J Toxicol Pathol 2002; 15: 1–6

Commentary Pathogenic Mechanisms of Endocrine Disease in Domestic and Laboratory Animals

Charles C. Capen1

1Department of Veterinary Biosciences, The Ohio State University, 1925 Coffey Road, Columbus, OH 43210, U.S.A.

Introduction blood cortisol levels resulting from the ACTH-stimulated and of the zonae fasciculata and The objective of this presentation is to summarize the reticularis of the adrenal cortex. In some aging dogs with major pathogenic mechanisms responsible for perturbations similar marked adrenal cortical enlargement and functional of endocrine function that result in important diseases in disturbances of cortisol-excess, there is no gross or domestic and laboratory animals. For each major category, histopathologic evidence of a in the pituitary several specific disease problems have been selected to gland. These animals may have a change in negative illustrate the functional and morphologic lesions that are feedback control with a reduced inhibition of ACTH characteristic for either a naturally occurring endocrinopathy production by the pars intermedia of the pituitary gland due or endocrine disturbances induced by the administration of to an age-related increase in monoamine oxidase-β in the xenobiotic chemicals. Disorders of the are hypothalamus and increased metabolism of dopamine. The encountered in a wide variety of animal species and, as in end result is severe corticotroph hyperplasia, elevated ACTH human patients, often present challenging diagnostic problems. The examples to be discussed, by necessity, will be highly selective and include disease problems investigated by our laboratory as well as data from the literature.

Primary Hyperfunction

One of the most important mechanisms of endocrine disease is primary hyperfunction (Fig. 1). A lesion (most often a neoplasm derived from endocrine cells) synthesizes and secretes a hormone at an autonomous rate in excess of the body’s ability to utilize and subsequently degrade the hormone, thereby, resulting in functional disturbances of hormone-excess. A number of specific examples occur in different animal species. Fig. 1. Secondary Hyperfunction

In secondary hyperfunction a lesion in one organ secretes an excess of trophic hormone that leads to long-term stimulation and hypersecretion of a target organ (e.g. adrenal cortex) (Fig. 2). A classic example of this pathogenic mechanism in animals is the ACTH-secreting tumor derived from pituitary corticotrophs in dogs. The functional disturbances and lesions primarily are the result of elevated

Mailing address: Charles C. Capen, Distinguished University Professor and Chairman, Department of Veterinary Biosciences, The Ohio State University, 1925 Coffey Road, Columbus, OH 43210, U.S.A. TEL: 1-614-292-4489 FAX: 1-614-292-6473 Fig. 2. E-mail: [email protected] 2 Mechanisms of Endocrine Disease levels in the blood, and long-term stimulation of the adrenal significant hypofunction of the adrenal cortex, follicular cortex resulting in the syndrome of cortisol-excess. cells of the thyroid, and gonads. The disruption of growth hormone secretion has little effect on body stature because Primary Hypofunction lesions of this type usually develop in adult to aged animals. Hypofunction of an endocrine organ also may be secondary In primary hypofunction, hormone secretion either is to a lack of raw materials (e.g. iodine) necessary for the subnormal due to excessive destruction of secretory cells by synthesis of hormone (T4, T3). Marginal deficiencies often a disease process, the failure of an endocrine organ to are associated with the presence of goitrogenic chemicals in develop properly (aplasia or ), or the result of a the diet that interfere with the process of hormone synthesis specific biochemical defect in the synthetic pathway of a by thyroid follicular cells. hormone (Fig. 3). Immune-mediated injury appears to be an important mechanism resulting in hypofunction of endocrine Endocrine Hyperactivity Secondary to Other glands in animals including the parathyroid, adrenal cortex, Conditions thyroid gland, pancreatic islets, and hypothalamus. The best known example of endocrine hyperactivity Secondary Hypofunction secondary to diseases of other organs in animals is hyperparathyroidism that develops secondary to either A destructive lesion in one organ (i.e. pituitary gland) chronic renal failure or nutritional imbalances (Fig. 5). In interferes with the secretion of trophic hormones and results the renal form, the retention of phosphorus early and in subnormal function of target endocrine glands in subsequent progressive destruction of cells in the proximal secondary hypofunction (Fig. 4). Large, endocrinologically- convoluted tubules intereferes with the metabolic activation inactive may interfere with the secretion of of vitamin D by 1α-hydroxylase in the kidney. This is the multiple pituitary trophic hormones and result in clinically rate-limiting step in the metabolic activation of vitamin D and is tightly controlled by parathyroid hormone and several other factors including the serum phosphorus concentration and other hormones. The impaired intestinal absorption of calcium results in the development of progressive hypocalcemia that leads to long-term parathyroid stimulation and development of generalized demineralization of the skeleton. Nutritional hyperparathyroidism develops in animals fed abnormal diets that are either low in calcium, high in phosphorus, or deficient in cholecalciferol (e.g. new world nonhuman primates). Hyperfunction of an endocrine organ also can be the result of hormonal imbalances induced by xenobiotic chemicals (Fig. 6). For example, hyperactivity of the pituitary gland in rodents during chronic toxicity testing often results in an increased development of tumors in the gonads or mammary glands. An excess production of Fig. 3.

Fig. 4. Fig. 5. Capen 3 luteinizing hormone (LH) usually due to disruption of result in persistent, often life-threatening, hypercalcemia. A negative feedback control by estrogen or testosterone well characterized example of this disease mechanism in increases the incidence of tubulo-stromal adenomas and animals is the adenocarcinoma derived from the apocrine granulosal cell tumors in the ovary of mice and Leydig glands of the anal sac in dogs. These tumors produced PTH- (interstitial) adenomas of the testes in rats. rP that results in an accelerated mobilization of calcium from bone by osteoclasts and leads to the development of Hypersecretion of Hormones by Nonendocrine persistent hypercalcemia. Serum PTH levels are lower in Tumors dogs with apocrine carcinomas than in controls and PTH levels are undetectable in tumor tissue. Certain neoplasms of nonendocrine tissues in both animals and man either secrete new humoral substances or Failure of Target Cells to Respond to Hormone hormones that share chemical and/or biologic characteristics with the “native” hormones secreted by an This mechanism of endocrine disease has been endocrine gland (Fig. 7). Most of the recently discovered appreciated coincident with the more complete humoral substances secreted by nonendocrine tumors are understanding of how hormones interact with target cells to peptides rather than steroids, iodothyronines or convey their biologic message. A failure of target cells to catecholamines, which require more complex biosynthetic respond to hormone may be due either to a lack of adenylate pathways. Humoral hypercalcemia of malignancy cyclase in the cell membrane or to an alteration in hormone (“pseudohyperparathyroidism”) is a clinical syndrome receptors on the cell surface (Fig. 8). Hormone is secreted in produced primarily by the autonomous hypersecretion of normal or increased amounts by the cells of the endocrine parathyroid hormone-related peptide (PTH-rP) by cancer gland. For example, insulin-resistance associated with cells. PTH-rP is able to interact with the parathyroid obesity in both animals and humans can result from a hormone receptor in target cells (e.g. bone and kidney) and decrease or “down regulation” of receptors on the surface of target cells. This develops in response to the chronic increased insulin secretion stimulated by the hyperglycemia resulting from the excessive food intake. Secretory cells in the corresponding endocrine gland (i.e. pancreatic islets) undergo compensatory hypertrophy and hyperplasia in an attempt to secrete additional hormone. An interesting form of hypoparathyroidism has been reported in human patients in which the inability of target cells to respond is due to a defect in the cAMP-mediated signal transduction resulting from a lack of specific nucleotide regulatory protein in the cell membrane. Patients with “pseudohypoparathyroidism” develop hypocalcemia and hyperphosphatemia in spite of hyperplastic parathyroids and elevated blood levels of PTH.

Fig. 6.

Fig. 7. *PEPTIDES NOT STEROIDS, IODOTHYRONINES OR Fig. 8. CATECHOLAMINES 4 Mechanisms of Endocrine Disease

Failure of Fetal Endocrine Function

Subnormal activity of the fetal endocrine system, especially in ruminants, may disrupt normal fetal development and result in prolongation of the gestation period (Fig. 9). In Guernsey and Jersey cattle, there is a genetically determined failure of development (aplasia) of the adenohypophysis. This results in a lack of fetal pituitary trophic hormone secretion during the last trimester and hypoplastic development of target endocrine organs. Fetal development is normal up to approximately seven months gestation but subsequently fetal growth ceases irrespective of how long the viable fetus is retained in utero. The concepts that have emerged from the study of these naturally occurring diseases are: first, fetal hormones are necessary for Fig. 9. final growth and development in utero in certain animals; and second, normal parturition at term in these species requires an intact fetal hypothalamic-adenohypophyseal- adrenal cortical axis working in concert with trophoblasts of the placenta.

Abnormal Degradation of Hormone

Increased degradation In laboratory rodents, the long-term administration of various xenobiotics (i.e. phenobarbital and others) results in the induction of liver enzymes (e.g. T4–UDP glucuronyl transferase) that increase the degradation of thyroxine (Fig. 10). This chronic disruption of the thyroid-pituitary axis and augmented TSH secretion in rodents, especially male rats, often increases the development of thyroid follicular cell tumors in chronic toxicity and oncogenicity studies with Fig. 10. certain drugs and chemicals (Fig. 11).

Decreased degradation The rate of secretion of hormone by an endocrine gland may be normal with this mechanism but blood levels are persistently elevated, thereby simulating a syndrome of hypersecretion, due to a decreased rate of degradation (Fig. 10). The classic example of this pathogenic mechanism is the syndrome of feminization due to hyperestrogenism associated with cirrhosis and decreased hepatic degradation of estrogens. Chronic renal disease in dogs occasionally is associated with hypercalcemia due, in part, to decreased degradation of PTH (along with decreased urinary excretion of calcium) by the diseased kidney.

Iatrogenic Syndromes of Hormone-Excess

The administration of hormone, either directly or indirectly, influences the activity of target cells with this mechanism and results in important functional disturbances (Fig. 12). It is well recognized that the administration of Fig. 11. potent preparations of adrenal cortical steroids at inappropriately high daily doses for prolonged intervals in the symptomatic treatment of various diseases can produce most of the functional disturbances associated with an Capen 5

end points of the thyroid gland. Toxicol Pathol 1997; 25: 39– 48. Capen CC. Chemically induced injury of the parathyroid glands: Pathophysiology and mechanistic considerations. In: Endocrine Toxicology, 2nd ed., JA Thomas, and H Colby (eds), Washington D.C.: Taylor and Francis, 1–42, 1997. Capen CC. Thyroid and parathyroid toxicology. In: Endocrine and Hormonal Toxicology, PW Harvey, K Rush and A Cockburn (eds), Sussex, England: John Wiley & Sons Ltd., 33–66, 1999. Capen CC, DeLellis RA, and Williams ED. Experimental thyroid carcinogenesis: Role of radiation and xenobiotic chemicals. In: Radiation and Thyroid Cancer, G Thomas, A Karaoglou, and ED Williams (eds), Singapore, New Jersey, London, Hong Kong: World Scientific Publishing, 167–176, 1999. Fig. 12. Capen CC. Tumors of the endocrine glands. In: Moulton’s Tumors in Domestic Animals, 4th ed., DJ Meuten (ed), Ames, IA: Iowa State University Press, in press. Capen CC. Anatomy, comparative anatomy, and histology of the thyroid. In: Werner and Ingbar’s The Thyroid: A endogenous hypersecretion of cortisol. Similarly, the Fundamental and Clinical Text, 8th ed., LE Braverman, and administration of excessively large doses of insulin can RD Utiger (eds), Philadelphia: Lippincott-Raven Publishers, result in hypoglycemia and an excess T4/T3 may result in 20–44, 2000. hyperthyroidism, especially in certain species (e.g. cats) that Capen CC. Endocrine System. In: Thomson's Special Veterinary have limited capacity to conjugate T4 with glucuronic acid Pathology, 3rd ed., D McGavin, WW Carlton, and JF and enhance biliary excretion. Zachary (eds), St. Louis: Mosby Publishers, 279–323, 2001. The administration of progestogens to dogs indirectly Clegg ED, Cook JC, Chapin RE, Foster PMD, and Daston GP. results in a syndrome of growth hormone-excess. The Leydig cell hyperplasia and adenoma formation: injection of medroxyprogesterone acetate for the prevention Mechanisms and relevance to humans. Reproduc Toxicol 1997; 11: 107–121. of estrus in dogs stimulates the expression of the growth Curran PG and DeGroot LJ. The effect of hepatic enzyme- hormone gene in the mammary gland and results in many of inducing drugs on thyroid hormones and the thyroid gland. the clinical manifestations of acromegaly due to elevated Endocrine Rev 1991; 12: 135–150. circulating growth hormone levels. Hotz KJ, Wilson AGE, Thake DC, Roloff MV, Capen CC, Kronenberg JM, and Brewster DW. Mechanism of References thiazopyr-induced effects on thyroid hormone homeostasis in male Sprague-Dawley rats. Toxicol Appl Pharmacol Alison RH, Capen CC, and Prentice DE. Neoplastic lesions of 1997; 142: 133–142. questionable significance to humans. Toxicol Pathol 1994; Lynch BS, Tischler AS, Capen CC, Monroe IC, McGirr LM, and 22: 179–186. McClain RM. Low digestible carbohydrate (polyols and Capen CC. The Endocrine glands. In: Pathology of Domestic lactose): Significance of adrenal medullary proliferative Animals, 4th ed., KVF Jubb, PC Kennedy, and N Palmer lesions in the rat. Regulatory Toxicol Pharmacol 1996; l23: (eds), New York: Academic Press Inc., 267–347, 1993. 256–297. Capen CC and Rosol TJ. Pathobiology of parathyroid hormone McClain RM, Posch RC, Bosakowski T, and Armstrong JM. and parathyroid hormone-related protein: Introduction and Studies on the mode of action for thyroid gland tumor evolving concepts. In: Pathology of the Thyroid and promotion in rats by phenobarbital. Toxicol Appl Pharmacol Parathyroid Gland: An Update, VA LiVolsi, and RA 1988; 94: 254–265. DeLellis (eds), Philadelphia: Williams and Wilkins Co., 1– McClain RM, Levin AA, Posch R, and Downing JC. The effects 33, 1993. of phenobarbital on the metabolism and excretion of Capen CC. Toxic responses of the endocrine system. In: Casarett thyroxine in rats. Toxicol Appl Pharmacol 1989; 99: 216– and Doull’s Toxicology: The Basic Science of Poisons, 5th 228. ed., CD Klaassen (ed), New York: McGraw Hill, 617–640, McClain RM. Mechanistic considerations in the regulation and 1995. classification of chemical carcinogens. In: Nutritional Capen CC, Dayan AD, and Green S. Receptor-mediated Toxicology, FN Kotsonis, M Mackey, and J Hjelle (eds), mechanisms in carcinogenesis: An overview. Mutation Res New York: Raven Press, Ltd., 273–304, 1994. 1995; 333: 215–224. Rosol TJ and Capen CC. Biology of disease. Mechanisms of Capen CC. Hormonal imbalances and mechanisms of chemical cancer-induced hypercalcemia. Lab Invest 1992; 67: 680– injury of thyroid gland. In: Endocrine System: Monographs 702. on the Pathology of Laboratory Animals, 2nd ed., TC Jones, Rosol TJ, Nagode LA, Couto CG, Hammer AS, Chew DJ, CC Capen and U Mohr (eds), Berlin, Heidelberg, New York: Peterson JL, Ayl RD, Steinmeyer CL, and Capen CC. International Life Sciences Institute, 217–238, 1996. Parathryoid hormone (PTH)-related protein, PTH, and 1,25- Capen CC. Mechanistic data and risk assessment of selected toxic dihydroxyvitamin D in dogs with cancer-associated 6 Mechanisms of Endocrine Disease

hypercalcemia. Endocrinology 1992; 131: 1157–1164. Neoplasia, 5th ed., B Feldman, J Zinkl, and N Jain (eds), Rosol TJ, Steinmeyer CL, McCauley LK, Grone A, DeWille JW, Baltimore: Williams and Wilkins, 660–666, 2000. and Capen CC. Sequences of the cDNAs encoding canine Studer H and Derwahl M. Mechanisms of nonneoplastic parathyroid hormone-related protein and parathyroid endocrine hyperplasia—A changing concept: A review hormone. Gene 1995; 60: 241–243. focused on the thyroid gland. Endocrine Rev 1995; 16: 411– Rosol TJ and Capen CC. Calcium-regulating hormones and 425. diseases of abnormal mineral (calcium, phosphorus, Yarrington JT, Latendresse JR, and Capen CC. Toxic responses magnesium) metabolism. In: Clinical Biochemistry of of the adrenal cortex. In: Comprehensive Toxicology, IG Domestic Animals, 5th ed., JJ Kaneko, JW Harvey and ML Sipes, CA McQueen, and AJ Gandolfi (eds-in-chief), Vol. Bruss (eds), New York: Academic Press, 619–702, 1997. 10, Chapter 49. Reproductive and Endocrine Toxicology, (K Rosol TJ and Capen CC. Humoral hypercalcemia of malignancy. Boekelheide, et al., eds), Oxford, New York, Tokyo: In: Schalm’s Veterinary Hematology. Section: Lymphoid Elsevier Science/Pergamon, 647–658, 1997.