Explore the role of GnRH and the use of deslorelin with the Suprelorin® hormone implant.

Castration of male dogs is one of the most common surgeries carried out in practice, in fact it is often one of the first you are happy to chalk up as a new graduate. As a relatively routine procedure, there are good reasons to castrate dogs, from disease prevention through to lifestyle management and a happy home. But there is a choice. There is an alternative to surgical castration widely available to pet owners, providing the benefits of castration without the need for surgery.

This article will talk you through the normal reproductive hormones, the use of GnRH agonists and the role deslorelin plays, and how Suprelorin can help you and your clients. It includes helpful tools, a video and a competition to win one of five copies of the BSAVA Manual of Canine and Feline Reproduction and Neonatology.

Why is there a need for an alternative?

There are several good reasons why there should be an alternative. The first is that, in several countries, routine castration – effectively done on a prophylactic basis – is considered surgical mutilation; this is particularly true in the Scandinavian countries where, for instance, in Norway only 7% of dogs are neutered (Kutzler, 2010).

These countries have a need for an alternative when the benefits of castration are required without the need for surgery.

While castration has some health benefits and is associated with population control, there are many cases where permanent castration may not be desired or be appropriate – it is important as vets we recognise these cases.

Consider these cases:

• the owner who is not sure whether they want to castrate – whether it be the general anaesthetic, or that they don’t want the testes removed, or they are just not sure – they may wish to trial the effects first
• the dog where permanent castration, with removal of the testes and thus the testosterone, could be detrimental if its behaviour is anxiety based and removal of testosterone worsens the situation (Heath, 2016)
• the breeder trying to manage a household with multiple stud dogs, not all being used for breeding at the same time
• the working dog in training where the trainer would like the desirable effects of a lack of testosterone but may want to breed in the future if the dog proves itself

In practice, every vet comes across these types of cases and it is important to consider the options – so that they make an informed decision, a cornerstone of veterinary medicine, and so that these clients are retained by the practice through good service and care.

A survey of 411 vets looked at attitudes to castration, finding that whilst 76% of vets recommended routine neutering of male dogs, only 52% offered an alternative to surgery (Adams et al., 2016). Another study found castration was recommended at around six months of age or once puberty had been reached (Diesel et al., 2010).

To better understand the options, first we should understand the physiology of the reproductive hormones.

The science behind the productive hormones

Several hormones play a key role in the reproductive system of the male dog, with the interaction of these hormones in both males and females long used to manipulate reproductive cycles.

In both genders, gonadotrophin-releasing hormone (GnRH) plays a key role in the production of other hormones along the hypothalamic-pituitary- gonadal axis. Released episodically from neurone endings in the hypothalamus, GnRH production is influenced by various neurotransmitters, neural and hormonal feedback loops, and exogenous influences, such as day length (involving melatonin).

GnRH stimulates the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland. These hormones then act upon either the testes or ovaries. Through feedback loops (e.g. involving the hormones activin and inhibin), the production and actions of these hormones are carefully controlled.

In the male, LH and FSH act upon the testes, stimulating the production of testosterone from the Leydig cells. Testosterone, in conjunction with FSH, acts on the seminiferous tubules (through androgen-binding proteins in the sertoli cells) and also directly on the germ cells, to stimulate sperm production. There is a negative feedback loop involving testosterone, which feeds back to both the hypothalamus and pituitary gland, controlling the subsequent release of GnRH, LH and FSH.

In the female, FSH exerts effects on the ovarian follicles, which in turn produce oestrogen; whereas LH acts on both the follicle and corpus luteum to produce progesterone – the extent to which depends on the stage of the oestrous cycle.

So how can we use GnRH?

The desire to find a way to neuter animals in areas where surgery is inappropriate has led to much work being done looking at the use of substances which can manipulate GnRH, be it direct GnRH agonists, indirect progestogens, or even immunisation against GnRH or LH.

While widely available and often short acting in nature, the use of progestogens (injection, implant or orally) has both positive and negatives towards their use and work through the feedback loops that exist. Given in female dogs, they can produce an artificial luteal phase, thus they should not be given to those intended for breeding and have been associated with increased risks of infertility and pyometra (Wiebe & Howard, 2009). In male dogs, they are short acting with side effects associated with longer term use, including increased appetite and diabetes mellitus (Kutzler, 2010).

The use of GnRH agonists has a direct action on the production of GnRH and has been used in numerous species, some you will be aware of, and are associated with few side effects.

Deslorelin is the active substance in both Suprelorin® (Virbac), licensed to produce temporary infertility in male dogs and ferrets, and Ovuplant® (Dechra in UK), licensed to induce ovulation in female equines (Suprelorin SPC, Ovuplant SPC). How can a GnRH agonist both stimulate and suppress? The physiology behind this is that short term use of GnRH agonists causes stimulation, whereas long term use causes an initial stimulation followed by long term suppression. The difference between the products is due to the dose effect and duration of action through the matrix in which they are impregnated.

Many vets will be aware of buserelin – better known as Receptal® (MSD) – injected for many years in farm animals and equine; it is used to stimulate GnRH production, synchronise and induce ovulation and improve fertility. Leuprolide is a GnRH agonist licensed in humans as a depot injection for sustained administration and thus GnRH suppression – for the treatment of some prostate cancers and endometriosis (Wilson et al., 2007).

Suprelorin® – the hormone implant containing deslorelin

The deslorelin in Suprelorin causes an initial stimulation followed by longer term suppression of GnRH because of the special lipid matrix used (shown) causing slow release over time.

This initial overstimulation sees sustained exposure of the hypothalamus to the GnRH agonist and thus downregulation, internalisation and signal uncoupling of GnRH receptors (Kutzler, 2010).

This suppression produces an effective infertility through reduced testosterone and libido – giving the desirable effects of castration without surgery.

With time, after the hormone has been released, normal hypothalamic-pituitary-gonadal activity will resume – providing reversible castration.

A study by Junaidi (1998) showed histologically the presence, absence and then subsequent return of spermatozoa in the seminiferous tubules in dogs following deslorelin use.

Key Facts on the two sizes available:

• licensed in entire male dogs
• infertility for a minimum 6 months
• functional infertility from 6 weeks
• return to normal testosterone within 12 months in 80%, by 18 months in 98% (Suprelorin SPC)

• licensed in entire male dogs and ferrets
• infertility for a minimum 12 months in dogs; up to 4 years in ferrets
• functional infertility from 8 weeks in dogs
• return to normal testosterone within 24 months in 68%, by 30 months in 95% of dogs (Suprelorin SPC)

Suprelorin provides a flexible, reversible alternative to castration – offering owners a choice

Virbac has put together a collection of tools to help you and your clients make an informed choice when it comes to castration:

• VIDEO – produced in conjunction with ITN and BVA, a video shows how castration with a hormone implant can offer an appropriate solution in many cases and can bring additional benefits to both the patient and to the practice. It highlights the role Suprelorin® can play for a practice’s clients – watch the video below.
  

WIN – for a limited period, enter a free prize draw for 1 of 5 copies of the BSAVA Manual of Canine and Feline Reproduction and Neonatology (T&Cs apply). Simply view www.virbac.co.uk/suprelorin and click “Win a Manual”.

_{Competition Terms and Conditions
Limited to 5 books, for a limited time only – those who enter before 31st December 2016. Participants must be over 18 years of age and in veterinary practice. One manual per successful respondent. Promotion is as stated and no cash payment or alternative will be provided. The promotion is not open to employees or agents (and their family members) of Virbac Limited or any of its affiliated companies or any other person connected with the management or provision of the promotion. It is open to residents of the UK only.}

_{Suprelorin 4.7mg contains deslorelin acetate POM-V. Indications for use: For the induction of temporary infertility in healthy, entire, sexually mature male dogs. Suprelorin 9.4mg contains deslorelin acetate POM-V. Indications for use: For the induction of temporary infertility in healthy, entire, sexually mature male dogs and ferrets. Further information regarding side effects, precautions, warnings and contraindications is available on the full SPC or on request from Virbac. Use medicines responsibly. www.noah.co.uk/responsible. Seek information from the medicine prescriber.}

_{For further information, please contact Virbac:
Virbac Ltd, Woolpit Business Park, Windmill Avenue, Woolpit, Bury St Edmunds, Suffolk IP30 9UP.
Tel: 01359 243243 Email: enquiries@virbac.co.uk   www.virbac.co.uk}