Off-Label Use and Misuse of Testosterone, Growth Hormone, Thyroid Hormone, and Adrenal Supplements: Risks and Costs of a Growing Problem

      ABSTRACT

      Over the past few decades, there has been an unprecedented rise in off-label use and misuse of testosterone, growth hormone, thyroid hormone, and adrenal supplements. Testosterone therapy is often promoted to men for the treatment of low energy, lower libido, erectile dysfunction, and other symptoms. Growth hormone is used in attempts to improve athletic performance in athletes and to attenuate aging in older adults. Thyroid hormone and/or thyroid supplements or boosters are taken to treat fatigue, obesity, depression, cognitive impairment, impaired physical performance, and infertility. Adrenal supplements are used to treat common nonspecific symptoms due to “adrenal fatigue,” an entity that has not been recognized as a legitimate medical diagnosis. Several factors have contributed to the surge in off-label use and misuse of these hormones and supplements: direct-to-consumer advertising, websites claiming to provide legitimate medical information, and for-profit facilities promoting therapies for men's health and anti-aging. The off-label use and misuse of hormones and supplements in individuals without an established endocrine diagnosis carries known and unknown risks. For example, the risks of growth hormone abuse in athletes and older adults are unknown due to a paucity of studies and because those who abuse this hormone often take supraphysiologic doses in sporadic intervals. In addition to the health risks, off-label use of these hormones and supplements generates billions of dollars of unnecessary costs to patients and to the overall health-care system. It is important that patients honestly disclose to their providers off-label hormone use, as it may affect their health and treatment plan. General medical practitioners and adult endocrinologists should be able to begin a discussion with their patients regarding the unfavorable balance between the risks and benefits associated with off-label use of testosterone, growth hormone, thyroid hormone, and adrenal supplements.
      Abbreviations: DHEA = dehydroepiandrosterone; FDA = U.S. Food and Drug Administration; GH = growth hormone; IGF-1 = insulin-like growth factor 1; LT3 = L-triiodothyronine; LT4 = levothyroxine; T3 = total triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone
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      REFERENCES

        • Handelsman D.J.
        Global trends in testosterone prescribing, 2000–2011: expanding the spectrum of prescription drug misuse.
        Med J Aust. 2013; 199 (doi: 10.5694/mja13.10111 [pii].): 548-551
        • Mintzes B.
        The marketing of testosterone treatments for age-related low testosterone or ‘low T.
        Curr Opin Endocrinol Diabetes Obes. 2018; 25 (doi: 10.1097/MED.0000000000000412 [doi].): 224-230
        • Oberlin D.T.
        • Masson P.
        • Brannigan R.E.
        Testosterone replacement therapy and the internet: an assessment of providers' health-related web site information content.
        Urology. 2015; 85 (doi: 10.1016/j.urology.2014.11.043 [doi].): 814-818
      1. Available at: www.navacenter.com. Accessed January 22, 2020.

        • Anderson L.J.
        • Tamayose J.M.
        • Garcia J.M.
        Use of growth hormone, IGF-I, and insulin for anabolic purpose: pharmacological basis, methods of detection, and adverse effects.
        Mol Cell Endocrinol. 2018; 464 (doi: S0303-7207(17)30337-4 [pii]): 65-74
        • Siebert D.M.
        • Rao A.L.
        The use and abuse of human growth hormone in sports.
        Sports Health. 2018; 10 (doi: 10.1177/1941738118782688 [doi].): 419-426
        • Vance M.L.
        Can growth hormone prevent aging?.
        N Engl J Med. 2003; 348 (doi: 10.1056/NEJMp020186 [doi].): 779-780
        • Holt R.I.G.
        • Ho KKY.
        The use and abuse of growth hormone in sports.
        Endocr Rev. 2019; 40 (doi: 10.1210/er.2018-00265 [doi].): 1163-1185
        • Guha N.
        • Dashwood A.
        • Thomas N.J.
        • Skingle A.J.
        • Sönksen P.H.
        • Holt R.I.
        IGF-I abuse in sport.
        Curr Drug Abuse Rev. 2009; 2 (doi: 10.2174/1874473710902030263 [doi].): 263-272
        • Jonklaas J.
        • Bianco A.C.
        • Bauer A.J.
        • et al.
        Guidelines for the treatment of hypothyroidism: Prepared by the American Thyroid Association task force on thyroid hormone replacement.
        Thyroid. 2014; 24 (doi: 10.1089/thy.2014.0028 [doi].): 1670-1751
        • Cadegiani F.A.
        • Kater C.E.
        Adrenal fatigue does not exist: a systematic review.
        BMC Endocr Disord. 2016; 16 (doi: 10.1186/s12902-016-0128-4 [doi].): 48
      2. Available at: https://adrenalfatigue.org/faq-on-adrenal-fatique/. Accessed January 22, 2020.

      3. Available at: https://www.jillcarnahan.com/2015/05/17/signs-you-might-have-adrenal-fatigue/. Accessed January 22, 2020.

      4. Available at: https://www.reportsanddata.com/report-detail/dietary-supplements-market. Accessed January 22, 2020.

        • Akturk H.K.
        • Chindris A.M.
        • Hines J.M.
        • Singh R.J.
        • Bernet V.J.
        Over-the-counter “adrenal support” supplements contain thyroid and steroid-based adrenal hormones.
        Mayo Clin Proc. 2018; 93 (doi: S0025-6196(17)30835-2 [pii].): 284-290
        • Bailey R.L.
        • Gahche J.J.
        • Lentino C.V.
        • et al.
        Dietary supplement use in the United States, 2003–2006.
        J Nutr. 2011; 141 (doi: 10.3945/jn.110.133025 [doi].): 261-266
        • Tucker J.
        • Fischer T.
        • Upjohn L.
        • Mazzera D.
        • Kumar M.
        Unapproved pharmaceutical ingredients included in dietary supplements associated with US Food and Drug Administration warnings.
        JAMA Netw Open. 2018; 1 (doi: 10.1001/jamanetworkopen.2018.3337 [doi].): e183337
        • Hoffman J.R.
        • Ratamess N.A.
        Medical issues associated with anabolic steroid use: are they exaggerated?.
        J Sports Sci Med. 2006; 5: 182-193
        • Solimini R.
        • Rotolo M.C.
        • Mastrobattista L.
        • et al.
        Hepatotoxicity associated with illicit use of anabolic androgenic steroids in doping.
        Eur Rev Med Pharmacol Sci. 2017; 21 (doi: 12427 [pii].): 7-16
        • Matsumoto A.M.
        Hormonal therapy of male hypogonadism.
        Endocrinol Metab Clin North Am. 1994; 23: 857-875
        • Chehab M.
        • Madala A.
        • Trussell J.C.
        On-label and off-label drugs used in the treatment of male infertility.
        Fertil Steril. 2015; 103 (doi: 10.1016/j.fertnstert.2014.12.122 [doi].): 595-604
        • Smit D.L.
        • de Ronde W.
        Outpatient clinic for users of anabolic androgenic steroids: an overview.
        Neth J Med. 2018; 76: 167
        • Bhasin S.
        • Brito J.P.
        • Cunningham G.R.
        • et al.
        Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.
        J Clin Endocrinol Metab. 2018; 103 (doi: 10.1210/jc.2018-00229 [doi].): 1715-1744
        • Wang C.
        • Nieschlag E.
        • Swerdloff R.
        • et al.
        ISA, ISSAM, EAU, EAA and ASA recommendations: investigation, treatment and monitoring of late-onset hypogonadism in males.
        Int J Impot Res. 2009; 21 (doi: 10.1038/ijir.2008.41 [doi].): 1-8
        • Travison T.G.
        • Vesper H.W.
        • Orwoll E.
        • et al.
        Harmonized reference ranges for circulating testosterone levels in men of four cohort studies in the United States and Europe.
        J Clin Endocrinol Metab. 2017; 102 (doi: 10.1210/jc.2016-2935 [doi].): 1161-1173
        • Matsumoto A.M.
        • Bremner W.J.
        Serum testosterone assays--accuracy matters.
        J Clin Endocrinol Metab. 2004; 89 (doi: 10.1210/jc.2003-032175 [doi].): 520-524
        • Rosner W.
        • Vesper H.
        Toward excellence in testosterone testing: a consensus statement.
        J Clin Endocrinol Metab. 2010; 95 (doi: 10.1210/jc.2010-1314 [doi].): 4542-4548
        • Layton J.B.
        • Kim Y.
        • Alexander G.C.
        • Emery S.L.
        Association between direct-to-consumer advertising and testosterone testing and initiation in the United States, 2009–2013.
        JAMA. 2017; 317 (doi: 10.1001/jama.2016.21041 [doi].): 1159-1166
        • Baillargeon J.
        • Urban R.J.
        • Kuo Y.F.
        • et al.
        Screening and monitoring in men prescribed testosterone therapy in the U.S., 2001–2010.
        Public Health Rep. 2015; 130 (doi: 10.1177/003335491513000207 [doi].): 143-152
        • Bhasin S.
        • Cunningham G.R.
        • Hayes F.J.
        • et al.
        Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline.
        J Clin Endocrinol Metab. 2010; 95 (doi: 10.1210/jc.2009-2354.): 2536-2559
        • Layton J.B.
        • Li D.
        • Meier C.R.
        • et al.
        Testosterone lab testing and initiation in the United Kingdom and the United States, 2000 to 2011.
        J Clin Endocrinol Metab. 2014; 99 (doi: 10.1210/jc.2013-3570 [doi].): 835-842
        • Kim S.D.
        • Cho K.S.
        Obstructive sleep apnea and testosterone deficiency.
        World J Mens Health. 2019; 37 (doi: 10.5534/wjmh.180017 [doi].): 12-18
        • Nguyen C.P.
        • Hirsch M.S.
        • Moeny D.
        • Kaul S.
        • Mohamoud M.
        • Joffe H.V.
        Testosterone and “age-related hypogonadism”--FDA concerns.
        N Engl J Med. 2015; 373 (doi: 10.1056/NEJMp1506632 [doi].): 689-691
      5. Available at: https://www.agelessmenshealth.com/. Accessed January 22, 2020.

      6. Available at: https://lowtcenter.com. Accessed January 22, 2020.

        • Rhoden E.L.
        • Morgentaler A.
        Risks of testosterone-replacement therapy and recommendations for monitoring.
        N Engl J Med. 2004; 350 (doi: 10.1056/NEJMra022251 [doi].): 482-492
        • Amory J.K.
        • Bremner W.J.
        The use of testosterone as a male contraceptive.
        Baillieres Clin Endocrinol Metab. 1998; 12 (doi: 10.1016/s0950-351x(98)80229-2 [doi].): 471-484
        • de Ronde W.
        Hyperandrogenism after transfer of topical testosterone gel: case report and review of published and unpublished studies.
        Hum Reprod. 2009; 24 (doi: 10.1093/humrep/den372 [doi].): 425-428
        • Basaria S.
        • Coviello A.D.
        • Travison T.G.
        • et al.
        Adverse events associated with testosterone administration.
        N Engl J Med. 2010; 363 (doi: 10.1056/NEJMoa1000485.): 109-122
        • Finkle W.D.
        • Greenland S.
        • Ridgeway G.K.
        • et al.
        Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men.
        PLoS One. 2014; 9 (doi: 10.1371/journal.pone.0085805 [doi].): e85805
        • Snyder P.J.
        • Bhasin S.
        • Cunningham G.R.
        • et al.
        Effects of testosterone treatment in older men.
        N Engl J Med. 2016; 374 (doi: 10.1056/NEJMoa1506119 [doi].): 611-624
        • Onasanya O.
        • Iyer G.
        • Lucas E.
        • Lin D.
        • Singh S.
        • Alexander G.C.
        Association between exogenous testosterone and cardiovascular events: an overview of systematic reviews.
        Lancet Diabetes Endocrinol. 2016; 4 (doi: S2213-8587(16)30215-7 [pii].): 943-956
        • Kim E.D.
        • McCullough A.
        • Kaminetsky J.
        Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement.
        BJU Int. 2016; 117 (doi: 10.1111/bju.13337 [doi].): 677-685
        • Shoshany O.
        • Abhyankar N.
        • Mufarreh N.
        • Daniel G.
        • Niederberger C.
        Outcomes of anastrozole in oligozoospermic hypoandrogenic subfertile men.
        Fertil Steril. 2017; 107 (doi: S0015-0282(16)63021-2 [pii].): 589-594
        • Chamberlain R.A.
        • Cumming D.C.
        Pulmonary embolism during clomiphene therapy for infertility in a male: a case report.
        Int J Fertil. 1986; 31: 198-199
        • Knight J.C.
        • Pandit A.S.
        • Rich A.M.
        • Trevisani G.T.
        • Rabinowitz T.
        Clomiphene-associated suicide behavior in a man treated for hypogonadism: case report and review of the literature.
        Psychosomatics. 2015; 56 (doi: 10.1016/j.psym.2015.06.003 [doi].): 598-602
        • Politou M.
        • Gialeraki A.
        • Merkouri E.
        • Travlou A.
        • Baltatzis S.
        Central retinal vein occlusion secondary to clomiphene treatment in a male carrier of factor V Leiden.
        Genet Test Mol Biomarkers. 2009; 13 (doi: 10.1089/gtmb.2008.0104 [doi].): 155-157
        • Sinha P.
        • Garg A.
        Could clomiphene kindle acute manic episode in a male patient? A case report.
        Gen Hosp Psychiatry. 2014; 36 (doi: 10.1016/j.genhosppsych.2014.05.011 [doi].): 549.e5-549.e6
        • Molitch M.E.
        • Clemmons D.R.
        • Malozowski S.
        • Merriam G.R.
        • Vance M.L.
        Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline.
        J Clin Endocrinol Metab. 2011; 96 (doi: 10.1210/jc.2011-0179 [doi].): 1587-1609
        • Yuen K.C.J.
        • Biller B.M.K.
        • Radovick S.
        • et al.
        American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of growth hormone deficiency in adults and patients transitioning from pediatric to adult care.
        Endocr Pract. 2019; 25 (doi: 10.4158/GL-2019-0405 [doi].): 1191-1232
        • Fleseriu M.
        • Hashim I.A.
        • Karavitaki N.
        • et al.
        Hormonal replacement in hypopituitarism in adults: an Endocrine Society clinical practice guideline.
        J Clin Endocrinol Metab. 2016; 101 (doi: 10.1210/jc.2016-2118 [doi].): 3888-3921
        • Jørgensen J.O.L.
        • Juul A.
        Therapy of endocrine disease: growth hormone replacement therapy in adults: 30 years of personal clinical experience.
        Eur J Endocrinol. 2018; 179 (doi: 10.1530/EJE-18-0306 [doi].): R47-R56
        • Rickert V.I.
        • Pawlak-Morello C.
        • Sheppard V.
        • Jay M.S.
        Human growth hormone: a new substance of abuse among adolescents?.
        Clin Pediatr (Phila). 1992; 31 (doi: 10.1177/000992289203101206 [doi].): 723-726
        • Wanjek B.
        • Rosendahl J.
        • Strauss B.
        • Gabriel H.H.
        Doping, drugs and drug abuse among adolescents in the State of Thuringia (Germany): prevalence, knowledge and attitudes.
        Int J Sports Med. 2007; 28 (doi: 10.1055/s-2006-924353 [doi].): 346-353
        • Brennan B.P.
        • Kanayama G.
        • Hudson J.I.
        • Pope Jr., H.G.
        Human growth hormone abuse in male weightlifters.
        Am J Addict. 2011; 20 (doi: 10.1111/j.1521-0391.2010.00093.x [doi].): 9-13
        • Brennan B.P.
        • Kanayama G.
        • Pope H.G.
        Performance-enhancing drugs on the web: a growing public-health issue.
        Am J Addict. 2013; 22 (doi: 10.1111/j.1521-0391.2013.00311.x [doi].): 158-161
        • Longobardi S.
        • Keay N.
        • Ehrnborg C.
        • et al.
        Growth hormone (GH) effects on bone and collagen turnover in healthy adults and its potential as a marker of GH abuse in sports: a double blind, placebo-controlled study. the GH-2000 study group.
        J Clin Endocrinol Metab. 2000; 85 (doi: 10.1210/jcem.85.4.6551 [doi].): 1505-1512
        • Wallace J.D.
        • Cuneo R.C.
        • Lundberg P.A.
        • et al.
        Responses of markers of bone and collagen turnover to exercise, growth hormone (GH) administration, and GH withdrawal in trained adult males.
        J Clin Endocrinol Metab. 2000; 85 (doi: 10.1210/jcem.85.1.6262 [doi].): 124-133
        • Wu Z.
        • Bidlingmaier M.
        • Dall R.
        • Strasburger C.J.
        Detection of doping with human growth hormone.
        Lancet. 1999; 353 (doi: S0140-6736(99)00775-8 [pii].): 895
        • Bidlingmaier M.
        • Strasburger C.J.
        Technology insight: detecting growth hormone abuse in athletes.
        Nat Clin Pract Endocrinol Metab. 2007; 3 (doi: ncpendmet0644 [pii].): 769-777
        • Hermansen K.
        • Bengtsen M.
        • Kjaer M.
        • Vestergaard P.
        • Jørgensen JOL.
        Impact of GH administration on athletic performance in healthy young adults: a systematic review and meta-analysis of placebo-controlled trials.
        Growth Horm IGF Res. 2017; 34 (doi: S1096-6374(17)30038-2 [pii].): 38-44
        • Meinhardt U.
        • Nelson A.E.
        • Hansen J.L.
        • et al.
        The effects of growth hormone on body composition and physical performance in recreational athletes: a randomized trial.
        Ann Intern Med. 2010; 152 (doi: 10.7326/0003-4819-152-9-201005040-00007 [doi].): 568-577
        • Guha N.
        • Nevitt S.P.
        • Francis M.
        • et al.
        The effects of recombinant human insulin-like growth factor-I/insulin-like growth factor binding protein-3 administration on body composition and physical fitness in recreational athletes.
        J Clin Endocrinol Metab. 2015; 100 (doi: 10.1210/jc.2015-1996 [doi].): 3126-3131
        • Saugy M.
        • Robinson N.
        • Saudan C.
        • Baume N.
        • Avois L.
        • Mangin P.
        Human growth hormone doping in sport.
        Br J Sports Med. 2006; 40 (doi: 40/suppl_1/i35 [pii].): i35-i39
        • Rudman D.
        • Feller A.G.
        • Nagraj H.S.
        • et al.
        Effects of human growth hormone in men over 60 years old.
        N Engl J Med. 1990; 323 (doi: 10.1056/NEJM199007053230101 [doi].): 1-6
        • Liu H.
        • Bravata D.M.
        • Olkin I.
        • et al.
        Systematic review: The safety and efficacy of growth hormone in the healthy elderly.
        Ann Intern Med. 2007; 146 (doi: 146/2/104 [pii].): 104-115
        • Barake M.
        • Arabi A.
        • Nakhoul N.
        • et al.
        Effects of growth hormone therapy on bone density and fracture risk in age-related osteoporosis in the absence of growth hormone deficiency: a systematic review and meta-analysis.
        Endocrine. 2018; 59 (doi: 10.1007/s12020-017-1440-0 [doi].): 39-49
        • Karges B.
        • Pfäffle R.
        • Boehm B.O.
        • Karges W.
        Acromegaly induced by growth hormone replacement therapy.
        Horm Res. 2004; 61 (doi: 10.1159/000076007 [doi].): 165-169
        • Eskander E.
        • Bonert V.
        Acromegaly as a complication of growth hormone therapy.
        AACE Clinical Case Rep. 2015; 1 (doi:10.4158/EP14165.CR [doi].): e68-e72
        • Child C.J.
        • Conroy D.
        • Zimmermann A.G.
        • Woodmansee W.W.
        • Erfurth E.M.
        • Robison L.L.
        Incidence of primary cancers and intracranial tumour recurrences in GH-treated and untreated adult hypopituitary patients: analyses from the hypopituitary control and complications study.
        Eur J Endocrinol. 2015; 172 (doi: 10.1530/EJE-14-1123 [doi].): 779-790
        • van Varsseveld N.C.
        • van Bunderen C.C.
        • Franken A.A.
        • Koppeschaar H.P.
        • van der Lely A.J.
        • Drent M.L.
        Tumor recurrence or regrowth in adults with nonfunctioning pituitary adenomas using GH replacement therapy.
        J Clin Endocrinol Metab. 2015; 100 (doi: 10.1210/jc.2015-1764 [doi].): 3132-3139
        • Chesnokova V.
        • Zhou C.
        • Ben-Shlomo A.
        • et al.
        Growth hormone is a cellular senescence target in pituitary and nonpituitary cells.
        Proc Natl Acad Sci U S A. 2013; 110 (doi: 10.1073/pnas.1310589110 [doi].): E3331-E3339
        • Perry J.K.
        • Wu Z.S.
        • Mertani H.C.
        • Zhu T.
        • Lobie P.E.
        Tumour-derived human growth hormone as a therapeutic target in oncology.
        Trends Endocrinol Metab. 2017; 28 (doi: S1043–2760(17)30067-X [pii].): 587-596
        • Boguszewski C.L.
        • Boguszewski MCDS.
        Growth hormone's links to cancer.
        Endocr Rev. 2019; 40 (doi: 10.1210/er.2018-00166 [doi].): 558-574
        • Brown P.
        • Brandel J.P.
        • Sato T.
        • et al.
        Iatrogenic Creutzfeldt-Jakob disease, final assessment.
        Emerg Infect Dis. 2012; 18 (doi: 10.3201/eid1806.120116 [doi].): 901-907
        • Holdaway I.M.
        • Bolland M.J.
        • Gamble G.D.
        A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortality in acromegaly.
        Eur J Endocrinol. 2008; 159 (doi: 10.1530/EJE-08-0267 [doi].): 89-95
        • Ritvonen E.
        • Löyttyniemi E.
        • Jaatinen P.
        • et al.
        Mortality in acromegaly: a 20-year follow-up study.
        Endocr Relat Cancer. 2016; 23 (doi: 10.1530/ERC-16-0106 [doi].): 469-480
        • Bolfi F.
        • Neves A.F.
        • Boguszewski C.L.
        • Nunes-Nogueira V.S.
        Mortality in acromegaly decreased in the last decade: a systematic review and meta-analysis.
        Eur J Endocrinol. 2018; 179 (doi: 10.1530/EJE-18-0255 [doi].): 59-71
        • Gadelha M.R.
        • Kasuki L.
        • Lim D.S.T.
        • Fleseriu M.
        Systemic complications of acromegaly and the impact of the current treatment landscape: an update.
        Endocr Rev. 2019; 40 (doi: 10.1210/er.2018-00115 [doi].): 268-332
        • Cook D.
        • Owens G.
        • Jacobs M.
        Human growth hormone treatment in adults: balancing economics and ethics.
        Am J Manag Care. 2004; 10 (doi: 2745 [pii].): S417-S419
        • Canaris G.J.
        • Steiner J.F.
        • Ridgway E.C.
        Do traditional symptoms of hypothyroidism correlate with biochemical disease?.
        J Gen Intern Med. 1997; 12 (doi: 10.1046/j.1525-1497.1997.07109.x [doi].): 544-550
        • Cappola A.R.
        The thyrotropin reference range should be changed in older patients.
        JAMA. 2019; ([Epub ahead of print]. doi: 10.1001/jama.2019.14728 [doi].)
        • Mooijaart S.P.
        • Du Puy R.S.
        • Stott D.J.
        • et al.
        Association between levothyroxine treatment and thyroid-related symptoms among adults aged 80 years and older with subclinical hypothyroidism.
        JAMA. 2019; ([Epub ahead of print]. doi: 10.1001/jama.2019.17274 [doi].): 1-11
        • Pollock M.A.
        • Sturrock A.
        • Marshall K.
        • et al.
        Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: randomised double blind placebo controlled crossover trial.
        BMJ. 2001; 323 (doi: 10.1136/bmj.323.7318.891 [doi].): 891-895
        • Dubois S.
        • Abraham P.
        • Rohmer V.
        • et al.
        Thyroxine therapy in euthyroid patients does not affect body composition or muscular function.
        Thyroid. 2008; 18 (doi: 10.1089/thy.2007.0037 [doi].): 13-19
        • Livadas S.
        • Bothou C.
        • Androulakis I.
        • Boniakos A.
        • Angelopoulos N.
        • Duntas L.
        Levothyroxine replacement therapy and overuse: a timely diagnostic approach.
        Thyroid. 2018; ([Epub ahead of print]. doi: 10.1089/thy.2018.0014 [doi].)
        • Cohen J.H.
        • Ingbar S.H.
        • Braverman L.E.
        Thyrotoxicosis due to ingestion of excess thyroid hormone.
        Endocr Rev. 1989; 10 (doi: 10.1210/edrv-10-2-113 [doi].): 113-124
        • Bhasin S.
        • Wallace W.
        • Lawrence J.B.
        • Lesch M.
        Sudden death associated with thyroid hormone abuse.
        Am J Med. 1981; 71 (doi: 0002-9343(81)90392-2 [pii].): 887-890
        • Beierwaltes W.H.
        • Ruff G.E.
        Thyroxin and triiodothyronine in excessive dosage to euthyroid humans.
        AMA Arch Intern Med. 1958; 101 (doi: 10.1001/archinte.1958.00260150057007 [doi].): 569-576
        • Danowski T.S.
        • Sarver M.E.
        • D Ambrosia R.D.
        • Moses C.
        Hydrocortisone and/or desiccated thyroid in physiologic dosage. X. Effects of thyroid hormone excesses on clinical status and thyroid indices.
        Metabolism. 1964; 13 (doi: 0026-0495(64)90016-2 [pii].): 702-716
        • Lovejoy J.C.
        • Smith S.R.
        • Bray G.A.
        • et al.
        A paradigm of experimentally induced mild hyperthyroidism: effects on nitrogen balance, body composition, and energy expenditure in healthy young men.
        J Clin Endocrinol Metab. 1997; 82 (doi: 10.1210/jcem.82.3.3827 [doi].): 765-770
        • Hollingsworth D.R.
        • Amatruda Jr, T.T.
        • Scheig R.
        Quantitative and qualitative effects of L-triiodothyronine in massive obesity.
        Metabolism. 1970; 19 (doi: 0026-0495(70)90040-5 [pii].): 934-945
        • Riggs D.S.
        • Man E.B.
        • Winkler A.W.
        Serum iodine of euthyroid subjects treated with desiccated thyroid.
        J Clin Invest. 1945; 24 (doi: 10.1172/JCI101657 [doi].): 722-731
        • Qato D.M.
        • Alexander G.C.
        • Conti R.M.
        • Johnson M.
        • Schumm P.
        • Lindau S.T.
        Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States.
        JAMA. 2008; 300 (doi: 10.1001/jama.2008.892 [doi].): 2867-2878
        • Mechanick J.I.
        • Brett E.M.
        • Chausmer A.B.
        • Dickey R.A.
        • Wallach S.
        American Association of Clinical Endocrinologists medical guidelines for the clinical use of dietary supplements and nutraceuticals.
        Endocr Pract. 2003; 9 (doi: C7TYMYF9E2MHNWHB [pii].): 417-470
        • Negro R.
        • Greco G.
        • Mangieri T.
        • Pezzarossa A.
        • Dazzi D.
        • Hassan H.
        The influence of selenium supplementation on postpartum thyroid status in pregnant women with thyroid peroxidase auto-antibodies.
        J Clin Endocrinol Metab. 2007; 92 (doi: jc.2006-1821 [pii].): 1263-1268
        • Hoang T.D.
        • Mai V.Q.
        • Clyde P.W.
        • Shakir M.K.
        Over-the-counter-drug-induced thyroid disorders.
        Endocr Pract. 2013; 19 (doi: 10.4158/EP12298.OR [doi].): 268-274
        • Kang G.Y.
        • Parks J.R.
        • Fileta B.
        • et al.
        Thyroxine and triiodothyronine content in commercially available thyroid health supplements.
        Thyroid. 2013; 23 (doi: 10.1089/thy.2013.0101 [doi].): 1233-1237
        • Han S.X.
        • Eisenberg M.
        • Larsen P.R.
        • DiStefano 3rd, J.
        THYROSIM app for education and research predicts potential health risks of over-the-counter thyroid supplements.
        Thyroid. 2016; 26 (doi: 10.1089/thy.2015.0373 [doi].): 489-498
        • Sherman S.I.
        • Ringel M.D.
        • Smith M.J.
        • Kopelen H.A.
        • Zoghbi W.A.
        • Ladenson P.W.
        Augmented hepatic and skeletal thyromimetic effects of tiratricol in comparison with levothyroxine.
        J Clin Endocrinol Metab. 1997; 82 (doi: 10.1210/jcem.82.7.4054 [doi].): 2153-2158
        • Bauer B.A.
        • Elkin P.L.
        • Erickson D.
        • Klee G.G.
        • Brennan M.D.
        Symptomatic hyperthyroidism in a patient taking the dietary supplement tiratricol.
        Mayo Clin Proc. 2002; 77 (doi: S0025–6196(11)62003-X [pii].): 587-590
        • Cohen-Lehman J.
        • Charitou M.M.
        • Klein I.
        Tiratricol-induced periodic paralysis: a review of nutraceuticals affecting thyroid function.
        Endocr Pract. 2011; 17 (doi: 10.4158/EP10137. RA [doi].): 610-615
        • Scally M.C.
        • Hodge A.
        A report of hypothyroidism induced by an over-the-counter fat loss supplement (tiratricol).
        Int J Sport Nutr Exerc Metab. 2003; 13 (doi: 10.1123/ijsnem.13.1.112 [doi].): 112-116
        • Ono F.
        • Miyoshi K.
        Clinical observations on thyreoidismus medicamentosus due to weight reducing pills in Japan.
        Endocrinol Jpn. 1971; 18 (doi: 10.1507/endocrj1954.18.321 [doi].): 321-325
        • Ohye H.
        • Fukata S.
        • Kanoh M.
        • et al.
        Thyrotoxicosis caused by weight-reducing herbal medicines.
        Arch Intern Med. 2005; 165 (doi: 165/8/831 [pii].): 831-834
        • Akinyemi E.
        • Bercovici S.
        • Niranjan S.
        • Paul N.
        • Hemavathy B.
        Thyrotoxic hypokalemic periodic paralysis due to dietary weight-loss supplement.
        Am J Ther. 2011; 18 (doi: 10.1097/MJT.0b013e3181c960a9 [doi].): e81-e83
        • Chou H.K.
        • Tsao Y.T.
        • Lin S.H.
        An unusual cause of thyrotoxic periodic paralysis: triiodothyronine-containing weight reducing agents.
        Am J Med Sci. 2009; 337 (doi: 10.1097/01. MAJ.0000310783.66897.b6 [doi].): 71-73
        • Panikkath R.
        • Nugent K.
        I lost weight, but I became weak and cannot walk--a case of nutraceutical (T3)-induced thyrotoxic periodic paralysis.
        Am J Ther. 2014; 21 (doi: 10.1097/MJT.0b013e318288a460 [doi].): e211-e214
        • Nippoldt T.
        Mayo Clinic office visit. Adrenal fatigue. An interview with Todd Nippoldt, M.D.
        Mayo Clin Womens Healthsource. 2010; 14: 6
        • Boynton P.M.
        • Greenhalgh T.
        Selecting, designing, and developing your questionnaire.
        BMJ. 2004; 328 (doi: 10.1136/bmj.328.7451.1312 [doi].): 1312-1315
      7. Available at: https://adrenalfatiguesolution.com/testing-for-adrenal-fatigue/. Accessed January 23, 2020.

      8. Available at: https://www.confirmbiosciences.com/products/healthconfirm-health-and-wellness-test/. Accessed January 23, 2020.

        • Marx C.E.
        • Lee J.
        • Subramaniam M.
        • et al.
        Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia.
        Psychopharmacology (Berl). 2014; 231 (doi: 10.1007/s00213-014-3673-4 [doi].): 3647-3662
        • Brown E.S.
        • Park J.
        • Marx C.E.
        • et al.
        A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression.
        Neuropsychopharmacology. 2014; 39 (doi: 10.1038/npp.2014.138 [doi].): 2867-2873
        • Vallée M.
        Neurosteroids and potential therapeutics: focus on pregnenolone.
        J Steroid Biochem Mol Biol. 2016; 160 (doi: 10.1016/j.jsbmb.2015.09.030 [doi].): 78-87
        • Marx C.E.
        • Keefe R.S.
        • Buchanan R.W.
        • et al.
        Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia.
        Neuropsychopharmacology. 2009; 34 (doi: 10.1038/npp.2009.26 [doi].): 1885-1903
        • Elraiyah T.
        • Sonbol M.B.
        • Wang Z.
        • et al.
        Clinical review: the benefits and harms of systemic dehydroepiandrosterone (DHEA) in postmenopausal women with normal adrenal function: a systematic review and meta-analysis.
        J Clin Endocrinol Metab. 2014; 99 (doi: 10.1210/jc.2014-2261 [doi].): 3536-3542
        • Cleare A.J.
        • Heap E.
        • Malhi G.S.
        • Wessely S.
        • O'Keane V.
        • Miell J.
        Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial.
        Lancet. 1999; 353 (doi: S0140-6736(98)04074-4 [pii].): 455-458
        • McKenzie R.
        • O'Fallon A.
        • Dale J.
        • et al.
        Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomized controlled trial.
        JAMA. 1998; 280 (doi: joc80695 [pii].): 1061-1066
        • Blockmans D.
        • Persoons P.
        • Van Houdenhove B.
        • Lejeune M.
        • Bobbaers H.
        Combination therapy with hydrocortisone and fludrocortisone does not improve symptoms in chronic fatigue syndrome: a randomized, placebo-controlled, double-blind, crossover study.
        Am J Med. 2003; 114 (doi: S0002934303001827 [pii].): 736-741
        • Saka K.
        • Konuma K.
        • Asai S.
        • Unuma K.
        • Nakajima M.
        • Yoshida K.
        Identification of active ingredients in dietary supplements using non-destructive mass spectrometry and liquid chromatography-mass spectrometry.
        Forensic Sci Int. 2009; 191 (doi: 10.1016/j.forsciint.2009.07.007 [doi].): e5-e10
        • Bornstein S.R.
        • Allolio B.
        • Arlt W.
        • et al.
        Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline.
        J Clin Endocrinol Metab. 2016; 101 (doi: 10.1210/jc.2015-1710 [doi].): 364-389
      9. Available at: https://www.hormone.org/. Accessed January 23, 2020.

      10. Available at: https://www.aace.com/disease-state-resources/search. Accessed January 23, 2020.

      11. Available at: https://www.mayoclinic.org/patient-care-and-health-information. Accessed January 23, 2020.

      12. Available at: https://my.clevelandclinic.org/health. Accessed January 23, 2020.