Congenital hypothyroidism in a boxer dog

Congenital central hypothyroidism was diagnosed in a one-year-old boxer dog. The dog was presented for investigation of lameness, lethargy and obesity. Survey skeletal radiographs revealed delayed bone maturation and epiphyseal dysgenesis. A diagnosis of hypothyroidism was confirmed on the basis of a low basal serum thyroxine (T₄) concentration that failed to increase following bovine thyroid stimulating hormone (TSH) administration. However, repeated administration of TSH resulted in reactivation of the thyroid gland suggesting a central rather than a primary problem. Consistently low basal plasma Cortisol concentrations were suggestive of a concurrent secondary or tertiary hypoadrenocorticism. Surprisingly, plasma growth hormone concentrations were elevated before treatment but decreased once thyroid replacement therapy had commenced.     

Thyrotropin-releasing hormone-induced growth hormone secretion in dogs with primary hypothyroidism

Primary hypothyroidism in dogs is associated with increased release of growth hormone (GH). In search for an explanation we investigated the effect of intravenous administration of thyrotropin-releasing hormone (TRH, 10 microg/kg body weight) on GH release in 10 dogs with primary hypothyroidism and 6 healthy control dogs. The hypothyroid dogs had a medical history and physical changes compatible with hypothyroidism and were included in the study on the basis of the following criteria: plasma thyroxine concentration < 2 nmol/l and plasma thyrotropin (TSH) concentration > 1 microg/l. In addition, (99m)TcO(4)(-) uptake during thyroid scintigraphy was low or absent. TRH administration caused plasma TSH concentrations to rise significantly in the control dogs, but not in the hypothyroid dogs. In the dogs with primary hypothyroidism, the mean basal plasma GH concentration was relatively high (2.3+/-0.5 microg/l) and increased significantly (P=0.001) 10 and 20 min after injection of TRH (to 11.9+/-3.5 and 9.8+/-2.7 microg/l, respectively). In the control dogs, the mean basal plasma GH concentration was 1.3+/-0.1 microg/l and did not increase significantly after TRH administration. We conclude that, in contrast to healthy control dogs, primary hypothyroid dogs respond to TRH administration with a significant increase in the plasma GH concentration, possibly as a result of transdifferentiation of somatotropic pituitary cells to thyrosomatotropes.     

Congenital Hypothyroid Dwarfism in a Family of Giant Schnauzers

Congenital hypothyroid dwarfism was diagnosed in a family of Giant Schnauzers. Three female and two male puppies from different litters were evaluated for dwarfism, lethargy, somnolence, gait abnormalities, and constipation. On physical examination, disproportionate dwarfism (n = 5), macroglossia (n = 3), hypothermia (n = 3), delayed dental eruption (n = 3), ataxia (n = 2), and abdominal distension (n = 1) were identified. Results of initial laboratory tests showed anemia (n = 4), hypercholesterolemia (n = 4), hypercalcemia (n = 2), and transudative abdominal effusion (n = 1). Radiographic skeletal surveys disclosed epiphyseal dysgenesis and delayed skeletal maturation (n = 5). A diagnosis of hypothyroidism was established on the basis of low basal serum thyroxine concentrations that failed to increase following the administration of TSH (n = 5) and markedly reduced to absent thyroid image when evaluated with gamma camera imaging of the thyroid gland (n = 4). In the two dogs that were most thoroughly evaluated, the results of thyroid histology, prolonged TSH testing, and repeat thyroid imaging, after three daily injections of TSH, were all consistent with secondary or tertiary, rather than primary, hypothyroidism. When TSH was administered over a period of 3 consecutive days (5 IU/day, subcutaneously), serum thyroid hormone response became normal and resulted in a normal thyroid image in the two dogs re-evaluated with gamma camera imaging. Daily treatment with oral levothyroxine (20 micrograms/kg) resulted in complete remission in puppies (n = 4) treated prior to 4 months of age. The other puppy failed to attain normal breed standards for height.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regulation of pituitary somatotroph differentiation by hormones of peripheral endocrine glands

Anterior pituitary somatotroph differentiation occurs during chick embryonic and rat fetal development. A number of findings support the hypothesis that differentiation of these growth hormone (GH) producing cells in the chick and the rat is regulated by adrenal glucocorticoids and thyroid hormones. Somatotroph differentiation can be induced in cultures of chick embryonic and rat fetal pituitary cells with adrenal glucocorticoids and this effect can be modulated by concomitant treatment with thyroid hormones. Plasma levels of thyroid hormones, corticosterone and adrenocorticotropic hormone increase during development, consistent with the ontogeny of somatotrophs. Treatment of chick embryos or rat fetuses with glucocorticoids in vivo induces premature somatotroph differentiation, indicating that the adrenal gland, and ultimately anterior pituitary corticotrophs, may function to regulate pituitary GH cell differentiation during development. Administration of thyroid hormones in vivo also increases somatotrophs prematurely, and administration of the thyroid hormone synthesis inhibitor methimazole inhibits somatotroph differentiation in vivo, suggesting that endogenous thyroid hormone synthesis contributes to normal somatotroph differentiation. Our working model for the regulation of somatotroph differentiation during normal development includes modulation by elements of the hypothalamo-pituitary-adrenal and hypothalamo-pituitary-thyroid axes. Additional research is reviewed defining the mechanism of action for these peripheral hormones in induction of pituitary GH gene expression during development.     

Ghrelin-stimulation test in the diagnosis of canine pituitary dwarfism

This study investigated whether ghrelin, a potent releaser of growth hormone (GH) secretion, is a valuable tool in the diagnosis of canine pituitary dwarfism. The effect of intravenous administration of ghrelin on the release of GH and other adenohypophyseal hormones was investigated in German shepherd dogs with congenital combined pituitary hormone deficiency and in healthy Beagles. Analysis of the maximal increment (i.e. difference between pre- and maximal post-ghrelin plasma hormone concentration) indicated that the GH response was significantly lower in the dwarf dogs compared with the healthy dogs. In none of the pituitary dwarfs, the ghrelin-induced plasma GH concentration exceeded 5 microg/l at any time. However, this was also true for 3 healthy dogs. In all dogs, ghrelin administration did not affect the plasma concentrations of ACTH, cortisol, TSH, LH and PRL . Thus, while a ghrelin-induced plasma GH concentration above 5 microg/l excludes GH deficiency, false-negative results may occur.     

Secondary hypothyroidism following head trauma in a cat

An 18-month-old female neutered domestic short hair cat was examined because of marked polydipsia and stunted growth following head trauma when it was 8 weeks old. Diagnostic evaluation revealed hyposthenuric urine, low concentrations of thyroid hormone and undetectable thyroid stimulating hormone concentrations which did not rise following thyroid releasing hormone administration. Lateral radiographs of the left and right tibiae revealed incomplete mineralisation of the greater tubercle and open physis. An almost empty sella turcica and a greatly reduced pituitary were visible on magnetic resonance images of the brain. A presumptive diagnosis of secondary hypothyroidism and central diabetes insipidus following head trauma was made.     

Thyroid Dysplasia in Wistar Hannover GALAS Rats

Thyroid dysplasia was recognized in WistarHan GALAS rats and confirmed as a heritable congenital disorder. The gene or genes involved were not identified, but homozygous animals with thyroid dysplasia also exhibited stunted growth, had reduced pituitary gland growth hormone (GH) and were hypothyroid. Heterozygous animals exhibited thyroid dysplasia with normal thyroid hormonal homeostasis and no difference in the incidence of preneoplastic or neoplastic lesions in oncogenicity studies.     

The chicken pituitary-specific transcription factor PIT-1 is involved in the hypothalamic regulation of pituitary hormones

Pit-1 is a pituitary-specific POU-domain DNA binding factor, which binds to and trans-activates promoters of growth hormone- (GH), prolactin- (PRL) and thyroid stimulating hormone-beta- (TSHbeta) encoding genes. Thyrotropin-releasing hormone (TRH) is located in the hypothalamus and stimulates TSH, GH and PRL release from the pituitary gland. In the present study, we successfully used the cell aggregate culture system for chicken pituitary cells to study the effect of TRH administration on the ggPit-l* (chicken Pit-1), GH and TSHbeta mRNA expression in vitro. In pituitary cell aggregates of 11-day-old male broiler chicks the ggPit-l * mRNA expression was significantly increased following TRH administration, indicating that the stimulatory effects of TRH on several pituitary hormones are mediated via its effect on the ggPit-l* gene expression. Therefore, a semiquantitative RT-PCR method was used to detect possible changes in GH and TSHbeta mRNA levels. TRH affected both the GH and TSHbeta mRNA levels. The results of this in vitro study reveal that ggPit-1 * has a role in mediating the stimulatory effects of TRH on pituitary hormones like GH and TSHbeta in the chicken pituitary.     

Functional and morphological changes in the adenohypophysis of dogs with induced primary hypothyroidism: loss of TSH hypersecretion, hypersomatotropism, hypoprolactinemia, and pituitary enlargement with transdifferentiation

From case studies in humans it is known that primary hypothyroidism (PH) may be associated with morphological and functional changes of the pituitary. There is no insight into the time scale of these changes. In this study, seven beagle dogs were followed up for 3 years after the induction of primary hypothyroidism. Three of these dogs were followed up for another 1.5 years while receiving l-thyroxine. Adenohypophyseal function was investigated at 2-month intervals with the combined intravenous injection of CRH, GHRH, GnRH, and TRH, and measurement of the plasma concentrations of ACTH, GH, LH, PRL, and TSH. In addition, after 2 years of hypothyroidism a single TRH-stimulation test and a somatostatin test were performed, with measurements of the same pituitary hormones. Every 6 months the pituitary gland was visualized by computed tomography (CT). Induction of PH led to high plasma TSH concentrations for a few months, where after concentrations gradually declined to values no longer significantly different from pre-PH values. A blunted response to stimulation of TSH release preceded this decline. Basal plasma GH concentrations increased during PH and there was a paradoxical hyperresponsiveness to TRH stimulation. Basal GH concentrations remained elevated and returned only to low values during l-thyroxine treatment. Basal PRL concentrations decreased significantly during PH and normalized after several months of l-thyroxine treatment. The pituitary gland became enlarged in all dogs. Histomorphology and immunohistochemical studies in 4 dogs, after 3 years of PH, revealed thyrotroph hyperplasia, large vacuolated thyroid deficiency cells, and decreased numbers of mammotrophs. Several cells stained for both GH and TSH. In conclusion, with time PH led to a loss of the TSH response to low T4 concentrations, hypersecretion of GH, and hyposecretion of PRL. The enlarged pituitaries were characterized by thyrotroph hyperplasia, large vacuolated thyroid deficiency cells, and double-staining cells, which are indicative of transdifferentiation.     

Combined pituitary hormone deficiency in german shepherd dogs with dwarfism

In German shepherd dogs pituitary dwarfism is known as an autosomal recessive inherited abnormality. To investigate whether the function of cells other than the somatotropes may also be impaired in this disease, the secretory capacity of the pituitary anterior lobe (AL) cells was studied by a combined pituitary AL stimulation test with four releasing hormones (4RH test) in four male and four female German shepherd dwarfs. In addition, the morphology of the pituitary was investigated by computed tomography. The physical features of the eight German shepherd dwarfs were primarily characterized by growth retardation and stagnant development of the hair coat. The results of the 4RH test confirmed the presence of hyposomatotropism. The basal plasma TSH and prolactin concentrations were also low and did not change upon stimulation. Basal plasma concentrations of LH were relatively low and responded only slightly to suprapituitary stimulation. With respect to the plasma FSH levels there was a clear gender difference. In the males plasma FSH concentrations remained below the detection limit throughout the 4RH test, whereas in the females the basal plasma FSH levels were slightly lower and there was only a small increase following suprapituitary stimulation, compared with the values in age-matched controls. In contrast, basal and stimulated plasma ACTH concentrations did not differ between the dwarfs and the controls. Computed tomography of the pituitary fossa revealed a normal sized pituitary with cysts in five dogs, an enlarged pituitary with cysts in two dogs, and a small pituitary gland without cysts in the remaining dog. The results of this study demonstrate that German shepherd dwarfs have a combined deficiency of GH, TSH, and prolactin together with impaired release of gonadotropins, whereas ACTH secretion is preserved. The combined pituitary hormone deficiency is associated with cyst formation and pituitary hypoplasia.     

Pituitary dwarfism in a German shepherd dog (author's transl)

Pituitary dwarfism has been described in more than 20 German shepherd dogs. Some cases probably were caused by persistent cysts of Rathke's pouch. This is the first histopathological, immunohistochemical and endocrinological study. A 13-month-old, 7-kg, dwarf purebred German shepherd bitch with alopecia and hyperpigmentation was admitted to the clinic for euthanasia. Retardation of growth was noticed when the dog was about two months old. No littermates had this condition. Two subsequent breedings from the same parents produced normal offspring. The clinical parameters in our dog (hematology, function of liver and kidney) were normal. Grossly, the pituitary gland had small and large multiple cysts, which light microscopy showed to be exclusively within the adenohypophysis. The latter had pressure atrophy, and immunohistochemically showed only remnants of the hormone-producing cells (growth hormone-GH; prolactin-PRL; thyrotropin-TSH; luteinizing hormone-LH; adrenocorticotrophin-ACTH/MSH). The thyroid was relatively small, and histologically showed focally resting follicles without lumen. Endocrinological studies showed a surprisingly high value for serum growth hormone (cGH 4.1 ng/ml; normal range 1.8-3.8 ng/ml as determined by a specific homologous radioimmunoassay) and a pathologically low serum somatomedin (SM 0.132; normal value more than 0.50 unit/ml, determined by 35S incorporation in piglet rib cartilage). Hypothyroidism was verified by a low T4 binding value (T4 0.9 micrograms/100 ml; normal 4.1 +/- 0.9 micrograms/100 ml) and a low thyroid binding index (TBI 0.54; normal 0.61 +/- 0.05). While ACTH was lowered (ACTH less than 10 pg/ml; normal 74-210 pg/ml), cortisol was normal (0.81 micrograms/100 ml; normal 0.5-2.5 micrograms/100 ml). Pituitary dwarfism in the 13-month-old bitch can be ascribed to the persistence of one end of the ductus craniopharyngeus, Rathke's pouch. Pressure atrophy of the adenohypophysis led to the loss of most of the hormone-producing tissue. An increase in growth hormone with lowered somatomedin raises questions. We have no conclusive explanation for this, due to the present lack of knowledge of how growth is regulated. High growth hormone and low somatomedin values are found in Laron's syndrome in infants. The literature indicates that pituitary dwarfism in German shepherd dogs may be a hereditary autosomal recessive trait.     

Effect of daily injections of growth hormone-releasing factor and thyrotropin-releasing hormone on growth and endocrine parameters in chickens

The control of growth is a complex mechanism regulated by several metabolic hormones including growth hormone (GH) and thyroid hormones. In avian species, as well as in mammals, GH secretion is regulated by hypothalamic hypophysiotropic hormones. Since thyrotropin-releasing hormone (TRH) and growth hormone-releasing factor (GRF) are potent GH secretagogues in poultry, we were interested in determining the influence of daily intravenous administration of either peptide or both simultaneously on circulating GH and IGF-I concentrations and whether an improvement in growth rate or efficiency would be obtained.

Male broiler chicks were injected once daily for a period of 21 days with either GRF (10 μg/kg), TRH (1 μg/kg) or both GRF and TRH (10 and 1 μg/kg respectively) between four and seven weeks of age. On the last day of the experiment, following intravenous injection of TRH, GRF or a combination of GRF and TRH, plasma GH levels were significantly (P<.05) increased to a similar extent in control chicks and in those which had received daily peptide injections for the previous 21 days. Circulating GH levels between 10 and 90 min post-injection were significantly (P<.05) greater and more than additive than GH levels in chicks injected with both GRF and TRH when compared to those injected with either peptide alone. Mean plasma T₃ concentrations during that same time period were significantly elevated (P<.05) above saline-injected control chick levels in birds treated with TRH or GRF and TRH respectively, regardless of whether the chicks had received peptide injections for the previous 21 days. There was no evidence of pituitary refractoriness to chronic administration of either TRH or GRF injection in terms of growth or thyroid hormone secretion.

Despite the large elevation in GH concentration each day, growth rate, feed efficiency and circulating IGF-I concentrations were not enhanced. Thus the quantity or secretory pattern of GH secretion induced by TRH or GRF administration was not sufficient to increase plasma IGF-I concentration or growth.     

Clinical hypothyroidism associated with trimethoprim-sulfadiazine administration in a dog

Treatment of a 9-year-old spayed female mixed-breed dog with trimethoprim-sulfadiazine for a prolonged period resulted in clinical signs of hypothyroidism, and results of thyroid gland function tests were indistinguishable from those associated with endogenous hypothyroidism. Drug-induced hypothyroidism was diagnosed on the basis of history, normal thyroid uptake of sodium pertechnetate, and complete recovery of thyroid gland function after administration of trimethoprim-sulfadiazine was discontinued.     

Acute effects of hypophysectomy and administration of pancreatic and thyroid hormones on circulating concentrations of somatomedin-C in young chickens: Relationship between growth hormone and somatomedin-C

The short-term control of plasma concentrations of somatomedin C (SmC) in young chicks was examined by either surgical removal of the pituitary gland or by the administration of hormones which affect plasma concentrations of growth hormone (GH). As expected, removal of the source of GH by hypophysectomy reduced plasma concentration of GH, these being suppressed by 95.7% within 1 hour. Hypophysectomy was rapidly followed by reductions in the plasma concentration of SmC. For instance, plasma concentrations of SmC were decreased to 53% of pretreatment one hour following hypophysectomy. This suggests both that SmC has a short half life and that the release of SmC into the circulation is tightly coupled to the presence of pituitary hormone(s), presumably including GH. Sham surgery also decreased plasma concentrations of GH but were without effect on plasma concentrations of SmC. The short term control of plasma concentrations of SmC was also examined by the acute administration of hormones, which affect GH secretion in vivo. Injections of thyroxine or triiodothyronine decreased the plasma concentration of GH but were without effect on the plasma concentration of SmC. On the other hand, the administration of either glucagon or insulin decreased the plasma concentration of both GH and SmC. The present data suggest that plasma concentrations of SmC do not simply reflect the GH status in young chickens.     

Progestin-induced growth hormone (GH) production in the treatment of dogs with congenital GH deficiency

The recent demonstration of the ability of progestins to induce the expression of the growth hormone (GH) gene in the mammary gland of dogs and cats opens possibilities for the treatment of some forms of GH deficiency with progestins. Therefore, one male and one female German shepherd dog with congenital dwarfism because of a pituitary anomaly were treated with subcutaneous injections of medroxyprogesterone acetate (MPA) in doses of 2.5–5.0 mg per kg body weight, initially at 3-wk intervals and subsequently at 6-wk intervals. In both dogs, body sizes increased and a complete adult hair coat developed. Undesirable side-effects were recurrent periods of pruritic pyoderma in both dogs and cystic endometrial hyperplasia with mucometra in the female dog. Parallel with the physical improvements, plasma insulin-like growth factor I concentrations rose sharply. Plasma GH concentrations tended to rise, but never exceeded the upper limit of the reference range. Nevertheless, one of the dogs developed slight acromegalic features, possibly because mammary GH, unlike pituitary GH, is released evenly throughout the day. Even moderate increases in circulating GH concentration may, therefore, give rise to overexposure. It is concluded that long-term treatment with MPA can be used as an alternative for heterologous GH in the treatment of congenital GH deficiency in the dog.     

Regulation of the growth hormone and luteinizing hormone response to endotoxin in sheep

Infectious disease processes cause physiological adaptations in animals to reorder nutrient partitioning and other functions to support host survival. Endocrine, immune and nervous systems largely mediate this process. Using endotoxin injection as a model for catabolic disease processes (such as bacterial septicemia), we have focused our attention on regulation of growth hormone (GH) and luteinizing hormone (LH) secretion in sheep. Endotoxin produces an increase in plasma GH and a decrease in plasma LH concentrations. This pattern can be reproduced, in part, by administration of various cytokines. Antagonists to both interleukin-1 (IL-1) and tumor necrosis factor (TNF) given intravenously (IV) prevented the endotoxin-stimulated increase in GH. Since endotoxin will directly stimulate GH and LH release from cultured pituitary cells, the data suggest a pituitary site of action of the endotoxin to regulate GH. Studies with portal vein cannulated sheep indicated that gonadotropin releasing hormone was inhibited by endotoxin, suggesting a central site of action of endotoxin to regulate LH. However, other studies suggest that endotoxin may also regulate LH secretion at the pituitary. Thus, IL-1 and TNF regulate GH release from the pituitary gland while endotoxin induces a central inhibition of LH release.     

Regulation of growth hormone expression by thyrotropin-releasing hormone through the pituitary-specific transcription factor Pit-1 in chicken pituitary

Pit-1 is a pituitary-specific POU-domain DNA binding factor, which binds to and trans-activates promoters of growth hormone- (GH), prolactin- (PRL) and thyroid stimulating hormone beta- (TSHbeta) encoding genes. Pit-1 has been identified in several mammalian and avian species. Thyrotropin-releasing hormone (TRH) is located in the hypothalamus and it stimulates TSH, GH and PRL release from the pituitary gland. In the present study, we successfully developed a competitive RT-PCR for the detection of Pit-1 expression in the chicken pituitary, that was sensitive enough to detect picogram levels of Pit-1 mRNA. Applying this method, the effect of TRH injections on Pit-1 mRNA expression was determined in the pituitary of chick embryos and growing chicks. In both 18-day-old embryos and 10-day-old male chicks the Pit-1 mRNA expression was significantly increased following TRH injection, thereby indicating that the stimulatory effects of TRH on several pituitary hormones is mediated via its effect on Pit-1 expression. Therefore, a semi-quantitative RT-PCR method was used to detect possible changes in GH levels. TRH affected the GH mRNA levels at both developmental stages. These results, combined with the data on Pit-1 mRNA expression, indicate that Pit-1 has a role in mediating the stimulatory effects of TRH on pituitary hormones like GH.     

Adenohypophyseal Function in Dogs with Primary Hypothyroidism and Nonthyroidal Illness

Background: A recent study of dogs with induced primary hypothyroidism (PH) demonstrated that thyroid hormone deficiency leads to loss of thyrotropin (TSH) hypersecretion, hypersomatotropism, hypoprolactinemia, and pituitary enlargement with large vacuolated "thyroid deficiency" cells that double-stained for growth hormone (GH) and TSH, indicative of transdifferentiation of somatotropes to thyrosomatropes.
Hypothesis: Similar functional changes in adenohypophyseal function occur in dogs with spontaneous PH as do in dogs with induced PH, but not in dogs with nonthyroidal illness (NTI).
Animals: Fourteen dogs with spontaneous PH and 13 dogs with NTI.
Methods: Adenohypophyseal function was investigated by combined intravenous administration of 4 hypophysiotropic releasing hormones (4RH test), followed by measurement of plasma concentrations of ACTH, GH, luteinizing hormone (LH), prolactin (PRL), and TSH. In the PH dogs this test was repeated after 4 and 12 weeks of thyroxine treatment.
Results: In 6 PH dogs, the basal TSH concentration was within the reference range. In the PH dogs, the TSH concentrations did not increase with the 4RH test. However, TSH concentrations increased significantly in the NTI dogs. Basal and stimulated GH and PRL concentrations indicated reversible hypersomatotropism and hyperprolactinemia in the PH dogs, but not in the NTI dogs. Basal and stimulated LH and ACTH concentrations did not differ between groups.
Conclusions and Clinical Importance: Dogs with spontaneous PH hypersecrete GH but have little or no TSH hypersecretion. Development of hyperprolactinemia (and possible galactorrhea) in dogs with PH seems to occur only in sexually intact bitches. In this group of dogs with NTI, basal and stimulated plasma adenohypophyseal hormone concentrations were not altered.     

Update on drugs used to treat endocrine diseases in small animals.

Drug therapy for the endocrine system is implemented to replace a hormone deficiency or to prevent or reduce the formation or effects of excess hormone. Treatment of endocrine disorders covers diseases of the pituitary, adrenal, parathyroid, and thyroid glands as well as the endocrine pancreas. This article focuses on new therapies currently available for specific diseases. Administration of trilostane for treatment of hyperadrenocorticism and use of insulin glargine, protamine zinc insulin (PZI), and porcine Lente insulin for diabetes mellitus are discussed. In addition, transdermal methimazole therapy for treatment of feline hyperthyroidism and administration of progestins for pituitary dwarfism are considered.