Downregulation, an Effective Alternative Method to Surgical Castration in the Male Dog: Indications and Results
World Small Animal Veterinary Association World Congress Proceedings, 2004
Bernd Hoffmann, DVM, Prof. Dr. med. Vet; Eva Engel, DVM, Dr. med. vet.
Klinik für Geburtshilfe, Gynäkologie und Andrologie der Groß-und Kleintiere mit Tierärztlicher Ambulanz
Gießen, Germany

Main indication for castration of male dogs is to prevent reproduction. Surgical castration is commonly accepted, however, in recent years the demand for alternative approaches has increased. This is based on animal welfare considerations, personal attitudes of pet owners, the specific use of dogs and medical indications. In addition pet owners are getting increasingly afraid of the side effects of castration (loss of temper, gain of body weight, skin and fur problems, incontinentia).

This demand is not new and so far the method of choice has been the application of progestagens. The pharmacodynamic activity of progestagens relates to their negative feedback mechanisms, causing an inhibition of the release of GnRH and hence of the anterior pituitary hormones LH and FSH, which consequently leads to a suppression of gonadal function. However, as a result of the sex specific differentiation of the central nervous system these negative feedback mechanisms are apparently less effective in the male compared to the female dog (Selman et al., 1997, England 1997). In addition and depending on the type of progestagen distinct side effects might be anticipated (Kooistra, Okkens 2001). It would therefore be desirable if inhibition of endocrine and germinal testicular activity could be achieved by other means.

As alternatives the following approaches are discussed:

 Immunisation against GnRH (Thompson 2000, Zeng et al., 2001)

 Application of GnRH antagonists (Sharpe et al. 2000)

 Application of GnRH analogues in a dose leading to a downregulation of pituitary GnRH receptors (Paramo et al., 1993, Vickery et al., 1989, Riesenbeck et al., 2002)

 Application of competitive androgen receptor blockers (Tsutsui et al. 2000)

 Competitive inhibition of 5a-reductase (Iguer-Quada, Verstegen, 1997, Sirinarumitr et al., 2001)

From these five approaches the first three lead to an indirect inhibition of hypothalamo-anterior pituitary function and hence also of testicular function. Competitive receptor and enzyme blockers act peripherally, not or only little affecting gonadal function. It is inherent to these therapeutic approaches that the induced effects are reversible.

Based on earlier reports by Paramo et al. (1993) and Vickery et al. (1998) on the use of GnRH analogues for downregulation of pituitary function in the dog and the availability of respective drugs for use in humans we have performed a controlled study with a limited number of animals and a still ongoing clinical study. In relation to the underlying indications the following parameters were determined: Endocrine and germinal testicular activity, reversibility, acceptance by the pet owner.

Materials and methods

Treatment and grouping of animals

6.6 mg of the GnRH analogue Buserelin (Profact®) were applied s c as a slow release implant. To counteract the initial testosterone increase the competitive androgen receptor blocker cyproterone acetate was given in an oral formulation for the first 4 days in a dose of 10 mg/dog/day.

The indications for presentation of the dogs are given in table 2. Prior to treatment the dogs were submitted to a general and andrological examination and retrospectively assigned to the following 3 groups:

Group 1: It consisted of 7 dogs, aged 5-7 years where an intensive clinical monitoring over an extended period of time was possible. Blood samples were collected prior to treatment and thereafter in 2-6 day intervals for assay of testosterone and estradiol-17b until testosterone concentrations were back to pre-treatment levels. As far as ejaculates could be obtained, volume of the sperm-rich fraction, forward motility and pathomorphology were established.

Group 2: It consisted of 52 patients presented until January 2002 for the reasons indicated in table 2. Evaluation of treatment was largely based on the reports by the pet owners. However, in 37 dogs blood sampling prior to and after treatment was possible, in 12 of these dogs further samples were collected for monitoring of testosterone allowing an analytical verification of the subjective observations.

Group 3: It comprises 44 dogs treated between February 2002 and December 2003 for the reasons indicated in table 2.

Histological examinations: The testes from two dogs surgically castrated 100 days after implantation were submitted to a histological examination in comparison to testes removed 645 and 399 days after implantation. Controls were testes from sexually mature animals castrated to prevent reproduction.

Results

Group I: The initial increase in testosterone and estradiol-17b concentrations following implantation lasted for 2 to 4 days. Both hormones had fallen to basal levels after about 15 days, indicating that downregulation of the hypothalamic pituitary gonadal axis has been achieved. Duration of downregulation was between 208 and 278 days (233 ± 28.2 days). End of downregulation was indicated by a rather rapid increase of testosterone and estradiol-17β, levels to initial concentrations within approximately 10 days (Table 1).

Table 1. Observations Group 1:

Testosterone

Initial concentration

13.90 ± 7.3 nmol/l

% Increase following implantation

76.7%

--Duration

2-4 days

Time to reach basal levels< 0.347 nmol/l

approx. 15 days

Duration of downregulation

233 ± 28.2 days

Time of increase from basal levels to initial concentration

approx. 10 days

Estradiol-17 b

Initial concentration

78.5 ± 34.4 pmol/l

 

% Increase following implantation

87%

 

--Duration

2 days

 

Time to reach basal levels between 4-97 pmol/l

approx. 15 days

Testicular consistency changed from firm to soft after about 50 days, accompanied by a 57.3 ± 13.8% decrease in size. In parallel a reduction of prostatic size by 71.2 ± 7.3% was observed. Testicular re-growth occurred concomitant with the increase of testosterone at the end of downregulation.

In 4 dogs semen collection was possible during a period up to 33 days. Volume of the sperm rich fractions started to decrease between 14 and 20 days. However, the total number of spermatozoa only decreased after about 21 days. This was paralleled by an increase in pathomorphology from 16.6 ± 5.0 to 71.5 ± 22.8%.

The histological examination of a testis 100 days after implantation showed a complete cessation of spermatogenesis with closed tubuli seminiferi contorti and only few spermatogonia remaining. There were no differences between the normal testis and the testis following cessation of downregulation 399 and 645 days after implantation.

Group 2: Mean plasma concentrations of testosterone and estradiol-17b determined in 37 dogs were 11.2 ± 7.6 nmol/l and 56.3 ± 27.3 pmol/l, respectively and resembled those of group 1. Based on testosterone analysis in 12 dogs efficacy of the implant lasted for 256.9 ± 76.8 days, testicular size was reduced by 67.4 ± 21.2%.

Table 2 lists the indications for castrations and subsequent downregulation.

Table 2. Indications for downregulation as an alternative to surgical castration

Sub-group

Indication for
downregulation

Indication for castration

Nr.
cases

1

risk of anaesthesia

benign prostatic hyperplasia (cysts)

10

 

 

aggressivity

2

 

 

epilepsy

1

 

 

hypersexuality

2

2

scruples concerning castration

aggressivity / hypersexuality

17

 

related side effects

restlessness

1

 

 

benign prostatic hyperplasia (cysts)

6

3

maintenance of breeding ability

hypersexuality

2

 

 

benign prostatic hyperplasia (cysts)

2

 

 

prostatitis

1

 

 

injury of the penis

1

 

 

prolapse urethral mucosa

2

4

risk of surgery

tumor of perianal glands

3

5

guard dog

hypersexuality

1

 

 

priapism / benign prostatic
hyperplasia (cysts)

1

In all sub-groups (1-5) a reduction of prostatic size with a disappearance of prostatic cysts was observed. Repeated treatments in sub-group 1 proved to be highly efficient, the periods of re-increased testosterone levels between treatments stimulated lifelines of the dogs, it also opened a window for the reuse of breeding studs. Owners of dogs falling in sub-group 2 reacted differently; in relation to the indication aggressivity, hypersexuality and restlessness some pet-owners wanted surgical castration at the end or during downregulation since no anticipated side-effects were observed, other pet-owners waved castration due to the phlegm their dogs had developed. Downregulation led to a regression of the tumours of the perianal glands, improving the conditions for surgical removal. Prolapse of urethral mucosa disappeared during treatment, but it re-occurred. Though subjectively, we think that downregulation had a beneficial effect of treatment of prostatitis with antibiotics.

Group 3: Initial testosterone and estradiol-17b concentrations in 39 dogs were 9.9 ± 4.8 nmol/l resp. 46.9 ± 20.3 pmol/l; around 8 weeks after treatment testosterone concentrations had decreased by around 90% (n=26) and estradiol concentrations by 57% indicating a successful downregulation. Repeated treatments were given in 4 dogs with problems related to prostatic hyperplasia, in 1 dog due to a dominant behaviour. A total of 16 dogs were treated for hypersexuality and/or dominant behaviour; as far as back reports were obtained no changes were observed in 3 dogs, while treatment was successful in 4 dogs.

Discussion

Neutering of male dogs to prevent reproduction is generally accepted. However, a changed ethical value of dogs and the provisions of animal welfare legislation have put pressure on the development of alternative methods to the surgical approach. The risk of anaesthesia, the wish to maintain breeding capacity or the temporary knockout of androgen production as a supportive therapeutic measure are further indications for the non-surgical approach. Interference with endocrine regulation of testicular function offers such an opportunity. The various approaches possible are given in the introduction. Regardless of the approach taken, the effects are reversible. The approach tested in this study was the use of a GnRH implant. The effect of downregulation was achieved in all dogs, efficacy of the implant lasted between 208 and 278 days as delineated from those dogs where hormone analysis was possible. Downregulation resembles the situation in seasonal animals, where a periodic loss of endocrine and germinal testicular function occurs. Repeated treatments are necessary to maintain the effect. However, as was observed in a number of dogs, the re-establishment of testicular activity over a short period of time increased lifelines. Apart from distinct medical indications downregulation also allows the pet-owners to test how their dog behaves as a castrate. As a consequence of such testing both reactions were observed, surgical castration and no castration what so ever.

References

1.  England GCW (1997): Effect of progesterons and androgens upon spermatogenesis and steroidogenesis in dogs. J. Reprod. Fert., Suppl. 51, 123-138

2.  Iguer-Ouada M, Verstegen JP (1997): Effect of finasteride (Proscar MSD) on seminal composition, prostate function and fertility in male dogs. J. Reprod. Fert., Suppl. 51, 139-149.

3.  Kooistra H, Okkens A (2001): Secretion of prolactin and growth hormone in relation to ovarian activity in the dog. Reprod. Dom. Anim. 36, 115-119.

4.  Paramo RM, Renton JP, Ferguson JM, Concannon PW (1993): Effects of medroxyprogesterone acetate or gonadotropin-releasing hormone agonist on suppression of spermatogenesis in the dog (Canis familiaris). J. Reprod. Fert. 47, 387-397.

5.  Riesenbeck A, Klein R, Hofmann B (2002): Downregulation, eine neue, reversible Möglichkeit zur Auss-chaltung der Hodenfunktion beim Rüden. Praktischer Tierarzt 83: 6, 512-520.

6.  Selman PJ, Mol JA, Rutteman GR, Van Garderen E, Van den Ingh TS, Rijnberk A (1997): Effects of progestin administration on the hypothalamic pituitary-adrenal axis and glucose homeostasis in dogs. J. Re-prod. Fert. Suppl. 51, 345-354.

7.  Sharpe RM, Walker M, Millar MR, Atanassov AN, Morris K, McKinnell C, Saunders PTK, Fraser HM (2000): Effect of neonatal gonadotropin-releasing hormone antagonist administration on Sertoli cell number and testicular development in the marmoset: Comparison with the rat. Biol. Reprod. 62, 1685-1693.

8.  Sirinarumitr K, Johnston SD, Kustritz MV, Johnston GR, Sarkar DR, Memon MA (2001): Effects of finasteride on size of the prostate gland and semen quality in dogs with benign prostatic hypertrophy. J. Am. Vet. Med. Assoc. 218, 1275-1280.

9.  Thompson DL (2000): Immunization against GnRH in male species (comparative aspects). Anim. Reprod. Sci. 60-61, 459-469.

10. Tsutsui T, Hori T, Shimizu M, Orima H, Kawakami E, Fukuda S (2000): Regression of prostatic hypertrophy by osaterone acetate in dogs. J. Vet. Med. Sci. 62, 1115-1119.

11. Vickery BH, McRae GI, Goodpasture IC, Sanders LM (1989): Use of potent LHRH analogues for chronic contraception and pregnancy. J. Reprod. Fert., Suppl.39,175-187.

12. Zeng XY, Turkstra JA, Van de Wil DFM, Guo DZ, Liu XY, Meloen RH, Schaaper WMM, Chen FQ, Oonk HB, Zhang X (2001): Active Immunization against gonadotropin-releasing hormone in Chinese male pigs. Reprod. Dom. Anim. 36, 101-105.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Bernd Hoffmann, DVM, Prof. Dr. med. Vet
Klinik für Geburtshilfe, Gynäkologie und Andrologie der Groß- und Kleintiere mit Tierärztlicher Ambulanz
Gießen, Germany

Eva Engel, DVM, Dr. med. vet.
Klinik für Geburtshilfe, Gynäkologie und Andrologie der Groß- und Kleintiere mit Tierärztlicher Ambulanz
Gießen, Germany


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