Abstract
Endocrine disruptors have gained widespread attention owing to their severe adverse health impacts. These produce enormous burden of disease and are associated with high economic cost especially in developed countries. Environmental pollutants causing endocrine disruption include pesticides, industrial wastes, packaging materials, food constituents, plastics, and cosmetic products. Likewise, pharmaceutical drugs have the endocrine disrupting potential through a wide array of mechanisms. Antipsychotic, antiepileptic, antihypertensive, antiviral, antidiabetic, and anticancer drugs are among the foremost non-hormonal endocrine disruptors. Several drugs affect thyroid hormone synthesis via interaction with iodine uptake to the release of T3 and T4 by thyrocytes. Prolonged use of some drugs increase susceptibility to diabetes mellitus either by direct destruction of β cells or enhanced insulin resistance. Other drugs may cause serious developmental defects in male or female reproductive system. Appropriate understanding of the mechanisms of endocrine disruption associated with non-hormonal drugs will guide future drug development and help us prevent and cure endocrine-related toxicity of pharmaceuticals. Therefore, this review focuses on endocrine disruption by pharmaceutical drugs as their side effect.
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Ahmed S, Van Gelder IC, Wiesfeld AC, Van Veldhuisen DJ, Links TP (2011) Determinants and outcome of amiodarone-associated thyroid dysfunction. Clin Endocrinol 75:388–394
Albert O et al (2013) Paracetamol, aspirin and indomethacin display endocrine disrupting properties in the adult human testis in vitro. Hum Reprod 28:1890–1898
Alberti KGMM, Zimmet Pf (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional Report of a WHO Consultation Diabetic Medicine 15:539–553
Aleksić Ž, Aleksić A (2011) Incidence of amiodarone-induced thyroid dysfunction and predictive factors for their occurrence. Med Pregl 64:533–538
Alonso-Magdalena P, Quesada I, Nadal A (2011) Endocrine disruptors in the etiology of type 2 diabetes mellitus. Nat Rev Endocrinol 7:346–353
Andreone P et al (2014) ABT-450, ritonavir, ombitasvir, and dasabuvir achieves 97% and 100% sustained virologic response with or without ribavirin in treatment-experienced patients with HCV genotype 1b infection. Gastroenterology 147:359–365. e351
Anway MD, Cupp AS, Uzumcu M, Skinner MK (2005) Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308:1466–1469
Barbesino G (2010) Drugs affecting thyroid function. Thyroid 20:763–770
Bartalena L, Brogioni S, Grasso L, Bogazzi F, Burelli A, Martino E (1996) Treatment of amiodarone-induced thyrotoxicosis, a difficult challenge: results of a prospective study. J Clin Endocrinol Metabol 81:2930–2933
Barzilay JI et al (2006) Fasting glucose levels and incident diabetes mellitus in older nondiabetic adults randomized to receive 3 different classes of antihypertensive treatment: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 166:2191–2201
Batcher EL, Tang XC, Singh BN, Singh SN, Reda DJ, Hershman JM, Investigators S-T (2007) Thyroid function abnormalities during amiodarone therapy for persistent atrial fibrillation. Am J Med 120:880–885
Bay K, Main KM, Toppari J, Skakkebæk NE (2011) Testicular descent: INSL3, testosterone, genes and the intrauterine milieu. Nat Rev Urol 8:187–196
Ben-Aharon I, Bar-Joseph H, Tzarfaty G, Kuchinsky L, Rizel S, Stemmer SM, Shalgi R (2010) Doxorubicin-induced ovarian toxicity. Reprod Biol Endocrinol 8:20
Benjamin RW, Calikoglu AS (2007) Hyperthyroidism and lupus-like syndrome in an adolescent treated with minocycline for acne vulgaris. Pediatr Dermatol 24:246–249
Bennet H et al (2016) Serotonin (5-HT) receptor 2b activation augments glucose-stimulated insulin secretion in human and mouse islets of Langerhans. Diabetologia 59:744–754
Benotti MJ, Trenholm RA, Vanderford BJ, Holady JC, Stanford BD, Snyder SA (2008) Pharmaceuticals and endocrine disrupting compounds in US drinking water. Environ Sci Technol 43:597–603
Berens S, Wolff J, Murphy D (1990) Lithium concentration by the thyroid. Endocrinology 87:1085–1087
Braverman LE, Cooper D (2012) Werner & Ingbar’s the thyroid: a fundamental and clinical text. Lippincott Williams & Wilkins
Brown TT et al (2005) Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study. Arch Intern Med 165:1179–1184
Burikhanov RB, Matsuzaki S (2000) Excess iodine induces apoptosis in the thyroid of goitrogen-pretreated rats in vivo. Thyroid 10:123–129
Caraccio N et al (2009) Effect of type I interferon (s) on cell viability and apoptosis in primary human thyrocyte cultures. Thyroid 19:149–155
Cooper RL, Kavlock RJ (1997) Endocrine disruptors and reproductive development: a weight-of-evidence overview. J Endocrinol 152:159–166
Cossburn M et al (2011) Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort. Neurology 77:573–579
Danaei G, Rodríguez LAG, Cantero OF, Hernán MA (2013) Statins and risk of diabetes: an analysis of electronic medical records to evaluate possible bias due to differential survival. Diabetes Care 36:1236–1240
De-Wit S et al (2008) Incidence and risk factors for new-onset diabetes in HIV-infected patients. Diabetes Care 31:1224–1229
Desai J et al (2006) Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med 145:660–664
Dobrzyńska MM, Czajka U, Słowikowska MG (2006) Reproductive effects after exposure of male mice to vincristine and to a combination of X-rays and vincristine. Reprod Fertil Dev 17:759–767
Frungieri MB, Gonzalez-Calvar SI, Parborell F, Albrecht M, Mayerhofer A, Calandra RS (2006) Cyclooxygenase-2 and prostaglandin F2α in Syrian hamster Leydig cells: inhibitory role on luteinizing hormone/human chorionic gonadotropin-stimulated testosterone production. Endocrinology 147:4476–4485
Gao X, Mizuyachi K, Terranova PF, Rozman KK (2001) 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin decreases responsiveness of the hypothalamus to estradiol as a feedback inducer of preovulatory gonadotropin secretion in the immature gonadotropin-primed rat. Toxicol Appl Pharmacol 170:181–190
Gao X, Petroff BK, Oluola O, Georg G, Terranova PF, Rozman KK (2002) Endocrine disruption by indole-3-carbinol and tamoxifen: blockage of ovulation. Toxicol Appl Pharmacol 183:179–188
Gareri P et al (2014) Use of atypical antipsychotics in the elderly: a clinical review. Clin Interv Aging 9:1363
Garry VF, Schreinemachers D, Harkins ME, Griffith J (1996) Pesticide appliers, biocides, and birth defects in rural Minnesota. Environ Health Perspect 104:394
Gianfrancesco FD, Grogg AL, Mahmoud RA, Wang R-h, Nasrallah HA (2002) Differential effects of risperidone, olanzapine, clozapine, and conventional antipsychotics on type 2 diabetes: findings from a large health plan database. The Journal of Clinical Psychiatry 63:920–930
Gonzalez-Rey M, Bebianno MJ (2012) Does non-steroidal anti-inflammatory (NSAID) ibuprofen induce antioxidant stress and endocrine disruption in mussel Mytilus galloprovincialis? Environ Toxicol Pharmacol 33:361–371
Group NDD (1979) Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28:1039–1057
Guenette MD, Hahn M, Cohn TA, Teo C, Remington GJ (2013) Atypical antipsychotics and diabetic ketoacidosis: a review. Psychopharmacology 226:1–12
Gupta C, Goldman AS (1986) The arachidonic acid cascade is involved in the masculinizing action of testosterone on embryonic external genitalia in mice. Proc Natl Acad Sci 83:4346–4349
Haliakon S et al (1997) Pioglitazone induces in vivo adipocyte differentiation in the obese Zucker fa/fa rat. Diabetes 46:1393–1399
Hamed SA, Moussa EM, Tohamy AM, Mohamed KO, Mohamad ME, Sherif TM, Abdellah MM (2015) Seminal fluid analysis and testicular volume in adults with epilepsy receiving valproate. J Clin Neurosci 22:508–512
Han S et al (2010) Endocrine disruption and consequences of chronic exposure to ibuprofen in Japanese medaka (Oryzias latipes) and freshwater cladocerans Daphnia magna and Moina macrocopa. Aquat Toxicol 98:256–264
Hayashi A, Sonoda R, Kimura Y, Takasu T, Suzuki M, Sasamata M, Miyata K (2004) Antiobesity effect of YM348, a novel 5-HT 2C receptor agonist, in Zucker rats. Brain Res 1011:221–227
Heindel JJ, Newbold R, Schug TT (2015) Endocrine disruptors and obesity nature reviews. Endocrinology 11:653–661
Hellman B, Grapengiesser E (2014) Glucose-induced inhibition of insulin secretion. Acta Physiol 210:479–488
Huerta B et al (2016) Determination of a broad spectrum of pharmaceuticals and endocrine disruptors in biofilm from a waste water treatment plant-impacted river. Sci Total Environ 540:241–249
Huhtaniemi IT, Korenbrot CC, Jaffe RB (1977) HCG binding and stimulation of testosterone biosynthesis in the human fetal testis. J Clin Endocrinol Metabol 44:963–967
Ivell R, Anand-Ivell R (2009) Biology of insulin-like factor 3 in human reproduction. Hum Reprod Update 15:463–476
Jensen MS et al (2010) Maternal use of acetaminophen, ibuprofen, and acetylsalicylic acid during pregnancy and risk of cryptorchidism. Epidemiology 21:779–785
Keith SW et al (2006) Putative contributors to the secular increase in obesity: exploring the roads less traveled. Int J Obes 30:1585–1594
Kinoshita S et al (2016) Risk factors for amiodarone-induced thyroid dysfunction in Japan. J arrhythmia 32:474–480
Kjærstad MB, Taxvig C, Nellemann C, Vinggaard AM, Andersen HR (2010) Endocrine disrupting effects in vitro of conazole antifungals used as pesticides and pharmaceuticals. Reprod Toxicol 30:573–582
Kristensen DM et al. (2010) Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat. Human Reproduction:deq323
Kristensen DM, Lesné L, Le Fol V, Desdoits-Lethimonier C, Dejucq-Rainsford N, Leffers H, Jégou B (2012) Paracetamol (acetaminophen), aspirin (acetylsalicylic acid) and indomethacin are anti-androgenic in the rat foetal testis. Int J Androl 35:377–384
Kroeze WK et al (2003) H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology 28:519
Laakso M, Kuusisto J (2017) Diabetes secondary to treatment with statins. Curr Diab Rep 17:10
Labrie F, Bélanger A, Cusan L, Gomez J-L, Candas B (1997) Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J Clin Endocrinol Metab 82:2396–2402
Lazarus JH (2009) Lithium and thyroid best practice & research. Clin Endocrinol Metab 23:723–733
Leslie WS, Hankey CR, Lean ME (2007) Weight gain as an adverse effect of some commonly prescribed drugs: a systematic review. QJM 100:395–404
Liew Z, Ritz B, Rebordosa C, Lee P-C, Olsen J (2014) Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders. JAMA Pediatr 168:313–320
Liu M, Hales BF, Robaire B (2014) Effects of four chemotherapeutic agents, bleomycin, etoposide, cisplatin, and cyclophosphamide, on DNA damage and telomeres in a mouse spermatogonial cell line. Biol Reprod 90(72):71–10
Lv Z, Chu Y, Wang Y (2015) HIV protease inhibitors: a review of molecular selectivity and toxicity. HIV/AIDS (Auckland, NZ) 7:95–99
Malhi GS, Tanious M, Das P, Coulston CM, Berk M (2013) Potential mechanisms of action of lithium in bipolar disorder. CNS drugs 27:135–153
Masaki T et al (2004) Involvement of hypothalamic histamine H1 receptor in the regulation of feeding rhythm and obesity. Diabetes 53:2250–2260
Massart C, Hody B, Condé D, Leclech G, Nicol M (1989) Effect of amiodarone and propranolol on the functional properties of human thyroid follicles cultured in collagen gel. Mol Cell Endocrinol 62:113–117
Mazaud-Guittot S et al (2013) Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent. J Clin Endocrinol Metabol 98:E1757–E1767
McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR (2012) Lithium toxicity profile: a systematic review and meta-analysis. Lancet 379:721–728
Mennigen JA et al (2008) Effects of fluoxetine on the reproductive axis of female goldfish (Carassius auratus). Physiol Genomics 35:273–282
Mezosi E et al (2005) Induction and regulation of Fas-mediated apoptosis in human thyroid epithelial cells. Mol Endocrinol 19:804–811
Mitchell R et al (2012) Do phthalates affect steroidogenesis by the human fetal testis? Exposure of human fetal testis xenografts to di-n-butyl phthalate. J Clin Endocrinol Metabol 97:E341–E348
Mortensen J, Woolner LB, Bennett WA (1955) Gross and microscopic findings in clinically normal thyroid glands. J Clin Endocrinol Metabol 15:1270–1280
Mostafalou S, Abdollahi M (2013) Pesticides and human chronic diseases: evidences, mechanisms, and perspectives. Toxicol Appl Pharmacol 268:157–177
Moutzouri E, Liberopoulos E, Mikhailidis D, Kostapanos M, Kei A, Milionis H, Elisaf M (2011) Comparison of the effects of simvastatin vs. rosuvastatin vs. simvastatin/ezetimibe on parameters of insulin resistance. Int J Clin Pract 65:1141–1148
Müller J (2003) Impact of cancer therapy on the reproductive axis. Horm Res Paediatr 59:12–20
Nakamura K et al (2011) Type 1 diabetes and interferon therapy. Diabetes Care 34:2084–2089
Parrella A, Lavorgna M, Criscuolo E, Russo C, Isidori M (2014) Estrogenic activity and cytotoxicity of six anticancer drugs detected in water systems. Sci Total Environ 485:216–222
Phan GQ, Attia P, Steinberg SM, White DE, Rosenberg SA (2001) Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma. J Clin Oncol 19:3477–3482
Phung OJ, Scholle JM, Talwar M, Coleman CI (2010) Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes. JAMA 303:1410–1418
Pollock AJ, Seibert T, Allen DB (2016) Severe and persistent thyroid dysfunction associated with tetracycline-antibiotic treatment in youth. J Pediatr 173:232–234
Posadas I, Santos P, Blanco A, Muñoz-Fernández M, Ceña V (2010) Acetaminophen induces apoptosis in rat cortical neurons. PLoS One 5:e15360
Prasad P, Ogawa S, Parhar IS (2015) Serotonin reuptake inhibitor citalopram inhibits GnRH synthesis and spermatogenesis in the male zebrafish. Biol Reprod 93(102):101–110
Radi F, Hasni M (2014) Obesogens as an environmental risk factor for obesity. Malaysian J Public Health Med 14:63–70
Ranade A, Rai R, Pai M, Nayak S, Krisnamurthy A, Narayana S (2008) Anatomical variations of the thyroid gland: possible surgical implications. Singap Med J 49:831
Rao A, Kremenevskaja N, Resch J, Brabant G (2005) Lithium stimulates proliferation in cultured thyrocytes by activating Wnt/β-catenin signalling. Eur J Endocrinol 153:929–938
Rao R, McCready V, Spathis G (1986) Iodine kinetic studies during amiodarone treatment. J Clin Endocrinol Metabol 62:563–568
Rizzo DC (2015) Fundamentals of anatomy and physiology. In: Cengage Learning
Røste L, Taubøll E, Mørkrid L, Bjørnenak T, Saetre E, Mørland T, Gjerstad L (2005) Antiepileptic drugs alter reproductive endocrine hormones in men with epilepsy. Eur J Neurol 12:118–124
Schulte PF, Bocxe JT, Doodeman HJ, van Haelst IM, Cohen D (2016) Risk of new-onset diabetes after long-term treatment with clozapine in comparison to other antipsychotics in patients with schizophrenia. J Clin Psychopharmacol 36:115–119
Serretti A, Mandelli L (2010) Antidepressants and body weight: a comprehensive review and meta-analysis. J Clin Psychiatry 71:1259–1272
Shine B, McKnight RF, Leaver L, Geddes JR (2015) Long-term effects of lithium on renal, thyroid, and parathyroid function: a retrospective analysis of laboratory data. Lancet 386:461–468
Sklar CA et al (2006) Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst 98:890–896
Soga T, Wong DW, Clarke IJ, Parhar IS (2010) Citalopram (antidepressant) administration causes sexual dysfunction in male mice through RF-amide related peptide in the dorsomedial hypothalamus. Neuropharmacology 59:77–85
Svalheim S, Sveberg L, Mochol M, Taubøll E (2015) Interactions between antiepileptic drugs and hormones. Seizure 28:12–17
Takano T, Takada K, Tada H, Nishiyama S, Amino N (1994) Genistein but not staurosporine can inhibit the mitogenic signal evoked by lithium in rat thyroid cells (FRTL-5). J Endocrinol 143:221–226
Tijani JO, Fatoba OO, Petrik LF (2013) A review of pharmaceuticals and endocrine-disrupting compounds: sources, effects, removal, and detections. Water Air Soil Pollut 224:1770
Toppari J, Kaleva M, Virtanen HE, Main KM, Skakkebæk NE (2007) Luteinizing hormone in testicular descent. Mol Cell Endocrinol 269:34–37
Trasande L et al (2015) Estimating burden and disease costs of exposure to endocrine-disrupting chemicals in the European Union. J Clin Endocrinol Metabol 100:1245–1255
Trip MD, Wiersinga W, Plomp TA (1991) Incidence, predictability, and pathogenesis of amiodarone-induced thyrotoxicosis and hypothyroidism. Am J Med 91:507–511
Vial T, Descotes J (1994) Clinical toxicity of the interferons. Drug Saf 10:115–150
Welsh M, Saunders PT, Fisken M, Scott HM, Hutchison GR, Smith LB, Sharpe RM (2008) Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J Clin Invest 118:1479–1490
Wiersinga W (1991) Propranolol and thyroid hormone metabolism. Thyroid 1:273–277
Xiaotian X, Hengzhong Z, Yao X, Zhipan Z, Daoliang X, Yumei W (2013) Effects of antiepileptic drugs on reproductive endocrine function, sexual function and sperm parameters in Chinese Han men with epilepsy. J Clin Neurosci 20:1492–1497
Zafrir B, Jain M (2014) Lipid-lowering therapies, glucose control and incident diabetes: evidence, mechanisms and clinical implications. Cardiovasc Drugs Ther 28:361–377
Zillich AJ, Garg J, Basu S, Bakris GL, Carter BL (2006) Thiazide diuretics, potassium, and the development of diabetes. Hypertension 48:219–224
Zornitzki T, Malnick S, Lysyy L, Knobler H (2015) Interferon therapy in hepatitis C leading to chronic type 1 diabetes. World J Gastroenterol: WJG 21:233
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Sabir, S., Akhtar, M.F. & Saleem, A. Endocrine disruption as an adverse effect of non-endocrine targeting pharmaceuticals. Environ Sci Pollut Res 26, 1277–1286 (2019). https://doi.org/10.1007/s11356-018-3774-4
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DOI: https://doi.org/10.1007/s11356-018-3774-4