GnRH agonists implants:
Mode of action and clinical application
Division of Small Animal Reproduction
Alfort Veterinary School, Paris, France

Hypothalamus
GnRH
Hypophyse
FSH LH
Key role in the reproductive function
Normal ovarian function
Oestradiol
Spermatogenesis
Testosterone

• GnRH: a decapeptide
– GnRH agonists: substitution of one or two amino-acids:
• Increased receptor affinity and enhanced stability

• GnRH agonists : how they act :
– Stimulation of production and release of pituitary gonadotropins

– But: when used at sustained doses:
• Short period of
stimulation…
• Then… inhibition of the hypothalamicpituitary axis
Hypothalamus
Desensitised
GnRH

 
Gonads
Normal ovarian function 
GnRH
Agonist
Spermatogenesis


• Compounds:
– More than 700 GnRH agonists have been synthesized
• Fertirelin, buserelin, nafarelin, lutrelin, deslorelin, leuprolide …
• Under normal conditions:
– short acting compounds
• Implants:
– Nafarelin (Gonazon®)
– Deslorelin (Ovuplant®- Suprelorin®)
• 6 months action
• 12 months action

Clinical application
In males
– Suppression of reproductive function
– Reduction of aggressiveness
– Postponement of puberty
– Control of testosterone related disease
– Stimulation of libido
In females
- Suppression of estrus
- Postponement of puberty
- Induction of estrus
- Urinary incontinence

Controlled release implant
Implantation:
Subcutaneous tissue
Size:
2.3 x 12.5mm (6 month)
2.3 x 25mm (12 month)
During 6 to 12 months…
Suprelorin

6 = 4.7mg
Suprelorin

12 = 9.4mg

GnRH implants and sterilization: why?
Non invasive procedure
Animal welfare
Transient effect  return to fertility

-100
10
8
6
14
12
4
2
0
0
Testosterone PT13 (DR049: 4.7mg deslorelin/50mg)
Suppression of testosterone secretion
100
Placebo
200 300
Tim e (days)
400 500 600
PW285
PW287
PW289
PW293
PW294
PW296
PW307
PW308
PW310
PW311
Placebo

Australian Registration Studies:
S6 Repeat Dosing and Recovery
Transient effect

Australian Registration Studies:
S6 Days to Testo. Suppression
78%

Australian Registration Studies:
S12 Days to Testo. Suppression

Australian Registration Studies:
S6 Days of Testo. Suppression

Australian Registration Studies:
S12 Weeks of Testo. Suppression
Group B Group D Group E

Suppression of hormone secretion
Short period of stimulation
BUT
Oestrus induction

Bitch Studies:
Occurrence of Induced Oestrous
Status
Anoestrous
Dioestrous
Pregnant
0 nd
0/10
0/2
Dose of deslorelin (mg)
3 6
1/1 4/4
3/8 nd
2/8
0/7
12 nd
4/9
0/4

Bitch Studies:
Oestrous Postponement
Status
Anoestrous
Dioestrous
Pregnant
0mg deslorelin
Mean Duration (Months)
3mg deslorelin
6mg deslorelin
12mg deslorelin nd 10 13.9
nd
5.5
8.5
10.7
nd
14.6
20.4
15.5
19.6

Bitch Studies:
Deslorelin Induced Oestrous
• How can this be prevented?
• Three alternatives:
– Oral progestins
• P J Wright et al / Journal of Repro.and Fert. Supp. 39 (2001) 263-268
– Implant in early dioestrous
• T E Trigg et al / Journal of Repro.and Fert. Supp. 39 (2001) 255-261
– Implant pre-pubertal pups
• T Swangchan-uthai et al / MS Thesis (Theriogenology), Chulalongkorn University 2004

GnRH implants:
 silencing the hypothalamo-pituitary axis
 No more hormonal secretion from the gonads
Each time a « curative » sterilisation is needed, can be considered as an alternative to surgery

Each time a « curative » sterilisation is needed, can be considered as an alternative to surgery
In males
– Prostatic disease (BPH,
Prostatitis)
– Anal carcinoma
– Diabetes mellitus
– …
In females
– Mammary tumors
– Vaginal prolapse
– Diabetes mellitus
– …

• Interesting when anaesthesia is not recommended
• Warning: short period of stimulation  can increase the severity of the disease!!!

• 7/13 bitches with USMI became continent after implantation
(Reichler et al., 2003)
• Mechanism?
– Continence linked to suppression of FSH/LH secretion?
– Presence of GnRH receptors in the bladder and urethra?

• Treatment of primary anoestrus
• Treatment of secondary anoestrus
– > 12 months ? (Kützler 2005)
• Missed matings:
– Diminution of inter-oestrous intervals ?
• Transfer embryos canine programs

– Preliminary studies:
• Before estrus:
– Pulsations every 70-90 minutes
• But pulsatility not essential: a continuous infusion works
(Concannon 1989)
– In practice:
• Protocols using short action
GnRH agonists are not clinically applicable (pulsatile infusion pumps – intravenous infusion)
• Implants:
– Subdermal implant of deslorelin in Australia:
Suprelorin®
Trigg et al. 2001
– (2.1 mg) – Ovuplant®: implanted beneath the vulval mucosa
• non longer available in the states
– Use of deslorelin in
BioRelease®: 1.5Mg/mL
(Kützler 2005)

• The problem is that:
– Prolonged GnRH administration:
• Pituitary hyperstimulation
• Suppression of LH secretion
• Secondary decreased progesterone plasma level
– Hypoluteoidism

• GnRH agonist implants, a kind of revolution in small animal reproduction?
• Large fields of application
• Useful for every practitionners
New opportunities for:
Treating sex hormon related disorders
Assisted reproduction