Introduction

Deslorelin is a long acting synthetic agonist of gonadotropin-releasing hormone (GnRH) marketed for veterinary use in most western countries as a 2.1 mg, 4.7 mg and 9.4 mg implant; the 2.1 mg implant is marketed for use in horses (Ovuplant™), but its extra-label use in dogs is rather common, while the 4.7 (Suprelorin™) and 9.4 (Suprelorin 12™) mg implants are currently marketed in Europe and Oceania for the control of fertility and aggressiveness in male dogs but their extra-label use in cats is becoming increasingly common. This paper will review current and potential clinical applications of GnRH agonists in the control of feline reproduction and reproductive-related conditions.

Delaying Puberty

Long-acting GnRH agonists act by initially over-stimulating and subsequently down-regulating GnRH receptors at the pituitary gonadotropes, thereby suppressing the function of the hypothalamic pituitary gonadal (HPG) axis and causing an arrest of secretion of gonadal steroids as well as their by-products. When HPG suppression occurs prior to the onset of puberty, puberal estrus is delayed for as long as the action of the GnRH agonist persists. The postponement of puberty following prepuberal administration of deslorelin has been reported in cats^1-5. We administered a 4.7 mg deslorelin implant to 9 prepuberal domestic shorthair European queens²: 3/9 queens showed signs of estrus (vaginal cheratinization) one week following implantation, but estrus signs gradually subdued and did not appear again for the following 14–25 months (at an age of 21–33 months). Similar results in prepuberal queens were obtained when comparing the effect of the 4.7 mg deslorelin implant in 15 treated and 15 control 4-month old queens followed for a maximum of 18 months with physical exams and vaginal cytology³. Average age at puberty was 281±21 and 178±11 days in treated and control queens, respectively, while there was no difference in weight at the end of the study³. A delayed puberty may be obtained also by implanting post-natal kittens with a1.6 mg deslorelin implant, although the reported delay was only 63±3 weeks^4,5, which is shorter than what was obtained by implanting queens right prior to puberty onset^1,2. We have implanted 3 tomcats prior to puberty: although their post-GnRH serum testosterone increased sample to adult levels prior to implantation, penile spikes and masculine behavior were not present at study onset and never appeared until puberty which occurred in the 3 toms at an age of 19–22 months¹. Although detailed information on onset of susceptibility to exogenous GnRH around the time of puberty is not available for dogs and cats, use of GnRH agonists can probably be regarded as a reasonably safe method to postpone puberty in cats; more data are necessary in tomcats to draw the same conclusion (although a similar effect is likely to occur).

Suppressing Cyclicity in Adult Queens

In adult queens administration of a 4.7 mg deslorelin implant initially stimulates follicular growth and oestradiol secretion, after which no further evidence of estrus is observed for periods of 4–14 months⁶ or up to 16–37 months^7,8. The initial stimulation of follicular growth may lead to a true heat in a small percentage of implanted queens. Small estrogen increases have been observed in 50% of treated queens 5–14 months after treatment^6,8. Deslorelin-treated queens may ovulate if bred early in the follicular phase⁸; progesterone increased significantly in all queens treated in the follicular phase until day 14 after treatment, then slowly decreased reaching basal level on day 56 post-treatment: duration of this luteal phase could be regarded as comparable to the normal, non-pregnant feline luteal phase⁸. Incidence of spontaneous ovulation at the induced heat and incidence of premature luteal failure at the induced pregnancy are unknown. More studies are needed on post-treatment luteal function in queens administered a deslorelin implant. General health and social behaviour have never shown any deviation from normality, and introduction of a male is not capable of reversing the deslorelin-induced cycle suppression⁶.

The 9.4 deslorelin implant is characterized by a longer action in queens. We looked at duration of effect of the 9.4 deslorelin implant in 15 adults (6 months to 5 yrs of age) queens. Based on vaginal cytology and serum P4 data induction of heat was observed in 40% of queens during the first month post-implantation. Subsequently, the first post-treatment heat was observed in 15% of queens after day 600, and by post-treatment day 720, 800 and 1090 percentages of queens in heat were 50%, 70% and 100%, respectively (unpublished data).

Inducing Oestrus in Adult Queens

Because of the high fertility of cats, estrus induction in queens is an unusual request to veterinarians except for wild felids in captivity which may be object of germ cell conservation programs. Historically, estrus induction in cats has been performed for decades using variable protocols with pregnant mare serum gonadotropins which is, however, characterized by excessive ovarian stimulation and sometimes equivocal results. The occurrence of signs of heat has been repeatedly observed when treating adult queens with 4.7 or 9.4 mg deslorelin implants, albeit not in all queens and not with the same intensity. We observed signs of heat (vaginal epithelial keratinization, and in some females also vocalization or crouching) in 19/20 treated queens 3–4 days after treatment with the 4.7 mg deslorelin implant (queens were implanted irrespective of oestrous cycle stage)⁷. In another study oestrus induction was observed in 2/20 queens when a 4.7 mg deslorelin implant was administered during the follicular phase or immediately post-estrus⁸. Recently, Zambelli et al. 11 treated 13 adult queens with a 4.7 mg deslorelin implant: all queens showed vaginal epithelial keratinization, and 7/13 queens showed behavioural signs of heat¹¹; three of these 7 queens were artificially inseminated and gave birth to normal litters⁹. In our 9.4 mg deslorelin study 40% of queens showed vaginal epithelial or behavioural signs of heat during the first month post-treatment (unpublished data). Deslorelin may be used to induce oestrus in adult queens. The induced oestrus is normal and fertile. As the cat is a seasonal breeder, time of the year may play a role in oestrus induction response to deslorelin.

Controlling Fertility and Reproductive Behaviour in Males

In adult tomcats, a 4.7 mg deslorelin implant is able to suppress the HPG axis leading to disappearance of serum testosterone and male urine odour. Following treatment, serum testosterone drops significantly to undetectable levels already during the second week post-treatment and does not start rising again often for one year or longer; penile spikes start disappearing at 60 days and are absent by 90 days; testicular volume decreases reaching ≤2/3 of normal volume by 7–8 months; also, food intake and body weight tend to increase in implanted cats, who often gain 10–20% of their initial body weight in about 6 months¹⁰. From a reproductive behaviour standpoint, roaming and mating behaviour decrease within 2 months and there is an improvement in friendliness towards humans in a high percentage of treated cats. Similarly to queens, the 9.4 deslorelin implant has a longer action in tomcats. When16 adult tomcats were implanted with the 9.4 formulation the average interval to resumption was 805 (range 750 to 850) days¹².

Deslorelin can be considered as a safe alternative to surgical castration in tomcats as it prevents them from displaying all unwanted effects of gonadal steroid secretion. However, it should be underlined that - unlike in dogs - not all cats respond to deslorelin. Out of approximately 45 tomcats implanted with either the 4.7 mg or 9.4 mg deslorelin we have observed 4 cases of tomcats becoming friendlier and more affectionate with humans and other cats as well but continuing to impregnate queens for the entire duration of the treatment period (unpublished observation). Owners and particularly breeders should be warned about this possibility. Likewise, in cats implanted with deslorelin the onset of sterility may be delayed beyond the second month post-implantation. In a group of 7 tomcats implanted with the 9.4 mg deslorelin implant semen quality actually improved during the first month and then decreased gradually during the second month; complete sterility was achieved from day 40 post-treatment onwards with one cat actually still being potentially fertile at 70 days post-implantation (capable of ejaculating fertile semen when penile spikes had disappeared and serum testosterone had already reached basal levels)¹¹.

Treatment of Urinary Incontinence in Queens

Urinary incontinence is a relatively common condition in neutered bitches, with an incidence of 5–10% depending on breed and age at neutering. It is due to a deficiency of the urethral sphincter mechanism developing after gonadectomy. Treatment includes the use of alpha-adrenergic compounds (i.e., phenylpropanolamine) or short acting estrogens such as estriol^13,14. Deslorelin also may be used as it has been shown to be effective in about 50% of cases. Urinary incontinence is anecdotally thought to be very rare or absent in cats. However, the condition was recently reported in a Norwegian Forest queen neutered 6 months prior to the onset of the condition¹⁵. A urethral sphincter incompetence was diagnosed and a 4.7 mg deslorelin implant was administered, which allowed full continence for a period of 15 months. Albeit a rare event, urinary incontinence may occur in the queen and deslorelin may be considered as a treatment.

References

1.  Romagnoli S, Salata P, Stelletta C, Milani C, Sontas H, Gelli D, Caldin M, Mollo A (2010). Postponement of puberty in male and female prepuberal cats with deslorelin: a preliminary study. In: Proceedings 7th EVSSAR Congress. Louvain-La- Neive, Belgium, 14–15 May 2010

2.  Risso A, Corrada Y, Barbeito C, Diaz JD, Gobello C – Long-term release GnRH agonists postpone puberty in domestic cats. Reprod Dom Anim 2012 Dec;47(6):936-8. doi:10.1111/j. 1439-0531.2012.01994.

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6.  Munson L, Bauman JE, Asa CS et al. Efficacy of the GnRH analogue deslorelin for suppression of oestrous cycles in cats. J Reprod Fertil Suppl. 2001;57:269–73.

7.  Pisu MC, Romagnoli S. Impiego clinico di un impianto di deslorelin nel gatto. Veterinaria, Anno 26 (1), February: 1–7, 2012.

8.  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(4):640–6.

9.  Zambelli D, Bini C, Küster DG, Molari V, Cunto M. First deliveries after estrus induction using deslorelin and endoscopic transcervical insemination in the queen. Theriogenology. 2015 Sep 15;84(5):773–8. doi: 10.1016/j.theriogenology.2015.05.010. Epub 2015 May 15.

10.  Novotny R, Cizek P, Vitasek R et al. Reversible suppression of sexual activity in tomcats with deslorelin implant. Theriogenology 2012; 78:848–857.

11.  Romagnoli S, Baldan A, Righetti C, Milani C, Mollo A, Stelletta C. Semen quality and interval to sterility in tom cats treated with a 9.4 mg deslorelin implant. J Feline Med Surg. 2017 Feb;19(2):194–199. doi: 10.1177/1098612X15623985

12.  Romagnoli S, Baldan A, Ferro S, Righetti C, Scenna L, Gabai G, Badon T, Fontaine C, Mollo A, Stelletta C, Milani C - Length of efficacy and effect of implant location in adult tomcats treated with a 9.4 mg deslorelin subcutaneous implant. Submitted to J Feline Med Surg, February 2018.

13.  Reichler I, Hubler M, Jockle W, et al. The effect of GnRH analogs on urinary incontinence after ablation of the ovaries in dogs. Theriogenology 2003; 60: 1207–1216.

14.  Ponglowhapan S, Church D and 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.

15.  Pisu MC, Veronesi MC. Effectiveness of deslorelin acetate subcutaneous implantation in a domestic queen with after-spaying urinary incontinence. J Feline Med Surg. 2014 Apr;16(4):366–8. doi: 10.1177/1098612X13498250. Epub 2013 Jul 19.