Clinical use of Gonadotropin-Releasing Hormone (GnRH) Agonists in Companion Animals: An Overview

In dogs, cats, ferrets, and pet birds, reproductive physiology is under the control of the hypothalamic­pituitary­-gonadal (HPG) axis. Many hormones are responsible for estrus and reproduction, the most significant being luteinizing hormone (LH), follicle stimulating hormone (FSH), and gonadotropin-releasing hormone (GnRH). Short-lived GnRH is released in a pulsatile fashion from the hypothalamus and acts on the pars distalis of the pituitary gland to stimulate the synthesis and release of the gonadotropins, FSH and LH (Figure 1). Secretion of these gonadotropins into the circulation lead to changes gonadal hormone production and reproductive function.

Figure 1: Regulation of gonadal secretion via the hypothalamic-pituitary-gonadal axis.

Chemical modification of the native short-acting GnRH molecule has led to development of long-acting, potent GnRH agonists, which have been used as a medical means of management for a number of reproductive issues and diseases of companion animals (1-3). GnRH agonists may either stimulate estrus or effectively sterilize the patient, depending on the duration of action and the dosage applied. These agents work by initially stimulating gonadotrophin secretion, followed shortly thereafter with desensitization of the GnRH receptor to the GnRH agonist (Figure 2). This results in a temporary but long-term, fully-reversible down-regulation of gonadotrophin secretion, leading to suppression of reproduction function in both male and female animals (4).

Figure 2: GnRH agonists initially stimulate pituitary LH and FSH secretion, followed by desensitization and down-relation of gonadotrophin secretion.

In recent years, effective low-dose, slow-release implants containing potent GnRH agonists have been released for use in veterinary medicine, especially in Europe and Australia. In companion animals, the deslorelin implant (Suprelorin, Virbac) is the most commonly GnRH agonist used in small animals (5). Deslorelin implants work by lowering pituitary gonadotrophin section. This is not a permanent change but depending on the deslorelin dose, can last up to many months. The implant does not have to be removed, but subsequent doses are needed to sustain the effect.

Unfortunately, GnRH agonist availability is limited in the United States. Although there are GnRH agonists available that are approved for the treatment of human diseases, such as prostate cancer, they are costly and not financially feasible for a pet owner to consider. To date, deslorelin acetate (Suprelorin, Virbac Animal Health, Fort Worth, TX, USA) is the only GnRH agonist that is currently available in the United States but only for the treatment of adrenal disease in ferrets (6). However, it is not legal to use Suporelin in non-ferret species in the United States and extra-label use is explicitly prohibited.

The aim of this blog is to review the applications and treatments of the deslorelin (GnRH agonist) currently used in companion animal medicine.

Deslorelin Use in Intact Male Dogs
In male dogs treated with deslorelin, this GnRH agonist leads to decreased gonadotropins secretion and resultant lowered plasma testosterone concentrations, decreased testicular volume, and azoospermia (1-3,7-9). However, the response to this GnRH agonist can be very variable from one dog to another, and the duration of inhibition of testosterone secretion depends both on the concentration of the deslorelin implant and the size of the dog.

Many studies have confirmed that use of GnRH agonists for reversible chemical sterilization in male dogs is both safe and well-tolerated (7-9). Furthermore, repeated implantation can be used to maintain circulating testosterone at low concentrations. If the deslorelin implants are stopped, the treated dogs will regain normal serum testosterone levels within a few weeks, with full recovery of seminal quality once the GnRH implant has lost its efficacy (10,11).

In addition to contraception, GnRH agonists have also been used to reduce the size of the prostate gland, an effect that may be useful in dogs with benign prostatic hyperplasia (12-14).

Deslorelin in Intact Male Cats
As in dogs, GnRH agonists are gaining increased importance in feline reproductive medicine (2,3,15). In intact male cats, deslorelin implants induce chemical sterilization, as in dogs. In these cats, testosterone concentrations decline rapidly to undetectable values by 3 weeks after implantation and remain low for weeks in the majority of the tomcats treated. As the circulating testosterone falls, the testicular volume decreases and penile spines disappear.

However, high individual variability has been reported, with the duration of efficacy varying between 6 and 24 months (15-17). Similar to dogs, it is possible to use repeated implantation of deslorelin to sustain the drug’s effect.

Deslorelin in Intact Bitches
Although deslorelin implants are only approved for male dogs in Europe (and again, not at all in the USA), studies have been performed in the bitch to investigate its use either as a contraceptive or a method of estrus induction (1-3,18-20).

The first step in the mechanism of action of all GnRH agonists is the stimulation in FSH and LH secretion (so-called "flare-up effect") (4). This followed within a few days by a profound hypogonadal effect (i.e., decrease in FSH and LH levels), which is achieved through receptor down-regulation by internalization of receptors. Generally this induced and reversible hypogonadism is the therapeutic goal, as noted above for the male dogs and cats (1-3).

The initial stimulating effect on gonadotrophin secretion is more pronounced in females than in males (18,19). Thus, estrus induction will be observed in the majority of bitches implanted in anestrus. If pregnancy is achieved, most recommend removal of the deslorelin implant either at the beginning of proestrus, at the time of the LH surge, or at the time of ovulation (2,3,18,19). However, some have reported that some bitches carried their pregnancies to term without the implant being removed, suggesting that down-regulation of gonadotrophin secretion may not be strong enough to induce luteal failure in all bitches.

For use as a contraceptive method, the main problem with using deslorelin implants in female dogs is estrus induction, as discussed above (20). For this reason, deslorelin implants cannot be considered a viable alternative to other, current used contraception in bitches.

Deslorelin in Intact Queens
In contrast to female dogs, the main indication for the use of deslorelin in the female queen is estrus inhibition. Studies have confirmed that this GnRH agonist can be used to effectively suppress ovarian activity (15,20-22), but the duration of inhibition was highly variable among the individual queens depending on the dosage administered. However, deslorelin generally suppresses ovarian activity for many months.

Deslorelin in Spayed Bitches with Urinary Incontinence
Ovariectomy results in elevated circulating concentrations of pituitary LH because of the lack of gonadal negative-feedback on the pituitary gland. LH receptors are present throughout the canine urinary tract (23-25), and it has been postulated that elevated gonadotropins may contribute to the development of urethral sphincter mechanism incompetence (26,27).

Treatment of bitches with long-acting GnRH agonists, such as delorelin, downregulates LH secretion for prolonged time periods and temporarily restores continence to incontinent bitches for varying durations, ranging from 50-738 days (26,27). Similar to alpha-adrenergic agonists (e.g., phenylpropanolamine; PPA), GnRH agonists are not completely effective for the treatment of this urinary incontinence. However, unlike PPA, no adverse effects to GnRH agonists have been reported.

Deslorelin in Ferrets with Adrenal Disease
As in dogs and cats, deslorelin is also a promising and suitable method for contraception in ferrets (28-31). However, GnRH agonists are useful in medical management of ferrets suffering from adrenal disease (hyperadrenocorticism) a common disease in castrated males and females (32-34). In one study of ferrets with adrenal disease, the clinical signs (e.g., vulvar swelling, pruritus, sexual behavior, and aggression) were reduced or markedly suppressed within 14 days of implantation of the deslorelin (34). The time for signs to recur in these ferrets ranged from 8.5–20.5 months (34).

References:

1. Trigg TE, Doyle AG, Walsh JD, et al. A review of advances in the use of the GnRH agonist deslorelin in control of reproduction. Theriogenology 2006;66:1507-1512. 
2. Fontaine E, Fontbonne A. Clinical use of GnRH agonists in canine and feline species. Reprod Domest Anim 2011;46:344-353. 
3. Lucas X. Clinical use of deslorelin (GnRH agonist) in companion animals: a review. Reprod Domest Anim 2014;49 Suppl 4:64-71. 
4. Ortmann O, Weiss JM, Diedrich K. Gonadotrophin-releasing hormone (GnRH) and GnRH agonists: mechanisms of action. Reprod Biomed Online 2002;5 Suppl 1:1-7. 
5. Suprelorin (deslorelin acetate). Summary report from the European Medicines Agency. 
6. Suprelorin F. Package insert. Fort Worth, Texas: Virbac Animal Health 
7. Junaidi A, Williamson PE, Martin GB, et al. Pituitary and testicular endocrine responses to exogenous gonadotrophin-releasing hormone (GnRH) and luteinising hormone in male dogs treated with GnRH agonist implants. Reprod Fertil Dev 2007;19:891-898. 
8. Junaidi A, Williamson PE, Martin GB, et al. Dose-response studies for pituitary and testicular function in male dogs treated with the GnRH superagonist, deslorelin. Reprod Domest Anim 2009;44:725-734. 
9. Romagnoli S, Siminica A, Sontas BH, et al. Semen quality and onset of sterility following administration of a 4.7-mg deslorelin implant in adult male dogs. Reprod Domest Anim 2012;47 Suppl 6:389-392. 
10. Trigg TE, Wright PJ, Armour AF, et al. Use of a GnRH analogue implant to produce reversible long-term suppression of reproductive function in male and female domestic dogs. J Reprod Fertil Suppl 2001;57:255-261. 
11. Gentil M, Hoffmann B, Spang A, et al. Restart of steroidogenesis in dogs during recrudescence of testicular function following downregulation with a GnRH-agonist implant. Cell Tissue Res 2012;350:513-523. 
12. Vickery BH, McRae GI, Bonasch H. Effect of chronic administration of a highly potent LHRH agonist on prostate size and secretory function in geriatric dogs. Prostate 1982;3:123-130. 
13. Nizanski W, Levy X, Ochota M, et al. Pharmacological treatment for common prostatic conditions in dogs - benign prostatic hyperplasia and prostatitis: an update. Reprod Domest Anim 2014;49 Suppl 2:8-15. 
14. Polisca A, Orlandi R, Troisi A, et al. Clinical efficacy of the GnRH agonist (deslorelin) in dogs affected by benign prostatic hyperplasia and evaluation of prostatic blood flow by Doppler ultrasound. Reprod Domest Anim 2013;48:673-680. 
15. Goericke-Pesch S, Wehrend A, Georgiev P. Suppression of fertility in adult cats. Reprod Domest Anim 2014;49 Suppl 2:33-40. 
16. Goericke-Pesch S, Georgiev P, Antonov A, et al. Clinical efficacy of a GnRH-agonist implant containing 4.7 mg deslorelin, Suprelorin, regarding suppression of reproductive function in tomcats. Theriogenology 2011;75:803-810. 
17. Goericke-Pesch S, Georgiev P, Fasulkov I, et al. Basal testosterone concentrations after the application of a slow-release GnRH agonist implant are associated with a loss of response to buserelin, a short-term GnRH agonist, in the tom cat. Theriogenology 2013;80:65-69. 
18. Volkmann DH, Kutzler MA, Wheeler R, et al. The use of deslorelin implants for the synchronization of estrous in diestrous bitches. Theriogenology 2006;66:1497-1501. 
19. Fontaine E, Mir F, Vannier F, et al. Induction of fertile oestrus in the bitch using Deslorelin, a GnRH agonist. Theriogenology 2011;76:1561-1566. 
20. Maenhoudt C, Santos NR, Fontaine E, et al. Results of GnRH agonist implants in oestrous induction and oestrous suppression in bitches and queens. Reprod Domest Anim 2012;47 Suppl 6:393-397. 
21. Goericke-Pesch S. Reproduction control in cats: new developments in non-surgical methods. J Feline Med Surg 2010;12:539-546. 
22. Goericke-Pesch S, Georgiev P, Atanasov A, et al. Treatment of queens in estrus and after estrus with a GnRH-agonist implant containing 4.7 mg deslorelin; hormonal response, duration of efficacy, and reversibility. Theriogenology 2013;79:640-646. 
23. Coit VA, Dowell FJ, Evans NP. Neutering affects mRNA expression levels for the LH- and GnRH-receptors in the canine urinary bladder. Theriogenology 2009;71:239–47.
24. Ponglowhapan S, Church DB, Khalid M. Differences in the expression of luteinizing hormone and follicle-stimulating hormone receptors in the lower urinary tract between intact and gonadectomised male and female dogs. Domest Anim Endocrinol 2008;34:339-351. 
25. Reichler IM, Welle M, Sattler U, et al. Comparative quantitative assessment of GnRH- and LH-receptor mRNA expression in the urinary tract of sexually intact and spayed female dogs. Theriogenology 2007;67:1134–42.
26. Reichler IM, Hubler M, Jöchle W, et al. The effect of GnRH analogs on urinary incontinence after ablation of the ovaries in dogs. Theriogenology 2003;60:1207–16.
27. Reichler IM, Jöchle W, Piché CA, , et al. Effect of a long-acting GnRH analogue or placebo on plasma LH/FSH, urethral pressure profiles and clinical signs of urinary incontinence due to sphincter mechanism incompetence in bitches. Theriogenology 2006;66:1227–36.
28. Schoemaker NJ, van Deijk R, Muijlaert B, et al. Use of a gonadotropin releasing hormone agonist implant as an alternative for surgical castration in male ferrets (Mustela putorius furo). Theriogenology 2008;70:161-167. 
29. Prohaczik A, Kulcsar M, Trigg T, et al. Comparison of four treatments to suppress ovarian activity in ferrets (Mustela putorius furo). Vet Rec 2010;166:74-78. 
30. Goericke-Pesch S, Wehrend A. The use of a slow release GnRH-agonist implant in female ferrets in season for oestrus suppression. Schweiz Arch Tierheilkd 2012;154:487-491. 
31. van Zeeland YR, Pabon M, Roest J, et al. Use of a GnRH agonist implant as alternative for surgical neutering in pet ferrets. Vet Rec 2014;175:66. 
32. Rosenthal KL, Peterson ME, Quesenberry KE, et al. Hyperadrenocorticism associated with adrenocortical tumor or nodular hyperplasia of the adrenal gland in ferrets: 50 cases (1987-1991). J Am Vet Med Assoc 1993;203:271-275. 
33. Schoemaker NJ, Teerds KJ, Mol JA, et al. The role of luteinizing hormone in the pathogenesis of hyperadrenocorticism in neutered ferrets. Mol Cell Endocrinol 2002;197:117-125. 
34. Wagner RA, Piche CA, Jochle W, et al. Clinical and endocrine responses to treatment with deslorelin acetate implants in ferrets with adrenocortical disease. Am J Vet Res 2005;66:910-914. 

Medical Treatment of Insulinomas

Dietary or medical management of insulinoma is recommended for animals that are showing signs of hypoglycemia and have previously undergone surgery and in those whose owners have declined surgery (1-6).

Specific chemotherapy can also be considered in animals in which all of the tumor cannot be resected and in those that have undergone previous surgery and again are showing signs of hypoglycemia. Just over half of dogs with insulinoma have metastases at the time of diagnosis (1-4), so it is reasonable to discuss the possibility of follow-up chemotherapy after surgery. Chemotherapy should be given only to patients with a confirmed histologic diagnosis of insulinoma.

Dietary management of hypoglycemia
Animals with insulinoma should be fed a diet that is high in protein, fat, and complex carbohydrates. Simple sugars, often contained in semimoist pet foods, should be avoided. Dogs should be fed small meals three to four times daily. Cats and ferrets may be fed free choice if they do not become obese. Exercise should be controlled and owners should attempt to limit excitement in these pets.

Glucocorticoids
Glucocorticoids are recommended when frequent feedings are no longer successful in controlling clinical signs of hypoglycemia. These drugs raise blood glucose by inhibiting glucose uptake in the peripheral tissues (creating insulin resistance) and stimulating hepatic glucose production (7-9).

Oral prednisone (or prednisolone) is started at the dosage of 0.25 mg/kg, twice daily (1-6). This dosage may be increased gradually as needed to control clinical signs or may be decreased if the disease is well controlled at the initial dosage. We should remember, however, that dosages of 1.1 mg/kg or higher given twice daily are considered immunosuppressive.

Diazoxide
Diazoxide (Proglycem, Teva Pharmaceuticals) is a nondiuretic benzothiadiazide that decreases insulin secretion, promotes gluconeogenesis and glycogenolysis, and inhibits the cellular uptake of glucose (10-12). Diazoxide can be difficult to obtain in the United States; however, reputable compounding pharmacies can often supply this drug.

The recommended starting dosage of diazoxide is 5 mg/kg, given orally twice daily (1-6,13). As with prednisone, the dosage may be increased as needed to control clinical signs. The maximal recommended dosage is 30 mg/kg twice daily.

The most common side effects of diazoxide are anorexia, vomiting, and diarrhea (1-6,13). These signs may be avoided or lessened by giving the medication with food. Ferrets find the diazoxide suspension distasteful, but because only small volumes are required, owners usually are able to administer it. Other potential side effects of diazoxide are hyperglycemia, bone marrow suppression, and sodium retention.

Octreotide acetate
Somatostatin is a polypeptide hormone that inhibits the secretion of insulin, glucagon, gastrin, secretin, and motilin. Octreotide acetate (Sandostatin, Novartis) is a long-acting somatostatin analogue that can be used in the management of patients with insulinoma (14).

Reports on the use of octreotide acetate in veterinary patients are limited and the response is mixed (4,12,15). About half of dogs with refractory hypoglycemia will show a response to octreotide acetate.  Ferrets refractory to other forms of treatment may show improvement in clinical signs in some, but certainly not all, cases.

The recommended dosage is 1 to 2 μg/kg given subcutaneously two to three times daily. This drug is relatively expensive, but may be practical for use in small dogs, cats, or ferrets due to their small size.

Currently, there is no way of predicting which patients will respond to octreotide acetate. Metastatic lesions may express fewer somatostatin receptors than the primary mass, so octreotide may be less effective in patients with advanced disease. This agent does appear to be safe and can be administered by owners at home. Thus, it should be considered for the treatment of animals with insulinoma that are refractory to or unable to tolerate traditional medical or surgical therapy (4,12).

Streptozotocin
Streptozotocin (Zanosar, Teva Pharmaceuticals) is a chemotherapeutic drug that selectively destroys pancreatic beta cells (16-19). When given alone, this drug may cause severe, acute renal failure in dogs. However, the drug can be administered safely if given with aggressive saline diuresis (17-19). Treatment is discontinued if there is clear tumor progression, resistant or recurrent hypoglycemia, or drug toxicity.

Streptozotocin may induce diabetes in some dogs, but the chemotherapy drug may be given along with appropriate insulin therapy if gross disease is still present.  No reports have described the use of streptozotocin in cats or ferrets with insulinoma. Further study of this agent is needed in all species.

Prognosis

The short-term prognosis for dogs with insulinoma is good, although most will eventually die of this disease. While survival time depends on the stage of the disease and the success of surgery, it also depends on the owners’ willingness to treat aggressively and follow up with symptomatic therapy once signs of hypoglycemia return.

Approximately two-thirds to three-quarters of dogs survive 6 months or longer after surgery (often over a year) before intractable hypoglycemia recurs. Reported median survival time is much longer in dogs initially treated with surgery than in those treated with medical management alone (1-5,20,21). Individualizing therapy with the use of combinations of medical and surgical therapy based on the stage and extent of disease may improve prognosis and survival time in any given patient.  

References:

1. Nelson RW, Salisbury SK. Pancreatic beta cell neoplasia In: Birchard SJ, Sherding RJ, eds. Saunders’ Manual of Small Animal Practice. 2nd ed. Philadelphia: WB Saunders, 2000;288–294.
2. Feldman EC, Nelson RW. Beta-cell neoplasia: Insulinoma In: Feldman EC, Nelson RW, eds. Canine and Feline Endocrinology and Reproduction. Philadelphia: Saunders Elsevier, 2004;616-644.
3. Kintzer PP. Insulinoma and other gastrointestinal tract tumours In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;148-155.
4. Meleo KA, Peterson ME. Treatment of insulinoma in the dog, cat, and ferret In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2013.
5. Leifer CE, Peterson ME, Matus RE. Insulin-secreting tumor: diagnosis and medical and surgical management in 55 dogs. J Am Vet Med Assoc 1986;188:60-64. 
6. Nelson RW, Foodman MS. Medical management of canine hyperinsulinism. J Am Vet Med Assoc 1985;187:78-82. 
7. Olefsky JM, Kimmerling G. Effects of glucocorticoids oncarbohydrate metabolism. Am J Med Sci 1976;271:202-210. 
8. Chap Z, Jones RH, Chou J, et al. Effect of dexamethasone onhepatic glucose and insulin metabolism after oral glucose in conscious dogs. J Clin Invest 1986;78:1355-1361. 
9. Moore GE, Hoenig M. Effects of orally administeredprednisone on glucose tolerance and insulin secretion in clinically normal dogs. Am J Vet Res 1993;54:126-129.
10. Tabachnick, II, Gulbenkian A. Mechanism of diazoxide hyperglycemia in animals. Ann N Y Acad Sci 1968;150:204-218. Koch-Weser J. Diazoxide. N Engl J Med 1976;294:1271-1273. 
11. Paulissian R. Diazoxide. Int Anesthesiol Clin 1978;16:201-237. 
12. Meleo K. Management of insulinoma patients with refractory hypoglycemia. Prob Vet Med 1990;2:602-609. 
13. Parker AJ, Musselman EM, O'Brien D. Diazoxide treatment of canine insulinoma. Vet Rec 1981;109:178-179. 
14. Maton PN. The use of the long-acting somatostatin analogue,octreotide acetate, in patients with islet cell tumors. Gastroenterol Clin North Am 1989;18:897-922. 
15. Simpson KW, Stepien RL, Elwood CM, et al. Evaluation of the long-acting somatostatin analogue octreotide in the management of insulinoma in three dogs. J Small Anim Pract 1995;36:161-165. 
16. Meyer DJ. Temporary remission of hypoglycemia in a dog with an insulinoma after treatment with streptozotocin. Am J Vet Res 1977;38:1201-1204. 
17. Moore AS, Nelson RW, Henry CJ, et al. Streptozocin for treatment of pancreatic islet cell tumors in dogs: 17 cases (1989-1999). J Am Vet Med Assoc 2002;221:811-818. 
18. Bell R, Mooney CT, Mansfield CS, et al. Treatment of insulinoma in a springer spaniel with streptozotocin. J Small Anim Pract 2005;46:247-250. 
19. Northrup NC, Rassnick KM, Gieger TL, et al. Prospective evaluation of biweekly streptozotocin in 19 dogs with insulinoma. J Vet Intern Med 2013;27:483-490. 
20. Tobin RL, Nelson RW, Lucroy MD, et al. Outcome of surgical versus medical treatment of dogs with beta cell neoplasia: 39 cases (1990-1997). J Am Vet Med Assoc 1999;215:226-230. 
21. Polton GA, White RN, Brearley MJ, et al. Improved survival in a retrospective cohort of 28 dogs with insulinoma. J Small Anim Pract 2007;48:151-156. 

Surgical Treatment of Insulinomas

Surgery is the initial treatment of choice for the long-term management of animals with insulinoma. Exploratory celiotomy is useful in confirming the diagnosis, staging the patient, and removing all identifiable pancreatic nodules (1-4). When possible, these pancreatic masses should be removed by partial pancreatectomy to ensure a more complete resection.

Preoperative Management
The serum glucose concentration should be stabilized before induction of anesthesia and surgery. While it is not necessary for the serum glucose to be in the normal range, the measured levels should be stable and the patient should be seizure-free for a few days prior to surgery.

Frequent feedings, continuous intravenous infusion of dextrose solution (5% dextrose or higher), or both, are the best ways to control symptomatic hypoglycemia (1-4). In some cases, use of prednisone or prednisolone may be helpful to help increase the low blood glucose concentrations. If these methods are unsuccessful, more aggressive medical management should be considered. In dogs, a constant rate infusion of glucagon can be considered to stabilize refractory patients (5). For more information, see my last post on Emergency management of hypoglycemia.

Identifying the Pancreatic Nodule(s)
Careful palpation of the entire pancreas and visualization of the liver and mesenteric lymph nodes is critical (4,6). Insulinomas are typically firmer than the normal parenchyma and may be small and obscured by the normal pancreatic tissue. Therefore, it can be difficult to localize a pancreatic nodule at time of surgery, especially in dogs (4,6-9).

When a nodule cannot be identified intraoperatively, biopsy specimens should be taken from the pancreas, liver, and mesenteric lymph nodes. In dogs, insulinoma develops within the right and left pancreatic lobes with equal frequency, and occult nodules are most common in the body of the pancreas. In addition, multiple nodules are seen in approximately 15% of dogs.  Thus, random removal of an entire pancreatic lobe offers no advantage and is not recommended (1-4,6).

In contrast to dogs, occult insulinoma appears to be rare in the ferret, making the pancreatic nodules less challenging to find. However, as compared to dogs and cats, multiple pancreatic nodules are more common than solitary nodules in ferrets. Full abdominal exploratory celiotomy is strongly recommended in ferrets, since concurrent nonpancreatic neoplasia (e.g., adrenal tumors) are not uncommon in this species (3,10,11).

Surgical Techniques for Partial Pancreatectomy
Surgical technique is similar in both the dog and cat (4,6,9). During surgery, the pancreas should be handled gently, and the surgeon should pay special attention to preserving the blood supply to the pancreas when performing a partial pancreatectomy. Any identifiable pancreatic nodules should be removed by partial pancreatectomy if possible, as this has been reported to result in longer survival times than simple excision of the tumor (12).

Partial pancreatectomy can be performed by the suture-fracture technique, the dissection-ligation technique, or through the use of an electrothermal bipolar vessel-sealing device (4,6,9,13). The bipolar vessel-sealing device (BVSD) denatures collagen and elastin within vessel walls and thus safely seals tissue and vessels while causing less tissue damage than is seen with the higher temperatures used in traditional cautery (13).

Using the BVSD to perform partial pancreatectomy in dogs decreases the incidence of post-operative pancreatitis when compared to dogs undergoing the suture fractionation technique. The BVSD is likely more effective in sealing pancreatic ducts during partial pancreatectomy and minimizes the leakage of pancreatic juices in to the remaining tissue that could cause local or generalized pancreatitis (13).

Whether or not metastatic lesions are visible, biopsy of the liver and mesenteric lymph nodes is recommended for staging (1-4).

Glucose Monitoring During and After Surgery
It is important to monitor the serum glucose concentration throughout and after surgery. Surgical manipulation of insulinoma can enhance the release of insulin from the tumor(s). Anesthesia will mask the signs of neuroglycopenia; thus, the only way of preventing serious hypoglycemia is to monitor the patient carefully and administer dextrose as needed.

While the surgeon is manipulating the pancreas and any metastatic lesions, the serum glucose concentration should be evaluated every 10-20 minutes. After surgery, the glucose concentration should be monitored every 30-60 minutes for the first 4-6 hours, and then every 2-4 hours until the glucose concentration has stabilized and the appropriate concentration of dextrose solution has been selected (1-4). The patient may have hyperglycemia after surgery, and intravenous fluids without dextrose may be appropriate.

Complications of Pancreatectomy
Potential complications include hyperglycemia, persistent hypoglycemia and pancreatitis (1-4,6,9).

• Hyperglycemia and diabetes mellitus— In some animals, the high concentration of circulating insulin secreted by the tumor suppresses the function of normal beta cells, leading to hyperglycemia once the insulin producing tumor is removed. As function of the beta cells returns, postsurgical hyperglycemia is resolved. If treatment with insulin is required after resection of an insulinoma, the clinician and the owner should be aware that endogenous insulin eventually may be produced either by the normal beta cells or by recurrent tumor cells. The owner should monitor glucose in the urine several times per week, and serum glucose should be checked at least monthly to avoid an iatrogenic hypoglycemic crisis.
• Persistent hypoglycemia—Persistent or recurrent hypoglycemia detected any time postoperatively should prompt consideration of symptomatic medical management or the use of chemotherapy. In patients who have had a significant hypoglycemia-free period after surgery, a second operation may result in several months of normoglycemia unless gross metastatic disease is present. In these cases medical management is indicated. This will be discussed in my next post.
• Pancreatitis— In dogs, the most common postoperative complication is pancreatitis. Documented or suspected pancreatitis has been reported in cats and ferrets as well postoperatively.

Relapse of Insulinoma
Although surgery is the most successful treatment we have for controlling hypoglycemia and prolonging survival, surgery will not be able to cure most animals with insulinoma. Almost all will show relapse of hypoglylcemia as the remaining tumor tissue grows and secretes high levels of insulin (1-4).

When a patient that has previously undergone surgery for insulinoma begins to show signs of hypoglycemia, a second surgery may be attempted or medical management instituted (see last post). If all visible tumor can be resected again, animals may remain symptom free for a number of additional months. Alternatively, many of these animals showing relapse can be controlled medically; I'll be discussing long-term medical management in my next post.

References:

1. Feldman EC, Nelson RW. Beta-cell neoplasia: Insulinoma In: Feldman EC, Nelson RW, eds. Canine and Feline Endocrinology and Reproduction. Philadelphia: Saunders Elsevier, 2004;616-644.
2. Kintzer PP. Insulinoma and other gastrointestinal tract tumours In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;148-155.
3. Meleo KA, Peterson ME. Treatment of insulinoma in the dog, cat, and ferret In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2013.
4. Nelson RW, Salisbury SK. Pancreatic beta cell neoplasia In: Birchard SJ, Sherding RJ, eds. Saunders’ Manual of Small Animal Practice. 2nd ed. Philadelphia: WB Saunders, 2000;288–294.
5. Fischer JR, Smith SA, Harkin KR. Glucagon constant-rate infusion: A novel strategy for the management of hyperinsulinemic-hypoglycemic crisis in the dog. J Am Anim Hosp Assoc 2000;36:27-32. 
6. Birchard SJ. The pancreas In: Williams M, Niles JD, eds. BSAVA Manual of Canine and Feline Abdominal Surgery. Gloucester: BSAVA Publications, 2005;210–219.
7. Mehlhaff CJ, Peterson ME, Patnaik AK, et al. Insulin producing islet cell neoplasms: Surgical considerations and general management in 35 dogs. J Am Anim Hosp Assoc 1985;21:607-612.
8. Leifer CE, Peterson ME, Matus RE. Insulin-secreting tumor: diagnosis and medical and surgical management in 55 dogs. J Am Vet Med Assoc 1986;188:60-64. 
9. Matthiesen DT, Mullen HS. Problems and complications associated with endocrine surgery in the dog and cat. Prob Vet Med 1990;2:627-667.
10. Caplan ER, Peterson ME, Mullen HS, et al. Diagnosis and treatment of insulin-secreting pancreatic islet cell tumors in ferrets: 57 cases (1986-1994). J Am Vet Med Assoc 1996;209:1741-1745. 
11. Chen S. Pancreatic endocrinopathies in ferrets. Vet Clin North Am Exot Anim Pract 2008;11:107-123.
12. Tobin RL, Nelson RW, Lucroy MD, et al. Outcome of surgical versus medical treatment of dogs with beta cell neoplasia: 39 cases (1990-1997). J Am Vet Med Assoc 1999;215:226-230. 
13. Wouters EG, Buishand FO, Kik M, et al. Use of a bipolar vessel-sealing device in resection of canine insulinoma. J Small Anim Pract 2011;52:139-145. 

Emergency Management of Insulinoma and Other Causes of Hypoglycemia

Karo syrup can be used by owners at home to help control hypoglycemia.
Figure from www.gotoaid.com.

Hypoglycemia is a medical emergency that may result in seizures and permanent brain damage (1-5). Mild cases of hypoglycemia can quickly become serious and life threatening if the low blood glucose concentration continues to fall.

Untreated, severe, prolonged hypoglycemia can lead to stupor, coma, and even death in some animals.

Emergency Management of Hypoglycemia

Oral glucose administration
Owners who witness a hypoglycemic seizure can be instructed to rub a sugar solution (e.g., Karo syrup or honey) on their pet’s gums. Most animals will respond rapidly. However, owners should be warned not to place their hands directly into the mouth of an animal that is having a seizure and not to pour a sugar solution into the mouth of an unconscious pet (2,3,6).

If the animal responds to intravenous or oral glucose administration, it then should be fed a small, high-protein meal and kept as quiet as possible. Owners who notice a pet is becoming weak may prevent a hypoglycemic seizure by feeding.

Intravenous glucose administration
All patients with serious neurologic signs referable to hypoglycemia should be treated immediately by intravenous administration of a 50% dextrose solution (1-5 ml is given slowly over 10 minutes).  If the animal responds clinically, continuous intravenous administration of fluids with a 5% dextrose solution should be considered  (2,3,6). Some clinicians prefer to dilute the initial dose in 5% dextrose or sterile water to create a 20-25% solution prior to injection and thereby reduce the osmolality of the infused solution.

Regardless of the glucose concentration chosen to be administered in an emergency, it is important to keep in mind that it is not necessary to completely normalize the serum glucose concentration, but rather, to eliminate the clinical signs related to hypoglycemia.

Intravenous glucagon infusion
When glucose is administered intravenously to a patient with insulinoma, the tumor may be stimulated to release massive amounts of insulin, leading to severe hypoglycemia. This may result in a viscous cycle of the patient receiving larger volumes and more frequent dosing of intravenous dextrose even as clinical signs become more severe (2,3,6,7).

In dogs with insulinoma, intravenous glucagon should be considered if hypoglycemia and associated clinical signs cannot be not stabilized with infusions of dextrose alone. Glucagon stimulates hepatic gluconeogensis and glycogenolysis, thereby raising the circulating glucose concentrations.

One milligram of lyophilized glucagon USP should be reconstituted according to package directions and mixed with 1 liter of 0.9% saline solution. This resulting 1.0 µg/ml solution is given at 5-10 ng/kg/minute (2,6,7). The rate of infusion is adjusted, as needed, to maintain the serum glucose at a concentration of 50-100 mg/dl.

When the dog is able to eat and maintain its own blood sugar, and/or other surgical or medical therapy is used to treat the insulinoma, the glucagon infusion may be slowly tapered over 1-2 days as the serum glucose and clinical signs are monitored (6,7).

Complications of Prolonged Hypoglycemia and Its Treatment

Acquired seizure disorder
Prolonged hypoglycemia can cause focal laminar and pseudolaminar necrosis of the cerebral cortex, which can result in an acquired seizure disorder (2-6). Anticonvulsants may be required long-term for some animals recovering from hypoglycemic seizures.

If seizures persist despite the correction of hypoglycemia, cerebral hypoxia and edema may be responsible. Glucocorticoids, mannitol, or both, should be administered to help treat cerebral edema. Diazepam and phenobarbital may be required to control the seizures. However, we should also consider the possibility that a condition other than hypoglycemia may be the cause of the seizures.

Secondary hypokalemia
Uptake of glucose by cells is accompanied by the transport of potassium from the circulation to the intracellular space. This can result in severe hypokalemia in some cases (2,6). Therefore, the serum potassium concentration should be monitored in patients receiving dextrose infusions and animals supplemented with potassium in most cases (e.g., 16 mEq KCl per liter of intravenous fluids). This is particularly important for animals that are unable or refuse to eat.

References:

1. Elie MS, Zerbe CA. Insulinoma in dogs, cats, and ferrets. Compend Contin Educ Vet 1995;17:51-59.
2. Feldman EC, Nelson RW. Canine and Feline Endocrinology and Reproduction. 3rd ed. St Louis: Elsevier Saunders; 2004;616–644.
3. Kintzer PP. Insulinoma and other gastrointestinal tract tumours In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;148-155.
4. Goutal CM, Brugmann BL, Ryan KA. Insulinoma in dogs: a review. J Am Anim Hosp Assoc  2012;48:151-163. 
5. Kraje AC. Hypoglycemia and irreversible neurologic complications in a cat with insulinoma. J Am Vet Med Assoc 2003;223:812-814.
6. Meleo KA, Peterson ME. Treatment of insulinoma in the dog, cat, and ferret In: Bonagura JD,Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2013 (in press)
7. Fischer JR, Smith SA, Harkin KR. Glucagon constant-rate infusion: a novel strategy for the management of hyperinsulinemic-hypoglycemic crisis in the dog. J Am Anim Hosp Assoc 2000;36:27-32.

Insulinoma in Dogs, Cat, and Ferrets: Confirming the Diagnosis

Insulinoma, or functional beta-cell tumor, originates from the islet cells of the endocrine portion of the pancreas (1,2). Insulinoma has been described most commonly in dogs and ferrets, and less commonly in cats. Although insulinoma cells produce a variety of polypeptides, most animals with insulinoma are examined because of clinical signs related to hyperinsulinism and resultant hypoglycemia.

Signalment
Insulinoma has been reported in dogs ranging from 3-15 years old but is most common in dogs older than 8 years old (3-8). Insulinoma is very common in domestic ferrets, with an age range from 2-7 years (9-11). No sex predilection has been reported in dogs, but male ferrets seem to be affected more commonly than females. Insulinoma appears to be a rare condition in cats, with only five cats having been reported; these cats ranged in age from 12-17 years (12-15).

Clinical Signs
Clinical signs in animals with insulinoma are caused by hyperinsulinism, which leads to hypoglycemia. In response to a low blood glucose concentration, catecholamines, glucagon, cortisol, ACTH, and growth hormone are released.

When there is a drop in blood glucose in clinically normal animals, these hormones (i.e., catecholamines, glucagon, cortisol, and growth hormone), in conjunction with a decrease in circulating insulin, help prevent progressive and potentially dangerously low blood glucose concentration. In animals with insulinoma, insulin is secreted even in the face of hypoglycemia and the increase in the counterregulatory hormones listed above. In these patients, the blood glucose is not stabilized, but continues to fall.

Dogs with insulinoma may be examined because of clinical signs related to neuroglycopenic symptoms produced by glucose deprivation of the central nervous system (e.g., hypoglycemia). Less commonly, some animals show adrenergic symptoms caused by catecholamines such as epinephrine (e.g., nervousness, tachycardia) (1,2,16).

The most common complaint for dogs with insulinoma is seizures (1-8). Other signs include collapse, lethargy, weakness, ataxia, mental dullness, muscle fasciculation, trembling, and nervousness (Table 1). Similar signs have been reported in cats with insulinoma (1,12-15). Peripheral neuropathy in association with insulinoma and hypoglycemia has been rarely reported in dogs with insulinoma (17,18).

Table 1: Clinical signs associated with insulinoma in dogs, cats, or ferrets (from reference 2).

Ferrets with insulinoma also commonly show signs of weakness and lethargy (9-11). As in dogs, these symptoms may be episodic. However, seizures are relatively uncommon in this species. Ptyalism is a clinical sign associated with insulinoma in ferrets that has not been described in dogs. The cause of this sign is not known, but ptyalism in ferrets may indicate nausea.

Confirming the Diagnosis— Fulfilling Whipple's Triad
A complete history may lead the clinician to suspect that a patient’s presenting clinical signs are related to hypoglycemia, and thus consider insulinoma as a differential diagnosis. A plasma glucose concentration of 40 mg/dl (2 mmol/L) or less supports the conclusion that the signs are caused by hypoglycemia (16).

If administration of glucose relieves the clinical signs of weakness, disorientation, seizures or trembling, we can conclude that these symptoms are caused by hypoglycemia. This full fills Whipple's triad (i.e, signs of hypoglycemia, biochemical confirmation of low blood glucose at time of clinical signs, and relief of clinical signs after glucose administration) (19,20). This positive response may be seen in animals with hypoglycemia for any reason, however, and is not diagnostic of insulinoma.

Other Causes of Hypoglycemia
In addition to insulinoma, there are many other possible causes of hypoglycemia in animals (1,2,16,21) (Table 2).

Table 2: Causes of hypoglycemia in the mature animal

Many of these differential diagnoses can be ruled out quickly during the initial history and physical examination. After consideration of these diseases is eliminated, insulinoma should be seriously considered in a mature patient with clinical signs of hypoglycemia.

Confirming the Diagnosis—Documenting Hyperinsulinemia
Hyperinsulinism is best diagnosed by the interpretation of serum insulin and glucose concentrations obtained from the patient at the same time. If the clinician suspects hyperinsulinism at the time of initial examination of an animal showing signs of hypoglycemia, serum samples for glucose and insulin measurements are best obtained at that time.

If attempts are made to document hyperinsulinism at a later date, blood samples should be obtained after fasting when the glucose is less than 50 mg/dl (<3.0 mmol/L). It is essential that patients suspected of having hyperinsulinism fast under supervision to allow intervention should signs of hypoglycemia occur.

A high insulin concentration in any animal with concurrent hypoglycemia is consistent with hyperinsulinism (1,2,16,22). If a hypoglycemic patient has an insulin concentration that is within the reference range, the animal again should fast, and the test should be repeated when two consecutive serum glucose readings of 50 mg/dl or less are obtained. If the patient is consistently hypoglycemic, an insulin level within the normal range is considered inappropriate and the patient likely has hyperinsulinism.

Identifying the Pancreatic Nodule
Whenever possible, abdominal ultrasound should be performed in dogs and cats with suspected insulinoma. It can be difficult to detect small pancreatic nodules via ultrasound, but it may be helpful in identifying abdominal metastases (2,22,23). In all species, abdominal ultrasonography may help rule out other neoplasms as a cause of hypoglycemia.

Computed tomography (CT) can also be used to accurately identify pancreatic nodules, and this procedure may be helpful in surgical planning (23).

Bottom Line

Although an accurate diagnosis of insulinoma can generally be made by clinical pathologic testing, histologic examination is required for a definitive diagnosis. Exploratory celiotomy is recommended in all patients with insulinoma if the owner wishes to pursue treatment, but long-term medical management can be helpful in many of these animals.

In my next post, I'll be discussing emergency management of hypoglycemia associated with insulinoma.  This is a critical issue—  if we can't control the immediate clinical signs of hypoglycemia, we will never be able to proceed to definitive or long-term treatment of this serious disorder.

References:

1. Elie MS, Zerbe CA. Insulinoma in dogs, cats, and ferrets. Compend Contin Educ Vet 1995;17:51-59.
2. Kintzer PP. Insulinoma and other gastrointestinal tract tumours In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;148-155.
3. Kruth SA, Feldman EC, Kennedy PC. Insulin-secreting islet cell tumors: establishing a diagnosis and the clinical course for 25 dogs. J Am Vet Med Assoc 1982;181:54-58. 
4. Leifer CE, Peterson ME, Matus RE. Insulin-secreting tumor: diagnosis and medical and surgical management in 55 dogs. J Am Vet Med Assoc 1986;188:60-64. 
5. Schrauwen E. Clinical peripheral polyneuropathy associated with canine insulinoma. Vet Rec 1991;128:211-212.
6. Trifonidou MA, Kirpensteijn J, Robben JH. A retrospective evaluation of 51 dogs with insulinoma. Vet Q 1998;20 Suppl 1:S114-115. 
7. Madarame H, Kayanuma H, Shida T, et al. Retrospective study of canine insulinomas: eight cases (2005-2008). J Vet Med Sci 2009;71:905-911. 
8. Goutal CM, Brugmann BL, Ryan KA. Insulinoma in dogs: a review. J Am Anim Hosp Assoc  2012;48:151-163. 
9. Caplan ER, Peterson ME, Mullen HS, et al. Diagnosis and treatment of insulin-secreting pancreatic islet cell tumors in ferrets: 57 cases (1986-1994). J Am Vet Med Assoc 1996;209:1741-1745.
10. Ehrhart N, Withrow SJ, Ehrhart EJ, et al. Pancreatic beta cell tumor in ferrets: 20 cases (1986-1994). J Am Vet Med Assoc 1996;209:1737-1740.
11. Weiss CA, Williams BH, Scott MV. Insulinoma in the ferret: clinical findings and treatment comparison of 66 cases.  J Am Anim Hosp Assoc 1998;34:471-475.
12. McMillan FD, Feldman EC. Functional pancreatic islet cell tumor in a cat. J Am Anim Hosp Assoc 1985;21:741-746.
13. Hawks D, Peterson ME, Hawkins KL, et al. Insulin-secreting pancreatic (islet cell) carcinoma in a cat. J Vet Intern Med 1992;6:193-196.
14. Kraje AC. Hypoglycemia and irreversible neurologic complications in a cat with insulinoma. J Am Vet Med Assoc 2003;223:812-814.
15. Greene SN, Bright RM. Insulinoma in a cat. J Small Anim Pract 2008;49:38-40. 
16. Schoeman JP. Investigation of hypoglycaemia In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;259-264.
17. Schrauwen E, Van Ham L, Desmidt M, et al. Peripheral polyneuropathy associated with insulinoma in the dog: Clinical, pathological, and electrodiagnostic features. Prog Vet Neurol 1996;7:16-19.
18. Braund KG, Steiss JE, Amling KA, et al. Insulinoma and subclinical peripheral neuropathy in two dogs. J Vet Intern Med 1987;1:86-90. 
19. Ariamkina OL, Doroshenko GM, Petrenko LV. On diagnostic value of Whipple's triad: a case of insulinoma diagnosis. Klin Med (Mosk) 1997;75:61-63. 
20. Hirshberg B, Livi A, Bartlett DL, et al. Forty-eight-hour fast: the diagnostic test for insulinoma. J Clin Endo Metab 2000;85:3222-3226. 
21. Murphy LA, Coleman AE. Xylitol toxicosis in dogs. Vet Clin North Am Small Anim Pract 2012;42:307-312. 
22. Goutal CM, Brugmann BL, Ryan KA. Insulinoma in dogs: a review. J Am Anim Hosp Assoc 2012;48:151-163. 
23. Robben JH, Pollak YW, Kirpensteijn J, et al. Comparison of ultrasonography, computed tomography, and single-photon emission computed tomography for the detection and localization of canine insulinoma. J Vet Intern Med 2005;19:15-22.