Corticoid production by four dogs with hyperfunctioning adrenocortical tumours during treatment with mitotane (o,p'-DDD).

In two dogs with hyperadrenocorticism due to an adrenocortical tumour, treatment with o,p'-DDD was started. Their hormonal response was monitored by measurements of the urinary corticoid/creatinine ratio. In one dog, two courses of 10 days treatment with o,p'-DDD were ineffective, whereas in the other dog the urinary corticoids decreased to very low levels after only six days of treatment, and corticosteroid supplementation had to be started. Two other dogs received o,p'-DDD according to a protocol used for the treatment of pituitary-dependent hyperadrenocorticism which aims at the complete destruction of the adrenal cortices, with substitution for the induced hyperadrenocorticism. Both dogs made a good recovery and their urinary corticoid/creatinine ratio decreased to within the reference range. In one of them the tumour had decreased considerably in size by five weeks after the start of the treatment.     

Results of non-selective adrenocorticolysis by o,p'-DDD in 129 dogs with pituitary-dependent hyperadrenocorticism

One hundred and twenty-nine dogs with pituitary-dependent hyperadrenocorticism were treated according to a protocol aimed at the complete destruction of the adrenal cortices by the administration of o,p'-DDD (mitotane) at a daily dose of 50 to 75 mg/kg bodyweight for 25 days. On the third day, glucocorticoid and mineralocorticoid supplementation was begun for the induced adrenocortical insufficiency. The first followup examination after completion of the 25-day course and the subsequent twice-yearly follow-up examinations included physical examination and measurements of plasma concentrations of sodium and potassium to optimise substitution therapy. In 19 dogs the full course of 25 days treatment could not be completed. Of the 110 dogs which received the full course of treatment, the administration had to be stopped temporarily in 32 because of side-effects, such as anorexia and vomiting. The actual dose of o,p'-DDD administered was not significantly different in the dogs with and without these side-effects. Clinical remission occurred in 111 dogs (86 per cent), of which 43 (39 per cent) had a relapse. The estimated one-year disease-free fraction was 77 per cent (95 per cent confidence interval [CI]: 67 to 85 per cent). The estimated one-year survival fraction was 80 per cent (95 per cent CI: 71 to 87 per cent), the two-year survival was 69 per cent (95 per cent CI: 59 to 78 per cent), and the three-year survival was 61 per cent (95 per cent CI: 49 to 71 per cent). The bodyweight and age of the dog, and vomiting occurring during the period of treatment, were positively correlated with the length of the disease-free period, whereas weakness during the treatment and resistance to dexamethasone suppression of the urinary corticoid/creatinine ratios at the start of the treatment were associated with a relatively short survival time.     

A Retrospective Study of Aldosterone Secretion in Normal and Adrenopathic Dogs

A retrospective study on stored plasma from normal dogs and dogs with pituitary dependent hyperadrenocorticism (PDH), pituitary dependent hyperadrenocorticism controlled by mitotane (o,p'-DDD),* iatrogenic hyperadrenocorticism, and hypoadrenocorticism was conducted to determine if alterations in aldosterone production exist in these disorders. The plasma aldosterone concentration (PAC) was measured by radioimmunoassay immediately before and 1 hour after adrenocorticotropic hormone (ACTH) administration (0.5 IU/kg, intravenously [IV]). PACs increased significantly when ACTH was administered to normal dogs. Dogs with PDH had a lower baseline PAC, but their PAC increased to levels similar to that of normal dogs after ACTH administration. In dogs with PDH controlled by o,p'-DDD therapy, the response to ACTH was significantly less than that of normal dogs or dogs with untreated PDH. Dogs with iatrogenic hyperadrenocorticism had a lower baseline and post-ACTH PAC than normal dogs. Dogs with hypoadrenocorticism had a normal basal PAC, but showed no significant increase in PAC following ACTH administration. These findings suggest that PACs are significantly altered in a variety of adrenal diseases, and that the ACTH stimulation test may be useful when evaluating aldosterone secretion in adrenopathic disorders. In addition, at therapeutic dosages, o,p'-DDD treatment was associated with a decrease in basal and post-ACTH PACs in dogs with PDH.     

Systemic availability of o,p'-DDD in normal dogs, fasted and fed, and in dogs with hyperadrenocorticism

The systemic availability of o,p'-DDD was studied in 12 normal dogs and seven dogs with pituitary-dependent hyperadrenocorticism (PDH). The drug was given by mouth at 50 mg kg-1 and plasma o,p'-DDD concentrations were determined by gas-liquid chromatography. First, six normal dogs were given the drug three times at intervals of one week in a Latin square pattern. Systemic drug availability was found to be very poor from intact tablets in fasted dogs, better with pure drug dissolved in maize oil given by stomach tube, and best with ground tablets mixed in oil poured on dog food. Then six normal dogs and five with PDH were given one dose of o,p'-DDD as intact tablets in dog food. Systemic drug availability was good in the normal animals and, for unknown reasons, better in dogs with PDH. The half-time of elimination was shorter in dogs with PDH than in normal ones. There was evidence of a gradual rise in plasma o,p'-DDD concentrations in seven dogs with PDH treated with 25 mg kg-1 every 12 hours for 14 or 20 days. The interaction between food and o,p'-DDD probably contributes to the variation in clinical response of dogs treated with the drug. The efficiency of therapy with o,p'-DDD should be improved considerably by administering the drug with food.     

Adrenal gland function in dogs given methylprednisolone

Serum cortisol (hydrocortisone) was measured by radioimmunoassay in dogs given methylprednisolone (MP) orally or methylprednisolone acetate (MPA) IM. The MP was given on a daily and on an alternate-day basis to different treatment groups and the MPA was administered weekly. Samples of blood were obtained twice a week over a 9-week treatment period for serum cortisol determination, and the adrenal gland response to ACTH was assessed on posttreatment days 1, 3, 5, and 7. Administration of MP on an alternate or daily basis caused a slight but significant (P < 0.05) depression in mean resting cortisol values over time. The MPA administration caused a severe depression of resting serum cortisol values. In response to ACTH, cortisol values invariably increased sharply in nontreated control dogs and in those dogs given MP on an alternate-day basis. Dogs given MP daily had a depressed response to ACTH. The MPA treatment resulted in adrenal cortices that were unresponsive to ACTH. Dogs given MPA, but not challenge exposed with ACTH, had markedly lowered cortisol values for at least 2 weeks after cessation of treatment. Consequently, a difference between daily- and alternate-day MP administration was detected after ACTH challenge exposure; MPA administration inhibited adrenal cortisol secretion for at least the duration of the experiment.     

Diseases of the adrenal cortex of dogs and cats

Of cases of hyperadrenocorticism in small animals 80-85% are the result of adrenocortical hyperplasia. Middle-aged or older Poodles, Dachshunds, Boston Terriers and Boxers are most commonly affected, and cats rarely. Clinical signs include polydipsia, polyuria, alopecia, abdominal distension, lethargy, weakness, hepatomegaly, calcinosis cutis, testicular atrophy and anestrus. Hematologic and biochemical changes may include neutrophilia, lymphopenia, monocytosis, eosinopenia, increased blood levels of alkaline phosphatase, SGPT, cholesterol, Na and glucose, and decreased K and T4 levels. The high-dosage dexamethasone suppression test helps differentiate pituitary-dependent hyperadrenocorticism from that caused by adrenal tumors. The low-dosage dexamethasone suppression test, determination of plasma ACTH levels, and ACTH response test are additional diagnostic aids in the diagnosis of Cushing's disease. Medical treatment involves oral use of mitotane (o,p'-DDD) at 50 mg/kg/day for 7 days and prednisone or prednisolone at 0.05 mg/kg/day. Hypophysectomy has been used with only 5% mortality in cases of pituitary-dependent hyperadrenocorticism. Adrenalectomy is indicated in cases of adrenal neoplasia.     

Hypophysectomy as a treatment for canine and feline Cushing's disease.

The microsurgical technique of transsphenoidal hypophysectomy performed with the dogs and cats positioned in sternal recumbency enables the treatment of Cushing's disease, independent of skull type, in a safe and effective manner. In dogs, the short-term survival rate after hypophysectomy is comparable to that after treatment with o,p'-DDD, whereas the recurrence rate in this period is lower. When the surgeon has gone through a learning curve, the results of the 1- to 3-year follow-up interval may be better than those after adrenocorticolysis with o,p'-DDD. CT enables assessment of localization and size of the pituitary before surgery. In general, dogs with Cushing's disease and normal-sized pituitaries or moderately enlarged pituitaries (up to 12 mm in diameter) are suitable candidates for transsphenoidal surgery. In dogs with larger pituitary tumors and tumor extension rostrally or caudally over the dorsum sellae, transsphenoidal debulking surgery may be only a palliative treatment. The main complications are postoperative hypernatremia, keratoconjunctivitis sicca, diabetes insipidus, and secondary hypothyroidism. In cats, special attention should be paid to closure of the soft palate. The neurosurgeon must be familiar with these complications so as to recognize them as early as possible and to treat them immediately and effectively. It is concluded that microsurgical transsphenoidal hypophysectomy in dogs and cats with Cushing's disease is an effective method of treatment.     

Medical Management of Pituitary-Dependent Hyperadrenocorticism: Mitotane versus Trilostane

Pituitary-dependent hyperadrenocorticism is a common endocrine disorder in dogs in the United States. Once a diagnosis is established, a decision must be made whether or not to pursue treatment, and if so, which medication to use. Historically, mitotane (Lysodren, o,p'-DDD, Bristol-Myers Squibb, New York) has been the most commonly used treatment for medical management. Its use is complicated and comes with many potential side effects, making many practitioners wary of its use. Recently, trilostane has been proven to be an effective treatment of pituitary-dependent hyperadrenocorticism and is approved for use in other countries. Treatment with trilostane is somewhat simpler and the incidence of side effects seems to be less when compared with mitotane therapy. Either treatment can be a safe and effective method of treatment for pituitary-dependent hyperadrenocorticism when the practitioner and client are well educated regarding their use and an appropriate monitoring protocol is used.     

Persistent polyuria in two dogs following adrenocorticolysis for pituitary-dependent hyperadrenocorticism

In two dogs with pituitary-dependent hyperadrenocorticism, adrenocorticolysis with o.p'-DDD led to the disappearance of the signs and symptoms except for the polyuria. After a modified water-deprivation test the osmoregulation of vasopressin release was studied by hypertonic saline infusion. In both dogs the hypertonicity, thus induced, resulted in very minimal responses of the vasopressin secretion.     

Medical management of pituitary-dependent hyperadrenocorticism: mitotane versus trilostane

Pituitary-dependent hyperadrenocorticism is a common endocrine disorder in dogs in the United States. Once a diagnosis is established, a decision must be made whether or not to pursue treatment, and if so, which medication to use. Historically, mitotane (Lysodren, o,p'-DDD, Bristol-Myers Squibb, New York) has been the most commonly used treatment for medical management. Its use is complicated and comes with many potential side effects, making many practitioners wary of its use. Recently, trilostane has been proven to be an effective treatment of pituitary-dependent hyperadrenocorticism and is approved for use in other countries. Treatment with trilostane is somewhat simpler and the incidence of side effects seems to be less when compared with mitotane therapy. Either treatment can be a safe and effective method of treatment for pituitary-dependent hyperadrenocorticism when the practitioner and client are well educated regarding their use and an appropriate monitoring protocol is used.     

FUNCTIONING ADRENOCORTICAL TUMOUR IN A DOG

Naturally-occurring hyperadrenocorticism was diagnosed in an 11-year-old female Dachshund with signs of polydipsia, polyuria, pendulous abdomen, weakness, depression and lethargy, and laboratory test abnormalities comprising lymphocytopaenia, eosinopaenia, hypercholesterolaemia and increased plasma alkaline phosphatase concentration. While awaiting hormonal test results, an adrenocorticolytic drug (o,p'-DDD) was administered for 14 days, during which the patient deteriorated. Hormonal assays suggested a functioning adrenocortical tumour, but the poor condition of the patient precluded adrenalectomy. An adrenocortical carcinoma with hepatic metastases was found at necropsy.     

Persistent isolated hypocortisolism following brief treatment with trilostane

A 12‐year‐old male neutered Miniature Poodle with confirmed pituitary‐dependent hyperadrenocorticism was treated with trilostane. After three doses, it developed clinical and laboratory changes suggestive of isolated hypocortisolism (‘atypical hypoadrenocorticism’), which persisted and progressed for more than 3 months despite immediate withdrawal of the trilostane. The clinical signs of hyperadrenocorticism resolved without further trilostane. After 3 months, prednisolone treatment was started and the clinical signs of hypocortisolism resolved. Prednisolone therapy was required for more than 1 year. Ultrasonography initially demonstrated large hypoechoic adrenal cortices, typical of dogs with hyperadrenocorticism, which then became small and heteroechoic, consistent with the development of adrenal necrosis. Persistent isolated hypocortisolism has not been reported previously as a complication of trilostane therapy. The case is also remarkable for the very short duration of trilostane therapy that elicited this complication. Clinicians should be aware that trilostane therapy may result in adrenal necrosis, even in the very earliest stages of therapy, but prompt action can prevent a life‐threatening situation.     

Acute renal failure following Bull ant mass envenomation in two dogs

Acute renal failure was diagnosed in a German Short Haired Pointer bitch and a Kelpie cross-bred dog following envenomation by Bull ants. Both dogs had been tethered over a Bull ant nest and had experienced mass envenomation. There was local reaction at the envenomation sites and each dog had experienced vomiting that was poorly controlled by symptomatic therapy. Intensive treatment of renal failure was successful in the German Short Haired Pointer and the bitch remains well 19 months after envenomation. The Kelpie cross-bred deteriorated despite intensive treatment and was euthanased 36 hours after presentation. Necropsy examination revealed haemorrhage and necrosis of the small intestine and myocardium, bilateral nephrosis with tubular necrosis, and patchy haemorrhage of the lung alveoli, pancreas and adrenal cortices. Electron microscopy revealed necrosis of the small intestine and hydropic swelling of proximal renal tubules with necrosis of medullary tubules.     

Polluting profiles of dieldrin and DDTs in laying hens of Osaka, Japan

Contaminating/accumulating levels of organochlorine pesticides in extractable fats from a basal diet, eggs and seven tissues (adipose tissue, blood, kidney, liver, muscle, ovary and oviduct) and excreta of laying hens that were kept in a general poultry farm of Japan were examined. No benzene hexachlorides or aldrin was detected [< 1 part per billion (p.p.b.)] overall. Dieldrin and all DDTs (p,p'-DDE, o,p'-DDT, p,p'-DDD and p,p'-DDT) were contaminated in the dietary fats (mean range 10-70 p.p.b.). Although dieldrin (4-58 p.p.b.), p,p'-DDE (65-196 p.p.b.) and p,p'-DDT (30-73 p.p.b.) were found to be accumulated in all the tissue fats and egg yolk fats, they were not detected in the dried excreta. Accumulations of o,p'-DDT and p,p'-DDD were found only in the liver fat (92 p.p.b.) and in the kidney fat (27 p.p.b.), respectively. In all the samples, p,p'-DDE levels were highest in comparison with the other compounds. For all organochlorine pesticides detected, the accumulated levels were well below the practical residue limits.     

Surgical treatment and long-term outcome of ferrets with bilateral adrenal tumors or adrenal hyperplasia: 56 cases (1994-1997).

OBJECTIVE: To determine signalment, clinical signs, concurrent diseases, response to surgical treatment, and long-term outcome of ferrets with bilateral adrenal tumors or adrenal hyperplasia. DESIGN: Retrospective study. ANIMALS: 56 ferrets with bilateral adrenal tumors or adrenal hyperplasia confirmed histologically following subtotal bilateral adrenalectomy. PROCEDURE: Medical records of all ferrets with bilateral adrenal tumors or hyperplasia examined between 1994 and 1997 were reviewed. Ferrets underwent a subtotal bilateral adrenalectomy or a unilateral adrenalectomy initially, followed by a unilateral subtotal adrenalectomy when tumors or hyperplasia later developed on the contralateral adrenal gland. A long-term follow-up of a minimum of 18 months after final adrenal gland surgery was obtained by examination of medical records and follow-up telephone conversations. RESULTS: Clinical signs of hyperadrenocorticism included bilaterally symmetric alopecia, return to male sexual behavior in castrated male ferrets, or swollen vulva in spayed female ferrets. Surgical treatment of bilateral adrenal disease by subtotal bilateral adrenalectomy (or unilateral adrenalectomy followed by contralateral unilateral subtotal adrenalectomy) was effective with a mortality rate of < 2%. Only 3 (5%) ferrets required glucocorticoid or mineralocorticoid replacement following subtotal bilateral adrenalectomy. Recurrence after bilateral adrenalectomy was 15% with a mean long-term follow-up period of 30 months. CONCLUSIONS AND CLINICAL RELEVANCE: Bilaterally symmetric alopecia, return to male sexual behavior in castrated male ferrets, or swollen vulva in spayed female ferrets are indicative of adrenal tumors or adrenal hyperplasia in ferrets. Surgical treatment of bilateral adrenal disease by subtotal bilateral adrenalectomy is effective, with a low rate of complications and postoperative recurrence rate.     

Effects of melatonin administration on the clinical course of adrenocortical disease in domestic ferrets

OBJECTIVE: To evaluate the effect of oral administration of melatonin on clinical signs, tumor size, and serum steroid hormone concentrations in ferrets with adrenocortical disease. DESIGN: Noncontrolled clinical trial. ANIMALS: 10 adult ferrets with clinical signs of adrenocortical disease (confirmed via serum steroid hormone concentration assessments). PROCEDURES: Melatonin (0.5 mg) was administered orally to ferrets once daily for 1 year. At 4-month intervals, a complete physical examination; abdominal ultrasonographic examination (including adrenal gland measurement); CBC; serum biochemical analyses; and assessment of serum estradiol, androstenedione, and 17alpha-hydroxyprogesterone concentrations were performed. Serum prolactin and dehydroepiandrosterone sulfate concentrations were evaluated at the first, second, and last examinations, and serum cortisol concentration was evaluated at the first and last examinations. RESULTS: Daily oral administration of melatonin greatly affected clinical signs of adrenocortical disease in ferrets; changes included hair regrowth, decreased pruritus, increased activity level and appetite, and decreased vulva or prostate size. Mean width of the abnormally large adrenal glands was significantly increased after the 12-month treatment period. Recurrence of clinical signs was detected in 6 ferrets at the 8-month evaluation. Compared with pretreatment values, serum 17alpha-hydroxyprogesterone and prolactin concentrations were significantly increased and decreased after 12 months, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that melatonin is a useful, easily administered, palliative treatment to decrease clinical signs associated with adrenocortical disease in ferrets, and positive effects of daily treatment were evident for at least an 8-month period. Oral administration of melatonin did not decrease adrenal gland tumor growth in treated ferrets.     

Evaluation of adrenal function in small-breed dogs receiving otic glucocorticoids

The objectives of this study were to evaluate adrenal function after otic glucocorticoid [Tresaderm (dexamethasone) and Otomax (betamethasone)] therapy in small-breed dogs without evidence of otitis and to evaluate the length of time needed for resolution of adrenal suppression after discontinuation of treatment. Fourteen clinically healthy, privately owned, small-breed dogs with normal ears and normal adrenocorticotropin (ACTH) stimulation tests were assigned to one of two treatment groups, receiving one of the medications at the manufacturer's recommended dosage twice daily for 2 weeks. All of the dogs in the betamethasone treatment group had normal ACTH stimulation tests after 2 weeks of treatment. In contrast, 5/7 (71.43%) in the dexamethasone group, had suppressed adrenocortical responses to exogenous ACTH. Three of these five dogs (42%) returned to normal values 1 week after ceasing the medication and two (28.57%) returned to normal values 2 weeks after ceasing the medication. In conclusion, it appears that adrenal function can be suppressed for up to 2 weeks in dogs receiving otic dexamethasone. A follow-up study repeating this work in dogs with inflamed ears is needed before further clinical recommendations can be made.     

Multiple endocrine neoplasias in a dog: Corticotrophic tumour,bilateral adrenocortical tumours,and pheochromocytoma

Summary

In a 10‐year‐old ovariohysterectomized standard Schnauzer, the finding of dexamethasone‐resistant hypersecretion of cortisol, the results of computed tomography, and elevated plasma concentrations of ACTH suggested the presence of both adrenocortical tumour and pituitary‐dependent hyperadrenocorticism. The dog made an uneventful recovery after bilateral adrenalectomy and remained in good health for 31/2 years with substitution for the induced hypoadrenocorticism. Then the enlarged pituitary caused neurological signs and eventually euthanasia was performed. The surgically excised right adrenal contained a well‐circumscribed tumour of differentiated adrenocortical tissue and in the left adrenal there were two adrenocortical tumours and a pheochromocytoma. The unaffected parts of the adrenal cortices were well developed and without regressive transformation. At necropsy there were no metastatic lesions. The cells of the pituitary tumour were immunopositive for ACTH and had characteristics of malignancy.

The present combination of corticotrophic tumour, adrenocortical tumours, and pheochromocytoma may be called ‘multiple endocrine neoplasia’ (MEN), but does not correspond to the inherited combinations of diseases known in humans as the MEN‐1 and the MEN‐2 syndromes. It is suggested that the co‐existence of hyperadrenocorticism and pheochromocytoma may be related to the vascular supply of the adrenals. Some chromaffin cells of the adrenal medulla are directly exposed to cortical venous blood, and intra‐adrenal cortisol is known to stimulate catecholamine synthesis and may promote adrenal medullary hyperplasia or neoplasia.     

The involvement of prolactin in the regulation of adrenal cortex function in pigs

We investigated the in vivo and in vitro effect of prolactin (PRL) on porcine adrenal cortex function. The in vivo study was performed on 10 multiparous sows. Blood was sampled every 4 h beginning on the 17th day of the estrous cycle and continuing for 6 subsequent days. Plasma was stored at -20 degrees C until steroid hormones analysis was completed. PRL or saline were administered iv for 48 h in 2 h intervals. Injections of PRL began 4-20 h after the preovulatory LH surge. At the end of the sampling period sows were slaughtered and adrenals were immediately dissected. Adrenals were frozen at -70 degrees C for determination of adrenal cortex steroid hormones content. At the end of PRL treatment period mean plasma level of cortisol in control sows was significantly lower than that of PRL-treated sows. Moreover, the area under the mean plasma cortisol concentration curve was significantly higher in PRL-treated sows in comparison to controls. The mean cortisol adrenal content was significantly higher in adrenal cortex of PRL-treated sows than that of controls. PRL did not affect adrenal cortex concentration of androstenedione (A(4)), testosterone (T), dehydroepiandrosterone (DHEA) and estradiol (E(2)). Dehydroepiandrosterone sulfate (DHEAS) was not found in porcine adrenal cortex. In the in vitro experiment adrenal glands were removed immediately after slaughter of 6 crossbred gilts. Dispersed adrenocortical cells were incubated for 8 h with or without porcine PRL. Prolactin stimulated cortisol secretion in a dose-dependent manner. These results suggest that PRL is one of the key factors involved in the regulation of adrenal cortex function in pigs.     

Primary Hypoadrenocorticism in Ten Cats

Primary hypoadrenocorticism was diagnosed in ten young to middle-aged cats of mixed breeding. Five of the cats were male, and five were female. Historic signs included lethargy (n = 10), anorexia (n = 10), weight loss (n = 9), vomiting (n = 4), and polyuria (n = 3). Dehydration (n = 9), hypothermia (n = 8), prolonged capillary refill time (n = 5), weak pulse (n = 5), collapse (n = 3), and sinus bradycardia (n = 2) were found on physical examination. Results of initial laboratory tests revealed anemia (n = 3), absolute lymphocytosis (n = 2), absolute eosinophilia (n = 1), and azotemia and hyperphosphatemia (n = 10). Serum electrolyte changes included hyponatremia (n = 10), hyperkalemia (n = 9), hypochloremia (n = 9), and hypercalcemia (n = 1). The diagnosis of primary adrenocortical insufficiency was established on the basis of results of adrenocorticotropic hormone (ACTH) stimulation tests (n = 10) and endogenous plasma ACTH determinations (n = 7). Initial therapy for hypoadrenocorticism included intravenous administration of 0.9% saline and dexamethasone and intramuscular administration of desoxycorticosterone acetate in oil. Three cats were euthanatized shortly after diagnosis because of poor clinical response. Results of necropsy examination were unremarkable except for complete destruction of both adrenal cortices. Seven cats were treated chronically with oral prednisone or intramuscular methylprednisolone acetate for glucocorticoid supplementation and with oral fludrocortisone acetate or intramuscular injections of repository desoxycorticosterone pivalate for mineralocorticoid replacement. One cat died after 47 days of therapy from unknown causes; the other six cats are still alive and well after 3 to 70 months of treatment.