingesting oral prednisone)
- 70-80% of endogenous CS from increased hypothalamic-pituitary ACTH secretion 51
- Hyperaldosterolism: increased mineralocorticoids
- Primary due to neoplasm or hyperplasia
- Secondary due to increased activation of the renin-angiotensin system, such as in pregnancy 51
- Adrenal insufficiency (AI) or Addison’s Disease
- Extensive exogenous glucocorticoids causes negative feedback 51
- >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 injuries 72
Epidemiology including risk factors and primary prevention
Adult Growth Hormone Deficiency
- Rare Disease 52,53
- 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.52,53
- Addition of cases of childhood-onset GHD persisting into adult life gives an overall prevalence of between 2 and 3 per 10,000 population53
- Associated with pituitary dysfunction after traumatic brain injury (TBI)54
- 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.52,53
- Risk increases with age, malnutrition states, chronic inflammatory diseases, and renal and liver disease 55,56
- 2x increase in cardiovascular-related mortality (reduced left ventricular ejection fraction, stroke volume, and atherogenic lipid profile)55-57
- 3x increase in cerebrovascular-related mortality1, 55-57
- 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 presents can be due to excessive ectopic GHRH or GH secretion from extra-pituitary sources58
- Rare (incidence 11 per 1,000,000 person years)59
- Left untreated, it is associated with near 100% prevalence of joint problems 1,60,
- With better detection and treatment, 50% 1,60
Androgen deficiency syndrome:
- Decline in testosterone levels, often age-related, but also seen in response to stress state61
- 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 62
- 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. 63
- Total testosterone decline of 0.8% per year of life, and free and bioavailable testosterone declines at 2% per year of life3
- Can predict future diabetes mellitus type 2, metabolic syndrome, cardiovascular events, mobility limitations and mortality.
- Risk factors: stress, poor sleep hygiene, history of TBI, BPA plastics
- Studies have demonstrated a clear increase in risk for developing hypopituitarism and chronic pituitary related morbidity following blast related TBI 64-67
- Risk factors: Iodine deficiency, overtraining, genetics (autoimmune disorder)2
- Overall US prevalence: 4.6%.4
- Risk factors: genetics (autoimmune disorder), changes in iodine intake2
- Overall US prevalence: 1.3%4
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,1 as GH and IGF-1 directly stimulate osteoblasts and modulate osteoclast turnover.6 There is an association between fibromyalgia and GH deficiency, attributed to alpha-delta sleep anomalies 67-69. In acromegaly, early musculoskeletal complaints include enlarged cartilage and joint capsules with hypermobility and instability 57. 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.7
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;8 within physiologic norms, it has been shown to increase the shortening velocity of skeletal muscle,9 which may be related to greater efficiency of exercising muscles.10
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 76-81. 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.11 Hypothyroidism has also been highly associated with neuropathies, most commonly CTS; however, the effects of thyroid hormones on peripheral nerves remains unclear.12
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.13
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,1, 3, 5,14-17 neuropathy/paresthesiaa,1, 12 CTS,1,12 fatigue/poor endurance,1-3,13,14osteoporosis,1-3, 5, 6, 14, 18, 19 avascular necrosis,19 fibromyalgia,1,11, 20heat illness,2 and cardiovascular manifestations.1-3, 13, 21
2. 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.70 When associated with concomitant reductions in ACTH, anorexia and weight loss can also manifest clinically.70
- CNS: Palpable peripheral nerves, CTS, symmetric sensorimotor polyneuropathy on electrodiagnostics 55
- CVS/MSK: cardiomegaly, enlarged distal structures (hands, feet), arthritis with hypermobility, sleep apnea55
- Headaches (60%), bitemporal hemianopsia, and cranial nerve palsies can result from somatotroph adenoma/macroadenomas55
- Decreased muscle mass, increased body fat, gynecomastia, body hair loss, loss of height71
- 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, cold intolerance
- Tachycardia, hypertension, muscle weakness2
- 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, vitiligo17,73
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).
- TSH, T4/Free T4
- Anti-thyroid peroxidase autoantibody
CS can be measured with 24-hour urine free cortisol, ACTH levels, and urine 17-hydroxycorticoids. Aldosterone and renin are measured for hyperaldosteronism.
- Brain MRI or CT to evaluate hypothalamus or pituitary
- Neck MRI or ultrasound to evaluate 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 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.22
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 taken into account. 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.75 Consideration of need for therapeutic use exemptions should be discussed with the patient. The potential side-effects of excessive treatment with oral and injectable glucocorticoids should be discussed.
3. 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.
- Use of GH or GH secretagogues in conjunction with hormone replacement therapy (HRT) has shown some benefit in treating low bone mineral density (BMD).1
In placebo-controlled trials, there is an increase in BMD in men, but not women.
GH replacement has been shown to increase lean body mass and decrease body fat in both men and women; however there is conflicting evidence if this improves muscle strength and endurance.27,28 There is conflicting consensus on whether to treat GH deficiency. The mild increase of BMD in men does not justify the very high cost and inconvenience of daily injections.
- Only hypogonadal men or elderly men, who show symptoms of low testosterone such as decreased libido or depressed mood, as well as have multiple, measured morning low serum total testosterone levels under (less than 200 – 300 ng/dL depending on the society) should receive testosterone replacement therapy.45 Testosterone replacement has been shown to increase muscle mass, strength and bone mineral density. 34 Treatment is based on patient preference. However, transdermal forms, especially gels, are recommended for ease of application and produce normal testosterone levels. The disadvantages are peripheral conversion into estrogen because of aromatase is present in adipose tissues and the potential for transfer to other patients. Long acting injectable testosterone replacement can achieve reliable physiologic levels and is inexpensive.45 Testosterone replacement is contraindicated in patient with a history of breast or prostate cancer, palpable prostate nodule.34 Patients should have their PSA level checked prior to rectal examination (so as to not falsely increase PSA levels), as well as be monitored for clinical response to treatment.
- Primary treatment of hypothyroidism includes hormone replacement, physical exercise and adjuvants, including yoga.2,23 Furthermore, addressing sleep deficiency and nutrition, such as vitamin B12 deficiency, can aid in treatment.31,32,33 In athletes, , over training syndrome may mimic hypothyroidism as both can present with fatigue and depression, however a normal TSH essentially rules out hypothyroidism.46 Some studies have demonstrated that intensive training in athletes have not lead to major changes in thyroid function. 47
- Exogenous steroids or other underlying causes should be addressed to treat CS.
- For primary adrenal insufficiency, exogenous steroid with careful monitoring of symptoms is the main treatment. Most patients will eventually need mineralocorticoid replacement as well. Women with impaired mood should also receive DHEA therapy.35 Management of AI should also include treatment of underlying psychosocial and/or physical stressors.
At different disease stages
- New onset/acute ◦Identify underlying endocrine dysfunction
- Reduce or remove environmental causes (excessive exercise, stress)
- For patients with acromegaly, transsphenoidal surgery to remove the pituitary tumor is the primary treatment with medical therapy if persistent symptoms 29
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/occupational therapists.
- Coordinate with oncology if cancer is suspected.
- An experienced neurosurgeon for pituitary adenoma or other mechanical cause.
- 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 DEXA37
- 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 musculoskeletal and endocrine system is important for patient compliance with treatments. Patients should also be educated regarding potential controversies.
Repeat blood work, symptoms and psychological mood are used to track progress of endocrine dysfunction.35,40 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. 38 The Brief Pain Inventory, VAS, 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, TBI, stroke, SCI, obesity, and/or pre-existing metabolic syndrome).
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
Cutting edge concepts and practice
- There is increasing interest and research being done in the use of growth factor containing substances to help stimulate regeneration of cartilage (ie., PRP, stem cells) in arthritic patients. One small study (14 patients) looked at intra-articular growth hormone injections for treatment of arthritis and showed improved range of motion, decreased pain, and regrowth of cartilage in 93% of their subjects. Other research has focused on adding GH to PRP injections which showed improved function in knee osteoarthritis in a short period.41
- Benefits of testosterone replacement in older males include improved subjective well-being, grip strength, walking speed, and functional mobility.13
- Women with hypopituitarism with severe androgen deficiency showed a positive effect on BMD and body composition.44 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 of 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 osteoarthritis41
- Yoga has been shown to improve cholesterol, serum TSH, and reduce the amount of thyroxine medication required in women30
5.GAPS IN THE EVIDENCE-BASED KNOWLEDGE
Gaps in the evidence-based knowledge
There are many controversies regarding treatment of endocrine disorders and their musculoskeletal manifestations.
- GH replacement therapy has gained more attention in the past 10 years and many studies have shown the beneficial effects, however long term effects, such as risk of malignancy, are still unknown.36 as well as best treatment methods. Development of oral secretagogues will likely lead to new data regarding long-term treatment of AGHD.
- GH replacement has been shown to only increase BMD in men and the reasons for the gender-specific effects are unknown.27,28
- There still remains the uncertainty of the risks of long term testosterone therapy, especially in elderly men with comorbidies.45,48 Further studies need to be done to determine how best to treat men with comorbid conditions as well as testosterone deficiency.
- “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 endocrinology society that recognizes adrenal fatigue as a medical diagnosis and studies have conflicting results with limited validity.43
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- 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.
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- 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.
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- Cranney A, Welch V, Adachi JD, et al, Calcitonin for preventing and treating corticosteroid-induced osteoporosis. Cochrane Database Syst Rev 2000;1:1-17.
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- Kaganov Y, Gattas N, Rimon D. Fibromyalgia-like syndrome secondary to Addison’s Disease. J Clin Rheumatol. 2000;6(1):27-29.
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- Zhou Q, Miao M, Ran M, et al. Serum bisphenol-A concentration and sex hormone levels in men. Fertil Steril. 2013;100(2):478-82.
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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. 09/20/2013.
Richard G. Chang, MD
2016 Foundation for PM&R; Richard S. Materson ERF New Investigator Grant: Research Grant; to be paid to institution: Principal Investigator
Kameron Bazmi, MD
Nothing to Disclose
Andrew Beaufort, MD,
Nothing to Disclose