Study of long-term survival after transsphenoidal hypophysectomy in clinically normal dogs.

Experimental hypophysectomies were performed in 7 clinically normal dogs, using a new modification of the transsphenoidal approach. This approach facilitated centering of the sphenoid bone trephination and allowed safe exposure of the hypophysis regardless of the size or shape of a dog's skull. Complications did not occur during surgery and all dogs recovered well from surgery. Growth hormone secretory capacity was measured over a 3-month period to assess completeness of hypophysectomies. One dog was euthanatized 2 months after surgery, 4 dogs were euthanatized at 3 months after surgery, and 2 dogs were allowed to survive and their progress was followed for 2.5 years. Soft palate dehiscence and keratoconjunctivitis sicca developed in 2 of the dogs. The technical deficiencies responsible for these complications were corrected shortly after the beginning of the study. In 4 of the 5 necropsied dogs, minute remnants of adenohypophyseal tissue were found in the sellae turcica. Measurement of in vivo growth hormone secretory capacity revealed that these remnants had an altered stage of functional activity. Although complete hypophysectomy was not achieved consistently, the main technical obstacle of hypophysectomy, the reliable identification and the avoidance of the vascular structures surrounding the hypophysis, has seemingly been overcome. The surgical technique proved to enhance the safety of hypophysectomy, and the procedure can be recommended to treat clinical cases of canine pituitary-dependent hyperadrenocorticism. The clinical significance of potential subtotal hypophysectomy remains yet to be evaluated.

Insulin-like growth factor I levels in proportionate dogs, chondrodystrophic dogs and in giant dogs.

Plasma insulin-like growth factor I concentrations from proportionate, chondrodystrophic and giant breeds were evaluated and compared with body size. IGF-I plasma concentrations were 91.2 +/- 10.9 micrograms/l in Keeshounds (proportionate dog), 122.6 +/- 25.4 micrograms/l in Bassethounds (chondrodystrophic dog) and 280 +/- 22.8 micrograms/l in German Shepherds (proportionate dog). The highest IGF-I level (389.6 +/- 24.2 micrograms/l) was found in the New Foundland, a giant breed (mean +/- SEM). The mean body weight was 11.8 +/- 0.4 kg in Keeshounds, 15.4 +/- 1.4 kg in Bassethounds, 32 +/- 1.5 kg in German Shepherds, and 45.6 +/- 1.7 kg in New Foundlands (mean +/- SEM). Body weight and plasma IGF-I concentration were significantly correlated (y (IGF-I) = -7.43 + 8.7 X (body weight); P less than 0.0001.

Medroxy-progesterone acetate administration to ovariohysterectomized, oestradiol-primed beagle bitches. Effect on secretion of growth hormone, prolactin and cortisol.

Growth hormone (GH), prolactin (Prl) and cortisol secretion was studied in 5 ovariohysterectomized dogs before and after oestradiol implantation and medroxyprogesterone acetate (MPA) administration. MPA was given at regular intervals during a period of 10 months in a total of 12 injections. Short-term effects of oestradiol were restricted to significantly enhanced Prl responses to thyrotropin-releasing hormone (TRH). MPA treatment after oestradiol implantation resulted in significantly elevated basal GH levels in all dogs, with a continuing increase in one dog. Only in the latter dog was a significant decrease in basal Prl levels seen. MPA administration did not significantly change Prl responses to TRH. The GH responses to clonidine were significantly reduced at 9 and 16 weeks of oestradiol and MPA treatment. In the one dog which exhibited the greatest rise in basal GH levels, GH responses were completely abolished at 9, 16 and 43 weeks of oestradiol and MPA treatment. TRH never evoked significant GH responses. Both basal and lysine-vasopressin (LVP)-stimulated cortisol levels were significantly suppressed during combined oestradiol-MPA treatment. These findings denote that in the dog. Oestradiol rapidly induces an enhanced Prl response to TRH. The oestradiol-MPA induced GH overproduction is associated with a reduced responsiveness of GH to clonidine and is not accompanied by GH responsiveness to TRH. Oestradiol-MPA treatment suppresses both basal and LVP-stimulated cortisol secretion.

Insulin-like growth factor I and growth hormone in canine starvation.

The roles of plasma insulin-like growth factor I (IGF I) and growth hormone (GH) were studied in 7 beagle dogs before and during starvation and during refeeding. IGF I levels significantly decreased from 75.2 +/- 5.9 ng/ml at 7 days prior to the start of starvation to 9 +/- 1.7 ng/ml at 19 days after the commencement of starvation (mean +/- SEM; P less than 0.0001). During refeeding IGF I significantly rose from 9 +/- 1.7 ng/ml to 55.5 +/- 7.5 ng/ml within 9 days (mean +/- SEM; P less than 0.002). During starvation plasma GH levels significantly increased (P less than 0.05) and these elevated levels returned to normal during refeeding. The dogs' GH secretory capacity significantly increased during starvation (P = 0.012) and became normal again during refeeding. The following conclusions can be drawn from this study: 1) starvation in the dog leads to a significant and drastic reduction of the circulating levels of IGF I, and 2) starvation in the dog, as in man, leads to increased circulating GH levels and to an increased GH-secretory capacity possibly brought about by a lack of a negative feedback normally exerted by IGF I.

Body size parallels insulin-like growth factor I levels but not growth hormone secretory capacity.

The relationships between body size, growth hormone (GH) secretory capacity and circulating insulin-like growth factor I (IGF I) levels were studied in genetically-determined subgroups of disparate size within one breed of dogs, the Poodle. Standard (large) Poodles exhibited six times the mean plasma IGF I concentration found in Toy Poodles. The mean IGF I level found in Standard Poodles significantly differed from the one found in Miniature and Toy Poodles (P less than 0.001). The correlation between circulating IGF I levels and body size was found to be highly significant (P less than 0.001; r = 0.88). All dogs secreted similar, normal amounts of GH in response to clonidine administration. The results show that body weight is correlated with IGF I levels rather than with the GH secretory capacity, thus providing indirect evidence for IGF I as an important in vivo growth-promoting principle.

Acromegaly in the dog.

The main characteristic findings in canine acromegaly are a visible increase in soft tissue mass, prominent skin folds, abdominal enlargement, and/or radiographic evidence of an increase in soft tissue mass in the orolingual, oropharyngeal, and orolaryngeal region. Acromegalic dogs almost invariably show some degree of respiratory stridor. Enlargement of the interdental spaces can be seen, but it is felt that these changes are less specific for the disease. Other possible findings include hyperglycemia, PU/PD, elevated SAP levels, and lowered PCV. For a conclusive diagnosis, the demonstration of elevated GH levels and, preferably, the demonstration of nonsuppressibility of these high GH levels is required. Basal plasma GH levels in acromegalic dogs varies considerably (for example, from 10 ng per ml to approximately 1500 ng per ml). GH-dependent circulating growth factor (that is, insulin-like growth factor I) is drastically elevated. Acromegaly is encountered in intact female dogs that were treated with progestagens to prevent estrus and in dogs during diestrus (progesterone phase). Progestagen withdrawal and/or ovariohysterectomy will result in a reduction of plasma GH and GH-dependent insulin-like growth factor concentrations and appreciable clinical improvement.

Growth hormone and insulin-like growth factor I in German shepherd dwarf dogs.

The roles of growth hormone (GH) and insulin-like growth factor I (IGF I) were studied in 9 German Shepherd dwarf dogs. GH deficiency was evidenced in all dogs by an absence of increase in GH levels in response to clonidine administration. While the mean IGF I concentration in normal adult German Shepherds was 280 +/- 23 ng/ml and 345 +/- 50 ng/ml in immature animals, the mean IGF I concentration in the dwarf dogs was 11 +/- 2 ng/ml (mean +/- SEM, P less than 0.001). In the affected animals, plasma thyroxine (T4) levels were only slightly subnormal and there was an increase in these levels in response to thyroid stimulating hormone (TSH) administration. The findings indicate 1) that dwarfism in German Shepherds is caused by primary GH-deficiency resulting in low circulating levels of IGF I and 2) that IGF I levels in the dog as in man are subject to control by GH.

Insulin-like growth factor I in the dog: a study in different dog breeds and in dogs with growth hormone elevation.

A radioimmunoassay (RIA) devised for the measurement of human insulin-like growth factor I (IGF I) was employed for the measurement of canine IGF I. Canine IGF I was extracted from plasma specimens by gel chromatography. Columns were eluted with 1 M acetic acid and the fractions representing the 55 to 85% bed volume were pooled, lyophilized and reconstituted with assay buffer. Serial dilutions of canine IGF I from both normal and acromegalic dogs when added to the RIA system gave a similar displacement pattern of human [125I]IGF I as the one obtained by the addition of unlabelled human IGF I. The dose-response curve obtained by canine IGF I paralleled the one obtained by human IGF I. Logit-log transformation and least squares fitting resulted in straight line fitting of the standard curve between 0.039 and 5 ng IGF I added per tube. The within-assay coefficient of variation (CV) was 16.7% and the between-assay CV was 21.8%. Plasma IGF I concentrations in normal dogs appeared to be a function of body size. The concentrations were 36 +/- 27 ng/ml in Cocker Spaniels, 87 +/- 33 ng/ml in Beagles, 117 +/- 34 ng/ml in Keeshonds, and 280 +/- 23 ng/ml in German Shepherds (mean +/- SEM). The mean IGF I level in a group of dogs with growth hormone (GH) elevation was 700 +/- 90 ng/ml. Though this group of dogs comprised both small and large dogs, the mean IGF I level significantly differed from the one found in German Shepherds, the largest breed studied (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Progesterone-controlled growth hormone overproduction and naturally occurring canine diabetes and acromegaly.

Female pet dogs exhibiting either glucose intolerance alone or glucose intolerance and acromegaly were investigated. Some dogs developed the disorder(s) during dioestrus and some animals developed the disorder(s) after they were given medroxyprogesterone acetate (MPA). Elevated fasting plasma glucose levels (12.3 +/- 1.9 mM, mean +/- SEM) were accompanied by fasting hyperinsulinaemia (144 +/- 21 microU/ml, mean +/- SEM) and drastic elevation of plasma growth hormone (GH) levels (112.6 +/- 45 ng/ml, mean +/- SEM). An iv glucose tolerance test (IVGTT) performed on all dogs revealed non-suppressibility of GH levels and glucose intolerance. Plasma concentrations of glucose, insulin and GH during IVGTT in affected dogs differed significantly from the concentrations measured in normal dogs during the same test. MPA withdrawal and/or ovariohysterectomy (OVx-HYx) in affected animals was followed by reversal of GH levels to normal and improved glucose tolerance. Acromegaly associated soft tissue changes were also reversible after MPA withdrawal and/or OVx-HYx when GH levels had dropped. In 5 dogs which had developed diabetes during dioestrus and in which a spontaneous decrease in plasma progesterone occurred during the investigation a concomittant decrease in GH levels was observed. Plasma GH measured at different stages of pregnancy in 45 dogs was found to be elevated in one animal only. The results show that the development of spontaneous diabetes/acromegaly occurring in some female dogs is related to progestagen (progesterone/MPA) exposure and that reversal of the signs is achieved by progesterone/MPA withdrawal. The results suggest that diabetes/acromegaly in the dogs studied was caused by progesterone/MPA-evoked GH elevation. Finally, the findings also suggest that the GH axis normally not appreciably responsive to progestagen exposure in some dogs becomes and/or is paradoxically controlled by physiologic levels of endogenous progesterone or low doses of MPA.

Influence of medroxyprogesterone acetate (Provera) on plasma growth hormone levels and on carbohydrate metabolism. I. Studies in the ovariohysterectomized bitch.

Six elderly ovariohysterectomized dogs were given medroxyprogesterone acetate (MPA 10 mg/kg body weight) at 3 week intervals in a total of 5 injections. Mean growth hormone (GH) levels increased significantly after the third injection, continued to increase slightly after the fourth and fifth injections and remained significantly elevated over control levels as late as 16 weeks after the last MPA administration (P less than 0.05). The mean glucose concentrations during iv glucose tolerance tests (IVGTT) were significantly elevated at 30, 45 and 60 min after a glucose load when performed after the third MPA injection. Following the second MPA injection, mean insulin levels were significantly elevated at rest, 30 and 45 min after glucose load. After the fourth and fifth MPA injections, mean insulin levels during IVGTT were significantly elevated at 30 min only. These findings denote that (1) after a lag phase of several weeks MPA induces moderate GH increase in ovariohysterectomized dogs; (2) MPA administration causes moderate disturbance of glucose homoeostasis.

Influence of medroxyprogesterone acetate (Provera) on plasma growth hormone levels and on carbohydrate metabolism. II. Studies in the ovariohysterectomized, oestradiol-primed bitch.

The combined effects of oestradiol and medroxyprogesterone acetate on growth hormone (GH) levels and carbohydrate metabolism were studied in 6 ovariohysterectomized dogs, which previously had shown moderate increments in GH after medroxyprogesterone acetate (MPA) administration. Oestradiol (Oe2) implants were administered 5 months after the last MPA injection, when MPA and GH levels tended to decrease. Following Oe2 administration GH levels rose significantly. Single MPA injections (100 mg) given 20 days after Oe2-priming were followed by still further increased GH levels. These GH levels were several-fold higher than GH levels achieved by previous MPA administration alone. GH levels decreased in 3 dogs after 35 days and remained elevated in the other 3 dogs as long as 70 days after MPA administration with Oe2 priming. Glucose assimilation became impaired and insulin response to a glucose load increased in relation to elevated GH levels. Oe2-primed control dogs, which received no MPA, failed to develop elevated GH levels. These findings indicate (1) that Oe2 and MPA induce overproduction in ovariohysterectomized dogs synergistically (2) that GH levels of the magnitude evoked are associated with glucose intolerance and insulin resistance.

Radioimmunoassay of canine growth hormone.

A sensitive radioimmunoassay (RIA) for canine growth hormone (GH) was developed. Antibodies were elicited in rhesus monkeys. One antiserum exhibited a working titer at a dilution of 1: 500 000. Radioiodination was performed enzymatically employing lactoperoxidase. Logit-log transformation and least squares fitting resulted in straight line fitting of the standard curve between 0.39 and 50 ng/ml. Formation of large-molecular [125I]GH during storage caused diminished assay sensitivity. Therefore [125I]GH was re-purified by gel chromatography. Using this procedure, high and reproducible assay sensitivity was obtained. Tracer preparations were used for as long as 3 months after iodination. Diluted plasma from normal and acromegalic dogs resulted in a dose-response curve parallel to the standard curve. Canine prolactin exhibited a cross-reactivity of 2%. The within-assay coefficient of variation (CV) was 3.8 and the between-assay CV was 7.2%. Mean plasma GH concentration in normal dogs was 1.92 +/- 0.14 ng/ml (mean +/- SEM). GH levels in acromegalic dogs were appreciably higher. Insulin-induced hypoglycaemia, arginine and ornithine administration resulted in inconsistent and sluggish GH increment. A better response was obtained by injecting a low dose of clonidine. Clonidine administration to hypopituitary dogs resulted in absent or poor GH increment.

[Prevention of oestrus and/or pregnancy in dogs by methods other than ovariohysterectomy (author's transl)]. / Preventie van loopsheid en/of dracht bij de hond door andere methoden dan ovario-hysterectomie.

The present paper is based on findings reported in the literature and concerned with various possible methods of preventing heat and/or pregnancy without resorting to ovariohysterectomy. The drugs used to suppress and prevent oestrus, such as progestagens, testosterone and 19-nortestosterone derivates, are reviewed, the mechanism of action, mode of administration and advantages and disadvantages being discussed. Progestagens are particularly found to affect the uterus (CEH) and mammary glands (increased incidence of mammary tumours), and they may also induce diabetes mellitus and acromegaly. On the other hand, the untoward side-effects of 19-nortestosterone derivatives are found to be mainly due to their androgenic action, resulting in enlargement of the clitoris, vaginitis, changes of behaviour and masculinization of puppies when the drug is administered during pregnancy. Subsequently, those mechanical and surgical procedures which are less commonly employed, are discussed. The pros and cons of the various methods and drugs as well as the possible causes of the difference in gestagenic effect of a number of progestational agents are discussed in greater detail.