mechanisms and manifestations of endocrine organ toxicity and...

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Mechanisms and Manifestations of EndocrineOrgan Toxicity and Carcinogenicity

TOXICOLOGIC PATHOLOGY, vol 29, no 1, pp 8–33, 2001Copyright 2001 by the Society of Toxicologic Pathologists

Overview of Structural and Functional Lesions in Endocrine Organsof Animals

CHARLES C. CAPEN

Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210

ABSTRACT

The objective of this review is to summarize the pathogenic mechanisms responsible for perturbations of endocrine function anddevelopment of structural lesions that result in important diseases in domestic and laboratory animals. For each major category, severalspeci� c disease problems have been selected to illustrate the functional and morphologic lesions that are characteristic for either anaturally occurring endocrinopathy or endocrine disturbances induced by the administration of large doses of xenobiotic chemicals.The major pathogenic mechanisms responsible for disruption of endocrine function include primary hyperfunction, secondary hyper-function, primary hypofunction, secondary hypofunction, endocrine hyperactivity secondary to other conditions, hypersecretion ofhormones by nonendocrine tumors, failure of target cells to respond to a hormone, failure of fetal endocrine function, abnormaldegradation (increased or decreased rate) of hormone, and iatrogenic syndromes of hormone excess (direct and indirect). Disorders ofthe endocrine system are encountered in a wide variety of domestic and laboratory animal species and often present challengingdiagnostic problems. The development of proliferative lesions, usually hyperplasia and benign tumors, in endocrine organs and hor-mone-responsive tissues are common � ndings in chronic studies with high doses of many nongenotox ic xenobiotic chemicals admin-istered to sensitive rodent species and may have limited signi� cance for human safety assessment.

Keywords. Endocrine lesions; hormonal imbalances; hyperthyroidism; hyperparathyroidism; congenital goiter; hypothyroidism;panhypopituitarism; testicular Leydig cell adenomas; tubulostromal tumors of ovary; humoral hypercalcemia of malignancy ; parathy-roid hormone–related protein; prolonged gestation; hormone degradation; iatrogenic syndromes of hormone excess

INTRODUCTION

The objective of this review is to summarize the majorpathogenic mechanisms responsible for perturbations ofendocrine function that result in important diseases in do-mestic and laboratory animals. For each major category,several speci� c disease problems have been selected toillustrate the functional and morphologic lesions that arecharacteristic for either a naturally occurring endocrinop-athy or endocrine disturbances induced by the adminis-tration of xenobiotic chemicals. Disorders of the endo-crine system are encountered in a wide variety of do-mestic and laboratory animal species and, as in humanpatients, often present challenging diagnostic problems.The development of proliferative lesions (usually hyper-plasia and benign tumors) in endocrine organs and hor-mone-responsive tissues are common � ndings in chronicstudies with high doses of many nongenotoxic xenobioticchemicals administered to sensitive rodent species andmay have limited signi� cance for human safety assess-ment (3, 60). The examples to be discussed, by necessity,

Address correspondence to: Dr Charles C. Capen, 1925 Coffey Road,Department of Veterinary Biosciences, The Ohio State University, Co-lumbus, OH 43210; e-mail: [email protected].

will be highly selective and include disease problems in-vestigated by my laboratory as well as data from the lit-erature.

PRIMARY HYPERFUNCTION

One of the most important mechanisms of endocrinedisease is primary hyperfunction. A lesion, usually a neo-plasm derived from a speci� c population of endocrinecells, synthesizes and secretes a hormone at an autono-mous rate in excess of the body’s ability to utilize andsubsequently degrade the hormone, thereby resulting infunctional disturbances of hormone excess. A number ofspeci� c examples occur in different animal species (Fig-ure 1).

Hyperthyroidism

There has been a dramatic increase in the incidence ofthyroid neoplasms and other focal proliferative lesions incats resulting in hyperthyroidism since the late 1970s,and at present it is one of the two most common endo-crine diseases in adult-age cats (diabetes mellitus beingthe other). Prior to 1980, clinical hyperthyroidism wasdiagnosed infrequently in cats. The reason(s) for the ap-parent increased incidence is (are) uncertain but appear(s)

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Vol. 29, No. 1, 2001 9OVERVIEW OF ENDOCRINE LESIONS

FIGURE 1.—Selected examples of primary hyperfunction of endocrineglands in animals.

to be related, in part, to (a) a larger population of oldercats seeking veterinary medical care, (b) improved assaysfor thyroid hormones, and (c) detailed characterization ofthe clinical syndrome and increased awareness of itscommon occurrence in adult to aged cats by veterinaryclinicians. In addition, there does appear to be a ‘‘real’’increase in the incidence of feline hyperthyroidism overthe last 30 years. Potential risk factors have been reportedto include a predominantly indoor environment, regulartreatment with � ea powders, exposures to herbicides andfertilizers, a diet primarily of canned food, and non-Sia-mese breeds (10 times greater occurrence) (102). It hasbeen suggested that wide variations (excessive to inade-quate) in dietary iodine intake over prolonged periodsmay play a role in the pathogenesis of thyroid disordersin cats (51).

The disease in cats is mechanistically different fromGrave’s disease in human patients, as hyperthyroid catsdo not have elevated circulating levels of thyroid-stimu-lating immunoglobulins comparable to long-acting thy-roid stimulator (LATS) (an autoantibody that binds to thethyroid-stimulating hormone (TSH) receptor and acti-vates follicular cells) (85). Puri� ed immunoglobulin G(IgG) preparations from hyperthyroid cats signi� cantlyincreased 3H -thymidine into DNA and stimulated cellproliferation 15-fold but did not stimulate intracellularcAMP (10). The former could be inhibited completely bya speci� c TSH receptor–blocking antibody. These datasuggest that elevated titers of thyroid growth IgGs arepresent in cats with hyperthyroidism and most likely actby the TSH receptor. This important thyroid disease incats most closely resembles toxic nodular goiter in humanpatients (43, 82). Hyperplastic and neoplastic thyroid tis-sue from cats is transplantable into athymic (nude) miceand continues to overproduce T4 and T3 in a subcuticularlocation.

Studies utilizing primary cultures of enzymatically dis-sociated follicles from thyroid proliferative lesions fromcats with hyperthyroidism have reported that organi� ca-tion and 3H -thymidine labeling continue in the absenceof TSH in contrast to follicles from normal cat thyroids(81). These � ndings suggest that an intrinsic alteration in

follicular cell function occurs in thyroids of cats withmultinodular goiter, leading to autonomy of cell growthand persistent overproduction of thyroid hormones. A re-cent study reported an overexpression of the c-ras on-cogene in areas of nodular hyperplasia and adenomas de-rived from follicular cells in cats with hyperthyroidism,suggesting that mutations in this oncogene may play arole in the pathogenesis of these proliferative lesions (64).

Point mutations in the thyrotropin receptor (TSHR)gene cause 2 forms of thyrotoxicosis in humans, namely,autonomously functioning toxic follicular adenomas andhereditary (autosomal dominant) toxic thyroid hyperpla-sia. The normal feline TSHR sequence between codons480 and 640 is highly homologous to that of other mam-malian TSHRs with 95%, 92%, and 90% amino acididentity between the canine, human, and bovine TSHRs,respectively (79). Analysis of single-stranded conforma-tional polymorphisms in thyroid DNA from sporadic cas-es of feline thyrotoxicosis and leukocyte DNA from 2cases of familial hyperthyroidism in cats failed to identifymutations between codons 480 and 640 of the TSHRgene. These interesting � ndings suggest that TSHR genemutations are not a common cause of the focal prolifer-ative lesions of thyroid follicular cells that result in felinethyrotoxicosis (79).

A number of reports have described a syndrome ofhyperthyroidism in aged cats associated with multinod-ular goiter, adenomas, and occasionally adenocarcinomasderived from follicular cells of the thyroid (47, 59, 73,83). Large adenomas and carcinomas may be detected bypalpation of swellings in the cranioventral cervical re-gion; however, thyroid tumors in cats occasionally aredisplaced caudally to the level of the � rst rib and anteriormediastinum. One or both thyroid lobes are enlarged inhyperthyroid cats. Solitary adenomas derived from thy-roid follicular cells are the most common lesions asso-ciated with hyperthyroidism in cats. The affected thyroidlobe is partially or completely incorporated by the ade-noma. The adenomas often develop in thyroid glandswith areas of multinodular hyperplasia of follicular cells.They appear as solitary, soft, lobulated nodules that en-large and distort the contour of the affected lobe. A thin,� brous connective tissue capsule separates the adenomafrom the adjacent, often compressed, thyroid parenchyma(Figures 2 and 3). The neoplastic cells form irregularlyshaped follicles with occasional papillary in-foldings ofepithelium and variable amounts of colloid. Focal areasof necrosis, mineralization, and cystic degeneration arepresent in larger adenomas. Multiple sections of adeno-mas fail to reveal histological evidence of either vascularor capsular invasion by tumor cells.

Functional thyroid adenomas in cats associated with aclinical syndrome of hyperthyroidism are composed ofcuboidal to columnar follicular cells that form folliclesof varying sizes and shapes (Figure 3). The follicles usu-ally are partially collapsed and contain little colloid be-cause of the intense endocytotic activity of neoplastic fol-licular cells. Long cytoplasmic projections often extendfrom the follicular cells into the lumen to phagocytizecolloid. As a result of the marked endocytotic activity,numerous colloid droplets are present in the apical cy-



10 TOXICOLOGIC PATHOLOGYCAPEN

FIGURE 2.—Follicular cell adenoma (A) in a cat with hyperthyroid-ism. The adenoma is lobulated re� ecting its likely origin from a coa-lescence of multifocal areas of adenomatous hyperplasia. The tumor issharply demarcated from a rim of normal thyroid (arrow). H&E.

FIGURE 3.—Follicular cell adenoma (A) composed of follicles withlittle stored colloid as a result of the autonomous secretion of thyroidhormones. Follicles in the rim of normal thyroid have undergone colloidinvolution (C) and are distended with colloid as a morphologic responseto suppressed TSH levels. A thin � brous capsule (arrow) separates theadenoma from the peripheral rim of thyroid. H&E.

FIGURE 4.—Serum thyroid hormone levels in cats with hyperthyroid-ism. There is a marked elevation of serum thyroxine [T4] (mean 15 g/dl) and triiodothyronine [T3] (mean 300 g/dl) in cats with hyperthy-roidism. From Peterson et al (84).

toplasm of follicular cells in close proximity to the manyelectron-dense lysosomal bodies. The neoplastic follicu-lar cells are considerably larger (2– 4 times) the size ofthe atrophic cells lining the follicles in the rim of normalthyroid. Follicles in the rim of ‘‘normal’’ thyroid arounda functional adenoma are enlarged and distended by anaccumulation of colloid (ie, colloid involution) (Figure3). The follicular cells are low cuboidal and atrophied,with little evidence of endocytotic activity in response tothe elevated levels of thyroid hormones and decreasedcirculating levels of TSH.

Thyroid adenomas must be differentiated from multi-nodular (‘‘adenomatous’’) hyperplasia (‘‘goiter’’) that oc-curs frequently in old cats. These multiple areas of thy-roid hyperplasia usually are microscopic and do not en-large the affected lobe of thyroid unless they are numer-ous. In contrast to adenomas, the areas of nodularhyperplasia are not encapsulated, and the adjacent thyroid

parenchyma is not compressed (105). Histopathological-ly, the hyperplastic nodules are composed of irregularlyshaped follicles lined by cuboidal follicular cells and con-tain variable amounts of colloid. Follicles between thenodules of hyperplasia often have undergone colloid in-volution, suggesting that these focal proliferative lesionsof follicular cells are producing thyroid hormones at anautonomous rate, resulting in decreased circulating TSHconcentrations.

Cats with hyperthyroidism usually have markedly el-evated serum thyroxine (T4) and tri-iodothyronine (T3)levels (Figure 4) (84). The serum thyroxine (T4) levels incats with hyperthyroidism range from 3.4 to 30 g/dl(normal range 1.5– 5.0 g/dl), and serum tri-iodothyron-ine (T3) levels range from 179 to 470 ng/dl (normal 60 –

200 ng/dl). Moderately increased liver-derived serum en-zyme levels, including AST, ALT, SGPT, SGOT, and es-pecially alkaline phosphatase, occur in hyperthyroid cats.The likelihood of developing clinical hyperthyroidism as-sociated with thyroid neoplasms in animals depends on(a) the capability of tumor cells to synthesize T4 and T3(eg, well-differentiated thyroid tumors that form folliclesand produce colloid are more likely to synthesize thyroid




hormones than poorly differentiated solid neoplasms) and(b) the degree of elevation of circulating levels of T4 andT3, which depends on a balance between the rate of se-cretion of thyroid hormones by the tumor and the rate ofdegradation of thyroid hormones. For example, dogs havea much more ef� cient enterohepatic excretory mecha-nism for thyroid hormones than cats and infrequentlyhave clinical signs associated with functional thyroid tu-mors. Cats are very sensitive to phenol and phenol de-rivatives (50) and have a poor ability to conjugate phe-nolic compounds (such as T4) with glucuronic acid andexcrete the T4-glucuronide conjugate into the bile. Thecapacity of conjugation of T3 with sulfate is limited andeasily overloaded. Therefore, cats with relatively smallfunctional proliferative lesions of thyroid follicular cellsoften have considerable elevations in circulating levels ofT4 and T3 with clinical signs of hyperthyroidism.

Primary Hyperparathyroidism

Functional adenomas and carcinomas of parathyroidglands develop in older dogs and cats and often secreteparathyroid hormone (PTH) in excess of normal, result-ing in a syndrome of primary hyperparathyroidism (15).The normal control mechanism of the parathyroid glandby the concentration of blood calcium ion is lost in func-tional parathyroid tumors. Parathyroid hormone secretionby functional tumors is excessive despite an increasedlevel of blood calcium. Cells of the renal tubules are sen-sitive to alterations in the amount of circulating parathy-roid hormone. The hormone acts on cells in the nephroninitially to promote the excretion of phosphorus (proxi-mal tubule) and retention of calcium (distal tubule). Aprolonged increased secretion of parathyroid hormonealso accelerates osteocytic and osteoclastic bone resorp-tion. Mineral is removed from the skeleton and replacedby immature � brous connective tissue and poorly min-eralized osteoid. The bone lesion of � brous osteodystro-phy is generalized throughout the skeleton but is accen-tuated in local areas of increased bone turnover, such asthe maxillae, mandibles, and a subperiosteal location oflong bones (17). Tumors of parathyroid chief cells do notappear to be sequelae of long-standing secondary hyper-parathyroidism of renal or nutritional origin (19). Theincidence of parathyroid adenomas is increased in a dose-dependent manner by both internal (131I) and external (lo-calized X) irradiation in rats (22, 56).

The functional disturbances observed with endocrinol-ogically active parathyroid tumors are the result of thepersistent hypercalcemia, increased urinary calcium andphosphorus excretion with the formation of calculi, andweakening of bones by excessive resorption. Lamenessdue to fractures of long bones may occur after relativelyminor physical trauma. In long-standing cases, compres-sion fractures of vertebral bodies may exert pressure onthe spinal cord and nerves, resulting in motor or sensorydysfunction or both. Facial hyperostosis with partialobliteration of the nasal cavity and loosening or loss ofteeth from alveolar sockets have been observed in dogswith primary hyperparathyroidism due in part to the an-abolic effect of PTH on stimulating osteoblasts to formpoorly mineralized osteoid (receptor-mediated process).

Hypercalcemia results in anorexia, vomiting, constipa-tion, depression, polyuria, polydipsia, and generalizedmuscular weakness due to decreased neuromuscular ex-citability. Radiographic evaluation reveals areas of sub-periosteal cortical bone resorption, loss of lamina duradentes around the teeth, soft-tissue mineralization, bonecysts, and a generalized decrease in bone density withmultiple fractures in advanced cases.

The laboratory tests most useful in establishing the di-agnosis of a primary hyperfunctioning of the parathyroidglands consist of quantitation of total blood calcium andphosphorus plus circulating levels of parathyroid hor-mone (N-terminal or immunoradiometric assay [IRMA]).Although other laboratory � ndings may be variable, per-sistent hypercalcemia ( 12 mg/dl) is a consistent � nding.Dogs evaluated with primary hyperparathyroidism oftenhave had a greatly elevated (13– 20 mg/dl or higher)blood calcium level. The blood phosphorus level is low(4 mg/dl) or in the low to normal range because of in-hibition of renal tubular resorption of phosphorus by ex-cess parathyroid hormone. Serum alkaline phosphataseactivity may be increased because of increased osteo-blastic activity as a response to mechanical stress ofbones weakened by excessive resorption or because ofdirect (receptor-mediated) stimulation of osteoblasts bythe elevated PTH level. The urinary excretion of calciumand phosphorus is increased and may predispose to thedevelopment of nephrocalcinosis and urolithiasis. Accel-erated bone matrix catabolism is re� ected by an increasedexcretion of hydroxyproline in the urine.

Chief cell adenomas result in considerable enlargementusually of a single parathyroid gland. They are locatedeither in the cervical region near the thyroids or rarelywithin the thoracic cavity near the base of the heart (26,55). Parathyroid neoplasms in the precardial mediastinumare derived from ectopic parathyroid tissue displaced intothe thorax along with the expanding thymus during em-bryonic development. The adenomas are sharply demar-cated and encapsulated from the adjacent thyroid gland(Figure 5). Multiple white foci may be seen in the thy-roids of animals with functional parathyroid tumors.These represent areas of C-cell hyperplasia in responseto the long-term hypercalcemia (20) (Figures 5 and 6).All parathyroid glands should be evaluated for evidenceof primary multinodular chief cell hyperplasia that canresult in macroscopic enlargement of multiple glands andpersistent hypercalcemia (37).

By comparison, diffuse chief cell hyperplasia is com-mon in animals as part of the compensatory reaction tochronic renal disease and nutritional imbalances. In sec-ondary (compensatory) chief cell hyperplasia, all 4 para-thyroids are enlarged 2– 5 times their normal size. Chiefcells undergo organellar hypertrophy initially and cellularhyperplasia later to increase parathyroid hormone synthe-sis and secretion in response to a hypocalcemic stimulus.A functional parathyroid adenoma enlarges a single glandto a much greater degree, while the remaining parathy-roids will be atrophic and smaller than normal. Histo-pathological demonstration of a compressed rim of para-thyroid parenchyma and a � brous capsule in an enlarged




FIGURE 5.—Chief cell adenoma (A) in the external parathyroid gland of a dog with primary hyperparathyroidism. The adenoma is sharplydemarcated and encapsulated from the adjacent thyroid gland (arrowhead). The cranial pole of the thyroid is compressed, and there are multifocalareas of C-cell hyperplasia (arrow).

FIGURE 6.—Multifocal C-cell hyperplasia (C) in a dog with primary hyperparathyroidism and persistent hypercalcemia. H&E.FIGURE 7.—Functional chief cell adenoma (A) in parathyroid gland sharply demarcated and partially encapsulated (arrows) from the rim of

adjacent nonneoplas tic parathyroid tissue that has undergon e severe atrophy in response to the persistent hypercalcemia. Prominent fat cells arepresent in the interstitium between the groups of atrophic chief cells in the suppressed parathyroid. H&E.

FIGURE 8.—Diffuse trophic atrophy of nonneoplas tic parathyroid gland in a dog with primary hyperparathyroidism and persistent hypercalcemia.There are prominent fat (F) cells in the interstitium between the groups of atrophic chief cells. H&E.

gland points to the diagnosis of adenoma rather than chiefcell hyperplasia (Figure 7).

Parathyroid adenomas are composed of closely packedchief cells subdivided into small groups by � ne connec-tive tissue septa with many capillaries (Figure 7). Thechief cells are cuboidal or polyhedral, and the abundantcytoplasm stains lightly eosinophilic. Neoplastic chiefcells can form follicle-like structures with a lumen con-taining minimal proteinic material that could (at lowpower) be confused with a thyroid follicular cell tumor.Adenomas are surrounded by a � ne, partial to completeconnective tissue capsule and may compress the adjacentthyroid gland. A rim of functionally suppressed parathy-roid parenchyma usually is present outside the capsule ofsmall endocrinologically active adenomas (Figure 7).These atrophic chief cells are small, are irregular inshape, and have a densely eosinophilic cytoplasm and apycnotic nucleus (94). Similar atrophic chief cells arepresent in the other parathyroid glands in response to the

persistent hypercalcemia (Figure 8). Chief cells compris-ing functional parathyroid adenomas ultrastructurally arein the actively synthesizing stage of the secretory cycle.Multiple large lamellar arrays of rough endoplasmic re-ticulum and clusters of free ribosomes are present in thecytoplasm. However, few mature secretory (‘‘storage’’)granules are present in the cytoplasm, suggesting thatparathyroid hormone is secreted at a faster rate than syn-thesis and storage in autonomous chief cells.

Successful removal of a functional parathyroid ade-noma results in a rapid decrease in circulating parathyroidhormone levels because the half-life of the hormone inplasma is less than 10 minutes. The plasma calcium lev-els in patients with functional chief cell adenomas andovert bone disease may decrease rapidly and be subnor-mal within 12– 24 hours, resulting in life-threatening hy-pocalcemic tetany (Figure 9). Postoperative hypocalce-mia is the result of depressed secretory activity in theremaining atrophic parathyroid tissue (Figure 8), result-




FIGURE 9.—Postoperative hypocalcem ia in dogs following surgicalremoval of the functional parathyroid adenomas. The remaining atro-phic parathyroid glands (as in Figure 8) were unable to maintain theserum calcium because of subnormal rate of PTH secretion. Supple-mental vitamin D and calcium carbonate slowly returned the blood cal-cium to the reference range (shaded area). From Berger and Feldman(8).

FIGURE 10.—Examples of secondary hyperfunction of an endocrinegland due to an abnormal trophic stimulus or change in negative feed-back control with different therapeutic approaches .

ing from long-term suppression by the chronic hypercal-cemia and decreased bone resorption combined with ac-celerated mineralization of organic matrix formed by thehyperplastic osteoblasts along bone surfaces. Infusion ofcalcium gluconate, feeding high-calcium diets, and sup-plemental vitamin D in pharmacological doses usuallywill correct this postoperative complication of primaryhyperparathyroidism.

SECONDARY HYPERFUNCTION

In secondary hyperfunction, a lesion in 1 endocrineorgan secretes an excess of trophic hormone that leads tolong-term stimulation and hypersecretion of a target or-gan (eg, adrenal cortex). A classic example of this path-ogenic mechanism in animals is the ACTH-secreting tu-mor derived from pituitary corticotrophs in dogs (Figure10) (13). The functional disturbances and lesions are theresult primarily of elevated blood cortisol levels resultingfrom the ACTH-stimulated hypertrophy and hyperplasiaof the zonae fasciculata and reticularis of the adrenal cor-tex. In some aging dogs with similar marked adrenal cor-tical enlargement and functional disturbances of cortisolexcess, there is no gross or histopathologic evidence ofa neoplasm in the pituitary gland. These animals mayhave a change in negative feedback control with a re-duced inhibition of ACTH production by the pars inter-media of the pituitary gland due to an age-related in-crease in monoamine oxidase- in the hypothalamus andincreased metabolism of dopamine. The end result is re-duced negative feedback on the pars intermedia, corti-cotroph hyperplasia, elevated ACTH levels in the blood,

and long-term stimulation of the adrenal cortex, resultingin the syndrome of cortisol excess.

Hyperadrenocorticism Associated with an ACTH-Secreting Pituitary Neoplasm

Functional (endocrinologically active) neoplasms aris-ing in the pituitary gland are derived from corticotroph(ACTH-secreting) cells in either the pars distalis or thepars intermedia of dogs. ACTH-secreting neoplasms re-sult in a clinical syndrome of cortisol excess (Cushing’sdisease) by causing secondary hyperfunction of the ad-renal cortex. These neoplasms are encountered most fre-quently in dogs, particularly in adult to aged boxers, Bos-ton terriers, and dachshunds. The pituitary gland is con-sistently enlarged (Figure 11); however, neither the oc-currence nor the severity of functional disturbancesappears to be directly related to the size of the ACTH-producing neoplasm. Since the diaphragma sella is in-complete in the dog, the line of least resistance favorsdorsal expansion of the gradually enlarging pituitarymass. This results in invagination into the infundibularcavity, dilatation of the infundibular recess and the thirdventricle with eventual compression or replacement of thehypothalamus (Figure 11), and possible extension of theneoplasm into the thalamus. Pituitary corticotroph ade-nomas are composed of well-differentiated, large orsmall, chromophobic cells supported by � ne connectivetissue septa. The cytoplasm of the neoplastic cortico-trophs usually contains few or is devoid of secretorygranules but stains immunocytochemically for ACTH andMSH. Hormone-containing small secretory granules canbe demonstrated by electron microscopy in functionalcorticotroph adenomas of dogs.

Bilateral enlargement of the adrenal glands occurs indogs with functional corticotroph adenomas (Figure 11).This enlargement is due to ACTH-mediated cortical hy-pertrophy and hyperplasia, primarily of the zonae fasci-culata and zona reticularis (Figure 12). Nodules of yel-low-orange cortical tissue often are found outside thecapsule as well as extending down into and compressingthe adrenal medulla. These hyperplastic zones are sus-




FIGURE 11.—Secondary hyperfunction of an endocrine gland. Corti-cotrophic (ACTH-secreting) adenom a (A) in the pituitary gland result-ing in bilateral hyperplasia of the adrenal cortices (arrowheads). This isthe most common pathogenic mechanism for the syndrome of cortisolexcess. The scale represents 1 cm.

FIGURE 12.—Secondary hyperfunction of adrenal cortex. Note theprominen t widening of the inner zona fasciculata (F) and reticularis (R)with compression of the outer zona multiformis (M) in a dog with anACTH-producing pituitary adenoma. H&E.

FIGURE 13.—Mechanisms of primary hypofunction of endocrineglands.

ceptible to chemotherapy, especially in dogs, with o,p -DDD (114).

The functional disturbances associated with the syn-drome of secondary hyperadrenocorticism result primar-ily from chronic overproduction of cortisol by hyperac-tive cells of the adrenal cortices. Affected dogs developa spectrum of functional disturbances and lesions fromthe combined gluconeogenic, lipolytic, protein catabolic,and anti-in� ammatory effects of the glucocorticoid hor-mones on many organs. The disease is insidious andslowly progressive. Cortisol excess is one of the mostcommon endocrinopathies in adult and aged dogs andoccurs infrequently in cats but rarely in other domesticand laboratory animals. The appetite and intake of food

often are increased as a direct result of either the hyper-cortisolism or the damage due to compression of hypo-thalamic appetite centers by a large dorsally expandingpituitary gland neoplasm. The muscles of the extremitiesand abdomen are weakened and atrophied, resulting ingradual abdominal enlargement, lordosis, muscle trem-bling, and a straight-legged, skeletal-braced posture as-sumed in order to support the body’s weight. Hepato-megaly caused by increased deposits of fat and glycogencan contribute to the development of the distended, oftenpendulous, abdomen. The muscular asthenia and wastingis the result of increased catabolism of structural proteinscombined with diminished protein synthesis under the in-� uence of long-term cortisol excess.

Cutaneous lesions occur frequently in animals with hy-percortisolism. The initial changes in the skin often areobserved over points of wear (eg, neck, � anks, behindthe ears) and over bony prominences. These initial cu-taneous changes spread in a bilaterally symmetric patternto involve a signi� cant percentage of the body surface.Cutaneous lesions caused by excessive cortisol includeatrophy of the epidermis and pilosebaceous apparatus,combined with loss of collagen and elastin in the dermisand subcutis. Cutaneous mineralization (‘‘calcinosis cu-tis’’) is a characteristic lesion in dogs with hypercorti-solism (up to 30%). Numerous calcium crystals are de-posited along collagen and elastin � bers in the dermisand can protrude through the atrophic and thinned epi-dermis. These calcium deposits occur in dogs with nor-mal blood calcium and phosphorus concentrations. Se-vere mineralization also occurs in other tissues, such asthe lungs, active skeletal muscles, and the wall of thestomach.

PRIMARY HYPOFUNCTION

In primary hypofunction, hormone secretion either issubnormal because of excessive destruction of secretorycells by a disease process, the failure of an endocrineorgan to develop properly (aplasia or hypoplasia), or aspeci� c biochemical defect in the synthetic pathway of ahormone (Figure 13). Immune-mediated injury is an im-portant mechanism resulting in hypofunction of endo-




FIGURE 14.—Primary hypofunction of the thyroid gland resultingfrom severe diffuse lymphocytic thyroiditis. There are prominent in� l-trations of lymphocytes (L) in the interstitium and numerous in� am-matory cells in the lumens of the remaining thyroid follicles (arrow).H&E.

crine glands in animals, including the thyroid gland, ad-renal cortex, pancreatic islets, parathyroid, and hypothal-amus. The following are selected examples of primaryhypofunction of endocrine organs.

Immune-Mediated Lymphocytic Thyroiditis andHypothyroidism

Lymphocytic thyroiditis in dogs, obese strains ofchickens, nonhuman primates, and Buffalo rats closelyresembles Hashimoto’s disease in human beings. Al-though the exact pathogenetic mechanisms in the dog arenot completely established, evidence suggests a polygen-ic pattern of inheritance similar to that observed in humanbeings. The immunologic basis of the development ofchronic lymphocytic thyroiditis in both human beings anddogs appears to be through production of autoantibodiesusually directed against thyroglobulin or a microsomalantigen (thyroperoxidase) and infrequently against theTSH receptor protein, nuclear antigen, or a second colloidantigen from thyroid follicular cells. Thyroglobulin au-toantibodies have been found in 48% of pet dogs withhypothyroidism (44). Laboratory beagle dogs with natu-rally occurring lymphocytic thyroiditis also have circu-lating thyroidal autoantibodies, but the focal thyroiditisusually is not associated with clinical signs of hypothy-roidism.

Microscopic lesions consist of multifocal to diffuse in-� ltrates of lymphocytes, plasma cells, and macrophagesand, sometimes, lymphoid nodules (Figure 14). Thyroidfollicles are small and lined by columnar epithelial cells;lymphocytes, macrophages, and degenerate follicularcells are often present in vacuolated colloid. Thyroid C-cells are present as small nests or nodules between fol-licles and often are more prominent than those in normaldogs. Some remaining follicular cells appear to be trans-formed into large oxyphilic cells with densely eosino-philic granular cytoplasm.

Hypothyroidism is a clinically important disease in

dogs following immune-mediated destruction of secre-tory cells but is encountered only occasionally in otheranimals. Although the disease occurs in many adult pure-bred and mixed-breed dogs, certain breeds (golden re-triever, Doberman pinscher, dachshund, Shetland sheep-dog, Irish setter, miniature schnauzer, cocker spaniel, andAiredale) are more commonly affected. Many functionaldisturbances associated with hypothyroidism are due to areduction in basal metabolic rate. A gain in body weightwithout an associated change in appetite occurs in somehypothyroid dogs. Thinning of the hair coat often is ac-companied by a bilaterally symmetrical alopecia. Areasaffected initially by hair loss are those receiving frictionalwear, such as the tail, cervical area, and over bony prom-inences. Hyperkeratosis is a consistent � nding in hypo-thyroidism and results in an increased scaliness of theskin and often involves the external root sheath resultingin follicular keratosis. Myxedema occurs in severe andchronic cases from the accumulation of mucins (neutraland acid mucopolysaccharides combined with protein) inthe dermis and subcutis. These substances bind consid-erable amounts of water and result in marked thickeningof the skin.

Hypothyroidism in dogs is accompanied by decreasedcirculating thyroid hormone concentrations and decreased131I uptake by the thyroid gland. In dogs with hypothy-roidism, the serum T4 concentration usually is below 0.8

g/dl (normal 1.5– 3.4 g/dl), and that of T3 is below 50ng/dl (normal 48– 150 ng/dl). In the euthyroid dog, theT4 concentrations will at least double 8 hours after intra-venous or intramuscular injection of TSH, whereas indogs with primary hypothyroidism (due to lymphocyticthyroiditis), the T4 concentrations do not change signi� -cantly after injection of TSH. The serum cholesterol con-centration often is increased greatly (300 – 900 mg/dl) inhypothyroid dogs (normal serum cholesterol 40 – 80 mg/dl). The marked hypercholesterolemia in long-standingand severe hypothyroidism results in a variety of second-ary lesions, including atherosclerosis, hepatomegaly, andglomerular and corneal lipidosis.

Pituitary Aplasia and Dwar� sm

Pituitary dwar� sm in German shepherd dogs usuallyis associated with a failure of the oropharyngeal ectodermof Rathke’s pouch to differentiate into trophic hormone–

secreting cells of the pars distalis. This results in a pro-gressively enlarging, multiloculated cyst in the sella tur-cica and a partial to complete absence of the adenohy-pophysis (1). The cyst is lined by pseudostrati� ed, oftenciliated, columnar epithelium with interspersed mucin-se-creting goblet cells. The mucin-� lled cysts eventually oc-cupy the entire pituitary area in the sella turcica and se-verely compress the pars nervosa and infundibular stalk.A few differentiated trophic homone– secreting chromo-phils may be present between the pituitary cysts that stainimmunocytochemically for 1 or more of the speci� c tro-phic hormones. An occasional small nest or rosette ofpoorly differentiated epithelial cells is interspersed be-tween multiloculated cysts, but the cell cytoplasm is usu-ally devoid of hormone-containing secretory granules.Cysts associated with pituitary dwar� sm morphologically




FIGURE 15.—Congenital goiter in a lamb with symmetrical diffuseenlargements of thyroid (T) lobes. The primary hypofunction of thethyroid was due to an inability of follicular cells to synthesize thyro-globulin. The thyroid enlargement was due to TSH-mediated hypertro-phy and hyperplasia of follicular cells in response to the low bloodthyroid hormone levels.

FIGURE 16.—Severe diffuse TSH-mediated follicular cell hypertrophyand hyperplasia in a lamb with congenital goiter (refer to Figure 15).Follicles have collapsed due to a lack of colloid from the inability tosynthesize thyroglobulin and have slit-like lumens (arrow). Periodicacid–Schiff.

are distinct from the cysts that develop following the ab-normal accumulation of colloid in the residual lumen ofRathke’s pouch. In the latter, the normally developed parsdistalis and pars nervosa are compressed to varying de-grees by the abnormal accumulation of colloid in a pre-formed normal cavity of the pituitary gland.

Pups with juvenile-onset hypopituitarism appear nor-mal or are indistinguishable from littermates at birth anduntil about 2 months of age. Subsequently, the slowergrowth rate than the littermates, retention of puppy haircoat, and lack of primary guard hairs gradually becomeevident in dwarf pups. German shepherd dogs with pi-tuitary dwar� sm appear coyote-like or fox-like becauseof their diminutive size and soft woolly coat (69). A bi-laterally symmetrical alopecia develops gradually and of-ten progresses to complete alopecia except for the headand tufts of hair on the legs. There is progressive hyper-pigmentation of the skin until it is uniformly brown-blackover most of the body. Adult German shepherd dogs withpanhypopituitarism vary in size from as tiny as 4 lb upto nearly half normal size, apparently depending on thedegree of penetrance of the inherited defect and whetherthe failure of formation of the adenohypophysis is nearlycomplete or only partial.

Panhypopituitarism in German shepherd dogs often oc-curs in littermates and related litters, suggesting a simpleautosomal recessive mode of inheritance (4, 5, 6, 57, 72,112). The activity of somatomedin, or insulin-like growthfactor-1, (a cartilage growth– promoting peptide whoseproduction in the liver and plasma activity are controlledby somatotrophin) is low in dwarf dogs (57). Interme-diate somatomedin activity is present in the phenotypi-cally normal ancestors suspected to be heterozygous car-riers. Assays for somatomedin (a non– species-speci� c,somatotropin-dependent peptide) provide an indirectmeasurement of circulating growth hormone activity indogs with suspected pituitary dwar� sm (108, 112).

Biochemical Defect in Synthesis of Thyroid Hormonesand Congenital Goiter

Sporadic outbreaks of hyperplastic goiter develop incalves, lambs, kids, and pups as a consequence of aninability to synthesize thyroglobulin or to an enzyme de-fect in the biosynthesis of the thyroid hormones by fol-licular cells (40, 87). The more prevalent forms of in-herited goiter in human patients include defects in theiodination of tyrosine, deiodination of iodotyrosines, syn-thesis and proteolysis of thyroglobulin, coupling of io-dotyrosines to form iodothyronines, and a disruption iniodide transport.

Congenital dyshormonogenetic goiter is inherited byan autosomal recessive gene in sheep (Corriedale, DorsetHorn, Merino, and Romney breeds) (87), Afrikander cat-tle (77), and Saanen dwarf goats (90). The subnormalgrowth rate, absence of normal wool development or arough sparse hair coat, myxedematous swellings of thesubcutis, weakness, and sluggish behavior suggest thatthe affected young clinically are hypothyroid. Most lambswith congenital goiter either die shortly after birth or arehighly sensitive to the effects of adverse environmentalconditions. Thyroid glands are symmetrically enlarged at

birth (Figure 15) because of an intense diffuse hyperpla-sia of follicular cells (12). Thyroid follicles are lined bytall columnar cells, but follicles often have collapsed be-cause of lack of colloid resulting from the marked en-docytotic activity (Figure 16). The tall columnar follic-ular cells lining thyroid follicles have extensively dilatedpro� les of rough endoplasmic reticulum and large mito-chondria, but there are relatively few dense granules as-sociated with the Golgi apparatus and few thyroglobulin-containing apical vesicles near the luminal plasma mem-brane. Numerous long microvilli extend from apical sur-faces of follicular cells into the follicular lumen.

A closely related or similar defect appears to be re-sponsible for congenital goiter in sheep, cattle, and goats.Although thyroidal uptake and turnover of 131I are greatlyincreased compared with euthyroid controls, circulating




FIGURE 17.—Primary hypofunction due to lack of an enzyme (1 -hydroxylase) in the kidney that converts inactive 25-OH vitamin D tothe active (hormonal) form 1,25-(OH)2 vitamin D. Vitamin D –depen-dent rickets develop in young pigs and children as a result of the hy-pocalcemia, hypophosph atemia, and failure of mineralization of osteoidin the physis of bones. Other defects reported in children occur in bothcytoplasmic and nuclear receptors for the hormonal form of vitamin Dand in postreceptor events.

FIGURE 18.—Mechanisms of secondary hypofunction of an endocrineorgan.

T4 and T3 levels are consistently low. There is a lack ofa defect in the iodide transport mechanism, organi� ca-tion, or dehalogenation but an absence of normal 19Sthyroglobulin in goitrous thyroids and only minuteamounts of thyroglobulin-related antigens (0.01% of nor-mal), suggesting an impairment in thyroglobulin biosyn-thesis in animals with congenital goiter. Although thy-roglobulin mRNA sequences are present in the goitroustissue, their concentration is markedly reduced (1/10 – 1/40 that of normal thyroid), and the intracellular distri-bution is abnormal (nuclear, 42% of normal; cytoplasmic,7%; membrane fraction, 1– 2%). The lack of thyroglob-ulin in these examples of congenital goiter in animalsappears to be due to a defect in thyroglobulin mRNAleading to aberrant processing of primary transcripts and/or transport of the thyroglobulin mRNA from the nucleusto the ribosomes on the endoplasmic reticulum in thecytoplasm of follicular cells.

Genetic Enzyme De� ciency and Vitamin D– DependentRickets

De� ciency of vitamin D may result from a lack of therenal 25-hydroxy-cholecalciferol-1 -hydroxy lase, an en-zyme essential for the metabolic activation of precursormolecules (eg, 25-OH cholecalciferol) to form the active(hormonal) form of vitamin D (eg, 1,25-[OH]2-cholecal-ciferol) (Figure 17) (111, 113). Vitamin D– dependentrickets in both pigs and humans is a familial disease in-herited by an autosomal recessive gene. Newborn pigsappear healthy and have normal concentrations of calci-

um and phosphorus in the blood; however, blood levelsof calcium and phosphorus decrease progressively after4 – 6 weeks of age, while alkaline phosphatase activityincreases. Clinically detectable rickets develops duringthe following 3– 4 weeks, and affected pigs develop de-formities of bone in the axial and abaxial skeleton andevidence severe pain. In response to the hypocalcemiacaused by a de� ciency of the hormonal form of vitaminD, plasma levels of parathyroid hormone are elevated inpigs with vitamin D–dependent rickets. Serum levels of25-OH cholecalciferol are elevated in pigs with clinicalrickets, whereas the circulating concentration of 1,25-(OH)2-CC is markedly depressed.

SECONDARY HYPOFUNCTION

A destructive lesion in 1 organ (ie, pituitary gland)interferes with the secretion of trophic hormones and re-sults in subnormal function of target endocrine glands insecondary hypofunction. Large, endocrinologically inac-tive neoplasms may interfere with the secretion of mul-tiple pituitary trophic hormones and result in clinicallysigni� cant hypofunction of the adrenal cortex, follicularcells of the thyroid, and gonads (Figure 18). The disrup-tion of growth hormone secretion has little effect on bodystature because lesions of this type usually develop inadult to aged animals. Hypofunction of an endocrine or-gan also may be secondary to a lack of raw materials (eg,iodine) necessary for the synthesis of hormone (T4, T3)(Figure 18). Marginal de� ciencies often are associatedwith the presence of goitrogenic chemicals in the diet thatinterfere with the process of hormone synthesis by thy-roid follicular cells.

Lack of Normal Trophic Stimulus and Adult-OnsetPanhypopituitarism

Nonfunctional (endocrinologically inactive) pituitarytumors are most common in dogs, cats, and certain strainsof laboratory rats and are uncommon in other species(115). Although these adenomas are endocrinologicallyinactive, they may result in signi� cant functional distur-bances by virtue of compression atrophy of the pars nerv-osa and pars distalis or extension into the overlying brain




FIGURE 19.—Secondary hypofunction of the adrenal cortex and thy-roid gland following the destruction of trophic hormone– secreting cellsin the adenohypop hysis by a nonfunctional pituitary adenoma (A) in adog. The adrenal glands (arrows) are markedly reduced in size becauseof trophic atrophy of the zonae fasciculata and reticularis. The atrophicthyroid gland is not reduced in size because of the excessive colloidaccumulation in follicles due to a lack of TSH (refer to Figure 20).

FIGURE 20.—Colloid involution of thyroid follicles due to subnormalproduction of TSH by the adenohypop hysis. The follicular cells haveundergon e trophic atrophy because of lack of TSH and are low cuboi-dal, and the follicles (F) are greatly distended by the accumulation ofcolloid. H&E.

and optic nerves. Animals with nonfunctional pituitaryadenomas usually have clinical disturbances related todysfunction of the central nervous and neurohypophysealsystems as well as a lack of secretion of pituitary trophichormones with diminished end-organ function (eg, thy-roid follicular cells, adrenal cortex, and gonads). The his-tory often includes depression, incoordination and otherdisturbances of balance, weakness, collapse with exer-cise, and a marked change in personality. In long-stand-ing cases, there may be evidence of blindness with dilatedand � xed pupils due to compression of optic nerves (46).The body condition varies from a progressive loss ofweight to obvious obesity. Another common � nding withpituitary tumors is the excretion of large volumes of di-lute urine with a low speci� c gravity and a correspondingincrease in water intake. The disturbances of water bal-ance are the result of an interference with the synthesisand release of antidiuretic hormone (ADH) (53). The pos-terior lobe, infundibular stalk, and hypothalamus oftenare compressed or disrupted by the in� ltration of neo-plastic cells. This interrupts the nonmyelinated axons thattransport ADH from the site of production in the hypo-thalamus (primarily in the supraoptic nucleus) to the siteof release in the capillary plexus of the posterior lobe.Compression of neurosecretory neurons in the hypothal-amus by a large dorsally expanding pituitary tumor alsomay result in decreased ADH synthesis.

Nonfunctional pituitary adenomas usually reach con-siderable size before they cause obvious clinical signs orkill the animal (Figure 19). The proliferating tumor cellsincorporate the remaining structures of the adenohypoph-ysis and infundibular stalk. The neoplasms are � rmly at-tached to the base of the sella turcica, but there usuallyis no evidence of erosion of the sphenoid bone. In dogs,cats, rats, and horses, the diaphragma sellae is incom-plete, so the line of least resistance favors dorsal expan-sion of the progressively enlarging adenoma, resultingeither in a broad-based indentation or extension into theoverlying brain (Figure 19). The entire hypothalamus of-ten is compressed and replaced by the tumor, which alsomay extend into the thalamus. The tumor cells are cu-boidal to polyhedral and either arranged in diffuse sheetsor subdivided into small packets by a � ne connectivetissue septa with numerous small capillaries. Special his-tochemical techniques for pituitary cytology fail to dem-onstrate speci� c secretory granules within the cytoplasmof tumor cells. The histogenesis of these nonfunctionaltumors is uncertain, but they appear to be derived frompituitary cells that have not differentiated suf� ciently tosynthesize and secrete a speci� c trophic hormone.

The target endocrine organs respond dramatically to alack of normal production of pituitary trophic hormones(Figure 19). The adrenal glands of animals with largenonfunctional pituitary adenomas are small and often dif-� cult to � nd at necropsy. The adrenals consist primarilyof medullary tissue surrounded by a narrow zone of atro-phic cortex. The adrenal cortex appears as a thin yellow-brown rim composed of a moderately thickened capsuleand secretory cells of the outer layer, zona multiformis(glomerulosa), which is not under primary ACTH con-trol. The zonae fasciculata and reticularis are severely

atrophied compared with those in normal adrenal glands,secrete subnormal amounts of glucocorticoid hormones,and have a blunted increase in cortisol or corticosteronefollowing the administration of exogenous ACTH. Bycomparison, thyroid glands in animals with large pitui-tary adenomas disrupting normal trophic hormone (eg,TSH) production either are near normal size or onlyslightly reduced in size to a much lesser degree than isthe adrenal cortex (Figure 19). The majority of thyroidfollicles are large, lined by � attened (atrophic) cuboidalfollicular cells, and distended with a densely stained col-loid with little evidence of endocytotic activity becauseof a lack of TSH (Figure 20). Seminiferous tubules inthe testis are small with little evidence of active sper-matogenesis and the ovarian cortex is devoid of func-tional graa� an follicles.




FIGURE 21.—Examples of hyperfunction of an endocrine gland (eg,parathyroid) secondary to other conditions (eg, chronic renal diseaseand nutritional imbalances).

FIGURE 22.—Chronic interstitial nephritis in a dog that resulted insecondary hyperparathyroidism due to the inability to excrete phospho-rus at a normal rate leading to hyperphosphatemia and decreased pro-duction of 1,25-(OH)2-vitamin D. Masson’s Trichrome.

Lack of Essential Raw Materials for Hormone Synthesisand Iodine-De� cient Goiter

Secondary hypofunction of an endocrine gland also oc-curs when insuf� cient iodide ion is available for thyroidfollicular cells to synthesize adequate amounts of thyroidhormones to meet the animal’s daily requirements. Thethyroid gland attempts to compensate by increasing theef� ciency of iodide trapping (by upregulating expressionof the genes for the sodium/iodide symporter in the ba-solateral membrane of follicular cells) and by preferen-tially synthesizing more T3 than T4, thereby saving a mol-ecule of iodide for every molecule of thyroid hormoneproduced. Dietary iodine de� ciency resulting in diffusehyperplastic goiter was common in many areas of theworld before the widespread addition of iodized salt toanimal diets and still occurs worldwide in domestic ani-mals and human beings living in iodine-de� cient areas.Marginally iodine-de� cient diets that contain goitrogeniccompounds may cause severe thyroid follicular cell hy-perplasia and goiter. Goitrogenic substances include thio-uracil, sulfonamides, anions of the Hofmeister series, anda number of plants of the family Brassicacceae. Off-spring of females fed iodine-de� cient diets are likely todevelop severe thyroidal follicular cell hyperplasia andhave clinical signs of hypothyroidism. The affected lobesare � rm and dark red because an extensive interfollicularcapillary network develops under the in� uence of long-term TSH stimulation. Follicles are irregular in size andshape in hyperplastic goiter because they contain varyingamounts of lightly eosinophilic and vacuolated colloid.Some follicles collapse because of the lack of colloid.Their lining epithelial cells are columnar and have a eo-sinophilic cytoplasm, partly vacuolated, and small hyper-chromatic nuclei that often are situated in the basilar por-tion of the cell. The follicles are lined by single or mul-tiple layers of hyperplastic follicular cells that form pap-illary projections into the lumens of some follicles.

ENDOCRINE HYPERACTIVITY SECONDARY TO OTHER

CONDITIONS

The classic example of endocrine hyperactivity sec-ondary to diseases of other organs in animals is hyper-

parathyroidism that develops secondary to either chronicrenal failure or nutritional imbalances (Figure 21). In therenal form, the retention of phosphorus early and subse-quent progressive destruction of cells in the proximalconvoluted tubules interferes with the metabolic activa-tion of vitamin D by the 25-OH Cholecalciferol-1 -hy-droxylase in the kidney. This is the rate-limiting step inthe metabolic activation of vitamin D and is tightly con-trolled by parathyroid hormone and several other factors,including the serum phosphorus concentration. The im-paired intestinal absorption of calcium results in the de-velopment of progressive hypocalcemia that leads tolong-term parathyroid stimulation and development ofgeneralized demineralization of the skeleton. Nutritionalhyperparathyroidism develops in animals fed abnormaldiets that are either low in calcium, high in phosphorus,or de� cient in cholecalciferol (Figure 21).

Renal Hyperparathyroidism

In this form of hyperparathyroidism, there is an exces-sive, but not autonomous, rate of parathyroid hormone(PTH) secretion as part of the body’s compensatorymechanisms to chronic renal failure. This disorder is en-countered most frequently in dogs but also occurs in cats,laboratory rats, and many other animal species. The se-cretion of parathyroid hormone by the diffusely hyper-plastic parathyroid glands of animals affected with thisdisorder usually remains responsive to � uctuations inblood calcium. Chronic renal insuf� ciency from intersti-tial nephritis, glomerulonephritis, nephrosclerosis (Figure22) in older animals, or amyloidosis and congenitalanomalies (such as cortical hypoplasia, polycystic kid-neys, and bilateral hydronephrosis) in young animals mayresult in a signi� cant reduction in glomerular � ltrationrate, leading to the retention of phosphorus and the de-velopment of progressive hyperphosphatemia.

Parathyroid stimulation in animals with chronic renaldisease can be directly attributed to the hypocalcemia thatdevelops. As the phosphorus concentration increases,blood calcium decreases reciprocally, largely because ofthe suppressive effects of the hyperphosphatemia on therenal 1 -hydroxylase, resulting in an interference in pro-




FIGURE 23.—Hyperparathyroidism secondary to chronic renal diseaseresulting in diffuse demineralization of the maxilla and mandibles(‘‘rubber jaw’’) due to activation of osteoclasts.

FIGURE 24.—Dietary imbalances in different animal species that re-sult in nutritional secondary hyperparathyroidism. The dietary imbal-ance most common in a particular species is indicated by the numberin parentheses.

duction of the active form of vitamin D (1,25-[OH]2-cho-lecalciferol), thereby reducing intestinal absorption ofcalcium. All 4 parathyroid glands are enlarged becauseof organellar hypertrophy initially and later because ofchief cell hyperplasia that results in an increased PTHsynthesis and secretion in response to the hypocalcemia.Although skeletal involvement is generalized with hy-perparathyroidism, it does not affect all bones uniformly.Bone lesions include resorption of alveolar socket boneand loss of lamina dura dentes, which occurs early in thecourse of the disease. This results in loose teeth that maybe dislodged easily and interfere with mastication. Be-cause of the accelerated rate of resorption, cancellousbones of the maxilla and mandible become weakened andare readily pliable (Figure 23), and the jaws fail to closeproperly.

Nutritional Hyperparathyroidism

Nutritional secondary hyperparathyroidism is charac-terized by the increased secretion of parathyroid hor-mone, which develops as part of the body’s compensatorymechanisms to disturbances of mineral homeostasiscaused by nutritional imbalances. The disease is commonin cats, dogs, certain nonhuman primates, and many lab-oratory and farm animal species (Figure 24). Dietarymineral imbalances of etiologic importance in the path-

ogenesis of nutritional hyperparathyroidism are (a) a lowcontent of calcium, (b) excessive phosphorus with normalor low levels of calcium, and (c) inadequate amounts ofvitamin D3 in New-World non-human primates. The endresult is hypocalcemia, which results in the stimulationof parathyroid chief cells.

A diet low in calcium fails to supply the daily require-ment and hypocalcemia develops even though a greaterproportion of ingested calcium is absorbed. Ingestion ofexcessive phosphorus results in the increased intestinalabsorption and elevation of blood levels of phosphoruswith a reciprocal lowering of the blood calcium. Hyper-phosphatemia does not stimulate the parathyroid glanddirectly but does so indirectly by virtue of its ability tolower blood calcium by decreasing intestinal calcium ab-sorption, similar to that described for the renal form ofthe disease. Diets containing inadequate amounts of vi-tamin D3, even with normal levels of vitamin D2, causethe diminished absorption of calcium by intestinal cellsand results in hypocalcemia in certain New World mon-keys because of their relative resistance to vitamin D2.

In response to nutritionally induced hypocalcemia, theparathyroid glands undergo chief cell hypertrophy andhyperplasia. Active chief cells stimulated by the diet-in-duced hypocalcemia become larger and more tightly ar-ranged together (Figure 25) compared to chief cells ofnormal animals (Figure 26). Because kidney function isnormal, the increased levels of PTH result in a dimin-ished rate of renal reabsorption of phosphorus and anincreased tubular reabsorption of calcium, and blood lev-els of calcium return toward normal. The continued in-gestion of an imbalanced diet sustains the state of com-pensatory hyperparathyroidism, which eventually leads tothe progressive development of metabolic bone disease.Nutritional hyperparathyroidism develops in young ani-mals fed a nonsupplemented all-meat diet. Clinical signsare dominated by disturbances in locomotion manifestedby a reluctance of animals to move, incoordinated gait,and posterior lameness.




FIGURE 25.—Diffuse chief cell hypertrophy and hyperplasia in a kit-ten fed a low-calcium (all-meat) diet. Note the expanded cytoplasmicarea of chief cells and narrow perivascular spaces (arrow). H&E.

FIGURE 26.—Parathyroid gland from an age-matched control kittenfed a normal diet at similar magni� cation. The cytoplasmic area is lessand the perivascular spaces are wider (arrow) than in the kitten withsecondary hyperparathyroidism (refer to Figure 25). H&E.

FIGURE 27.—Hyperfunction of the pituitary gland as a result of dis-ruption of hormonal feedback by xenobiotic chemicals through one ofseveral mechanisms leading to an overproduc tion of luteinizing hor-mone (LH) or prolactin. In sensitive rodent species, these hormonalimbalances frequently lead to an increased incidence of ovarian, testic-ular, or mammary tumors in chronic studies with large doses of thecompound.

FIGURE 28.—Tubulostromal adenoma in a mouse ovary following achronic overproduc tion of LH subsequent to xenobiotic chemical-in-duced destruction of ovarian follicles. The tumor is composed of tubulardown-growths of the surface epithelium (arrow) and proliferating inter-stitial cells (C). H&E.

Hormonal Imbalances Induced by Xenobiotic Chemicals

Hyperfunction of an endocrine organ also can be theresult of hormonal imbalances induced by xenobioticchemicals. For example, hyperactivity of the pituitarygland in rodents during chronic toxicity testing often re-sults in an increased development of tumors in the gonadsor mammary glands (Figure 27). An excess productionof luteinizing hormone (LH), usually due to disruption ofnegative feedback control by estrogen or testosterone, in-creases the incidence of tubulostromal adenomas andgranulosa cell tumors in the ovary of mice and Leydig(interstitial) cell adenomas of the testes in rats.

Ovarian Tumorigenesis. The tubular (or tubulostromal)adenomas are the most important of the ovarian tumorsin mice and are the tumors whose incidence often is in-creased by various endocrine perturbations associatedwith chronic exposure to xenobiotic chemicals, senes-cence, or inherited genic deletion (71). Tubular adenomasare a unique lesion that develops frequently in the mouseovary, accounting for approximately 25% of naturally oc-curring ovarian tumors in this species (3, 89). They are

uncommon in rats, rare in other animal species, and notrecognized in the ovaries of women. In some ovariantumors of this type in mice, there is an intense prolifer-ation of stromal (interstitial) cells of sex cord origin.These tumors often are designated tubulostromal adeno-mas or carcinomas to re� ect the bimorphic appearance.

The tubulostromal adenomas in mice are composed ofnumerous tubular pro� les derived from the surface epi-thelium, plus abundant large luteinized stromal cells fromthe ovarian interstitium (Figure 28). The differences inhistological appearance of this type of unique ovariantumor in mice are interpreted to represent a morpholog-ical spectrum with variable contributions from the surfaceepithelium and sex cord– derived ovarian interstitiumrather than being 2 distinct types of ovarian tumors. The




FIGURE 29.—Multiple pathogenic mechanisms of ovarian tumorigen-esis in mice resulting in decreased negative feedback on the hypothal-amus-pituitary by diminished levels of gonadal steroids (eg, estrogen).

FIGURE 30.—Mechanisms of ovarian tumorigenesis in mice. The de-creased circulating estrogen levels release the hypothalamus-pituitarygland from negative feedback inhibition. The increased gonadotrophinlevels (LH and FSH) result in the mouse ovary being at greater risk ofdeveloping tubular adenomas and granulosa cell tumors in chronic stud-ies.

histogenic origin of this unique ovarian tumor in micehas been a controversial topic in the literature, but mostinvestigators currently agree that it is derived from theovarian surface epithelium, with varying contributionsfrom stromal cells of the ovarian interstitium.

Factors that destroy or greatly diminish the numbersof ovarian follicles, such as senescence, genetic deletionof follicles, X-irradiation, drugs and xenobiotic chemicalssuch as nitrofurantoin, and early thymectomy with thedevelopment of autoantibodies to oocytes, all diminishsex steroid hormone secretion by the ovary. This resultsin elevated circulating levels of gonadotrophins, espe-cially LH, because of decreased negative feedback on thehypothalamic-pituitary axis by estrogens and possiblyother humoral factors produced by the graa� an follicles(25). The long-term stimulation of stromal (interstitial)cells, which have receptors for LH (106), and, indirectly,the ovarian surface epithelium appears to place the mouseovary at increased risk for developing the unique tubularor tubulostromal adenomas. The � nding of similar tubularadenomas in the ovaries of the xenobiotic-treated and ge-netically sterile mice not exposed to exogenous chemicalssupports the concept of a secondary (hormonally medi-ated) mechanism of ovarian oncogenesis associated withhormonal imbalances. The ovarian tumors developedonly in sterile mice in which the pituitary-hypothalamicaxis was intact, and the administration of exogenous es-trogen early in the course will prevent ovarian tumor de-velopment.

Experimental ovarian carcinogenesis has been inves-tigated in inbred and hybrid strains of mice and inducedby a diversity of mechanisms, including X-irradiation,oocytotoxic xenobiotic chemicals, ovarian grafting to ec-topic or orthotopic sites, neonatal thymectomy, mutantgenes reducing germ cell populations, and aging (Figure29). Disruptions in the function of graa� an follicles by avariety of mechanisms results in a spectrum of ovarianproliferative lesions, including tumors. The � ndings inmutant mice support the concept of a secondary (hor-monally mediated) mechanism of ovarian carcinogenesis

associated with sterility. Multiple pathogenetic factorsthat either destroy or diminish the numbers of graa� anfollicles in the ovary result in decreased sex hormonesecretion (especially estradiol-17 ), leading to a compen-satory overproduction of pituitary gonadotrophins (par-ticularly LH) that places the mouse ovary at an increasedrisk for developing tumors (Figure 30) (14). The intenseproliferation of ovarian surface epithelium and stromal(interstitial) cells with the development of unique tubularadenomas in mice as a response to sterility does not havea counterpart in the ovaries of human adult females.

Testicular Tumorigenesis. Leydig (interstitial) cells ofthe testis frequently undergo proliferative changes withadvancing age and following chronic exposure to largedoses of xenobiotic chemicals that result in hormonal im-balances in rodents. Pathogenic mechanisms reported tobe important in the development of proliferative lesionsof Leydig cells include hormonal imbalances, irradiation,species and strain differences, exposure to certain chem-icals such as cadmium salts and 2-acetoamino� uorene(86), as well as certain physiological perturbations suchas cryptorchidism, a compromised blood supply to thetestis, and heterotransplantation into the spleen.

Hormonal imbalances are important factors in the de-velopment of focal proliferative lesions of Leydig cells,including increased estrogenic steroids in mice and ham-sters and elevated pituitary gonadotrophins in rats result-ing from the chronic administration of xenobiotic chem-icals (Figure 31) (27, 34). Many xenobiotic chemicals,when administered chronically to rats, disrupt the hypo-thalamic-pituitary-testis axis at one of several possiblesites (eg, androgen receptor antagonists, 5 -reductase in-hibitors, testosterone biosynthesis inhibitors, GnRH ag-onists, and aromatase inhibitors), interfering with nega-tive feedback control, resulting in hyperfunctioning of thepituitary gland and an overproduction of LH that leadsto the proliferative changes (hyperplasia and adenoma) inLeydig cells (Figure 32). For example, chronic exposureto chemicals with antiandrogenic activity, such as pro-




FIGURE 31.—Disruption of the hypothalamic-pituitary-testis axis atmultiple sites by xenobiotic chemicals results in LH overproduc tion andpredisposes the rat testis to develop an increased incidence of Leydigcell tumors in chronic studies. Modi� ed from Cook et al (1999).

FIGURE 32.—Leydig cell adenoma (A) of testis in a rat associatedwith LH overproduc tion caused by the chronic administration of a xe-nobiotic chemical. The adenoma is sharply demarcated and compressesadjacent seminiferous tubules. H&E.

cymidone due to binding to the androgen receptor, in-creases circulating levels of LH and results in stimulationof Leydig cells, leading to an increased incidence of hy-perplasia and adenomas in rats (70).

Another important mechanism by which xenobioticchemicals result in hormonal imbalances that increase theincidence of Leydig cell tumors in rats is by inhibitionof testosterone synthesis by cells in the testis. For ex-ample, lansoprazole is a substituted benzimidzole that in-hibits the hydrogen-potassuim ATPase (proton pump) re-sponsible for acid secretion by the parietal cells in thefundic mucosa of the stomach (41). The presence of theimidazole moiety in lansoprazole suggested a possible di-rect effect on the testis since several imidazole com-pounds (eg, ketoconazole and miconazole) are known toinhibit testosterone synthesis. Lansoprazole resulted indecreased circulating levels of testosterone, compensa-tory increased levels of LH, and an increased incidenceof Leydig cell hyperplasia and adenomas in chronic stud-ies in rats (41). The most sensitive site for inhibition oftestosterone synthesis by lansoprazole was the transportof cholesterol to the cholesterol side chain cleavage en-zyme.

Although several hormonal imbalances result in an in-creased incidence of Leydig cell tumors in rodents, hu-man patients with several disease conditions associatedwith chronic elevations in serum LH (including Kline-felter’s syndrome and gonadotroph adenomas of the pi-tuitary gland) have not been associated with an increaseddevelopment of this type of rare testicular tumor in men.There are a number of reports of marketed drugs thatincreased the incidence of proliferative lesions of Leydigcells in chronic toxicology/carcinogenicity studies in rats.These include indomethacin, lactitol, muselergine, cimet-idine, gem� brozil, and � utamide, among many others(27, 34). Although a number of xenobiotic chemicalshave been reported to increase the incidence of Leydigcell adenomas in chronic studies in rats, similar com-pounds (eg, cimetidine, ketoconizole, and certain calciumchannel blocking agents) have not resulted in an in-

creased incidence of Leydig cell neoplasia in man. Ley-dig cell tumors are a frequently occurring tumor in rats,often associated mechanistically with hormonal imbal-ances; however, they are not an appropriate model forassessing the potential risk to human males of developingthis rare testicular tumor following exposure to a xeno-biotic chemical.

HYPERSECRETION OF HORMONES BY NONENDOCRINE

TUMORS

Certain neoplasms of nonendocrine tissues in both an-imals and human secrete either hormones or humoral sub-stances that share chemical and/or biologic characteristicswith the ‘‘native’’ hormones secreted by an endocrinegland. Most of the recently discovered humoral substanc-es secreted by nonendocrine tumors are peptides ratherthan steroids, iodothyronines, or catecholamines, whichrequire more complex biosynthetic pathways. For ex-ample, humoral hypercalcemia of malignancy (‘‘pseudo-hyperparathyroidism’’) is a clinical syndrome producedprimarily by the autonomous hypersecretion of parathy-roid hormone– related peptide (PTH-rP) by cancer cells(Figure 33) (23). PTH-rP is able to interact with the para-thyroid hormone receptor in target cells (eg, bone andkidney) and result in persistent, often life-threatening, hy-percalcemia.

Humoral Hypercalcemia of Malignancy

Humoral hypercalcemia of malignancy (HHM) is asyndrome associated with diverse malignant neoplasmsin animal and human patients (95, 96). Characteristic� ndings in patients with HHM include hypercalcemia,hypophosphatemia, hypercalciuria (often with decreasedfractional calcium excretion), increased fractional excre-tion of phosphorus, increased nephrogenous cAMP, andincreased osteoclastic bone resorption. Hypercalcemia isproduced by the effects of PTH-rP on bone, kidney (Fig-ure 34), and possibly the intestine. Increased osteoclasticbone resorption is a consistent � nding in HHM with in-creased calcium release from bone. The kidney plays a




FIGURE 33.—Examples of hypersecretion of hormones by nonendo-crine tumors.

FIGURE 34.—Humoral hypercalcemia of malignancy (HHM) developsin animal and human patients when neoplasms constitutively secreteparathyroid hormone– related protein (PTH-rP). PTH-rP binds to recep-tors on osteoblasts, which subsequent ly signal osteoclasts to increasebone resorption and renal epithelial cells in the distal nephron to en-hance calcium reabsorption (decreasing fractional (F) calcium (Ca )excretion), resulting in persistent hypercalcemia. cAMP cyclic aden-osine monophospha te.

critical role in the pathogenesis of hypercalcemia and hy-pophosphatemia since renal calcium reabsorption is stim-ulated by PTH-rP and phosphorus reabsorption is inhib-ited because of binding to and activation of the renalPTH/PTH-rP receptors. PTH-rP binds to the N-terminalPTH/PTH-rP receptor in bone and kidney but does notcross react immunologically with native PTH. PTH-rPstimulates adenylate cyclase and increases intracellularcalcium ion in bone and kidney cells by binding to andactivating the cell membrane PTH/PTH-rP receptors.This results in a stimulation of osteoclastic bone resorp-tion, increased renal tubular calcium reabsorption, anddecreased renal tubular phosphorus reabsorption. In someforms of HHM, there are increased serum 1,25-dihydro-xyvitamin D levels that may increase calcium absorptionfrom the intestine (100). Although excessive secretion ofbiologically active PTH-rP plays a central role in thepathogenesis of hypercalcemia in most forms of HHMcytokines such as interleukin-1, tumor necrosis factor-al-pha, transforming growth factors, and 1,25-dihydroxyvi-tamin D may have synergistic or cooperative actions withPTH-rP (45, 65, 66).

A well-characterized example of this disease mecha-nism in animals is the adenocarcinoma derived from theapocrine glands of the anal sac in dogs. Serum PTH lev-els are lower in dogs with apocrine carcinomas than incontrols, and PTH levels are undetectable in tumor tissue(67, 100). The parathyroid glands are small and dif� cultto locate or not visible macroscopically in dogs with per-sistent cancer-associated hypercalcemia (67). Atrophicparathyroid glands are characterized by narrow cords ofinactive chief cells with an abundant � brous connectivetissue stroma and widened perivascular spaces. The in-active chief cells have a markedly reduced cytoplasmicarea, prominent hyperchromatic nuclei, and relativelystraight cell membranes with uncomplicated interdigita-tions and are closely packed together. These morphologic� ndings indicate that the malignant neoplasms are notproducing a substance that stimulates parathyroid hor-mone secretion by chief cells but rather that the parathy-roid glands are responding to the persistent hypercalce-mia by undergoing trophic atrophy. Thyroid parafollicu-

lar cells (C-cells) often respond to the persistent elevationin blood calcium by undergoing diffuse or nodular hy-perplasia (67). Most dogs with HHM with different typesof cancer have increased circulating concentrations ofPTH-rP. Plasma concentrations of PTH-rP were greatest(10 – 100 pM) in dogs with adenocarcinomas derived fromapocrine glands of the anal sac and sporadic carcinomasassociated with HHM (97, 100). The serum calcium con-centrations in these dogs correlated well with circulatingPTH-rP concentrations and was consistent with the con-cept that PTH-rP plays a primary role in the pathogenesisof HHM.

Physiologic Role for Parathyroid Hormone– RelatedProtein. Parathyroid hormone– related protein (PTH-rP) isa 139 – 173 amino acid peptide, originally isolated fromhuman and animal tumors associated with humoral hy-percalcemia of malignancy (98). The PTH-rP peptideshares 70% sequence homology with � rst 13 amino acidsof intact PTH. The N-terminal region of PTH-rP (aminoacids 1– 34) binds and stimulates PTH receptors in boneand kidney cells with equal af� nity as PTH. However,PTH-rP is not strictly a calcium-regulating hormone, asit appears to have an important physiologic role in manynormal tissues (Figure 35). It has been determined thatPTH-rP is widely produced in the body and acts as aparacrine factor in the tissues in which it is produced.

The fetus maintains higher concentrations of serumcalcium compared to the dam. Because the fetal parathy-roid glands produce low levels of PTH, the mechanismof maintaining increased serum concentrations of calciumwas unknown until the � nding that PTH-rP maintains cal-cium balance in the fetus and is the major hormone se-creted by the chief cells of the fetal parathyroid glands(24). The PTH-rP produced by the placenta also stimu-lates the uptake of calcium by the fetus. Parathyroid hor-mone– related peptide plays a role in the differentiationof many tissues during gestation and is especially im-




FIGURE 35.—Summary of evolving physiologic roles for parathyroidhormone – related protein.

FIGURE 36.—Examples of failure of target cells to respond to hor-mone. The corresponding endocrine organ is normal or hyperactive inan attempt to compensate for the unresponsive target cells.

portant in the growth and development of bone. Growthof cartilage at the epiphyseal plate is regulated by theactions or PTH-rP, which stimulates chondrocyte prolif-eration, inhibits apoptosis, and inhibits the maturation ofchondrocytes from the proliferative zone to the hypertro-phic zone (109).

Many tissues in adult animals, including endocrineglands; smooth, skeletal, and cardiac muscles; brain; lym-phocytes; lactating mammary gland; kidney; prostate gland;lung; skin; and bone produce PTH-rP. The function of PTH-rP in most of these tissues is poorly understood but likelyis an autocrine or paracrine regulatory factor. Circulatingconcentrations of PTH-rP in normal animals and humansare low ( 1 pM) (11, 98), and the PTH/PTH-rP receptoris often expressed on the same or adjacent cells in tissuesthat synthesize PTH-rP. Epidermal keratinocytes producePTH-rP, which plays a role in their proliferation or differ-entiation.

The greatest concentration of PTH-rP is found in milk(10 – 100 nmol/L) and is 10,000- to 100,000-fold greaterthan in the serum (88). The function of PTH-rP in themammary gland and in milk is poorly understood at pre-sent. However, overexpression of PTH-rP in the mam-mary gland during glandular development prior to lac-tation results in glandular hypoplasia due to a reductionin the morphogenesis and branching of the mammaryducts. Biologically active PTH-rP produced by alveolarepithelial cells during lactation results in the high con-centration of PTH-rP in milk, and this PTH-rP may playa role in stimulating the transport of calcium by alveolarepithelial cells from serum to milk (7, 78). Synthesis ofPTH-rP by the mammary gland abruptly ceases whensuckling stops and the gland undergoes involution. ThePTH-rP peptide is enzymatically cleaved in milk, but theN-terminal PTH-rP fragment retains biologic activity.Smooth muscle, including blood vessels, uterus, urinarybladder, gastrointestinal tract, and the oviduct of the hen,produce PTH-rP. In general, PTH-rP expression is in-creased when smooth muscle is stretched and PTH-rPinduces relaxation of smooth muscle and attenuation ofcontraction. With progressive distension of the uterus

during pregnancy or during descent of the ovum in thehen’s oviduct, PTH-rP likely functions as a paracrine reg-ulator of vascular tone, causing vasodilation and modu-lating vasoconstriction by other vasoactive compounds.

FAILURE OF TARGET CELLS TO RESPOND TO HORMONE

This mechanism of endocrine disease has been appre-ciated coincident with the more complete understandingof how hormones interact with target cells to convey theirbiologic message. A failure of target cells to respond tohormone may be due either to a lack of adenylate cyclasein the cell membrane or to an alteration in hormone re-ceptors on the cell surface (Figure 36). Hormone is se-creted in normal or increased amounts by the cells of theendocrine gland.

Insulin resistance associated with obesity in both ani-mals and humans can result from a decrease or ‘‘down-regulation’’ of receptors on the surface of target cells.This develops in response to the chronic increased insulinsecretion stimulated by the hyperglycemia resulting fromthe excessive food intake. For example, animals withlarge pituitary neoplasms that extend dorsally out of thesella turcica often destroy critical hypothalamic nucleithat regulate the intake of food (Figure 37). They oftendevelop insulin-resistant hyperglycemia and glycosuria asa result of a down-regulation of insulin receptors on tar-get cells induced by the chronic excessive intake of foodand hyperinsulinemia (Figure 38). Secretory cells in thecorresponding endocrine gland (ie, pancreatic islets) un-dergo compensatory hypertrophy and hyperplasia in anattempt to secrete additional hormone and lower theblood glucose concentration.

An interesting form of hypoparathyroidism has beenreported in human patients in which the inability of targetcells to respond is due to a defect in the cAMP-mediatedsignal transduction resulting from a lack of speci� c nu-cleotide regulatory protein in the cell membrane. Patientswith ‘‘pseudohypoparathyroidism’’ develop hypocalce-mia and hyperphosphatemia despite hyperplastic parathy-roids and elevated blood levels of PTH. Similarly, ani-mals and humans with nephrogenic diabetes have defects




FIGURE 37.—Dorsal extension of pituitary adenoma (A) (pars inter-media origin) with compression and destruction of autonomic centersin ventral-medial region of hypothalamus (H) that regulate the intakeof food resulting in insulin-resistant hyperglycemia (see Figure 38). Theoptic nerve (O) also is compressed. Scale represents 1 cm. Equine pi-tuitary.

FIGURE 38.—Down-regulation of insulin receptors on target cells inresponse to chronic increased food intake resulting in decreased insulinsensitivity (resistance) and hyperglycemia.

FIGURE 39.—Examples of failure of fetal endocrine function resultingin prolongation of the gestation period. B bovine; O ovine; A.C.

adrenal cortex.

in the vasopressin receptor on cells of the distal nephronand collecting ducts in the kidney, resulting in a lack ofadenylate cyclase stimulation and generation of cyclicAMP after vasopressin binding to its receptor on targetcells.

FAILURE OF FETAL ENDOCRINE FUNCTION

Subnormal function of the fetal endocrine system, es-pecially in ruminants, may disrupt normal fetal devel-opment and result in prolongation of the gestation period(Figure 39). In Guernsey and Jersey cattle, a geneticallydetermined failure of development (aplasia) of the ade-nohypophysis results in a lack of fetal pituitary trophichormone secretion during the last trimester and hypo-plastic development of target endocrine organs (eg, ad-renal cortex, thyroid follicular cells, and gonads). Fetaldevelopment is normal up to approximately 7 monthsgestation, but subsequently fetal growth ceases, regard-less of how long the viable fetus is retained in utero.

Prolongation of the gestation period also occurs inewes that ingest the plant Veratrum californicum early ingestation. Toxins in the plant cause extensive malforma-tions of the central nervous system (CNS) and hypothal-amus in lambs. Although the adenohypophysis is present,it is unable to secrete normal amounts of trophic hor-mones (eg, adrenocorticotropin [ACTH]) because it lacksthe necessary � ne control derived from the releasing hor-mones of the hypothalamus. Target endocrine organs inthe fetus are hypoplastic, and the adrenal cortex does notdifferentiate completely into the 3 distinctive zones thatsecrete corticosteroid hormones. The plant contains po-tent steroidal alkaloids that inhibit neural tube develop-ment when ingested by the ewe between the 9th and 14thday of gestation. Cyclopia and extensive CNS malfor-mations are found in lambs. Arrhinencephalia and lackof development of nasal bones accompany the formationof a proboscis-like structure. The lambs retained in the

uterus continue to grow beyond the normal gestation pe-riod.

The concepts that have emerged from the study ofthese naturally occurring diseases are, � rst, that fetal hor-mones are necessary for � nal growth and development inutero in certain animals and, second, that normal partu-rition at term requires an intact fetal hypothalamic-ade-nohypophyseal-adrenal cortical axis in these speciesworking in concert with trophoblasts of the placenta. Al-though the presence or absence of functional adenohy-pophyseal tissue determines whether the fetus continuesto grow in utero, the pathogenesis of prolongation of thegestational interval is similar in these examples. The sub-normal development of the fetal adrenal cortex results inan inadequate secretion of cortisol and a failure to inducethe 17 -hydroxy lase in the placenta that converts pre-cursor molecules (eg, progesterone) to estrogen. The fetaladrenal gland is small, and there is incomplete develop-ment of the 3 distinct zones of the cortex (Figure 40).The dam’s circulating progesterone is maintained nearmidgestational concentrations, and there is a lack of the




FIGURE 40.—Failure of fetal endocrine function. Adrenal cortical hy-poplasia in calf with prolongation of the gestation period. The adrenalcortex (C) is markedly reduced in thickness , and the adrenal medulla(M) is relatively more prominent. The scale represents 1 cm.

FIGURE 41.—Examples of abnormal (either increased or decreased)degradation of hormone.

FIGURE 42.—Hepatic microsomal enzyme induction by the chronicadministration of xenobiotic chemicals leading to thyroid follicular cellhyperplasia and neoplasia in chronic studies with large doses of com-pound in rodents .

marked increase in estrogens that normally occurs nearterm and results in parturition by stimulating the localsynthesis of prostaglandins in the uterus. This normallyresults in the smooth muscle contractions and biochemi-cal changes in collagen along the birth canal that permitsdelivery of the fetus.

ABNORMAL DEGRADATION OF HORMONE

Increased Degradation of Hormone

In laboratory rodents, the long-term administration ofvarious xenobiotics (ie, phenobarbital and others) resultsin the induction of liver enzymes (eg, T4-uridine diphos-phate [UDP]-glucuronyl transferase) that increases thedegradation of thyroxine. Endocrine gland and target cellfunction are normal (Figure 41) (16, 17). The chronicdisruption of the thyroid-pituitary axis and augmentedTSH secretion in rodents, especially male rats, often in-creases the development of thyroid follicular cell tumorsin chronic toxicity and oncogenicity studies with certaindrugs and chemicals (14).

Thyroid Tumorigenesis. Hepatic microsomal enzymesplay an important role in thyroid hormone economy be-cause glucuronidation is the rate-limiting step in the bil-iary excretion of T4 and sulfation primarily by phenolsulfotransferase for the excretion of T3. Long-term ex-posure of rats to a wide variety of different chemicalsinduces these enzyme pathways and results in chronicstimulation of the thyroid by disrupting the hypothalam-ic-pituitary-thyroid axis (36). The resulting chronic stim-ulation of the thyroid by increased circulating levels ofTSH often results in a greater risk of developing tumorsderived from follicular cells in chronic (2-year or life-time) toxicity/carcinogenicity studies with these com-pounds in rats (Figure 42). The activation of the thyroidgland during the treatment of rodents with substances thatstimulate thyroxine catabolism is a well-known phenom-enon and has been investigated extensively with manycompounds (36). It occurs particularly in rats, � rst be-cause UDP-glucuronyl transferase can easily be induced

in rodent species and second because thyroxine metabo-lism takes place very rapidly in rats in the absence ofthyroxine-binding globulin in the circulation. In humans,a lowering of the circulating T4 level but no change inTSH and T3 concentrations has been observed only withhigh doses of very powerful enzyme-inducing com-pounds, such as rifampicin with and without antipyrine.

Xenobiotic chemicals that induce liver microsomal en-zymes and disrupt thyroid function in rats include CNS-acting drugs (eg, phenobarbital and benzodiazepines),calcium channel blockers (eg, nicardipine and bepridil),steroids (spironolactone), retinoids, chlorinated hydrocar-bons (eg, chlordane, DDT, and TCDD), and polyhalo-genated biphenyls (PCB and PBB), among others (36).Most of the hepatic microsomal enzyme inducers haveno apparent intrinsic carcinogenic activity and producelittle or no mutagenicity or DNA damage. Their promot-




FIGURE 43.—Hepatic thyroxine glucuronyltransferase activity in con-trol and phenobarbi tal-treated rats (100 mg/kg/day in the diet for 4weeks). Glucuronyltransferase activity was measured in hepatic micro-somes using thyroxine as a substrate. Phenobarb ital treatment inducedthyroxine-glucuronyltransferase in both male and female rats; however,the response was quantitatively larger in male rats. From McClain et al(62). *Statistically signi� cant difference compared to control, p 0.05.

FIGURE 44.—Thyroid follicular cell adenoma (A) in a male Sprague-Dawley rat exposed to FD&C Red No. 3 in utero and fed at the 4%level for the lifetime of 30 months. Feeding a large dose of the colorresulted in perturbations in thyroid hormone economy, thereby increas-ing TSH secretion that promoted an increased incidence of benign thy-roid tumors (21.8% only in male rats) by a secondary mechanism as-sociated with the hormona l imbalances. The adenoma is well circum-scribed (arrows), and adjacent follicles are slightly compressed. Thehyperchrom atic neoplastic cells line a cystic space and form papillaryprojections into the lumen. H&E. From Borzelleca JF, Capen CC, Hal-lagan JB (1987). Lifetime toxicity/carcinogen icity study of FD&C RedNo. 3 (Erythrocine) in rats. Fd Chem Toxic 25: 723–733.

ing effect on thyroid tumors usually is greater in rats thanin mice, with males more often developing a higher in-cidence of tumors than females. In certain strains of mice,these compounds alter liver cell turnover and promote thedevelopment of hepatic tumors from spontaneously ini-tiated hepatocytes.

Phenobarbital has been studied extensively as the pro-totype for hepatic microsomal inducers that increase aspectrum of cytochrome P-450 isoenzymes (62, 63).McClain et al reported that the activity of UDP-GT, therate-limiting enzyme in T4 metabolism, is increased inpuri� ed hepatic microsomes of male rats when expressedas picomoles per minute per milligram of microsomalprotein (1.3-fold) or as total hepatic activity (3-fold) (Fig-ure 43). This resulted in a signi� cantly higher cumulative(4-hour) biliary excretion of 125I-T4 and bile � ow than incontrols. Most of the increase in biliary excretion wasaccounted for by an increase in T4-glucuronide due to anincreased metabolism of thyroxine in phenobarbital-treat-ed rats. This is consistent with enzymatic activity mea-surements that result in increased hepatic T4-UDP-glu-curonyl transferase activity in phenobarbital-treated rats.These results are consistent with the hypothesis that thepromotion of thyroid tumors in rats by phenobarbital wasnot a direct effect of the compound on the thyroid glandbut rather an indirect effect mediated by TSH secretionfrom the pituitary secondary to the hepatic microsomalenzyme– induced increase of T4 excretion in the bile.

There is no convincing evidence that humans treatedwith drugs or exposed to chemicals that induce hepaticmicrosomal enzymes are at increased risk for the devel-opment of thyroid cancer (36). In a study on the effectsof microsomal enzyme– inducing compounds on thyroidhormone metabolism in normal healthy adults, pheno-barbital (100 mg daily for 14 days) did not affect theserum T4, T3, or TSH levels (74). A decrease in serumT4 levels was observed after treatment with either a com-

bination of phenobarbital plus rifampicin or a combina-tion of phenobarbital plus antipyrine; however, thesetreatments had no effect on serum T3 or TSH levels (75).Phenobarbital has been used clinically as an anticonvul-sant for more than 80 years, and relatively high micro-somal enzyme– inducing doses have been used chronical-ly, sometimes for lifetime exposures, to control seizureactivity in human beings. Epidemiological studies of pa-tients treated with therapeutic doses of phenobarbitalhave reported no increase in risk for the development ofthyroid neoplasia (29, 30, 31, 32, 42, 76, 104, 110). High-ly sensitive assays for thyroid and pituitary hormones arereadily available in a clinical setting to monitor circulat-ing hormone levels in patients exposed to chemicals po-tentially disruptive of pituitary-thyroid axis homeostasis.

Many chemicals and drugs disrupt 1 or more steps inthe synthesis, secretion, or metabolism of thyroid hor-mones, resulting in subnormal levels of T4 and T3, as-sociated with a compensatory increased secretion of pi-tuitary TSH (49). When tested in highly sensitive species,such as rats and mice, these compounds in acute andsubchronic studies result in follicular cell hypertrophy/hyperplasia and increased thyroid weights, and in long-term studies they produce an increased incidence of thy-roid tumors (usually adenomas) by a secondary (indirect)mechanism associated with hormonal inbalances. In thesecondary mechanism of thyroid oncogenesis in rodents,the speci� c xenobiotic chemical or physiological pertur-bation evokes another stimulus (eg, chronic hypersecre-tion of TSH) that promotes the development of the pro-liferative lesions (eg, adenomas [Figure 44]) derived fromfollicular cells. Thresholds for ‘‘no effect’’ on the thyroidgland can be established by determining the dose of the




FIGURE 45.—Examples (direct and indirect) of iatrogenic syndromesof hormone excess.

FIGURE 47.—Failure of hypophysec tomy to decrease circulatinggrowth hormone (GH) levels in progestin-treated dogs. From Selman etal (103).

FIGURE 48.—Rapid reduction in plasma growth hormone (GH) levelsin progestin-administered dogs following mammary resection. FromSelman et al (103).

FIGURE 46.—Elevation of circulating concentrations of growth hor-mone (GH), insulin-like growth factor (IGF), and insulin by the admin-istration of synthetic progestins to dogs. Data from Selman et al (103).

xenobiotic chemical that fails to elicit an elevation in thecirculating level of TSH. Compounds acting by this in-direct (secondary) mechanism with hormonal imbalancesusually have little or no evidence for mutagenicity or forproducing DNA damage.

In human patients who have marked changes in thyroidfunction and elevated TSH levels, as is common in areaswith a high incidence of endemic goiter due to iodinede� ciency, there is little if any increase in the incidenceof thyroid cancer (36, 38). The relative resistance to thedevelopment of thyroid cancer in humans with elevatedplasma TSH levels is in marked contrast to the responseof the thyroid gland to chronic TSH stimulation in ratsand mice. The human thyroid is much less sensitive tothis pathogenetic phenomenon than rodents. The litera-ture suggests that prolonged stimulation of the humanthyroid by TSH will induce neoplasia only in exceptionalcircumstances, possibly by acting together with some oth-er metabolic or immunologic abnormalities (28, 35, 36,80).

Decreased Degradation of Hormone

The rate of secretion of hormone by an endocrinegland may be normal with this mechanism, but bloodhormone levels are persistently elevated, thereby simu-lating a syndrome of hypersecretion, because of a de-creased rate of hormone degradation (Figure 41). Theclassic example of this pathogenic mechanism is the syn-drome of feminization due to hyperestrogenism associ-ated with cirrhosis and decreased hepatic degradation ofestrogens. Chronic renal disease in dogs occasionally isassociated with persistent hypercalcemia due, in part, todecreased degradation of PTH (along with decreased uri-nary excretion of calcium) by the diseased kidney.

IATROGENIC SYNDROMES OF HORMONE EXCESS

Direct Effects

The administration of hormone, either directly or in-directly, in� uences the activity of target cells with thismechanism of endocrine disease and results in importantfunctional disturbances (Figure 45). It is well recognizedthat the daily administration of potent preparations of ad-renal cortical steroids at inappropriately high daily dosesfor prolonged intervals in the symptomatic treatment ofvarious diseases can produce most of the functional dis-turbances associated with an endogenous hypersecretionof cortisol. Similarly, the administration of excessivelylarge doses of insulin can result in hypoglycemia, and anexcess T4/T3 may result in hyperthyroidism, especially in




FIGURE 49.—Tissue distribution of growth hormone (GH) immuno-reactivity in progestin-administered dogs demonstrating a high contentin both normal and neoplastic mammary tissue compared to many othertissues. From Selman et al (103).

certain species (eg, cats) that have limited capacity toconjugate T4 with glucuronic acid and enhance biliaryexcretion.

Indirect Effects

The administration of progestins to dogs indirectly re-sults in a syndrome of growth hormone excess. The in-jection of medroxyprogesterone acetate for the preventionof estrus in dogs appears to stimulate expression of thegrowth hormone gene in the mammary gland, leading toan elevation in circulating growth hormone levels, andresults in the classic clinical manifestations and lesionsof acromegaly (eg, excessive skin folds, respiratory stri-dor due to increased soft tissue in oropharyngeal region,expansion of interdental spaces, and hyperglycemia).

It was assumed initially that the reversibly elevatedcirculating levels of growth hormone (GH) in responseto the administration of synthetic progestins in dogs wasfrom stimulation of somatotrophs in the pituitary gland(91); however, somatotroph hyperplasia and adenomashave not been found in the adenohypophysis of proges-tin-treated dogs. The elevated GH levels were associatedwith progressively increasing circulating concentrationsof insulin-like growth factor-1 (IGF-1) and insulin (Fig-ure 46) (68). The progestin-induced excessive GH secre-tion in dogs was characterized by a disappearance of thepulsatile secretion pattern and insensitivity to stimulationof GH secretion by both growth hormone-releasing hor-mone and clonidine as well as inhibition of GH releasewith a somatostatin analogue. Transphenoidal hypophy-sectomy 4 – 6 weeks after the last progestin injection indogs with markedly elevated plasma GH concentrationsdid not change the circulating levels of GH (92, 103)(Figure 47). Subsequent removal of all mammary tissuein the progestin-treated dogs resulted in a rapid declineof plasma GH concentrations to values in the referencerange (Figure 47). Measurement of GH immunoreactivityin tissue homogenates from progestin-administered dogsrevealed that the highest GH content was present in nor-

mal and neoplastic mammary tissue (Figure 48). Immu-nohistochemical evaluation further con� rmed the mam-mary gland as the source of the excessive GH production.In the dogs treated with progestins, GH immunoreactivitywas present in the cytoplasm of both normal active ductalepithelial cells and benign neoplasms derived from mam-mary ductal epithelium (Figure 49). There was no GHimmunoreactivity in the stroma or in mammary tissuefrom control dogs (103). Interestingly, progestins therapyhas been used successfully to treat dogs with juvenile-onset panhypopituitarism and dwar� sm due to a failureof development of the adenohypophysis and severe GHde� ciency (54).

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