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. 

What's the Best Way to Confirm Ovarian Remnant Syndrome in Cats?

In the queen, the most common cause of behavioral and physical signs of estrus after ovariohysterectomy is remnant ovarian tissue that has regained folliculogenesis and production of estrogens (1). 

In most cats, the "ovarian remnant syndrome" certainly is caused by failure to completely remove both ovaries at ovariohysterectomy. It is possible to have a small piece of ovarian tissue inadvertently drop back into the abdominal cavity during the spaying procedure and subsequently revascularize, resulting in signs of estrus (2). However, this syndrome can be also associated with the presence of accessory ovarian tissue that can be extremely difficult to detect at the time of routine ovariohysterectomy.

Whether entrapped in a ligature or accidentally dropped into the peritoneal cavity, revascularization of remnants by the omental blood supply can occur (2). The ovarian tissue can remain hormonally functional and even ovulate.  Although this condition is generally called the ovarian remnant syndrome, there is much contention among veterinary surgeons that it is not a syndrome but a surgical error

Diagnosis of ovarian remnant syndrome can sometimes be challenging but is based on a combination of history and clinical signs, vaginal cytology, and hormonal testing (1,3-6).

Vaginal cytology

The first step in the workup of a cat in which ovarian remnant or ectopic ovarian tissue is suspected is to perform vaginal cytology during the time your cat is showing signs of estrus. The only thing that causes a cat's vaginal smear to contain a high number of cornified vaginal epithelial cells is the presence of estrogen. This finding on vaginal cytology is a great bioassay for the presence of high levels of estrogen in the circulation (6).

In general, the use of vaginal cytology as a bioassay for feline estrogen is more accurate than a single serum sample. Vaginal cytological changes in queens in estrus tends to be more subtle than those of dogs but usually include an increase in cornified vaginal epithelial cells and clearing of normal background mucous (6).

Serum estradiol concentrations

Why not simple measure serum estradiol, the main estrogen in the cat? In queens during estrus, estradiol levels rise sharply to more than 20 pg/ml before returning rapidly to basal concentrations in as few as 48 hours. Thus blood sampling for estradiol is generally not helpful because the timing of the sample may not coincide directly with the period of peak estrus activity.

Therefore, the finding of high serum estradiol concentrations (>20 pg/ml) in a cat showing sign of estrus is consistent with ovarian remnant syndrome, the diagnosis can never be excluded if lower levels of estradiol are measured (1).

Serum luteinizing hormone (LH) concentrations

The hormonal serum test that is most useful in this situation is a basal luteinizing hormone (LH) determination (7). For this LH testing, we generally use a commercially available LH assay from Synbiotics. Although originally designed as a canine ovulation timing aid, this LH test may be used to distinguish between ovariohysterectomized and sexually-intact queens (or bitches). One advantage of using the serum LH test over vaginal cytology is it can be run at any time, not just when the cat is showing signs of estrus. If you do LH test, the manufacturer recommends two tests at least 24 hours apart to rule out the LH surge.

In the intact queen, LH is maintained at basal concentrations through the negative feedback influence of ovarian estradiol secretion on the pituitary gonadotropins. Following ovariectomy, this control is lost and LH concentrations increase resulting in a positive test.

Therefore, if a high serum LH concentration is found, then it is unlikely that the cat has any ovarian tissue. On the other hand, if the serum LH is low (less than 1 ng/ml), that indicates there is estrogen present in the circulation suppressing pituitary LH secretion (7). The source of this circulating estrogen could be from either endogenous or exogenous sources. If it's of endogenous origin, that means that the cat does indeed have an ovarian remnant or ectopic ovarian tissue.

The only problem with the use of serum LH determination is that some cats ultimately found to have an ovarian remnant will have falsely high LH values. The reason for this discrepancy in the expected pituitary-ovarian feedback loop is unknown, but it is clear that the finding of a high LH value alone can never rule out an ovarian remnant with 100% certainty. So it's still best to use vaginal cytology in conjunction with the serum LH measurements.

Provocative testing with hCG or GnRH analogues

The most efficient diagnostic aid for ovarian remnant syndrome is a hormone challenge testing (1,3-5). The goal of these stimulation tests is to cause ovulation of a follicle by exogenous LH-like compounds, thus confirming the presence of functional ovarian tissue. 

For these protocols, it is important that the queen be in true estrus. The procedure for testing is as follows:

1. Collect blood needed to measure the basal concentration of serum progesterone (and estradiol if desired).
2. Inject the cat with human chorionic gonadotropin (hCG), 44 IU/kg BW or 250-500 IU total dose, IM.
3. Alternatively, inject the cat with gonadotropin-releasing hormone (GnRH), 2 μg/kg BW or 25 μg total dose, IM.
4. Collect a post-stimulation blood sample for serum progesterone 1-3 weeks later.

Documenting a high serum progesterone level (>2 ng/ml) after hGC or GnRH stimulations confirms a diagnosis of ovarian remnant syndrome (1).

GnRH stimulation testing for cats not currently in estrus

Finally, a recent study demonstrated that measurement of plasma estradiol 2 hours after stimulation with a gonadotropin-releasing hormone (GnRH)-analogue appeared to be a reliable method to diagnose the presence of ovarian tissue in the female cat not currently showing signs of estrus (8).  With this protocol, a serum estradiol concentration greater than 3 pg/ml is consistent with the presence of ovarian tissue.

References:

1. Little SE. Female reproduction. In: Little SE (ed). The Cat: Clinical Medicine and Management. Saunders Elseiver 2012; 1195-1227.
2. DeNardo GA, Becker K, Brown NO, et al. Ovarian remnant syndrome: revascularization of free-floating ovarian tissue in the feline abdominal cavity. Journal of the American Animal Hospital Association 2001;37:290-296.
3. Wallace MS. The ovarian remnant syndrome in the bitch and queen The Veterinary Clinics of North: America Small Animal Practice 1991;21:501-507. 
4. Miller DM. Ovarian remnant syndrome in dogs and cats: 46 cases (1988-1992). Journal of Veterinary Diagnostic Investigation 1995;7:572-574.
5. Ball RL, Birchard SJ, May LR, et al. Ovarian remnant syndrome in dogs and cats: 21 cases (2000-2007). Journal of the American Veterinary Medical Association 2010;236:548-553
6. Mills JN, Valli VE, Lumsden HH. Cyclical changes of vaginal cytology in the cat. Canadian Veterinary Journal 1979;20:95–101.  
7. Scebra LR, Griffin B. Evaluation of a commercially available luteinizing hormone test to distinguish between ovariectomized and sexually intact queens. Proc Am Coll Vet Intern Med Forum 2003. 
8. Axner E, Gustavsson T, Strom Holst B. Estradiol measurement after GnRH-stimulation as a method to diagnose the presence of ovaries in the female domestic cat. Theriogenology 2008;70:186-191.

Low-Dose ACTH Stimulation Testing in Cats

Cortisol and Aldosterone Response to Various Doses of Cosyntropin in Healthy Cats

Amy E. DeClue, Linda G. Martin, Ellen N. Behrend, Leah A. Cohn, David I. Dismukes, and Hollie P. Lee

Journal of the American Veterinary Medical Association 2011;238:176-182. 

Adrenocorticotropic hormone (ACTH) stimulation testing is commonly used to evaluate adrenocortical function in both dogs and cats (1-3). In cats, ACTH stimulation testing has been used primarily to test adrenocortical production of cortisol (4-6), but has also been used to evaluate the adrenal sex steroid (progestins and androgens) response (7-10).

Although the primary regulators of aldosterone secretion are the renin-angiotensin system and extracellular potassium concentration (11,12), ACTH acts as an additional stimulant (13). In accord with that fact, administration of exogenous ACTH to cats has been reported to cause a reliable increase in aldosterone secretion. Therefore, ACTH stimulation testing can also be used for evaluation of adrenal mineralocorticoid function (14).

Traditionally, a standard dose of cosyntropin (125 μg/cat, IV) has been recommended for ACTH stimulation testing (5). A previous study (15) documented that lower doses of cosyntropin will stimulate maximal cortisol secretion in cats. However, that study used per-cat dosing as opposed to per-body-weight dosing and did not evaluate the serum aldosterone response to ACTH stimulation.

The purpose of the study reported here by DeClue et al (16) were to determine the lowest dose of cosyntropin (Cortrosyn) on a per-body-weight basis that would produce maximal cortisol and aldosterone secretion in cats.  A secondary purpose was to determine the ideal timing of blood sample collection for cortisol and aldosterone concentrations after ACTH injection in these healthy cats.

Objective—To determine the lowest dose of cosyntropin on a per body weight basis that would produce maximal cortisol and aldosterone secretion and the ideal timing of blood sample collection after ACTH stimulation in healthy cats.

Design—Randomized crossover trial.

Animals—7 adult sexually intact male purpose-bred cats.

Procedures—Each cat received saline (0.9% NaCl) solution (control) and 5 doses (125 μg/cat and 10, 5, 2.5, and 1 μg/kg) of cosyntropin IV with a 2-week washout period between treatments. Blood samples were obtained before (baseline) and at 15, 30, 45, 60, 75, and 90 minutes after administration of saline solution or cosyntropin.

Results—Serum cortisol and aldosterone concentration increased significantly, compared with baseline values, after administration of all cosyntropin doses. Lower doses of cosyntropin resulted in an adrenocortical response equivalent to the traditional dose of 125 μg/ cat.

The lowest doses of cosyntropin that stimulated a maximal cortisol and aldosterone response were 5 and 2.5 μg/kg, respectively. Lower doses of cosyntropin resulted in a shorter interval between IV administration of cosyntropin and peak serum cortisol and aldosterone concentrations.

Conclusions and Clinical Relevance—Low-dose ACTH stimulation testing with IV administration of cosyntropin at 5 μg/kg followed by blood sample collection at 60 to 75 minutes resulted in concurrent peak serum cortisol and aldosterone concentrations that were equivalent to those achieved following administration of cosyntropin at 125 μg/cat, the standard dose currently used.

My Bottom Line:

This study confirms our earlier work that low doses of ACTH (e.g., 5 μg/kg body weight of cosyntropin) will maximally stimulate cortisol secretion in cats (15). In the cats of this study, as in our previous study, lower doses of cosyntropin resulted in an adrenocortical response that was equivalent to the traditional dose of 125 μg/cat (15, 16). The efficacy of of this low-dose ACTH stimulation testing protocol is also well documented in dogs (17-19), and has become a widely used testing dosage in clinical practice for evaluation of both hyper- and hypoadrenocorticism.

Based on the results of these cat studies, the following test protocol can be recommended:

1. Collect blood sample for basal cortisol (± aldosterone or sex steroids).
2. Calculate the cosyntropin (Cortrosyn) dosage (5 μg/kg of cat's body weight). To draw up this amount, it's best to reconstitute and dilute the Cortrosyn powder and store the remaining ACTH product (20).
3. Administer the cosyntropin dose to the cat by the IV route.
4. Collect a post-ACTH blood sample at 60-75 minutes after cosyntropin injection.

It is extremely important to point out that cosyntropin must be administered by the IV route in cats, especially when this low-dose protocol is used for ACTH stimulation testing. When given intramuscularly (IM) to cats, cosyntropin is not well absorbed and will not produce a maximal adrenocortical response (21). In cats, ACTH given by the IV route induces a greater and more prolonged adrenocortical stimu­lation than intramuscular administration.

This difference in the cortisol response between IV and IM administration is in contrast to the situation in dogs, in which IV or IM low-dose ACTH stimulation protocols produce similar adrenocortical responses (22). This difference between cats and dogs should not surprise us— we all know that cats are not just small dogs, especially when it comes down to endocrinology!

References:

1. Behrend EN, Kemppainen RJ. Diagnosis of canine hyperadrenocorticism. Vet Clin North Am Small Anim Pract 2001;31:985-1003.
2. Church DB. Canine hypoadrenocorticism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;156-166.
3. Herrtage ME, Ramsey IK. Canine hyperadrenocorticism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;167-189.
4. Peterson ME, Greco DS, Orth DN. Primary hypoadrenocorticism in ten cats. J Vet Intern Med 1989;3:55-58. 
5. Duesberg C, Peterson ME. Adrenal disorders in cats. Vet Clin North Am Small Anim Pract 1997;27:321-347. 
6. Peterson ME. Feline hyperadrenocorticism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;199-203.
7. DeClue AE, Breshears LA, Pardo ID, et al. Hyperaldosteronism and hyperprogesteronism in a cat with an adrenal cortical carcinoma. J Vet Intern Med 2005;19:355-358. 
8. Briscoe K, Barrs VR, Foster DF, et al. Hyperaldosteronism and hyperprogesteronism in a cat. J Feline Med Surg 2009;11:758-762. 
9. Quante S, Sieber-Ruckstuhl N, Wilhelm S, et al. Hyperprogesteronism due to bilateral adrenal carcinomas in a cat with diabetes mellitus. Schweiz Arch Tierheilkd 2009;151:437-442. 
10. Meler EN, Scott-Moncrieff JC, Peter AT, et al. Cyclic estrous-like behavior in a spayed cat associated with excessive sex-hormone production by an adrenocortical carcinoma. J Feline Med Surg 2011;13:473-478. 
11. Gogerly RL, Coghlan JP, Morgenroth P, et al. A compartmental model of acute stimulation of aldosterone secretion in vivo by potassium and ANG II. Am J Physiol 1993;265:E190-196. 
12. Pratt JH. Role of angiotensin II in potassium-mediated stimulation of aldosterone secretion in the dog. J Clin Invest 1982;70:667-672. 
13. Crabbe J, Reddy WJ, Ross EJ, et al. The stimulation of aldosterone secretion by adrenocorticotropic hormone (ACTH). J Clin Endocrinol Metab 1959;19:1185-1191. 
14. Zimmer C, Horauf A, Reusch C. Ultrasonographic examination of the adrenal gland and evaluation of the hypophyseal-adrenal axis in 20 cats. J Small Anim Pract 2000;41:156-160. 
15. Peterson ME, Kemppainen RJ. Dose-response relation between plasma concentrations of corticotropin and cortisol after administration of incremental doses of cosyntropin for corticotropin stimulation testing in cats. Am J Vet Res 1993;54:300-304. 
16. DeClue AE, Martin LG, Behrend EN, et al. Cortisol and aldosterone response to various doses of cosyntropin in healthy cats. J Am Vet Med Assoc 2011;238:176-182. 
17. Frank LA, Oliver JW. Comparison of serum cortisol concentrations in clinically normal dogs after administration of freshly reconstituted versus reconstituted and stored frozen cosyntropin. J Am Vet Med Assoc 1998;212:1569-1571. 
18. Kerl ME, Peterson ME, Wallace MS, et al. Evaluation of a low-dose synthetic adrenocorticotropic hormone stimulation test in clinically normal dogs and dogs with naturally developing hyperadrenocorticism. J Am Vet Med Assoc 1999;214:1497-1501. 
19. Lathan P, Moore GE, Zambon S, et al. Use of a low-dose ACTH stimulation test for diagnosis of hypoadrenocorticism in dogs. J Vet Intern Med 2008;22:1070-1073. 
20. Peterson ME. How to extend your supply of cortrosyn and lower the cost of ACTH stimulation testing. Insights into Veterinary Endocrinology, Blog post, March 22, 2011.
21. Peterson ME, Kemppainen RJ. Comparison of intravenous and intramuscular routes of administering cosyntropin for corticotropin stimulation testing in cats. Am J Vet Res 1992;53:1392-1395. 
22. Behrend EN, Kemppainen RJ, Bruyette DS, et al. Intramuscular administration of a low dose of ACTH for ACTH stimulation testing in dogs. J Am Vet Med Assoc 2006;229:528-530. 

Top Endocrine Publications of 2010: The Canine and Feline Reproductive Endocrinology

 Fertility axis. GnRH, LH & FSH
stimulate secretion of testosterone,
progesterone, estrogen, & inhibin.
Controlled via negative feedback
on hypothalamus & pituitary gland.

In my 9th compilation of the canine and feline endocrine publications of 2010, I’m moving on to endocrine disorders of the canine gonads and mammary gland.

Listed below are 9 research papers written in 2010 that deal with a variety of issues of clinical importance in reproductive endocrinology in dogs.

These range from the investigations of the pituitary-ovarian axis in dogs with a functional granulosa cell tumor (1) to studies of the expression of estrogen and progesterone receptors in sebaceous gland tumors (2); and from studies of gonadotropin-releasing hormone (GnRH)-agonist implants in the treatment of reproductive disorders in the male dog (3) to a review of non-surgical methods for reproductive control in cats (4).

Finally, a number of studies investigate markers of malignancy for mammary gland tumors (6,7,8). Finally, the last paper reviews alternative ways to treat benign prostatic hyperplasia, including hormonal suppression of testicular function with GnRH-depot-analogues, inhibition of the 5-alpha-reductase, or peripheral androgen action with anti-androgens (9).

References:

1. Buijtels JJ, de Gier J, Kooistra HS, et al. Alterations of the pituitary-ovarian axis in dogs with a functional granulosa cell tumor. Theriogenology 2010;73:11-19.
2. Ginel PJ, Lucena R, Millan Y, et al. Expression of oestrogen and progesterone receptors in canine sebaceous gland tumours. Veterinary Dermatology 2010;21:297-302.
3. Goericke-Pesch S, Wilhelm E, Ludwig C, et al. Evaluation of the clinical efficacy of Gonazon implants in the treatment of reproductive pathologies, behavioral problems, and suppression of reproductive function in the male dog. Theriogenology 2010;73:920-926.
4. Goericke-Pesch S. Reproduction control in cats: new developments in non-surgical methods. J Feline Med Surg. 2010 12:539-46
5. Groppetti D, Pecile A, Arrighi S, et al. Endometrial cytology and computerized morphometric analysis of epithelial nuclei: a useful tool for reproductive diagnosis in the bitch. Theriogenology 2010;73:927-941.
6. Klopfleisch R, Klose P, Gruber AD. The combined expression pattern of BMP2, LTBP4, and DERL1 discriminates malignant from benign canine mammary tumors. Veterinary Pathology 2010;47:446-454.
7. Millanta F, Caneschi V, Ressel L, et al. Expression of vascular endothelial growth factor in canine inflammatory and non-inflammatory mammary carcinoma. Journal of Comparative Pathology 2010;142:36-42.
8. Queiroga FL, Perez-Alenza D, Silvan G, et al. Serum and intratumoural GH and IGF-I concentrations: prognostic factors in the outcome of canine mammary cancer. Research in Veterinary Science 2010;89:396-403.
9. Renggli M, Padrutt I, Michel E, et al. Benign prostatic hyperplasia: treatment options in the dog. Schweizer Archiv fur Tierheilkunde 2010;152:279-284.