Growth Hormone Disorders Flashcards
Describe the clinical presentation and findings in kittens with congenital hyposomatotrophism (pituitary dwarfism)
- Failure to grow after 1-2 months of age
- If only GH is deficient, then the dwarphism will be proportionate
- Dull hair coat
- Retention of deciduous teeth
- Hypoglycaemia may be seen due to the fragile nature of a small kitten, or the lack of gluconeogenic stimulation from GH
What are the important differentials for failure to thrive / proportionate dwarfism in kittens?
- Hepatic disease
- Porto-systemic vascular anomaly
- Malnutrition
- Gatrointestinal disease
- Renal disease
- Cardiac disease
Discuss the testing options for investigation of growth hormone deficiency or excess in cats.
What are the benefits of IGF-1 testing over serum GH concentration?
- There is no validated GH assay for cats
- GH also has pulsatile secretion and there are significant random variations in the GH concentration in nnormal animals
- GH stimulates the release of IGF-1 from the liver
- IGF-1 release is non-pulsatile and reflects the GH concentration over the preceding ~ 24 hours
- Provocative testing of GH or IGF-1 have not been validated in cats.
- IGF-1 can be reduced with other disease states:
- Newly diagnosed DM
- Hepatic insufficiency
- Lymphoma
- Renal disease
How does growth hormone interfere with insulin and glucose regulation?
- Growth hormone exerts both direct and indirtect effects
- Direct antagonism of insulin and the effects of insulin
- Indirect:
- Growth hormone stimulates the release of IGF-1 from the liver
- Both growth hormone and moreso IGF-1 antagonise the effect of insulin
- IGF-1 binds to the insulin receptor and the IGF-1 receptor
- IGF-1 competitively inhibits insulin binding at the insulin receptor
- Binding to the insulin receptor essentially blocks intracellular signalling
- IGF-1 stimulates the insulin receptor at ~ 0.1 times efficiency as insulin
- The net effect is increased glucose / hyperglycaemia and insulin resistance.
What is the primary pathological process in feline hypersomatotropism?
Describe the potential environmental and genetic causes for the disease
- Most cases of feline hypersomatotrophism are caused by a pituitary adenoma. A tumour of the growth hormone producing somatotrophs
Environmental:
- Organohalogenated contaminants have been implicated
- Polychlorinated biphenyls
- Brominated flame retardants (BFRs)
- One study identifed increased levels of all contaminants in cats with hypersomatotrophism
- The dust of these chemicals may be particularly relevant in cats due to being indoors and grooming habits
Genetic:
A single non-conservative SNP of the AIP gene has been identifed in 2 of 10 cats with acromegaly. 40% of humans with acromegaly have similar mutations.
The AIP gene produces a tumour suppressor protein
AIP also has a range of effects, including the activation of xenobiotic metabolizing enzymes - therefore a mutation may lead to reduced activity and increased xenobiotic concentrations
Describe the early and chronic signs of hypersomatotropism in cats.
Note the associated clinical signs and relevant clinicopathological findings in each case
Early signs:
- Insulin resistance is the first and most clinically relevant sign of acromegaly
- Signs of polyuria/polydipsia and polyphagia have been reported.
- Solitary polyphagia may be evident in cats with hypersomatotrophism without diabetes mellitus
Chronic signs:
- Upper respiratory tract stridor due to tissue overgrowth
- Increased head width
- Increased interdental spacing - most evident for the incisors
- PU/PD/PP mostly due to poor diabetes control
- PP may be independent of DM control
- Prognathia inferior - protrusion of the mandible
- Abdominal organomegaly - enlarged liver and kidneys
- Heart murmur and CHF
- CNS signs with a macroadenoma
List the diagnostic tests that may assist in the diagnosis of feline hypersomatotropism.
Note the potential limitations of each test.
- IGF-1 assay is the test of choice as it has a non-pulsatile secretion profile, unlike GH
- As IGF-1 levels may be suppressed in the absence of portal insulin, a diagnosis may be missed in the newly diagnosed diabetic cat ~ 9% of the time
- IGF-1 assays are not widely available
- A result > 1000 ng/ml has a positive predictive value of 95%
- Advanced Imaging
- Useful to document a macroadenoma when investigating for hypersomatropism
- A functional microadenoma could be missed
- CT can be useful in documenting TMJ abnormalities, prognathia inferior and soft tissue overgrowth
- Alternative blood tests:
- Serum type III polypeptide - increased in FeHS due to increased collagen turnover
- Ghrelin is usually reduced, likely due to GH inhibition of release (as ghrelin normally stimulates GH release)
- Ghrelin was not different in FeHS when compared to cats with primary DM
List the various treatment options for feline hypersomatotropism.
What is the expected response rate to each treatment with regards to diabetes mellitus control? What are the potential complications and prognosis?
- Surgery - Hypophysectomy
- Low dose treatment with corticosteroid, levothyroxine and desmopressin acetate is necessary
- Access to experienced surgeon is a problem
- Perioperative mortality of ~ 10% in experienced hands
- 15% have good glycaemic control with usual insulin doses
- 85% enter diabetic remission within 1-2 months
- Medical management:
- Pasireotide - a long acting somatostatin analogue with high binding affinity
- Has shown to reduce IGF-1 and insulin resistance
- 3/8 cats enetered diabetic remission with treatment and insulin requirements markedly dropped in the others
- Radiation therapy
- May be used, but the response is unpredictable
- IGF-1 fails to normalise in most cats
- Diabetic control may improve but FeHS changes can continue to progress
- DM treatment only
- Suggested if definitive treatment is declined or not available
- Prepare for management of other co-morbidities - renal insufficiency, cardiac disease, arthropathy, CNS signs (rare)
Describe the role of ghrelin in growth hormone regulation
What is the major role of ghrelin in young dogs?
- Ghrelin is a potent stimulator of GH release
- Ghrelin is produced and release from the stomach in the interdigestive period.
- Also present in the duodenum, pancreas, lungs, adrenal glands and the CNS
- Ghrelin stimulates appetite and levels are reduced following eating and with gastric distension
Ghrelin is the major stimulator of growth hormone secretion in young dogs. Moreso than growth hormone releasing hormone. Ghrelin binds to non-GHRH receptors in the pituitary
Describe the available diagnostic tests for acromegaly in dogs.
Why is IGF-1 a more reliable test than GH?
- GH is expected to be increased with hypersomatotropism, however due to the pulsatile nature of the hormone, levels may be normal.
- IGF-1 is more reliably increased with hypersomatotropism, with levels more stable due to non-pulsatile secretion and protein binding in circulation
- IGF-1 is highly correlated with body size, so breed specific reference ranges are recommended
- Lack of suppression after administration of somatostatin fails to suppress GH levels or GHRH fails to stimulate GH levels. Unfortunately, GH assays are not widely available.
What are the treatment options for the various causes of acromegaly in dogs?
- Progesterone induced acromegaly causes excessive growth hormone release from the mammary ductular epithelium
- Ovohysterectomy can effectively manage this form of acromegaly
- Progestagen induced acromegaly - stop administration of the medication
- Hypothyroidism induced acromegaly
- Levothyroxine treatment should normalise serum GH levels
- For dogs with a somatotroph adenoma, medical, radiation or surgical management are options.
- Minimal surgical experience for this specific disease described
- Radiation may not be effective and recurrence is common
- Medical management via somatotroph analoges (octreotide) - described to normalise plasma IGF-1 and reduce tumour size in ~ 50% of people
- GH receptor antagonists are available for people
Describe the common deficiencies in congenital pituitary dwarphism in the German Shepherd Dog.
What normal pituitary function is typically maintained?
- Growth hormone, TSH and prolactin are typically reduced in the German Shepherd with pituitary dwarphism
- ACTH levels are typically maintained and adrenal function is normal
- The neurohypophysis function is also maintained.
- Normal ADH release and oxytocin
- GnRH is also reduced
Describe the main clinical features of pituitary dwarphism in dogs.
- Proportionate growth retardation
- Retention of the puppy coat (lanugo hairs)
- Lack or primary guard hairs
- Males are often cryptorchid due to insufficient GnRH
- Females are often infertile and fail to ovulate due to absence of an LH surge
- Secondary hypothyroidism tends not to occur until 2-3 years of age
Describe the growth hormone stimulation test procedure.
How are the results interpreted, including sensitivity and specificity?
- Basal GH should be measured immediately prior to administration of a GH secretagogue
- GHRH can be used if available
- Clonidine or xylazine - both alpha adrenergic drugs can also be used to stimulate GH release
- Ghrelin may also be used
- GH should be measured at 20-30 minutes after IV administration of the secretagogue
- A normal dog should have an increase in GH concentration of 2-4 fold.
- A minimal rise suggests deficiency
- Partial GH deficiency may return a normal result on stimulation testing
Describe the role of advanced imaging in the diagnosis of pituitary dwarphism in dogs?
- Advanced imaging is rarely needed to confirm a diagnosis of congenital pituitary dwarphism
- When performed a cystic structure in Rathke’s pouch is often present
- Despite the presence of cysts, the pituitary is typically very small, consistent with hypoplasia
