Transcript GnRH agonists implants: Mode of action and clinical

GnRH agonists implants:
Mode of action and clinical
application
Division of Small Animal Reproduction
Alfort Veterinary School, Paris, France
Introduction
Hypothalamus
GnRH
Hypophyse
FSH
Normal ovarian function
Oestradiol
LH
Spermatogenesis
Testosterone
Key role in the
reproductive
function
GnRH and analogs
• GnRH: a decapeptide
– GnRH agonists:
substitution of one
or two amino-acids:
• Increased
receptor affinity
and enhanced
stability
GnRH and analogs
• GnRH agonists: how
they act :
– Stimulation of
production and
release of
pituitary
gonadotropins
GnRH and analogs
– But: when used at
Hypothalamus
GnRH
sustained doses:
Agonist
GnRH
• Short period of Desensitised
Pituitary
stimulation…
LH
 and FSH

• Then…
inhibition of
Gonads
the
hypothalamicSpermatogenesis
Normal ovarian function


Testosterone
Oestradiol
pituitary axis



GnRH agonists
• 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
GnRH agonist implants
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
How to use these implants?
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
Suppression of reproductive
function
GnRH implants and sterilization: why?
Non invasive procedure
Animal welfare
Transient effect return to fertility
In the male dog
Australian Registration Studies...
T e sto ste ro n e P T 13 (D R 049: 4.7mg d e slo re lin /50mg )
Suppression of
testosterone secretion
14
12
PW 287
PW 289
10
T est o ( n g /m l)
PW 285
Place b o
PW 293
PW 294
8
PW 296
6
PW 307
PW 308
4
PW 310
PW 311
2
Plac ebo
0
- 100
0
100
200
300
T im e ( d ays )
400
500
600
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
In the female
Suppression of hormone
secretion
BUT
Short period of
stimulation
Oestrus
induction
Bitch Studies:
Occurrence of Induced Oestrous
Dose of deslorelin (mg)
Status
0
3
6
12
Anoestrous
nd
1/1
4/4
nd
Dioestrous
0/10
3/8
2/8
4/9
Pregnant
0/2
nd
0/7
0/4
Bitch Studies:
Oestrous Postponement
Mean Duration (Months)
Status
0mg
3mg
6mg
12mg
deslorelin
deslorelin
deslorelin
deslorelin
Anoestrous
nd
10
13.9
nd
Dioestrous
5.5
10.7
14.6
15.5
Pregnant
8.5
nd
20.4
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
Other fields of application
Alternative for surgery
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
Alternative for surgery
Each time a « curative »
sterilisation is needed, can be
considered as an alternative
to surgery
In females
In males
– Prostatic disease (BPH,
Prostatitis)
– Anal carcinoma
– Diabetes mellitus
– …
–
–
–
–
Mammary tumors
Vaginal prolapse
Diabetes mellitus
…
Alternative for surgery
• Interesting when
anaesthesia is not
recommended
• Warning: short period of
stimulation can
increase the severity of
the disease!!!
Urinary incontinence
• 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?
Oestrus induction in the bitch
Indications of oestrus induction
• Treatment of primary anoestrus
• Treatment of secondary anoestrus
– > 12 months ? (Kützler 2005)
• Missed matings:
– Diminution of inter-oestrous intervals ?
• Transfer embryos canine programs
GnRH agonists
– 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)
GnRH agonists
• The problem is that:
– Prolonged GnRH administration:
• Pituitary hyperstimulation
• Suppression of LH secretion
• Secondary decreased progesterone plasma level
– Hypoluteoidism
Conclusion
• 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
Thank you very much!!!