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
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
- Bennett R. Growth hormone in musculoskeletal pain states. Curr Pain Headache Rep. 2005;9(5):331-338.
- Duhig TJ, McKeag D. Thyroid disorders in athletes. Curr Sports Med Rep. 2009;8(1):16-19.
- Cunningham GR, Toma SM. Clinical review: Why is androgen replacement in males controversial? J Clin Endocrinol Metab. 2011;96(1):38-52.
- Golden SH, Robinson KA, Saldanha I, Anton B, Ladenson PW. Clinical review: 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.
- Bauman W, Spungen AM, Adkins RH, Kemp BJ. Metabolic and endocrine changes in persons aging with spinal cord injuries. Topics in Spinal Cord Injury Rehabilitation Assist.Technol. 1999;11(2):88-96.
- Caiozzo VJ HR, Baldwin KM. The influence of hyperthyroidism on the maximal shortening velocity and myosin is form distribution in slow and fast skeletal muscles. Am. J. Physiol. 1991;261:285-296.
- 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.
- 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.
- Maitra A. Robbins and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia, PA: Elsevier Saunders; 2005.
- 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 JD, et al, Calcitonin for preventing and treating corticosteroid-induced osteoporosis. Cochrane Database Syst Rev 2000;1:1-17.
- 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.
- 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.
- Singh P, Singh B, Dave R, Udainiya R. The impact of yoga upon female patients suffering from hypothyroidism. Complement Ther Clin Pract. 2011;17(3):132-134.
- Davis SR, Worsley R. Androgen treatment of postmenopausal women. J Steroid Biochem Mol Biol. 2013; doi:pii: S0960-0760(13)00077-0. 10.1016/j.jsbmb.2013.05.006 (Epub ahead of Print)
- Head KA, Kelly GS. Nutrients and botanicals for treatment of stress: adrenal fatigue, neurotransmitter imbalance, anxiety, and restless sleep. Altern Med Rev. 2009;14(2):114-140.
- Nippoldt T. Mayo Clinic office visit. Adrenal fatigue. An interview with Todd Nippoldt, MD. Mayo Clin Womens Healthsource. 2010;14(3):6.
- Bengtsson BA, Edén S, Lönn L, et al. Treatment of adults with growth hormone (GH) deficiency with recombinant human GH. The Journal of Clinical Endocrinology & Metabolism. 1999;76(2):309-317.
- Widdowson M, Gibney J. The effect of growth hormone (GH) replacement on muscle strength in patients with GH-deficiency: a meta-analysis. Clinical Endocrinology. 2010;72: 787–792.
- Katznelson L, Laws ER, Melmed S, et al. Acromegaly: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism. 2014;99(11)3933–3951.
- Nilakanthan S, Metri K, Raghuram N, et al. Clinical Roundup: Selected Treatment Options for Migraine—Part 2. Alternative and Complementary Therapies. 2017;23(3)115.
- Complete Guide to Boosting Thyroid Hormones and Function Naturally. Thyroid Advisor. https://thyroidadvisor.com/complete-guide-to-boosting-thyroid-hormone-function-naturally/. Published July 29, 2017. Accessed November 4, 2017.
- Benvenga S, Bartolone L, Pappalardo MA, et al. Altered Intestinal Absorption of L-Thyroxine Caused by Coffee. Thyroid. 2008;18(3):293-301.
- Jabbar A, Yawas A, Wasim S, et al. Vitamin B12 deficiency common in primary hypothyroidism. J Pak Med Assoc. 2008;58(5):258-261.
- Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism. 2010;95(6):2536-2559.
- Nieman LK. Treatment of adrenal insufficiency in adults. In: Lacrois A, Martin KA, ed. UpToDate. Waltham, Mass.: UpToDate; 2017. https://www.uptodate.com/contents/treatment-of-adrenal-insufficiency-in-adults?source=search_result&search=addisons%20disease%20treatment&selectedTitle=1~150. Accessed November 4, 2017.
- Rucker K, de Sá L, Arbex A. Growth Hormone Replacement Therapy in Patients without Adult Growth Hormone Deficiency: What Answers Do We Have So Far?. Health. 2017;9:799-810.
- Boguszewski CL. Growth Hormone Deficiency (GHD) in Adults: To Treat or Not To Treat?. Rev. argent. endocrinol. Metab. 2010;47(3):30-38.
- Ruggeri RM, Trimarchi F, Biondi B. Management of Endocrine Disease: L-Thyroxine replacement therapy in the frail elderly: A challenge in clinical practice. European Journal of Endocrinology. 2017;1-17.
- Snyder PJ. Growth hormone deficiency in adults. In: Cooper DS, Martin KA, ed. UpToDate. Waltham, Mass.: UpToDate; 2017. https://www.uptodate.com/contents/growth-hormone-deficiency-in adults?source=search_result&search=growth%20hormone%20therapy&selectedTitle=3~150#H18. Accessed November 4, 2017.
- Rahimzadeh P, Imani F, Faiz S, et al. Adding Intra-Articular Growth Hormone to Platelet Rich Plasma under Ultrasound Guidance in Knee Osteoarthritis: A Comparative Double-Blind Clinical Trial. Anesthesiology and Pain Medicine. 2016;6(6): e41719.
- Dumond H, Presle N, Terlain B, et al. Evidence for a key role of leptin in osteoarthritis. Arthritis & Rheumatism. 2003;48:3118–3129.
- Cadegiani FA, Kater CE. Adrenal fatigue does not exist: a systematic review. BMC endocrine disorders. 2016;16(1):48.
- 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. The Journal of Clinical Endocrinology & Metabolism. 2006;91(5):1683-1690.
- Snyder PJ. Testosterone treatment of male hypogonadism. In: Matsumoto AM, Martin KA, ed. UpToDate. Waltham, Mass.: UpToDate; 2017. https://www.uptodate.com/contents/testosterone-treatment-of-male-hypogonadism?source=search_result&search=testosterone%20replacement%20therapy&selectedTitle=1~68#H3937937. Accessed November 3, 2017.
- Howard TM. Overtraining syndrome in athletes. In: O’Connor FG, Grayzel J, ed. UpToDate. Waltham, Mass.: UpToDate; 2017. https://www.uptodate.com/contents/overtraining-syndrome-in-athletes?source=search_result&search=hypothyroidism%20in%20athletes&selectedTitle=1~150#H6159003. Accessed November 3, 2017.
- Alen M, Pakarinen A, Häkkinen K. Effects of prolonged training on serum thyrotropin and thyroid hormones in elite strength athletes. Journal of sports sciences. 1993;11(6):493-497.
- Snyder PJ. Overview of testosterone deficiency in older men. In: Matsumoto AM, Schmader KE, Martin KA, ed. UpToDate. Waltham, Mass.: UpToDate; 2017. https://www.uptodate.com/contents/overview-of-testosterone-deficiency-in-older-men?source=search_result&search=low%20testosterone%20treatment&selectedTitle=2~150#H313824889. Accessed November 2, 2017.
- Zimmermann MB, Andersson M. Update on iodine status worldwide. Curr Opin Endocrinol Diabetes Obes. 2012;19(5):382-7.
- Hackney AC, Kallman A, Hosick KP et al. Thyroid hormone responses to intensive interval vs steady state endurance exercise sessions. Hormones (Athens). 2012;11(1):54-60.
- Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014;383(9935):2152-67.
- Fukuda I, Hizuka N, Muraoka T, Ichihara A. Adult growth hormone deficiency: current concepts. Neurol Med Chir (Tokyo). 2014;54(8):599-605.
- Monson JP, Brooke AM, Akker S. Adult Growth Hormone Deficiency. [Updated 2015 May 19]. In: De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK278982/
- Tanriverdi F, Schneider HJ, Aimaretti G, et al. Pituitary Dysfunction After Traumatic Brain Injury: A Clinical and Pathophysiological Approach. Endocrine Reviews. 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):301-42.
- Giovannini L, Tirabassi G, Muscogiuri G, et al. Impact of adult growth hormone deficiency on metabolic profile and cardiovascular risk [Review]. Endocr J. 2015;62(12):1037-48.
- Melmed S. Chapter 12: Acromegaly. In: Jameson JL, De Groot LJ, eds Endocrinology: Adult and Pediatric. 7th ed. Philadelphia, PA Saunders/Elsevier; 2016:209-226e7.
- Broder MS, Chang E, Cherepanov D, Neary MP, Ludlam WH. Incidence and prevalence of acromegaly in the United States: a claims based analysis. Endocrine Practice. 2016;22(11)1327-1335.
- Killinger Z, Payer J, Lazúrová I, et al. Arthropathy in acromegaly. Rheum Dis Clin North Am. 2010;36(4):713-20.
- Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab. 2007 Nov;92(11):4241-7.
- 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 (Oxf). 2012;77(5):755-63.
- Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab. 2007;92(11):4241-7.
- Baxter D, Sharp DJ, Feeney C, et al. Pituitary dysfunction after blast traumatic brain injury: The UK BIOSAP study. Ann Neurol. 2013;74(4):527-36.
- 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. Frontiers in Neurology. 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):4929-36.
- Bennett RM, Clark SC, Walczyk J. A randomized, double-blind, placebo-controlled study of growth hormone in the treatment of fibromyalgia. Am J Med. 1998;104(3):227-31.
- 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):1138-40.
- 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):4331-7.
- Burt MG, Ho KY. Chapter 11: Hypopituitarism and Growth Hormone Deficiency. In: Jameson JL, De Groot LJ, eds Endocrinology: Adult and Pediatric. 7th ed. Philadelphia, PA Saunders/Elsevier; 2016:188-208e5.
- Allan CA, McLachlan RI. Chapter 139: Androgen Deficiency Disorders. In: Jameson JL, De Groot LJ, eds Endocrinology: Adult and Pediatric. 7th ed. Philadelphia, PA Saunders/Elsevier; 2016:2394-2420e13.
- Handelsman D. Chapter24: Performance Enhancing Hormone in Sports Doping. In: Jameson JL, De Groot LJ, eds Endocrinology: Adult and Pediatric. 7th ed. Philadelphia, PA Saunders/Elsevier; 2016:441-454e4.
- Barthel A, Willenberg HS, Gruber M. Chapter 102. Adrenal Deficiency. In: Jameson JL, De Groot LJ, eds Endocrinology: Adult and Pediatric. 7th ed. Philadelphia, PA Saunders/Elsevier; 2016:1762-1774e4.
- Wilson M, Morganti AA, Zervoudakis I, et al. Blood pressure, the renin-aldosterone system and sex steroids throughout normal pregnancy. Am J Med. 1980;68(1):97-104.
- World Anti-Doping Agency. What is Prohibited. https://www.wada-ama.org/en/prohibited-list. 2017. Accessed November 9, 2017.
- Staykova ND, Geneva-Popova MG, Troev DD, et al. Immune profile and thyroid function in patients with rheumatoid arthritis. Folia Med. 2000;42(4):30-3.
- 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):111-5.
- 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 JH, Williams GR. Adult mice lacking the type 2 iodothyronine deiodinase have increased subchondral bone but normal articular cartilage. Thyroid. 2015;25(3):269-77.
- Bos SD, Bovée JV, 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 JH, Williams GR. Thyroid hormone metabolism in skeletal development and adult bone maintenance. Trends Endocrinol Metab. 2012;23(4):155-162.
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