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RECENT ADVANCES IN ENDOCRINOLOGY Oncocrinology Sanjay Kalra,1 Gagan Priya,2 Saptarshi Bhattacharya,3 Rakesh Sahay4

Abstract Table-1: Domains of oncocrinology. Oncocrinology is the science which studies the complex Domain Examples bi-directional relationship between cancer and the , including pathophysiological links, Common etiologies of cancer u Endocrine disruptor chemicals clinical presentation and the impact of cancer and endocrine disease u Genetic syndromes that increase the treatment and endocrine therapy. This review describes risk of both endocrinopathy and cancer the vast spectrum of the complex, multifacted u relationship between the endocrine system and Endocrine etiologies of cancer u Obesity malignancy. It also includes the endocrine aspects of u – type 2 and pancreatic diabetes u anti-cancer treatment, and the need for oncovigilance Acromegaly u Chronic lymphocytic thyroiditis with endocrine therapy. u Polycystic ovary syndrome Keywords: Cancer, Endocrine cancer, Endocrine Cancers of endocrine glands u Single glands u neoplasia, Endocrinology, Malignancy, Oncology, Multiple endocrine glands u Single glands with metastasis to other Oncovigilance. endocrine structures Introduction u Non-endocrine tumors with metastasis to endocrine glands The fields of oncology and endocrinology have much in Endocrine effect of cancers u Endocrine paraneoplastic syndromes common. Both are young specialties, and have u Direct effects experienced marked growth in recent years. A sudden Endocrine markers for diagnosis u Serum β-hCG (human chorionic gonadotrophin) and sustained rise in the prevalence of both cancer and /monitoring of cancer u AFP (alfa fetoprotein) endocrinopathy has stimulated interest in these u PSA (prostate specific antigen) subjects. This has led to enhanced understanding of the u Urinary and plasma metanephrines pathophysiology and natural history of disease. This, in and catecholamines u Growth and IGF-1 turn, has encouraged development of newer modes of u Serum cortisol and ACTH (including screening, diagnosis, therapy and monitoring. suppression tests) Endocrinology and oncology overlap each other at u Serum thyroglobulin multiple points along this pathway. This review u Serum , phosphorus, PTH, PTHrP describes the vast spectrum of this complex, bi- and FGF-23 directional relationship, under the umbrella term u Calcitonin ‘oncocrinology’. u Serum (, DHEAS) Endocrine therapy for cancers u Medical Definition and Domains u Surgical Oncocrinology is the science which studies the complex Endocrine side effects of u Immune checkpoint inhibitors cancer therapy u Interferon alpha bi-directional relationship between cancer and the u Vinca alkaloids endocrine system, including pathophysiological links, u mTOR inhibitors clinical presentation and the impact of anticancer u Tyrosine kinase inhibitors treatment on functioning of endocrine glands cancer u Metyrapone and mitotane treatment and endocrine therapy. The subject of u Radiation and gamma knife therapy oncocrinology includes several domains as discussed Neoplastic side effects of u Pioglitazone – risk of bladder cancer endocrine therapy u Risk of malignancy with glargine (controversial) Department of Endocrinology, 1Bharti Hospital, Karnal, 2Fortis and Ivy u Risk of malignancy with Hospitals, Mohali, 3Max Hospital, New Delhi, 4Osmania Medical College, therapy (controversial) Hyderabad, India. u -progesterone therapy – risk of Correspondence: Sanjay Kalra. Email: [email protected]

J Pak Med Assoc Oncocrinology 758 below and summarized in Table-1. tumours; dysfunction in thyroid cancers; hypercortisolism, primary hyperaldosteronism or Common Etiology pheochromocytoma due to adrenal tumours; secondary Cancer and endocrine disease are multifactorial in diabetes related to pancreatic carcinoma; menstrual etiology. This is evident from research implicating disturbances in gynaecological malignancies; bad endocrine disruptor chemical in not only endocrinopathy, obstetric outcomes in gestational trophoblastic disease; but congenital anomalies and malignancy as well.1-3 and hirsutism, reproductive, sexual or urinary dysfunction Exposure to supraphysiological hormonal levels, in -dependent tumours. (endocrine drugs) is also implicated in causation of certain hormone-dependent tumours, such as carcinoma Paraneoplastic endocrine syndromes are characterized by endometrium (unopposed estrogen), carcinoma breast, endocrine manifestations occurring at a site distant from and carcinoma prostate.4-6 In addition, diabetes mellitus the primary tumour or its metastasis, as summarized in and obesity are associated with increased risk of several Table-2. Common paraneoplastic syndromes include malignancies including breast, colorectal and pancreatic Cushing’s syndrome due to ectopic ACTH cancer.7,8 Chronic thyroiditis is associated with increased (adrenocorticotrophic hormone) secretion, SIADH risk of thyroid cancer.9 Individuals with acromegaly have a (syndrome of inappropriate antidiuretic hormone significantly increased risk of colon polyps and cancer.10 secretion), oncogenic osteomalacia, and tumour-induced hypoglycaemia. Cancers of Endocrine Organs Cancer may affect any organ in the body, and endocrine At times, tumours present with, and are diagnosed by glands are no exception. Cancer can afflict any endocrine specific endocrine phenomena. These include gland, from pituitary to the gonads. Metastatic tumours prolactinoma, acromegaly or gigantism, Cushing’s may spread to involve endocrinologically active syndrome due to pituitary or adrenal tumour, parathyroid structures (such as the bone). Some malignancies, adenoma, -secreting tumours, characterized by multi-glandular involvement, are termed pheochromocytoma, insulinoma, nesidioblastosis, as multiple endocrine neoplasia (MEN). Neuroendocrine glucagonoma, and carcinoid tumours. Carcinoid tumours tumours and carcinoid tumours are unique malignancies of the midgut are characterized by the occurrence of of the endocrine system and often manifest with carcinoid syndrome. It occurs primarily when extensive endocrine system hyperfunction which can be the hepatic metastases from midgut carcinoid circumvents presenting feature of the disease.11 the hepatic inactivation of bioactive amines secreted by the tumour. Foregut carcinoids and metastases into areas Endocrine Effects of Cancers not drained by portal circulation can also cause atypical Certain cancers are associated with endocrine carcinoid syndrome.12 dysfunction, either directly or indirectly. Direct effects Endocrine Diagnosis and Monitoring may include hypopituitarism, acromegaly, hypercortisolism or hyperthyroidism related to pituitary Some cancers can be detected by the use of endocrine

Table-2: Common endocrine paraneoplastic syndromes.

Manifestation Mechanism Tumor

Hypercalcaemia Parathyroid hormone-related protein Squamous cell carcinomas (lung, head, and neck) or renal, bladder, breast, or ovarian carcinomas Osteolytic metastasis Multiple myeloma, breast cancer Increased production of 1,25-dihydroxyvitamin D Hodgkin and non-Hodgkin lymphoma, ovarian dysgerminoma Cushing’s syndrome Ectopic ACTH secretion Small cell lung cancer, carcinoid tumour, medullary thyroid carcinoma, pancreatic neuroendocrine tumours, pheochromocytoma, ganglioneuromas Ectopic CRH production Medullary thyroid carcinoma, paragangliomas, , islet cell neoplasms Precocious , Human chorionic gonadotrophin secretion Choriocarcinomas, testicular embryonal carcinomas, seminomas, lung and pancreatic cancer, Hypoglycaemia Increased IGF-II production Mesenchymal tumours, fibromas, carcinoid, myelomas, lymphomas, hepatocellular, and colorectal carcinomas SIADH Increased ADH secretion Small cell cancer of lungs, head and neck cancer, olfactory neuroblastoma Tumour induced osteomalacia FGF 23 secretion Mesenchymal tumours (osteoblastomas, giant cell osteosarcomas, haemangiopericytomas, haemangiomas, nonossifying fibromas

Vol. 70, No. 4, April 2020 759 S. Kalra, G. Priya, S. Bhattacharya, et al

Table-3: Endocrine therapy of cancer.

Endocrine Drug Indication

Cabergoline or bromocriptine Prolactinoma Somatostatin analogues, e.g, octreotide, lanreotide or pasireotide Acromegaly, Cushing’s syndrome, intestinal neuroendocrine tumors , aromatase inhibitors, eg, anastrazole, letrozole Carcinoma breast Thyroxine Postoperative suppression of TSH in thyroid cancer Medroxyprogesterone acetate Carcinoma endometrium GNRH analogues Carcinoma ovary, prostate Glucocorticoids Acute leukaemia, adjuvant to chemotherapy Metformin Adjuvant for carcinoma breast; primary prevention of carcinoma colon Surgical Gonadectomy?

Table-4: Anticancer drug induced endocrine dysfunction.

Endocrine Gland Disorder Medication

Pituitary Hypophysitis Immune checkpoint inhibitors Interferon Alpha SIADH Vinca alkaloids: Vincristine, vinblastine, vinorelbine Platinum compounds: Cisplatin, carboplatin Alkylating compounds: Cyclophosphamide, ifosfamide, melphalan Others: Methotrexate, interferon alpha and gamma Central hypothyroidism Bexarotene Hypopituitarism Radiation, Gamma knife Thyroid Primary Hypothyroidism Immune checkpoint inhibitors, tyrosine kinase inhibitors, interferon alpha, interleukin 2, analogues, radioiodine-based cancer therapy, radiation Thyroiditis Immune checkpoint inhibitors, tyrosine kinase inhibitors, inteferon alpha, interleukin 2, thalidomide analogues Graves’ disease Alemtuzumab Central hypothyroidism Immune checkpoint inhibitors, bexarotene Pancreas/Glucose metabolism Hyperglycaemia/ Diabetes mellitus Immune checkpoint inhibitors mTOR (mammalian target of rapamycin) kinase inhibitors (e.g. everolimus) Tyrosine kinase inhibitors 5-fluorouracil based chemotherapy Glucocorticoids Hypoglycaemia 6-Mercaptopurine, thiogunaine Adrenal Adrenalitis/ primary Immune checkpoint inhibitors adrenal insufficiency Primary adrenal insufficiency Mitotane, Metyrapone, Abiraterone Glucocorticoids Opiates Gonads Akylating agents Other chemotherapy agents Radiation therapy Bone/ Calcium metabolism Osteoporosis Aromatase inhibitors: anastrozole, letrozole, Androgen Deprivation Therapy Medical or surgical oophorectomy Glucocorticoids Hypocalcaemia Cisplatin 5-fluorouracil and leucovorin Bisphosphonates, Denosumab Lipid Metabolism Dyslipidaemia Androgen deprivation therapy, Tamoxifen, Aromatase inhibitors Hypertriglyceridaemia Bexarotene, Asparaginase

J Pak Med Assoc Oncocrinology 760 markers. These biomarkers can also be used to monitor endocrine care. progress or relapse of the disease. Examples include β- hCG (human chorionic gonadotrophin) in gestational Summary trophoblastic disease, AFP (alfa fetoprotein) in The oncocrinology rubric encompasses a vast spectrum of extragonadal germ cell tumours, PSA (prostate specific pathophysiological processes and disorders. Detailed antigen) in prostate cancer, urinary catecholamines in understanding of these concepts is necessary to avoid childhood neuroblastoma and calcitonin in medullary endocrine dysfunction related morbidities which might thyroid cancer.13 Biochemical diagnoses of some of the result from the tumour itself or its therapy. Besides, endocrine tumours make use of the dynamicity of increased awareness about carcinogenic potential of endocrine axis. Examples are GH suppression test for some of the endocrine therapies and endocrinopathies acromegaly, dexamethasone suppression for Cushing’s might lead to early detection and treatment of certain syndrome and saline load test for diagnosis of primary cancers. It is believed that detailed understanding of the hyperaldosteronism including aldosterone secreting interconnection between endocrinology and oncology adrenal tumours. will optimise patient care and outcome. Endocrine Therapy of Cancers References Many cancers are amenable to hormonal or endocrine 1. Kabir ER, Rahman MS, Rahman I. A review on endocrine disruptors and their possible impacts on human health. Environ Toxicol therapy. These include estrogen/androgen dependent Pharmacol. 2015; 40:241-258. tumours, as well as tumours with sex receptors. 2. Emfietzoglou R, Spyrou N, Mantzoros CS, Dalamaga M. Could the Breast cancer, endometrial cancer and carcinoma endocrine disruptor bisphenol-A be implicated in the prostate or testes are conditions where endocrine drugs pathogenesis of oral and oropharyngeal cancer? Metabolic 14-18 considerations and future directions. Metabolism. 2019; 91:61-69. are used as first line therapy (Table-3). Prolactinoma is 3. Raghavan R, Romano ME, Karagas MR, Penna FJ. Pharmacologic a tumour where medical endocrine intervention is and Environmental Endocrine Disruptors in the Pathogenesis of considered the treatment of choice.19 Glucocorticoids Hypospadias: a Review. Curr Environ Health Rep. 2018; 5:499-511. have for long been an important adjunct to of 4. Shields TS1, Weiss NS, Voigt LF, Beresford SA. The additional risk of endometrial cancer associated with unopposed estrogen use in chemotherapy as adjuvant drugs. Endocrinotropic women with other risk factors. Epidemiology. 1999; 10:733-738. molecules such as metformin have also been successfully 5. Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. exapted for use as neoadjuvant therapy in breast cancer, N Engl J Med. 2006; 354:270-82. and primary prevention of ovarian malignancy.20 6. DeLay KJ, Kohler TS. Testosterone and the Prostate: Artifacts and Truths. Urol Clin North Am. 2016; 43:405-412. Endocrine Side Effects of Anti-Cancer 7. Saito E, Charvat H, Goto A, et al. Burden of cancer associated with type 2 diabetes mellitus in Japan, 2010-2030. Cancer Sci. 2016; Therapy 107:521–527. As newer anti-cancer agents are being developed, and 8. Himbert C, Delphan M, Scherer D, Bowers LW, Hursting S, Ulrich used with greater frequency, unique endocrine side CM. Signals from the Adipose Microenvironment and the Obesity- Cancer Link-A Systematic Review. Cancer Prev Res (Phila). 2017; effects are being uncovered. Immune checkpoint 10:494–506. inhibitors, for example, are associated with the possibility 9. Chen YK, Lin CL, Cheng FT, Sung FC, Kao CH. 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