Top Endocrine Publications of 2014: Canine and Feline Reproductive Endocrinology

As I've done for the last 5 years, I’ve now finished compiling a fairly extensive list of references concerning canine and feline endocrinology that were written last year (in 2014). I’ll be sharing these with you over the next few months, as well as reviewing a few of the best papers from my lists of clinical endocrine publications.

In my last post, I provided my last list for the 2013 papers on canine and feline endocrine reproduction, so I've decided to start this year off with papers that deal with the same theme of endocrine disorders of the canine and feline gonads, prostate, and mammary gland.

Listed below are 23 papers published in 2014 that deal with a variety of topics of importance for reproductive endocrinology in dogs and cats. These range from the identification and study of kisspeptin (a protein ligand that activate GnRH neurons) in dogs (1) to the use of relaxin measurements to diagnose pregnancy status (2); as well as from a study of the effects of GnRH agonist and antagonists during the postnatal period in cats (3) to the effects of GnRH immunization for treatment of urinary incontinence in spayed bitches (4).

Other publication included studies dealing with suppression of fertility in dogs and cats (4-6,12,13,14,21) to endocrinologic investigations of pyometra (9), ovarian cysts (10), mammary neoplasia (16,19), and benign prostatic hyperplasia and prostatitis (17); and finally, from a study of oxytocin and social bonding in dogs (20) to a review of the influence of sex hormones on seizures in dogs and man (22).

References:

1. Albers-Wolthers KH, de Gier J, Kooistra HS, et al. Identification of a novel kisspeptin with high gonadotrophin stimulatory activity in the dog. Neuroendocrinology 2014;99:178-189.
2. Bergfelt DR, Peter AT, Beg MA. Relaxin: a hormonal aid to diagnose pregnancy status in wild mammalian species. Theriogenology 2014;82:1187-1198.
3. Carranza A, Faya M, Merlo ML, et al. Effect of GnRH analogs in postnatal domestic cats. Theriogenology 2014;82:138-143.
4. Donovan CE, Gordon JM, Kutzler MA. Gonadotropin-releasing hormone immunization for the treatment of urethral sphincter mechanism incompetence in ovariectomized bitches. Theriogenology 2014;81:196-202.
5. Fagundes AK, Oliveira EC, Tenorio BM, et al. Injection of a chemical castration agent, zinc gluconate, into the testes of cats results in the impairment of spermatogenesis: a potentially irreversible contraceptive approach for this species? Theriogenology 2014;81:230-236.
6. Favre RN, Bonaura MC, Praderio R, et al. Effect of melatonin implants on spermatogenesis in the domestic cat (Felis silvestris catus). Theriogenology 2014;82:851-856.
7. Goericke-Pesch S, Wehrend A, Georgiev P. Suppression of fertility in adult cats. Reprod Domest Anim 2014;49 Suppl 2:33-40.
8. Hoglund OV, Hagman R, Olsson K, et al. Intraoperative changes in blood pressure, heart rate, plasma vasopressin, and urinary noradrenalin during elective ovariohysterectomy in dogs: repeatability at removal of the 1st and 2nd ovary. Veterinary Surgery 2014;43:852-859.
9. Jitpean S, Holst BS, Hoglund OV, et al. Serum insulin-like growth factor-I, iron, C-reactive protein, and serum amyloid A for prediction of outcome in dogs with pyometra. Theriogenology 2014;82:43-48.
10. Knauf Y, Bostedt H, Failing K, et al. Gross pathology and endocrinology of ovarian cysts in bitches. Reprod Domest Anim 2014;49:463-468.
11. Kobayashi M, Hori T, Kawakami E. Efficacy of low-dose human chorionic gonadotropin therapy in dogs with spermatogenic dysfunction: a preliminary study. Reprod Domest Anim 2014;49:E44-47.
12. Lucas X. Clinical use of deslorelin (GnRH agonist) in companion animals: a review. Reprod Domest Anim 2014;49 Suppl 4:64-71.
13. Maenhoudt C, Santos NR, Fontbonne A. Suppression of fertility in adult dogs. Reprod Domest Anim 2014;49 Suppl 2:58-63.
14. Marino G, Rizzo S, Quartuccio M, et al. Deslorelin implants in pre-pubertal female dogs: short- and long-term effects on the genital tract. Reprod Domest Anim 2014;49:297-301.
15. Meloni T, Comin A, Rota A, et al. IGF-I and NEFA concentrations in fetal fluids of term pregnancy dogs. Theriogenology 2014;81:1307-1311.
16. Michel E, Rohrer Bley C, Kowalewski MP, et al. Prolactin--to be reconsidered in canine mammary tumourigenesis? Vet Comp Oncol 2014;12:93-105.
17. 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.
18. Parker K, Snead E. Atypical presentation of ovarian remnant syndrome in a dog. J Am Anim Hosp Assoc 2014;50:e1-5.
19. Queiroga FL, Perez-Alenza MD, Gonzalez Gil A, et al. Clinical and prognostic implications of serum and tissue prolactin levels in canine mammary tumours. Vet Rec 2014;175:403.
20. Romero T, Nagasawa M, Mogi K, et al. Oxytocin promotes social bonding in dogs. Proc Natl Acad Sci U S A 2014;111:9085-9090.
21. Schafer-Somi S, Kaya D, Gultiken N, et al. Suppression of fertility in pre-pubertal dogs and cats. Reprod Domest Anim 2014;49 Suppl 2:21-27.
22. Van Meervenne SA, Volk HA, Matiasek K, et al. The influence of sex hormones on seizures in dogs and humans. Vet J 2014;201:15-20.
23. Volta A, Manfredi S, Vignoli M, et al. Use of contrast-enhanced ultrasonography in chronic pathologic canine testes. Reprod Domest Anim 2014;49:202-209.

Top Endocrine Publications of 2013: Canine and Feline Reproductive Endocrinology

In my tenth compilation of the canine and feline endocrine publications, I’m moving on to endocrine disorders of the canine and feline gonads and mammary gland. Listed below are 20 papers published in 2013 that deal with a variety of topics of importance for reproductive endocrinology in dogs and cats.

Of all of these publications, one of the most common and clinically useful topics involves the use of gonadotropin-releasing hormone (GnRH) agonists for management of a variety of disorders. These include the use of GnRH agonist for treatment of queens in estrus and after estrus (3), for reproductive control in queens (4) and tom cats (5), and in dogs affected by benign prostatic hyperplasia (12).

On my next blog post, I will review the mechanism of action for the GnRH agonists, along with their many potential uses and dosage forms.

References:

1. Adams GP, Ratto MH. Ovulation-inducing factor in seminal plasma: a review. Anim Reprod Sci 2013;136:148-156. 
2. Faya M, Carranza A, Miotti R, et al. Fecal estradiol-17beta and testosterone in prepubertal domestic cats. Theriogenology 2013;80:584-586. 
3. 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. 
4. Goericke-Pesch S, Georgiev P, Atanasov A, et al. Treatment with Suprelorin in a pregnant cat. J Feline Med Surg 2013;15:357-360. 
5. 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. 
6. Greenberg M, Lawler D, Zawistowski S, et al. Low-dose megestrol acetate revisited: a viable adjunct to surgical sterilization in free roaming cats? Vet J 2013;196:304-308. 
7. Leroy C, Conchou F, Layssol-Lamour C, et al. Normal canine prostate gland: repeatability, reproducibility, observer-dependent variability of ultrasonographic measurements of the prostate in healthy intact beagles. Anat Histol Embryol 2013;42:355-361. 
8. Luu VV, Hanatate K, Tanihara F, et al. The effect of relaxin supplementation of in vitro maturation medium on the development of cat oocytes obtained from ovaries stored at 4 degrees C. Reprod Biol 2013;13:122-126. 
9. Marino G, Zanghi A. Activins and inhibins: expression and role in normal and pathological canine reproductive organs: a review. Anat Histol Embryol 2013;42:1-8. 
10. Mattoso CR, Takahira RK, Beier SL, et al. Evaluation of von Willebrand factor during pregnancy, lactation and oestrous cycle in bitches affected and unaffected by von Willebrand disease. Reprod Domest Anim 2013;48:416-422. 
11. Nishida CR, Everett S, Ortiz de Montellano PR. Specificity determinants of CYP1B1 estradiol hydroxylation. Mol Pharmacol 2013;84:451-458. 
12. 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. 
13. Poppl AG, Mottin TS, Gonzalez FH. Diabetes mellitus remission after resolution of inflammatory and progesterone-related conditions in bitches. Res Vet Sci 2013;94:471-473. 
14. Rota A, Tursi M, Zabarino S, et al. Monophasic teratoma of the ovarian remnant in a bitch. Reprod Domest Anim 2013;48:e26-e28. 
15. Serafim MK, Silva GM, Duarte AB, et al. High insulin concentrations promote the in vitro growth and viability of canine preantral follicles. Reprod Fertil Dev 2013;25:927-934. 
16. Sozmen M, Kabak YB, Gulbahar MY, et al. Immunohistochemical characterization of peroxisome proliferator-activated receptors in canine normal testis and testicular tumours. J Comp Pathol 2013;149:10-18. 
17. Spankowsky S, Heuwieser W, Arlt SP. Does oral administration of the amino acid tyrosine affect oestradiol-17beta concentration and sexual behaviour in the bitch? Vet Rec 2013;172:212. 
18. Trisolini C, Albrizio M, Roscino MT, et al. Leptin and queen ovary: new insights about ovulation. Res Vet Sci 2013;94:707-710. 
19. Tvarijonaviciute A, Carrillo-Sanchez JD, Ceron JJ. Effect of estradiol and progesterone on metabolic biomarkers in healthy bitches. Reprod Domest Anim 2013;48:520-524. 
20. Wongbandue G, Jewgenow K, Chatdarong K. Effects of thyroxin (T4) and activin A on in vitro growth of preantral follicles in domestic cats. Theriogenology 2013;79:824-832. 

Atypical Hypoadrenocorticism In A Cat

My patient is an 8-year old, female DSH cat that has been on oral megestrol acetate (Ovaban) for the last 6 years. This progestin was prescribed by another veterinarian for behavioral problems (i.e., inter-cat aggression, and inappropriate urination). In addition to this cat, two other cats in the household have also been on the drug for the same prolonged period.

This cat presented for signs of anorexia, lethargy, and weight loss of 6-weeks duration, all of which started after the owner abruptly stopped the megestrol in all three cats. Fortunately, the other two cats in the household remain clinically normal after stopping the drug.

In this sick cat, routine blood testing was fairly unremarkable, with normal renal function and serum electrolytes. An abdominal ultrasound revealed a hyperechoic liver (thought to be due to mild hepatic lipidosis secondary to anorexia) and small adrenal glands.

Because of the clinical signs and small adrenals, an ACTH stimulation test was performed by collecting serum for cortisol determination before, 1 and 2 hours after the intravenous injection of 0.125 mg cosyntropin (Cortrosyn). After the ACTH stimulation test was completed, we administered 1 mg of dexamethasone, IM, and the cat ate some food about an hour later.

The results of the ACTH stimulation test showed undetectable serum concentrations of cortisol, both before and after ACTH stimulation. The cat’s appetite is again very poor 2 days after the glucocorticoid injection.

My questions are the following:

1. The low cortisol levels are diagnostic for hypoadrenocorticism. However, there have been no electrolyte abnormalities. Is this atypical hypoadrenocorticism in a cat?
2. If so, is this atypical Addison’s disease caused by the chronic administration of megestrol?
3. Should I continue the glucocorticoids if this cat continues to respond to them?
4. Do I still need to provide mineralocorticoid treatment (Florinef or Percorten) if electrolytes remain normal?

My Response

Is this cat’s hypoadrenocorticism related to the megestrol treatment?
Megestrol acetate (Ovaban, Ovarid, or Megace), a progestational compound that has been widely used in the past for treatment of a variety of feline dermatologic and behavioral disorders, commonly induces severe adrenocortical suppression that is even more profound than that produced by high-dose glucocorticoids (1-4). Such marked adrenocortical suppression develops in cats treated with standard dosages of the drug (2.5 to 5.0 mg every other day) for as little as one to two weeks (1,2).

Progestational agents, such as megestrol acetate, act via the negative feedback effects on the HPA axis to suppress pituitary ACTH secretion, which leads to a “secondary” form of hypoadrenocorticism in cats. The deficient ACTH secretion results in a decrease in glucocorticoid production caused by atrophy of the zona fasciculata and zona reticularis (4,5). The adrenal zona glomerulosa is preserved because ACTH has little stimulatory effect on mineralocorticoid production.

The clinical signs are due to deficiency in glucocorticoid production and so are similar to those observed in cats with primary hypoadrenocorticism (5-8). However the derangements associated with mineralocorticoid deficiency (and subsequent electrolyte disturbances) are absent. Consequently, clinical signs observed are usually less severe than those that develop in cats with primary hypoadrenocorticism.

Is this a case of feline atypical hypoadrenocorticism?
In this cat, this isn't “atypical” hypoadrenocorticism because we know what the cause is — it's drug-induced secondary adrenal atrophy. The subnormal resting and ACTH-stimulated serum cortisol concentrations that develop during treatment will normalize within a few weeks after cessation of megestrol acetate (1,5).

How should this cat be managed?
I’d start this cat on glucocorticoid replacement with oral prednisolone, at the lowest daily dose that will get the cat to feel better. I’d then slowly taper the daily prednisolone dose down to 1.25 to 2.5 mg per day, and then decrease to alternate day therapy (5,6). It may take a few months before all glucocorticoid supplementation can be stopped.

Again, megestrol causes secondary hypoadrenocorticism, with pituitary ACTH suppression. Mineralocorticoid secretion should remain normal, and I would not expect serum electrolyte abnormalities to develop. Therefore, neither fludrocortisone acetate (Florinef) nor desoxycorticosterone pivalate (Percorten-V) should be required in this cat.

My Bottom Line
Megestrol is not a recommended treatment for cats because of the high incidence of adverse effects, including profound adrenal suppression and diabetes mellitus.  Although it does work very well for treatment of a variety of dermatologic conditions (e.g., miliary dermatitis, eosinophilic granulomata) and behavior problems, the disadvantages outweigh the benefits of the drug.

I would never dispense this drug for a cat, unless I had exhausted every other treatment option and believed that this was the only chance to prevent the cat from being euthanized. In that case, you must inform the owners about the high risk of side effects associated with megestrol and other progestational drugs in cats.

References

1. Peterson ME. Effects of megestrol acetate on glucose tolerance and growth hormone secretion in the cat. Research in Veterinary Science 1987;42:354-357.
2. Middleton DJ, Watson AD, Howe CJ, et al. Suppression of cortisol responses to exogenous adrenocorticotrophic hormone, and the occurrence of side effects attributable to glucocorticoid excess, in cats during therapy with megestrol acetate and prednisolone. Canadian Journal of Veterinary Research 1987;51:60-65. 
3. Watson AD, Church DB, Emslie DR, et al. Comparative effects of proligestone and megestrol acetate on basal plasma glucose concentrations and cortisol responses to exogenous adrenocorticotrophic hormone in cats. Research in Veterinary Science 1989;47:374-376. 
4. Chastain CB, Graham CL, Nichols CE. Adrenocortical suppression in cats given megestrol acetate. American Journal of Veterinary Research 1981;42:2029-2035.
5. Peterson ME, Randolph JF, Mooney CT. Endocrine diseases, In: Sherding RG (ed): The Cat: Diagnosis and Clinical Management. (2nd Ed) New York, Churchill Livingstone, 1994;1404-1506.
6. Peterson ME, Baral R. Adrenal gland disorders, In: Little, S.E. (ed), The Cat: Clinical Medicine and Management. Philadelphia, Elsevier Saunders. 2012; 592-610. 
7. Duesberg C, Peterson ME. Adrenal disorders in cats. Veterinary Clinics of North America: Small Animal Practice 1997;27:321-347, 1997.
8. Peterson ME, Greco DS, Orth DN. Primary hypoadrenocorticism in ten cats. Journal of Veterinary Internal Medicine 1989;3:55-58.