Hans S. Kooistra, DECVIM-CA
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University
Utrecht, The Netherlands
Pituitary growth hormone (GH) secretion is pulsatile in nature. Pituitary GH secretion is regulated predominantly by the opposing actions of the stimulatory hypothalamic peptide GH-releasing hormone (GHRH) and the inhibitory hypothalamic peptide somatostatin. Each GH secretory episode seems to be initiated by a burst of GHRH into the hypophyseal portal system, preceded by a reduction of somatostatinergic input to the pituitary. This regulatory system is influenced by negative feedback from peripherally formed growth factors, particularly insulin-like growth factor-1 (IGF-1). The amplitude and frequency of GH secretory pulses are regulated by a complex array of external and internal stimuli including age, gender, estrous cycle phase, genetic background, nutritional status, disease status and body composition. In addition, hormones such as progesterone, glucocorticoids and thyroid hormones influence the pulsatile secretion pattern of GH. GH release can also be elicited by synthetic GH secretagogues, that exert their effect on GH release by acting through receptors different from those for GHRH. In 1999, Kojima et al. characterized the endogenous ligand for these receptors, i.e., ghrelin.1 The main source of circulating ghrelin appears to be the stomach. Also in the dog ghrelin stimulates GH secretion.2
In the dog, GH is not only produced in the pituitary gland but also in the mammary gland, under the influence of endogenous or exogenous progestins.3,4 These progestin-stimulated plasma GH levels do not have a pulsatile secretion pattern, are not sensitive to stimulation with GHRH or the α-adrenergic agonist clonidine, and are not inhibited by somatostatin. Mammary-derived GH is biochemically identical to pituitary GH.
The pulsatile secretion pattern of GH also changes during the luteal phase of healthy bitches, with higher basal GH secretion and less GH secreted in pulses during stages with a high plasma progesterone concentration.5 It is likely that this is caused by a partial suppression of pituitary GH release by progesterone-induced GH production in the mammary gland, indicating that progestin-induced mammary GH production is not just an aberration, but a normal physiological event during the luteal phase of the estrous cycle in healthy cyclic bitches. Ovariectomy of bitches in the mid-luteal phase lowers basal plasma GH levels and restores GH pulsatility.6
Changes in the release of other hormones may also affect GH release. For example, canine primary hypothyroidism is associated with elevated basal GH release and less GH secreted in pulses.7 Pituitary-dependent hyperadrenocorticism in dogs leads to a decrease in pulsatile GH release, while basal GH release remains unaltered low.8
The pathogenesis of acromegaly is completely different in dogs compared with other species. In middle-aged and elderly female dogs, either endogenous progesterone (luteal phase of the estrous cycle) or exogenous progestins (used for estrus prevention) may give rise to GH hypersecretion of mammary origin. GH excess due to a pituitary tumor is extremely rare in dogs.
Signs and symptoms of GH hypersecretion tend to develop slowly and are characterized initially (particularly in the dog) by soft tissue swelling of the face and the abdomen. In some acromegalic dogs severe hypertrophy of soft tissues of the mouth, tongue, and pharynx causes snoring and even dyspnea. Usually the dogs are also presented with polyuria (and sometimes polyphagia). The polyuria is usually without glucosuria, but manifest diabetes mellitus can develop due to insulin resistance. Physical examination may reveal thick skin folds, especially in the neck, and prognathism and wide interdental spaces. Prolonged GH excess also leads to generalized visceromegaly resulting in abdominal enlargement.
The diagnosis of GH excess can generally be established by measuring basal plasma GH levels. The basal plasma GH level in acromegalic animals often exceeds the upper limit of the reference range. However, if the disease is mild or just beginning, the basal plasma GH levels may be only slightly elevated. Conversely, a high value may be the result of a secretory pulse in a normal subject. Nonresponsiveness of normal or elevated GH levels to stimulation may further support the diagnosis.
Measurement of elevated plasma IGF-I levels may also contribute to the diagnosis. Being bound largely to proteins, the IGF-I level is much less subject to fluctuation than is GH. However, there is some overlap in plasma IGF-I levels between healthy animals and individuals with acromegaly.
Canine acromegaly can be treated easily and effectively by withdrawal of exogenous progestagens and/or ovario(hyster)ectomy. The animal may then change dramatically, owing to the reversal of the soft tissue changes. In cases in which the GH excess did not lead to complete exhaustion of the pancreatic beta cells, the elimination of the progesterone source may prevent persistent diabetes mellitus. Progesterone-receptor blockers may also be useful.
Pituitary Dwarfism or Congenital GH Deficiency
Congenital growth hormone deficiency is primarily known to occur in German shepherd dogs as an autosomal recessive inherited condition,9 which is characterized by profound dwarfism with retention of puppy hairs and lack of primary guard hairs. Basal plasma concentrations of GH and IGF-I, prolactin, thyrotropin, and luteinizing hormone are low. In a combined anterior pituitary function test, employing four releasing hormones, there is very consistently no response of GH, TSH, and prolactin, while there is a minor response of LH and FSH. The response of ACTH is not impaired.10
Pituitary dwarfs are usually presented to the veterinarian at the age of 2-5 months because of proportionate growth retardation and an abnormally soft and woolly hair coat. The latter is due to retention of secondary hairs and lack of guard hairs. The hairs are easily epilated and there is gradual development of truncal alopecia, beginning at the points of wear and sparing the head and the extremities. The skin becomes progressively hyperpigmented and scaly. Secondary bacterial infections of the skin are quite common.
There does not appear to be a gender predilection for pituitary dwarfism. In male dwarfs unilateral or bilateral cryptorchidism is a common finding, whereas in female dwarfs persistent oestrus is quite common. Persistent oestrus in these female dwarfs is characterized by swelling of the vulva, attractiveness to male dogs, and bloody vaginal discharge of more than four weeks duration. The plasma progesterone concentration in these bitches remains low, often below 3 nmol/l, indicating that ovulation does not occur. Physical examination may also reveal a continuous heart murmur due to a patent ductus arteriosus.10 Initially, pituitary dwarfs are usually lively and alert. With time the animals develop inappetence and become less active. This situation is usually reached at the age of two or three years and has been ascribed to secondary hypothyroidism and impaired renal function.
Routine laboratory examination usually does not reveal abnormalities, except for an elevated plasma creatinine concentration. Because pituitary dwarfism is often the result of combined pituitary hormone deficiency, in most pituitary dwarfs there is also secondary hypothyroidism. Plasma IGF-I concentrations are low in pituitary dwarfs, even when age and body size are taken into account. Nevertheless, IGF-I measurements do not provide such a definitive diagnosis as do the measurements of GH before and after stimulation.
Since basal plasma GH values may also be low in healthy animals, the definitive diagnosis GH deficiency is based upon the results of a stimulation test. For this purpose GHRH or ghrelin (1-2 µg/kg bodyweight) or a-adrenergic drugs, such as clonidine (10 µg/kg bodyweight) or xylazine (100 µg/kg bodyweight), can be used. The plasma GH concentration should be determined at least immediately before and 20-30 minutes after intravenous administration of the stimulant. In the normal dog, plasma GH concentrations should increase at least two- to four-fold after administration of the stimulant. In dogs with pituitary dwarfism there is no significant rise in circulating GH levels. Administration of xylazine or clonidine may give rise to sedation, bradycardia, hypotension, and vomiting.
Porcine growth hormone, which is identical to canine growth hormone,11 can be used for treatment in subcutaneous doses of thrice weekly 0.1-0.3 IU per kg body weight. Use of heterologous GH such as bovine and human GH cannot be recommended because of the development of antibodies.12 Treatment with porcine GH may result in GH excess and consequently side effects such as diabetes mellitus may develop. Monitoring of the plasma concentrations of GH, IGF-I and glucose is therefore of utmost importance. Subsequent treatment with heterologous GH (dosage and interval) after this induction period should also depend on measurements of the plasma concentrations of GH and IGF-I. Treatment often does not result in a significant increase in body size, because the growth plates in most dwarfs have already closed or are about to close at the time GH treatment is initiated. The hairs that grow back is mainly primary hair; growth of guard hairs is variable.
The demonstration of the ability of progestagens to induce the expression of the GH gene in the canine mammary gland and the subsequent secretion of this GH into the systemic circulation has raised the possibility of treatment of dogs with congenital GH deficiency with progestagens. Treatment of young German shepherd dwarfs with subcutaneous injections of medroxyprogesterone acetate in doses of 2.5-5.0 mg per kg body weight, initially at 3-week intervals and subsequently at 6-week intervals, has resulted in some increase in body size and the development of a complete adult hair coat. Parallel with the physical improvements, plasma IGF-I concentrations rose sharply, whereas plasma GH concentrations did rise but never exceeded the upper limit of the reference range.13 Treatment of dogs with congenital GH deficiency with progestagens may give rise to several side effects, such as recurrent periods of pruritic pyoderma, skeletal maldevelopment, development of mammary tumours, acromegaly, diabetes mellitus and cystic endometrial hyperplasia. As with the treatment using porcine GH, monitoring of the plasma concentrations of GH, and especially, IGF-I and glucose are important to prevent side effects. Bitches should be ovariohysterectomized before the start of the progestagen treatment. Despite the possible side-effects, long-term treatment with progestagens can be used as an alternative for porcine GH in the treatment of dogs with congenital GH deficiency. Thyroid hormone replacement should be started as soon is there is evidence of secondary hypothyroidism.
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13. Kooistra HS, et al. Domest Anim Endocrinol 1998;15:93.