J.J.C.W.M. Buijtels

Effects of trilostane on the pituitary-adrenocortical and renin-aldosterone axis in dogs with pituitary-dependent hypercortisolism.

The medical records of 63 dogs with pituitary-dependent hypercortisolism (PDH) before and during treatment with trilostane were reviewed retrospectively. The correct trilostane dosage in dogs with PDH was based on the resolution of clinical signs and the results of an adrenocorticotropic hormone (ACTH) stimulation test. The mean (+/-SD) dose rate of trilostane to achieve good clinical control was 2.8+/-1.0mg/kg bodyweight. Trilostane treatment resulted in a significant decline in basal plasma cortisol concentrations. The median plasma ACTH concentration (39 pmol/L, range 7-132 pmol/L; n=60) at the optimal trilostane dosage time was significantly higher (P<0.001) than before treatment (13 pmol/L, range 2-102 pmol/L). These values did not overlap with plasma ACTH concentrations (range 212-307 pmol/L) of five PDH dogs with trilostane-induced hypocortisolism. The median cortisol/ACTH ratio in well-controlled dogs (0.23, range 0.03-2.5; n=46) was significantly lower (P<0.001) than before treatment (2.59, range 0.27-13.25). Trilostane treatment resulted in an insignificant decrease in plasma aldosterone concentration (PAC), but the median plasma renin activity (PRA) at the time the trilostane dosage was considered optimal (265 fmol/L/s, range 70-3280 fmol/L/s; n=18) was significantly higher (P<0.001) than prior to treatment (115 fmol/L/s, range 15-1330 fmol/L/s). Similarly, the median PAC/PRA ratio during trilostane treatment (0.16, range 0.003-0.92; n=17) was significantly lower (P<0.001) than before treatment (median 0.44, range 0.04-1.33). Trilostane affected both the hypothalamic-pituitary-adrenocortical and the renin-aldosterone axes. The results also suggested that basal plasma ACTH concentration may be used to detect trilostane overdosage.

Successful Treatment of Acromegaly in a Diabetic Cat with Transsphenoidal Hypophysectomy

Patient and surgical treatment An 11-year-old, castrated male cat was referred for insulin-resistant diabetes mellitus. It had a ravenous appetite, increased body weight, polyuria/polydipsia and a dull hair coat. The cat was receiving 25 IU insulin four times daily but blood glucose concentrations remained elevated. Plasma concentrations of growth hormone (GH) (51 μug/l, reference range 0.8–7.2 μg/l) and insulin-like growth factor 1 (IGF-1) (3871 μg/l, reference range 39–590 μg/l) were highly elevated, whereas those of alpha-melanocyte-stimulating hormone, adrenocorticotropic hormone and Cortisol were normal. Computed tomography revealed a thick palatum molle and an enlarged pituitary gland, indicating a pituitary neoplasm. Microsurgical transsphenoidal hypophysectomy was performed and microscopic examination of the surgical specimen revealed an acidophilic, infiltrative pituitary adenoma that showed positive immunostaining for GH. Outcome The clinical signs resolved and 3 weeks after surgery the cat no longer required insulin administration. One year after hypophysectomy the plasma concentrations of GH and IGF-1 were 2.4 μg/l and 113 μg/l, respectively. Practical relevance This is the first report detailing transsphenoidal hypophysectomy as a feasible and effective treatment for feline acromegaly due to a pituitary somatotroph adenoma. Moreover, in this patient, concurrent insulin-resistant diabetes mellitus resolved completely. The surgery is discussed in the context of human and other feline therapies for acromegaly.

Urinary Corticoid : Creatinine Ratios in Dogs with Pituitary-Dependent Hypercortisolism during Trilostane Treatment

BACKGROUND The adrenocorticotropic hormone (ACTH) stimulation test is used to evaluate trilostane treatment in dogs with hypercortisolism. HYPOTHESIS The urinary corticoid : creatinine ratio (UCCR) is a good alternative to the ACTH stimulation test to determine optimal trilostane dose. ANIMALS Eighteen dogs with pituitary-dependent hypercortisolism. METHODS In this prospective study, the dose of trilostane was judged to be optimal on the basis of resolution of clinical signs of hypercortisolism and results of an ACTH stimulation test. The owners collected urine for determination of UCCR at 2-week intervals for at least 8 weeks after achieving the optimal trilostane dose. RESULTS The UCCRs were significantly higher before treatment (11.5-202.0 x 10(-6); median, 42.0 x 10(-6)) than at rechecks 2 months after optimal dosing, but they did not decrease below the upper limit of the reference range in the majority of dogs. The UCCRs of 11 dogs that initially were dosed insufficiently (range, 7.5-79.0 x 10(-6); median, 31.0 x 10(-6)) did not differ significantly from UCCRs when the dosage was optimal (8.2-72.0 x 10(-6); median, 33.0 x 10(-6)). Post-ACTH cortisol concentrations did not correlate significantly with UCCRs at rechecks during trilostane treatment. Long-term follow-up indicated that the decrease in UCCR below the upper limit of the reference was associated with hypocortisolism. CONCLUSION AND CLINICAL IMPORTANCE The UCCR cannot be used as an alternative to the ACTH stimulation test to determine the optimal dose of trilostane, but might be helpful in detecting dogs at risk for developing hypocortisolism during trilostane treatment.

Endocrine Diseases in Animals

Background: Several endocrine disorders that affect humans also occur as endocrinopathies in companion animals. Spontaneous endocrine disorders in animals may provide valuable information for their counterparts in human endocrinology. For example, the discovery of progesterone-induced growth hormone production in the mammary gland of dogs may have important consequences for understanding the pathogenesis of breast cancer in women. In addition, the majority of diabetic cats have a type of diabetes mellitus that closely resembles type 2 diabetes mellitus in humans and therefore may serve as an animal model for this disease in humans. This review describes several endocrine diseases in companion animals that are quite similar to those in humans and emphasizes their usefulness as spontaneous animal models for human endocrine disorders.

Effects of gonadotropin-releasing hormone administration on the pituitary-gonadal axis in male and female dogs before and after gonadectomy

GnRH-stimulation tests were performed in 14 female and 14 male client-owned dogs of several breeds, before and 4 to 5 mo after gonadectomy. The aim of the study was to obtain more insight into the pituitary-gonadal axis in intact and neutered dogs and to establish reference values. Basal plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations were increased significantly after gonadectomy in both bitches and male dogs. In both males and females ranges of the basal plasma FSH concentrations, before and after gonadectomy, did not overlap as opposed to the overlap in ranges of the basal plasma LH concentrations. Before gonadectomy basal plasma LH concentrations were lower and basal plasma FSH concentrations were higher in bitches than in male dogs. After gonadectomy these basal values did not differ significantly. GnRH administration before gonadectomy resulted in an increase in plasma LH and FSH concentrations in both genders. GnRH administration after gonadectomy produced an increase only in plasma LH concentrations in both genders, and a just significant increase in plasma FSH in castrated male dogs. GnRH administration before gonadectomy resulted in a significant increase in plasma testosterone concentration in both genders. In males ranges of basal and GnRH-stimulated plasma testosterone concentrations before and after gonadectomy did not overlap. Basal plasma estradiol concentrations were significantly higher in intact males than in castrated males and their ranges did not overlap. The basal estradiol concentrations in bitches before and after ovariectomy were not significantly different. At 120 min after GnRH administration, ranges of plasma estradiol concentration of intact and ovariectomized bitches no longer overlapped. In conclusion, basal plasma FSH concentration appears to be more reliable than basal plasma LH concentration for verification of neuter status in both male and female dogs. The basal plasma testosterone concentration appears to be reliable for verification of neuter status in male dogs. The plasma estradiol concentration at 120 min after GnRH administration can be used to discriminate between bitches with and without functional ovarian tissue.

Alterations of the pituitary-ovarian axis in dogs with a functional granulosa cell tumor

Information on the pituitary-ovarian axis in dogs with a granulosa cell tumor (GCT) is lacking. Therefore, we investigated the plasma concentrations of luteinizing hormone (LH) and estradiol before and after gonadotropin-releasing hormone (GnRH) administration in seven bitches with a functional GCT (GCT-total), of which three were intact (GCT-intact) and four had remnant ovarian tissue (GCT-ROT). The results of the GnRH stimulation test were compared with those in six anestrous and six ovariectomized bitches. The most noteworthy results were as follows. The basal plasma LH concentrations of the GCT-ROT bitches were higher (P<0.05) than those of the anestrous bitches. The increment in the plasma LH concentration after GnRH administration in the GCT-total bitches was lower (P<0.001) than the increments in both the anestrous and ovariectomized bitches. The basal plasma estradiol concentrations in the GCT-total bitches were higher (P<0.001) than those in the anestrous and ovariectomized bitches. In conclusion, the pituitary-ovarian axis is affected in bitches with a functional GCT and is characterized by relatively high plasma LH concentrations in GCT-ROT bitches and a subnormal LH response to GnRH stimulation in all GCT bitches compared with those in anestrous and ovariectomized bitches. The relatively high proportion of dogs with remnant ovarian tissue among the GCT bitches suggests a pathogenetic role for elevated gonadotropin secretion in the pathogenesis of GCT.

The pituitary-ovarian axis in dogs with remnant ovarian tissue.

It can be difficult to confirm the presence of remnant ovarian tissue (ROT) in bitches that are presumed to be ovariohysterectomised. A GnRH stimulation test can be used to distinguish ovariectomised bitches from those in anoestrus, but it is uncertain whether the GnRH-induced changes in plasma LH and oestradiol concentrations that occur in intact bitches also occur in ROT-bitches. We report here eighteen ROT-bitches and compare the results of GnRH stimulation tests with those of six ovariectomised and six bitches in anoestrus. The basal (n = 17) and/or GnRH-stimulated (n = 18) plasma oestradiol concentration was above the detection limit of the assay, i.e., < 7 pmol/l, in all ROT-bitches but below the detection limit in all ovariectomised bitches. Basal plasma LH concentration was significantly higher in ROT-bitches (4.1 ± 0.7 μg/L) than those in anoestrus (0.64 ± 0.04 μg/L), and significantly lower than in ovariectomised bitches (20.2 ± 3.6 μg/L). Basal plasma LH concentration was relatively high in bitches in which there was a long interval between ovariectomy and appearance of oestrus. GnRH administration resulted in a significant increase in plasma LH and oestradiol concentrations in ROT-bitches. The GnRH-induced increase and subsequent decline in plasma LH concentration were significantly less in ROT-bitches than in either ovariectomised bitches or those in anoestrus. The GnRH-induced increase in plasma oestradiol concentration was significantly smaller in ROT-bitches than in those in anoestrus. In conclusion, the results of this study demonstrate that in dogs ROT is associated with noticeable changes in the pituitary-ovarian axis and suggest that a GnRH stimulation test may be used to distinguish between completely ovariectomised bitches and those with ROT.

Disorders of sexual development and associated changes in the pituitary-gonadal axis in dogs.

Normal sexual differentiation depends on completion of chromosomal sex determination, gonadal differentiation, and development of the phenotypic sex. An irregularity in any of these three steps can lead to a disorder in sexual development (DSD). We examined nine dogs with DSD by abdominal ultrasonography, laparotomy, histologic examination of the gonads, and reproductive tract, cytogenetic analysis, and mRNA expression of the SRY gene. We also determined the plasma concentrations of luteinizing hormone (LH), estradiol-17β, and testosterone before and after administration of gonadotropin-releasing hormone (GnRH) and compared these results with those obtained in anestrous bitches and male control dogs. The gonads of three dogs with DSD contained both testicular and ovarian tissue, while in the other six only testicular tissue was found. Each of the dogs had a uterus. Based on gynecologic examination, cytogenetic analysis, and the histology of the gonads, seven of the nine dogs appeared to be XX sex reversals. Three of these were XX true hermaphrodites and four were XX males; the other two dogs had incomplete XY gonadal dysgenesis. All seven XX sex-reversed dogs were found to be negative for the SRY gene by polymerase chain reaction. The basal plasma luteinizing hormone (LH) concentration was significantly higher in dogs with DSD than in anestrous bitches but not significantly different from that in male dogs. The basal plasma LH concentration increased significantly after GnRH administration in all dogs with DSD. The basal plasma estradiol concentration was significantly higher in dogs with DSD than in anestrous bitches but not significantly different from that in male dogs. The basal plasma testosterone concentration was lower in dogs with DSD than in male dogs. In all dogs with DSD both the basal and GnRH-induced plasma testosterone concentrations were above the upper limit of their respective ranges in the anestrous bitches. In conclusion, the secretion of LH and estradiol in these dogs with DSD, all of which had testicular tissue in their gonads, was similar to that in male control dogs. These results indicate that the basal and/or GnRH-stimulated plasma testosterone concentration might be used to detect the presence of testicular tissue in dogs with DSD.

Central Hypothyroidism in Miniature Schnauzers

Background Primary hypothyroidism is a common endocrinopathy in dogs. In contrast, central hypothyroidism is rare in this species. Objectives The objective of this article is to describe the occurrence and clinical presentation of central hypothyroidism in Miniature Schnauzers. Additionally, the possible role of the thyroid‐stimulating hormone (TSH)‐releasing hormone receptor (TRHR) gene and the TSHβ (TSHB) gene was investigated. Animals Miniature Schnauzers with proven central hypothyroidism, based on scintigraphy, and the results of a 3‐day‐TSH‐stimulation test, or a TSH‐releasing hormone (TRH)‐stimulation test or both, presented to the Department of Clinical Sciences of Companion Animals at Utrecht University or the Department of Medicine and Clinical Biology of Small Animals at Ghent University from 2008 to 2012. Methods Retrospective study. Pituitary function tests, thyroid scintigraphy, and computed tomography (CT) of the pituitary area were performed. Gene fragments of affected dogs and controls were amplified by polymerase chain reaction (PCR). Subsequently, the deoxyribonucleic acid (DNA) sequences of the products were analyzed. Results Central hypothyroidism was diagnosed in 7 Miniature Schnauzers. Three dogs had disproportionate dwarfism and at least one of them had a combined deficiency of TSH and prolactin. No disease‐causing mutations were found in the TSHB gene and the exons of the TRHR gene of these Schnauzers. Conclusions and clinical importance Central hypothyroidism could be underdiagnosed in Miniature Schnauzers with hypothyroidism, especially in those of normal stature. The fact that this rare disorder occurred in 7 dogs from the same breed suggests that central hypothyroidism could have a genetic background in Miniature Schnauzers.