Introduction to the Endocrine System: Mechanisms of Disease
Mark J. Hoenerhoff, DVM, PhD, DACVP Associate Professor, In Vivo Animal Core Unit for Laboratory Animal Medicine University of Michigan Medical School
1.1 Lairmore and Rosol, Vet Pathol. 2008 May;45(3):285-286.
1.2 HORMONES CONTROL EVERYTHING!!
1.3 quora.com “CAPEN’S TEN LAWS” OF ENDOCRINE DISEASE 1. Primary Hyperfunction 2. Secondary Hyperfunction 3. Primary Hypofunction 4. Secondary Hypofunction 5. Endocrine Hyperactivity 2o to Other Organ Disease 6. Hypersecretion of Hormones by Non-endocrine Tumors 7. Endocrine Dysfunction due to Failure of Target Cell Response 8. Failure of Fetal Endocrine Function 9. Endocrine Dysfunction 2o to Abnormal Hormone Degradation 10. Syndromes of Iatrogenic Hormone Excess
1.4 Capen CC. Endocrine Glands. In: Maxie G, ed. Jubb, Kennedy & Palmer’s Pathology of Domestic Animals. 5th ed. Elsevier; 2007:325-326. Papadopoulos and Cleare, Nat Rev Endocrinol. 2011 Sept 27;8(1):22-32 1.5 Bassett and Williams, Bone. 2008 Sep;43(3):418-426. 1. PRIMARY HYPERFUNCTION OF ENDOCRINE ORGANS
• Often result of functional neoplastic disease of endocrine gland • Autonomous secretion of hormones – DIRECT effect on target organ • Outpaces body’s ability to utilize and degrade hormone • Functional disturbance of hormone excess • Parathyroid chief cell tumors Hyperparathyroidism • Thyroid follicular tumors Hyperthyroidism
1.6 1. PRIMARY HYPERFUNCTION
• Parathyroid tumors Hyperparathyroidism
Parathyroid PTH
Solar Arias et al, Open Vet J. 2016;6(3):165-171. 1.7 Bassett and Williams, Bone. 2008 Sep;43(3):418-426. 1. PRIMARY HYPERFUNCTION
• Parathyroid tumors Hyperparathyroidism
Parathyroid PTH
https://ntp.niehs.nih.gov/nnl/index.htmSolar Arias et al, Open Vet J, 2016 1.7 Bassett and Williams, Bone. 2008 Sep;43(3):418-426. 1. PRIMARY HYPERFUNCTION
• Thyroid follicular tumors/hyperplasias Hyperparathyroidism
Thyroid
http://www.animalcancersurgeon.com/
Vet Times. 1.8 Wakeling, 2008 Bassett and Williams, Bone. 2008 Sep;43(3):418-426. 1. PRIMARY HYPERFUNCTION
• Thyroid follicular tumors/hyperplasias Hyperparathyroidism
Thyroid
http://www.animalcancersurgeon.com/ T4 + T3
amcny.org 1.8 Wakeling, Vet Times, 2008 Bassett and Williams, Bone. 2008 Sep;43(3):418-426. 1. PRIMARY HYPERFUNCTION
• Thyroid follicular tumors/hyperplasias Hyperparathyroidism
Thyroid
http://www.animalcancersurgeon.com/ T4 + T3
Freeman et al, Cardiol Res. 2017 Aug;8(4):139-142. amcny.org askjpc.org 1.8 Wakeling, Vet Times, 2008 Bassett and Williams, Bone. 2008 Sep;43(3):418-426. 1. PRIMARY HYPERFUNCTION
• Thyroid follicular tumors/hyperplasias Hyperparathyroidism
Thyroid
http://www.animalcancersurgeon.com/ TT4 4++ T T3 3
Freeman et al, Cardiol Res 2017 amcny.org askjpc.orgmerckvetmanual.com 1.8 Sparkes et al, J Feline Med Surg. 2016 Mar;18(3):219Wakeling, Vet-239. Times, 2008 Bassett and Williams, Bone. 2008 Sep;43(3):418-426. 2. SECONDARY HYPERFUNCTION OF ENDOCRINE ORGANS
• Primary lesion secreting excess trophic hormone • Leads to long-term secondary stimulation of a target organ • INDIRECT effect on target organs
• ACTH-secreting pituitary tumor in dogs (Hyperadrenocorticism) • Pitutiary corticotroph tumor from pars distalis/intermedia • ↑ ACTH Hypertrophy and hyperplasia of zona fasciculata/reticularis • ↑ Cortisol downstream metabolic effects Cushing’s Disease
1.9 2. SECONDARY HYPERFUNCTION
ACTH
CORTISOL
Metabolic Effects 1.10 LaPerle and Capen,. Pathologic Basis of Veterinary Disease. 6th ed. Elsevier; 2016. Papadopoulos and Cleare, Nat Rev Endocrinol. 2011 Sept 27;8(1):22-32 2. SECONDARY HYPERFUNCTION
ACTH
CORTISOL
Metabolic Effects 1.10 Zachary, Pathologic Basis of Veterinary Disease, amcny.org2016 Papadopoulos and Cleare, Nat Rev Endocrinol. 2011 Sept 27;8(1):22-32 3. PRIMARY HYPOFUNCTION OF ENDOCRINE ORGANS
• Hormone secretion is subnormal A. Destruction of secretory cells by a disease process • Autoimmune thyroiditis B. Failure of endocrine gland to develop properly • Pituitary dwarfism C. Biochemical defect in hormone synthesis / lack of specific enzyme • Rickets, goiter
1.11 3. PRIMARY HYPOFUNCTION
A. Destruction of secretory cells by disease process
• Autoimmune thyroiditis askjpc.org • Autoantibodies to thyroid components • Destruction of thyroid cells Hypothyroidism
1.12 horshamvethospital.com.au 3. PRIMARY HYPOFUNCTION
B. Failure of endocrine gland to develop properly • Pituitary dwarfism (panhypopituitarism) in dogs • Failure of oropharyngeal ectoderm in Rathke’s pouch to develop into hormone secreting cells of the adenohypophysis • Benign craniopharyngiomas, cyst formation • Loss of growth hormone
1.13 3. PRIMARY HYPOFUNCTION
C. Biochemical defect in hormone synthesis pathway • Vitamin D-dependent rickets in pigs • Disorder of 1α-hydroxylation (25-dihydroxycholecalciferol-1-a-hydroxylase) • Hypocalcemia/hypophosphatemia • 2○ hyperparathyroidism • Skeletal abnormalities • Thickened growth plates X • Bowed limbs
1.14 3. PRIMARY HYPOFUNCTION
C. Biochemical defect in hormone synthesis pathway • Congenital dyshormonogenetic goiter • Inability of follicular cells to synthesize thyroglobulin • Major component of colloid • Due to defective mRNA processing • Marked reduction in iodination, formation of T3/T4 • Negative feedback (TSH) Thyroid follicular hyperplasia and hypertrophy
1.15 4. SECONDARY HYPOFUNCTION OF ENDOCRINE ORGANS
A. Destructive lesion interferes with secretion of trophic hormones • Large non-functional pituitary adenomas • Loss of secretion of multiple pituitary trophic hormones • Hypofunction of target endocrine organs (adrenal, thyroid, gonads)
B. Insufficient iodide ion available for thyroid hormone synthesis • Calves, piglets, lambs, kids • Inadequate maternal thyroid hormone during development • Fetal thyroid TSH Diffuse hyperplastic goiter
1.16 4. SECONDARY HYPOFUNCTION
Target endocrine organs respond DRAMATICALLY to a lack of normal trophic pituitary hormones 1.17 4. SECONDARY HYPOFUNCTION
Target endocrine organs respond DRAMATICALLY to a lack of normal trophic pituitary hormones 1.17 5. ENDOCRINE HYPERACTIVITY 2O TO OTHER ORGAN DZ
• Secondary Hyperparathyroidism • Chronic renal disease • Nutritional deficiency • Xenobiotic exposure
1.18 5. ENDOCRINE HYPERACTIVITY 2O TO OTHER ORGAN DZ
• Secondary Hyperparathyroidism
Nutritional Renal Low Ca, High Phos Loss of 1-a-hydroxylase in kidney Destruction of PCT cells Low Vit D3 (NHPs)
Loss of Vit D synthesis
Decreased absorption of Ca from gut
Hypocalcemia
Parathyroid chief cell hyperplasia Production of PTH
Resorption of Ca from bone
1.19 Fibrous Osteodystrophy, Rickets 5. ENDOCRINE HYPERACTIVITY 2O TO OTHER ORGAN DZ
• Secondary hyperparathyroidism – Xenobiotic exposure (Rodents) • Chronic exposure pituitary hyperstimulation • Chronic secretion of pituitary gonadotrophins • Androgen or estrogen antagonists Excess LH • ovarian tumors (mice), Leydig cell tumors (rats)
http://www.informatics.jax.org
1.20 5. ENDOCRINE HYPERACTIVITY 2O TO OTHER ORGAN DZ
• Secondary hyperparathyroidism – Xenobiotic exposure (Rodents) • Chronic exposure pituitary hyperstimulation • Chronic secretion of pituitary gonadotrophins • Androgen or estrogen antagonists Excess LH • ovarian tumors (mice), Leydig cell tumors (rats)
• Dopamine antagonists Excess prolactin http://www.informatics.jax.org • Mammary hyperplasia and tumors
www.askjpc.org 1.20 6. HYPERSECRETION OF HORMONES BY NON-ENDOCRINE TUMORS • Humoral hypercalcemia of malignancy “Pseudohyperparathyroidism” • Parathyroid hormone-related peptide (PTH-rp) from tumor cells • Interacts with PTH receptors in bone and kidney • Direct (bone, kidney) and indirect (SI) effects cause hypercalcemia • Osteoclastic bone resorption, increased Ca reabsorption by kidney
1.21 6. HYPERSECRETION BY NON-ENDOCRINE TUMORS
• Apocrine gland adenocarcinoma of anal sac (dogs) • Low serum PTH levels, hypercalcemia • Atrophic parathyroid glands Decreased numbers of inactive chief cells • Tumor PTH-rp does not stimulate chief cells to produce PTH • Responding to persistent hypercalcemia by trophic atrophy • Thyroid C-cells often undergo hyperplasia due to persistent hypercalcemia
1.22 7. ENDOCRINE DYSFUNCTION DUE TO FAILURE OF TARGET CELL RESPONSE • Obesity-induced Insulin Resistance (IR) • Excessive food intake hyperglycemia hyperinsulinemia • Downregulation of insulin receptors on target cells • β-cells in pancreatic islets undergo hypertrophy/hyperplasia
• Large pituitary tumors • Destroy hypothalamic nuclei that control food intake
1.23 8. FAILURE OF FETAL ENDOCRINE FUNCTION
• Due to failure of fetal endocrine organ development • Causes disruption of fetal development and prolongs gestation 1. Aplasia of the adenohypophysis in Jersey and Guernsey cattle 2. Ingestion of Ventrum californicum by ewes early in gestation
Fetal hormones are necessary for final growth and development in utero Normal parturition at term requires an intact hypothalamic-pituitary-adrenal- placental axis
1.24 8. FAILURE OF FETAL ENDOCRINE FUNCTION
• Aplasia of the adenohypophysis in Jersey and Guernsey cattle • Loss of pituitary hormones in last trimester • Fetal development normal up to 7mo gestation, then ceases • Hypoplasia of 2○ endocrine organs Adrenal cortex, thyroid, gonads
Cornillie et al., Vet Rec. 2007;161(11):388-391.
1.25 8. FAILURE OF FETAL ENDOCRINE FUNCTION
• Ingestion of Ventrum californicum by ewes early in gestation • Consumption ~ 9-14 days gestation • Steroidal alkaloids • Malformations in CNS, hypothalamus → Loss of ACTH production → Abnormal development of AC → Lack of cortisol • Birth defects, elongated parturition
1.26 9. ENDOCRINE DYSFUNCTION 2O TO ABNORMAL HORMONE DEGRADATION • Decreased degradation of hormone • Chronic renal disease in dogs and persistent hypercalcemia • Decreased degradation of PTH
• Increased degradation of hormone due to enzyme induction • Induction of liver enzymes by xenobiotics
1.27 9. ENDOCRINE DYSFUNCTION 2O TO ABNORMAL HORMONE DEGRADATION
• Increased degradation of hormone due to enzyme induction
• Chronic xenobiotic exposure (rodents) • Induction of UDP-glucuronyl transferase (liver) • Increased T4 conjugaton, excretion • Negative feedback increased TSH
1.28 Capen CC., Toxicol Pathol. 2001 29(1):8-33 9. ENDOCRINE DYSFUNCTION 2O TO ABNORMAL HORMONE DEGRADATION
• Increased degradation of hormone due to enzyme induction
• Stimulation of thyroid gland (“vicious cycle”) • Follicular hyperplasia/hypertrophy • Thyroid follicular tumors
ntp.niehs.nih.gov ntp.niehs.nih.gov 1.28 Capen CC., Toxicol Pathol. 2001 29(1):8-33 10. SYNDROMES OF IATROGENIC HORMONE EXCESS
• Administration of exogenous hormones • Direct effects • Chronic administration of corticosteroids iatrogenic Cushing’s • Insulin administration hypoglycemia • Exogenous T3/T4 hyperthyroidism (cats) • Indirect effects • Administration of progestins in dogs syndrome of GH excess • Stimulates expression of GH gene classic manifestation of acromegaly
1.29 HORMONES CONTROL EVERYTHING!!
1.30 quora.com References 1. Arias, E.A., et al., Multiple endocrine neoplasia similar to human subtype 2A in a dog: Medullary thyroid carcinoma, bilateral pheochromocytoma and parathyroid adenoma. Open Vet J, 2016. 6(3):165-171. 2. Bassett, J.H. and G.R. Williams, Critical role of the hypothalamic-pituitary-thyroid axis in bone. Bone, 2008. 43(3):418-26. 3. Capen, C.C., Overview of structural and functional lesions in endocrine organs of animals. Toxicol Pathol, 2001. 29(1):8-33. 4. Capen, C.C., Endocrine Glands, in Jubb, Kennedy & Palmer’s Pathology of Domestic Animals, G. Maxie, Editor. 2007, Elsevier. pp. 325-326. 5. Cornillie, P., W. Van den Broeck, and P. Simoens, Prolonged gestation in two Belgian blue cows due to inherited adenohypophyseal hypoplasia in the fetuses. Vet Rec, 2007. 161(11):388-91. 6. Castillo, V., et al., Post-surgical treatment of thyroid carcinoma in dogs with retinoic acid 9 cis improves patient outcome. Open Vet J, 2016. 6(1):6-14. 7. Freeman, L.M., et al., Feline Hypertrophic Cardiomyopathy: A Spontaneous Large Animal Model of Human HCM. Cardiol Res, 2017. 8(4):139-142. 8. Lairmore, M. and T. Rosol, Dr. Charles C. Capen--an enduring legacy in veterinary pathology. Vet Pathol, 2008. 45(3):285-6. 9. LaPerle, K.M.D. and C.C. Capen, Endocrine System, in Pathologic Basis of Veterinary Disease, M.D. McGavin and J.F. Zachary, Editors. 2007, Mosby: St. Louis. 10. Papadopoulos, A.S. and A.J. Cleare, Hypothalamic-pituitary-adrenal axis dysfunction in chronic fatigue syndrome. Nat Rev Endocrinol, 2011. 8(1):22-32. 11. Sparkes, A.H., et al., ISFM Consensus Guidelines on the Diagnosis and Management of Feline Chronic Kidney Disease. J Feline Med Surg, 2016. 18(3):219-39. 1.32