Effect of mitotane on pituitary corticotrophs in clinically normal dogs

OBJECTIVE: To evaluate the effects of mitotane administration on the function and morphology of pituitary corticotrophs in clinically normal dogs. ANIMALS: 12 clinically normal adult Beagles. PROCEDURES: Dogs were randomly assigned to the control group or the mitotane treatment group. In mitotane treatment group dogs, mitotane was administered for 1 month. In both groups, ACTH stimulation testing and corticotrophin-releasing hormone (CRH) stimulation testing were performed. Magnetic resonance imaging (MRI) of the pituitary gland and brain was performed in mitotane treatment group dogs before and after administration of mitotane. After CRH stimulation testing and MRI, dogs were euthanatized and the pituitary gland and adrenal glands were excised for gross and histologic examination. RESULTS: ACTH concentrations in mitotane treatment group dogs were significantly higher than in the control group dogs following CRH stimulation. Magnetic resonance imaging revealed that pituitary glands were significantly larger in treatment group dogs after administration of mitotane, compared with before administration. On gross and histologic examinations, the adrenal cortex was markedly atrophied. Immunohistochemistry revealed hypertrophy of corticotrophs in pituitary glands of mitotane treatment group dogs. CONCLUSIONS AND CLINICAL RELEVANCE: These findings indicate that inhibition of the adrenal cortex by continuous administration of mitotane leads to functional amplification and morphologic enhancement of corticotrophs in clinically normal dogs. In instances of corticotroph adenoma, hypertrophy of individual corticotrophs induced by mitotane may greatly facilitate enlargement of the pituitary gland and increases in ACTH secretion.     

Comparison of mitotane treatment for adrenal tumor versus pituitary-dependent hyperadrenocorticism in dogs.

The purpose of this study was to determine the sensitivity of dogs with hyperadrenocorticism to treatment with the adrenocorticolytic agent mitotane. Specifically, we looked for differences in response to treatment using this drug in dogs with adrenocortical tumors (adrenal tumor hyperadrenocorticism, ATH) vs those with pituitary-dependent hyperadrenocorticism (PDH). For inclusion in this study, each dog must have had clinical signs, data base laboratory abnormalities, and endocrine screening test results consistent with the diagnosis of hyperadrenocorticism. Further, each dog had to have been treated for at least 6 months with mitotane and have histologic evidence for adrenocortical or pituitary neoplasia (all dogs were necropsied). Thirteen dogs with ATH (8 carcinomas, 5 adenomas) were identified. The ages and body weights of these 13 dogs were computer-matched to 13 dogs with PDH. All dogs were initially treated with approximately 50 mg of mitotane/kg/d of body weight. Reexaminations were performed after 7, 30, 90, and 180 days of treatment. Individual dosages varied widely after the initial 5 to 12 days of treatment. The mean (+/- SD) dose of mitotane (mg/kg/d) for the first 7 days of treatment was 47.5 +/- 9.4 for dogs with ATH vs 45.7 +/- 11.9 for dogs with PDH. The mean plasma cortisol concentrations 1 hour after ACTH administration at the 7-day recheck were significantly higher in dogs with ATH (502 +/- 386 nmol/L) than in dogs with PDH (88 +/- 94 nmol/L).(ABSTRACT TRUNCATED AT 250 WORDS)     

Dynamic computed tomography of the pituitary gland in dogs with pituitary-dependent hyperadrenocorticism

Dynamic computed tomography (CT) of the pituitary gland was performed in 55 dogs with pituitary-dependent hyperadrenocorticism (PDH) that underwent transsphenoidal hypophysectomy. On routine contrast-enhanced CT images, microadenomas of the pituitary gland often are indistinguishable from nontumorous pituitary tissue because of isoattenuation. Dynamic CT may allow visualization of these adenomas. The changes in the contrast-enhancement pattern of the pituitary during dynamic CT in 55 dogs with PDH were correlated with surgical and histopathologic findings. In 36 dogs, dynamic CT identified distinct contrast enhancement of the neurohypophysis (pituitary flush). In 24 dogs, this pituitary flush was displaced, which indicated the presence of an adenoma. This observation was confirmed surgically and histopathologically in 18 of the 24 dogs. In 19 dogs, there was a diffusely abnormal contrast-enhancement pattern. CT findings agreed with surgical findings in 13 of these dogs and with histopathologic findings in all 19 dogs. It is concluded that a dynamic series of scans should be included in the CT protocol of the pituitary gland in dogs with PDH because it allows for identification of an adenoma or a diffusely abnormal pituitary gland.     

Assessing the immune state of dogs suffering from pituitary gland dependent hyperadrenocorticism by determining changes in peripheral lymphocyte subsets

In order to evaluate the immune state of dogs suffering from pituitary-dependent hyperadrenocorticism (PDH), peripheral lymphocyte subsets were examined. Twenty seven PDH dogs and eight healthy control dogs were used in the current study. Eight healthy dogs served as the control group. Twenty seven PDH dogs were categorized into 4 groups based on their post serum cortisol concentrations by ACTH stimulation test: 2−5, excellent control (n = 8); 5−20, fair control (n = 7); >20, poor control (n = 4); and untreated (n = 8). Cell counts were executed with white blood cells (WBC), lymphocytes, CD3⁺ (T lymphocytes), CD4⁺ (Helper T lymphocytes), CD8⁺ (Cytotoxic T lymphocytes), CD21⁺ (B lymphocytes) cells in addition to calculating CD4⁺/CD8⁺ ratio. Results indicated a significant difference in lymphocyte numbers and lymphocyte subset populations (CD3⁺, CD4⁺, CD8⁺, and CD21⁺ cells) between PDH and control dogs. Moreover, comparison of the PDH groups (excellent control; fair control; poor control; untreated) demonstrated that all groups had a significant decrease in lymphocytes numbers (CD3⁺, CD4⁺ and CD21⁺ cell counts) as compared to control group. Meanwhile, no significant differences were observed in WBC counts and CD4⁺/CD8⁺ ratio between groups. Furthermore, lymphocyte subset distribution in excellent control PDH dogs without concurrent disease (n = 4) better resembled that of control dogs as compared to PDH dogs with concurrent disease (n = 4). PDH dogs may be suffering from an immuno-depressed state as evidenced by significant differences in lymphocyte subset populations. Furthermore, treatment of both PDH and concurrent disease might improve lymphocyte subset distribution.     

Dynamic computed tomographic evaluation of the pituitary gland in healthy dogs

OBJECTIVE: To determine the contrast enhancement pattern of the pituitary gland in healthy dogs via dynamic computed tomography (CT). ANIMALS: 17 dogs. PROCEDURE: With each dog in sternal recumbency, transverse CT scans were made perpendicular to the skull base from the rostral clinoid processes to the dorsum sellae. At the position of the image that contained the largest cross section of the pituitary gland, a series of 9 to 11 scans was made during and after IV injection of contrast medium (dynamic CT scans). The contrast enhancement pattern of the pituitary gland and surrounding arteries was assessed visually and by use of time-density curves. RESULTS: After strong enhancement of the maxillary arteries, the intracavernous parts of the internal carotid arteries, and the communicating arteries of the arterial cerebral circle, there was a strong enhancement of the central part of the pituitary gland followed by enhancement of its peripheral part. On the last images of the dynamic series of the pituitary gland, the central part was hypodense, compared with the peripheral part. Time-density curves confirmed an early, strong enhancement of the central part and a delayed, less strong enhancement of the peripheral part of the gland. CONCLUSIONS AND CLINICAL RELEVANCE: The difference in enhancement between the central and peripheral parts of the pituitary gland was attributable to a difference in vascularization of the neurohypophysis and adenohypophysis, respectively. Distortion or disappearance of the strong central enhancement (pituitary flush) may be used for the detection and localization of pituitary abnormalities in the adenohypophysis.     

Thin-slice three-dimensional gradient-echo magnetic resonance imaging of the pituitary gland in healthy dogs

OBJECTIVE: To evaluate thin-slice 3-dimensional gradient-echo (GE) magnetic resonance imaging (MRI) of the pituitary gland in healthy dogs. ANIMALS: 11 healthy dogs. PROCEDURES: By use of a 0.2-Tesla open magnet, MRI of the skull was performed with T1-weighted GE sequences and various protocols with variations in imaging plane, slice thickness, and flip angle before and after administration of contrast medium; multiplanar reconstructions were made. The pituitary region was subjectively assessed, and its dimensions were measured. Image quality was determined by calculation of contrast-to-noise and signal-to-noise ratios. RESULTS: Best-detailed images were obtained with a T1-weighted GE sequence with 1-mm slice thickness and 30 degrees flip angle before and after administration of contrast medium. Images with flip angles > 50 degrees were of poor quality. Quality of multiplanar reconstruction images with 1-mm slices was better than with 2-mm slices. The bright signal was best seen without contrast medium. With contrast medium, the dorsal border of the pituitary gland was clearly delineated, but lateral borders were more difficult to discern. CONCLUSIONS AND CLINICAL RELEVANCE: MRI of the canine pituitary gland with a 0.2-Tesla open magnet should include a T1-weighted GE sequence with 1-mm slice thickness and flip angle of 30 degrees before and after administration of contrast medium. The neurohypophysis was best visualized without contrast medium. The MRI examination permitted differentiation between the pituitary gland and surrounding structures.     

Stereological study of the adrenal gland of calves treated with clenbuterol

Stereological methods were used to investigate the morphometric variations in the adrenal cell population of calves dosed orally with clenbuterol at an anabolic dose of 20 microg/kg bodyweight per day for 12 weeks. In the treated group the size of the nuclei increased with respect to the control group, and the increases were significant for the maximum linear parameters in all the regions except the zona fasciculata. The largest increases were observed in the epinephrine-producing cells. The quantitative stereological data showed highly significant increases in the nuclear volume fraction, the nuclear surface density and the numerical density in the zona fasciculata of the treated group.     

Evaluating the correlation between adrenal gland dimensions and aortic diameter in healthy dogs

In the present study, the relationship of normal adrenal dimensions with weight, aortic diameter, age and sex was evaluated. Moreover, a formula for estimating the normal dimensions of adrenal gland was provided. Thirty‐two intact adult dogs that were considered healthy based on history, physical examination, routine blood works and specific adrenal tests as well as absence of any abnormal ultrasonographic findings were included. Adrenal glands and abdominal aorta were imaged in the sagittal plane by ultrasound. Length, maximal height of the cranial and caudal poles, area and circumference of the left and right adrenal glands and also the internal diameter of the abdominal aorta were measured. Analysis showed that there is a positive correlation between the adrenal gland dimensions and weight and aortic diameter. The ratio of adrenal gland dimensions and the aortic diameter was calculated, but this ratio showed a great amount of variability in tandem with a significant correlation to the weight; Meaning that the ratio of the adrenal gland dimensions to the aortic diameter was not a reliable index for evaluating the size of the normal adrenal gland in animals with different weights. Therefore, we used the weight along with adrenal measurements in a linear regression model, and then, we were able to estimate the adrenal gland dimensions in different weights. Knowing the relationship of normal adrenal dimensions with the indices such as weight, age, sex and diameter of abdominal aorta can help the clinicians to diagnose the adrenal gland diseases.     

Multiple metastases of thyroid cancer in the cranium and pituitary gland in two dogs

Two dogs, a 14-year-old, female American Eskimo dog and a 14-year-old, male Maltese dog, were presented with thalamic syndromes, including lowered levels of consciousness, poor postural responses and presence of masses in the neck region. In both dogs, magnetic resonance imaging revealed multiple masses inside the cranium, including the pituitary gland. One dog died from status epilepticus two days after magnetic resonance imaging and the other died two months after magnetic resonance imaging from respiratory failure. These dogs were histopathologically diagnosed with multiple metastases of thyroid cancer occurring inside the cranium, including the pituitary gland. To the authors' knowledge, this is the first time this tumour pattern has been reported in dogs, but it is possible that it is not uncommon.     

Effect of glucocorticoid administration on adrenal gland size and sonographic appearance in beagle dogs

Our aim was to evaluate the influence of glucocorticoids on the adrenal gland using ultrasonography. Eleven healthy beagles were used in a prospective placebo-controlled study. All dogs received hydrocortisone at 10 mg/kg twice a day per os for 4 months or a gelatin capsule twice a day per os as a placebo. Clinical and endocrinologic examination of the dogs and ultrasonographic evaluation of adrenal echogenicity, shape, and measurement of the length and height of the cranial and caudal pole were performed at baseline (TO), at 1 (T1) and 4 months (T4) after the beginning of treatment, and 2 months after the end of the treatment including 1 month of tapering and 1 month without treatment (T6). The dogs were assigned randomly to the glucocorticoid (n = 6) and placebo groups (n = 5). At T1, the difference between the two groups for the height of the cranial and caudal pole was not ultrasonographically remarkable despite a statistically significant difference (P = 0.0165 and P = 0.0206). Decreased height and length of entire gland were observed at T4 (P < 0.0001, P = 0.0015, and P = 0.0035, respectively). Percentages of atrophy were variable between dogs. Both adrenal glands regained normal size and shape 1 month after cessation of glucocorticoid administration. As not all dogs developed marked adrenal gland atrophy and the degree of atrophy varied widely between individuals, ultrasonography cannot be the technique of choice to detect iatrogenic hypercortisolism. Ultrasonographic changes are reversible within 1 month after the end of glucocorticoid administration.     

Comparison of ultrasonographic characteristics of the thyroid gland in healthy small-, medium-, and large-breed dogs

OBJECTIVE: To determine ultrasonographic characteristics of the thyroid gland in healthy small-, medium-, and large-breed dogs and evaluate the relationships of thyroid gland size and volume with body weight and body surface area (BSA). ANIMALS: 72 dogs of small (6 Toy and 6 Miniature Poodles), medium (12 Beagles), and large breeds (12 Akitas and 36 Golden Retrievers). PROCEDURE: Each dog's thyroid gland was examined ultrasonographically with a 10- to 5-MHz multifrequency linear-array transducer. Size, shape, echogenicity, and homogeneity of thyroid lobes were evaluated on longitudinal and transverse images. Thyroid lobe volume was estimated by use of the equation for an ellipsoid (pi/6 [length x height x width]). RESULTS: Thyroid lobes appeared fusiform or elliptical on longitudinal images and triangular or round to oval on transverse images. In most dogs, thyroid lobes were hyperechoic or isoechoic, compared with surrounding musculature, and had a homogeneous echogenic pattern. Mean length, width, height, and volume of thyroid lobes were significantly greater in Akitas and Golden Retrievers, compared with findings in Beagles or Poodles; mean length, width, and height were significantly greater in Beagles, compared with findings in Poodles. Total thyroid gland volume correlated with body weight (r = 0.73) and BSA (r = 0.74). CONCLUSIONS AND CLINICAL RELEVANCE: Among the dog breeds examined ultrasonographically, thyroid lobe size and volume were more variable than shape, echogenicity, and homogeneity. The correlation of thyroid gland volume with BSA suggests that size of the dog, rather than breed, should be considered when assessing thyroid glands ultrasonographically.     

Effects of radiotherapy on pituitary corticotroph macrotumors in dogs: a retrospective study of 12 cases

The efficacy of low doses of radiotherapy for the treatment of pituitary corticotroph macrotumors in dogs is evaluated retrospectively. Twelve dogs with pituitary-dependent hyperadrenocorticism and a large pituitary tumor treated with 36 Gy of radiation were included. Radiation was delivered in 12 fractions of 3 Gy over a 4- to 6-week period. Effects of radiation therapy on tumor size were assessed by computed tomography scans; a decrease was observed in 11 dogs (decrease > 50% in 6 dogs). Three dogs were reirradiated due to major tumor regrowth or a lack of tumor decrease (mean total dose: 22 Gy given in 3-Gy fractions over 3 or 4 weeks). The mean and median survival times following the initiation of radiotherapy were 22.6 months (688 days) and 17.7 months (539 days), respectively. These data are consistent with previous findings, based on high-dose radiation, showing that radiotherapy is a useful option for treating pituitary corticotroph macrotumors in dogs. Furthermore, computed tomography follow-up of the treated dogs demonstrates objectively the efficacy of radiotherapy against corticotroph tumors in dogs.     

Ultrasonographic adrenal gland measurements in clinically normal small breed dogs and comparison with pituitary-dependent hyperadrenocorticism

Ultrasonography is a sensitive and specific screening method for assessing the adrenal glands. The upper limit of the normal adrenal gland width is used as 7.5 mm. It is not known if adrenal gland width remains consistent with body weight. A reliable criterion of adrenal gland width in small breed dogs should be established. Small breed dogs with body weights of less than 10 kg were divided into two groups: 189 normal dogs and 22 dogs with pituitary-dependent hyperadrenocorticism (PDH). A retrospective study was conducted on dogs seen between January 1, 2006, and February 10, 2008. One hundred eighty-nine dogs of 14 different small breeds were enrolled in the normal adrenal gland group; the median gland width was 4.20 mm. Twenty-two dogs were in the PDH group; the median gland width was 6.30 mm. The cut-off value between normal adrenal glands and PDH was 6.0 mm. This figure gave a sensitivity and specificity of 75 and 94%, respectively, for detecting PDH. The adrenal gland appeared as a peanut shape with homogeneous hypoechoic parenchyma in normal dogs and in most dogs with PDH as well. This study was performed in a large population of small breed dogs and suggests that the normal adrenal gland size in small breed dogs is smaller than previously reported. We believe that a cut-off of 6.0 mm may be used as the criterion for differentiating a normal adrenal gland from adrenal hyperplasia.     

Effects of long-term phenobarbital treatment on the thyroid and adrenal axis and adrenal function tests in dogs

Phenobarbital can interfere with the thyroid axis in human beings and rats by accelerating hepatic thyroxine metabolism because of enzyme induction. In human beings, it also can interfere with the low-dose dexamethasone suppression test (LDDST) used to assess adrenal function by accelerating dexamethasone metabolism. This effect can cause a lack of suppression of pituitary ACTH and subsequent adrenal cortisol release after dexamethasone administration. The effects of phenobarbital on the thyroid axis, the adrenal axis, and adrenal function tests were prospectively investigated in 12 normal, adult dogs. Phenobarbital was administered at 5 mg per kilogram of body weight (range, 4.8–6.6 mg/kg) PO q12h for 29 weeks, resulting in therapeutic serum concentrations (20–40 μg/mL). Serum total thyroxine (TT4), free thyroxine (FT4) by equilibrium dialysis, total triiodothyronine (TT3), thyrotropin (TSH), and cholesterol were determined before and during phenobarbital treatment. LDDST, ACTH stimulation tests, and ultra-sonographic evaluation of the adrenal glands were performed before and during treatment. TT4 and FT4 decreased significantly ( P ≤ .05), TT3 had minimal fluctuation, TSH had only a delayed compensatory increase, and cholesterol increased during phenobarbital treatment. The delayed increase in TSH, despite persistent hypothyroxinemia, suggests that accelerated hepatic thyroxine elimination may not be the only effect of phenobarbital on the thyroid axis. There was no significant effect of phenobarbital on either of the adrenal function tests. With the methods employed, we did not find any effects of the drug on the hormonal equilibrium of the adrenal axis.     

Comparison of non-selective adrenocorticolysis with mitotane or trilostane for the treatment of dogs with pituitary-dependent hyperadrenocorticism

Forty-six dogs with pituitary-dependent hyperadrenocorticism were treated with mitotane by the non-selective adrenocorticolysis protocol and 40 were treated twice a day with trilostane. The treatment groups were compared by chi-squared tests, and survival data were analysed using Kaplan-Meier survival plots and a Cox proportional hazard method. The non-selective adrenocorticolysis protocol was very effective (89 per cent), its toxicity was moderate (24 per cent) and there were fewer recurrences (29 per cent) than reported with the classical selective adrenocorticolysis protocol (58 per cent). In a multivariate model, age and bodyweight at diagnosis were significantly negatively correlated with survival time. The median survival time of the dogs treated with trilostane twice a day (900 days) was longer (P=0.05) than that of the dogs treated with mitotane (720 days).     

Effects of sildenafil citrate on five dogs with Eisenmenger's syndrome

Objectives : To determine the effect of sildenafil for dogs with Eisenmeger's syndrome and secondary erythrocytosis. Methods : This is a prospective, single arm, open‐label study. Five clinical dogs with Eisenmeger's syndrome and secondary erythrocytosis were included. New York Heart Association functional class, packed cell volume, pulmonary artery acceleration time to ejection time ratio and serum erythropoietin concentration were evaluated before and after sildenafil therapy (0·5 mg/kg, twice a day). Results : New York Heart Association functional class was significantly improved after one (median 2; range 1 to 2, P=0·031) and three months (median 2; range 1 to 2, P=0·031) of sildenafil therapy, compared with the baseline (median 3, range 2 to 3). Packed cell volume was significantly decreased after three months (median 59%; range 56 to 63, P=0·031) of therapy, compared with the baseline (median 71%; range 58 to 74). Acceleration time to ejection time ratio had increased and serum erythropoietin concentration had decreased particularly after 1 month of therapy, but there was no statistical significance. Clinical Significance : Sildenafil improved the clinical signs and secondary erythrocytosis in dogs with Eisenmeger's syndrome. Sildenafil therapy could be a useful treatment for dogs with Eisenmeger's syndrome.