3. Goericke-Pesch_REC

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Slow release GnRH agonist implants- mode of action and their use as a contraceptive for dogs and cats Sandra Goericke-Pesch Klinikum Veterinärmedizin, Clinic for Obstetrics, Gynecology and Andrology for Large and Small Animals with Veterinary Ambulance, Justus-Liebig-University, Giessen, Germany 5th International Symposium on Non-Surgical Contraceptive Methods of Pet Population Control June 22, 2013, Portland, Oregon, U.S.

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Contents Mode of action Use in male dogs Use in male cats Use in queens

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Secretion of GnRH physiologically pulsatile => upregulation of GnRH receptors A higher and constant release of GnRH, e.g. by application of a slow release GnRH-implant, causes downregulation of the pituitary GnRH-receptors Efficacy is proven in male and female dog, cat and ferret GnRH Pituitary FSH LH LEYDIG CELL SERTOLI CELL GERM CELLS androgens, estrogens paracrine factors Peripheral Organs Hypothalamus Principle of Downregulation

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Initial changes in testosterone concentrations: Use in male dogs Junaidi et al. 2003 stimulation after 40 min peak after 60 min Figure from Junaidi et al. 2003

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Long-term basal testosterone concentrations: Use in male dogs Junaidi et al. 2003 basal T after 21-27 days Figure from Junaidi et al. 2003

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Use in male dogs Further changes as a consequence of testosterone withdrawal: significant decrease of testicular size to 35% of initial size after 14 weeks significant decrease of prostate volume Junaidi et al. 2003, 2007, 2009; Goericke-Pesch et al. 2009; Romagnoli et al. 2012 Figure from Junaidi et al. 2003

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Use in male dogs Further changes as a consequence of testosterone withdrawal: changes in semen quality: initial decrease in semen concentration and motility and increase in pathomorphology (Junaidi et al. 2003) BUT initial increase in semen quality post treatment (Romagnoli et al. 2012) Junaidi et al. 2003 Figure from Junaidi et al. 2003

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Use in male dogs Further changes as a consequence of testosterone withdrawal: no ejaculates to be obtained after 42 days (Junaidi et al. 2003), complete sterility on days 23-84 (23, 40, 51, 60, 70, 84) (Romagnoli et al. 2012) histological arrest of spermatogenesis on spermatogonia/spermatocytes Riesenbeck et al. 2002; Junaidi et al. 2003; Goericke-Pesch et al. 2009

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Use in male dogs All effects are fully reversible: testosterone increase, back to normal increase of testicular and prostate volume normal semen parameters and recovery of spermatogenesis Riesenbeck et al. 2002; Junaidi et al. 2003; Goericke-Pesch et al. 2009 Figure from Junaidi et al. 2003

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Use in male dogs Further indications androgen-related disorders: benign hyperplasia of the prostate, adenomas of the hepatoid glands treatment of behavioural problems (hypersexuality, aggressiveness) => identify dogs where castration may not be beneficial alopecia X Riesenbeck et al. 2002; Goericke-Pesch et al., 2010; de Gier et al. 2012

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Initial changes in testosterone concentrations: Goericke-Pesch et al. 2011 0 1 2 3 4 5 10 13 17 20 24 28 days after treatment ng/ml 7 6 5 4 3 2 1 0 Use in tom cats 5 of 10 toms basal T after 20 days 9 of 10 toms basal T after 11 weeks

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Long-term changes in testosterone concentrations: 0 1 2 3 5 10 13 17 20 24 28 56 84 112 140 168 196 224 252 days after treatment Goericke-Pesch et al. 2011 T<0.1 ng/mL over > 15 months in all toms Use in tom cats

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Use in tom cats As a consequence of testerone withdrawal significant decrease of testicular volume: [%] 100 80 60 40 20 0 1 4 8 12 16 20 24 28 32 36 week Goericke-Pesch et al. 2011

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Use in tom cats As a consequence of testosterone withdrawal a loss of penile spines was observed: Goericke-Pesch et al. 2011, Novotny et al. 2012

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Use in tom cats Goericke-Pesch et al. 2011, Novotny et al. 2012 Further changes as a consequence of testosterone withdrawal: initially increased sexual behaviour in 8/10 cats afterwards significantly decreased sexual behaviour from week 11/16 on no more urine marking temporary infertility: TSC↓, motility ↓ but: highly variable testicular histology

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Use in tom cats Full reversibility regarding all effects induced: rapid testosterone increase mean duration of efficacy: 551.9 ± 90.1 days; high variability Goericke-Pesch et al.

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Use in prepubertal queens Postponement of puberty: Treatment at 50% adult body weight postponed feline puberty without altering growth rate. 114.4 ± 12.7 days old queens (n=30), 1.5 ± 0.1 kg treatment with 4.7 mg deslorelin implant (n=15) age at puberty: 281.2 ± 21.6 (180-428) days [deslorelin] vs 177.8 ± 10.8 (134–286) days [controls]; p < 0.01 no puberty observed after 18 months (n=1) [deslorelin] body weight at puberty: 2.6 ± 0.1 kg [deslorelin] vs 2.5 ± 0.1 kg [controls]; p > 0.1 Side effects: estrus induction (n=1), 13 days after treatment pyometra (n=1), 92 days after treatment Risso et al. 2012

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Use in adult queens Reversible contraception and suppression of estrus: initial estrus induction possible: increase in fecal E2, clinical estrous signs 10/10 Munson et al. 20/21 Toydemir et al. 4/10 Ackermann et al., 1 ovulated, 3/6 without estrous signs, but ovulation Significantly lower E2 after combined megestrol acetate treatment, but also estrus induction 6/7. induction of ovulation (100% in estrus, 40%) possible induced estrus may be fertile! possible influence on luteal function (early P4 decrease) Munson et al. 2001, Rubion et al. 2006, Goericke-Pesch et al. 2010, Toydemir et al. 2012, Ackermann et al. 2012

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Use in adult queens estrus during treatment possible (after 138 and 155 days, resp.) variable duration of efficacy (4.7 mg: 483 – 1025 days, 1x > 1102 days; 680.4 ± 62.0 days; 6 mg: 7.5 – 14 months; 9.4 mg: >18 months) reversibility of effects induced estrus and ovulation induction possible naturally occuring estrus reversible infertility => 7/8 conceived in the first post-treatment estrus 1/8 conceived in the third estrus litter size 1-5 kittens (3.3±1.5 kittens) Munson et al. 2001, Rubion et al. 2006, Goericke-Pesch et al. 2010, Toydemir et al. 2012, Ackermann et al. 2012

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Conclusions Male dog/Tom: reversible downregulation of endocrine and germinative testicular function tom: high variability of the onset of endocrine downregulation, of the duration of efficacy and of the degree of germinative downregulation Queen: initial estrus induction possible (short/long-term) suppression of estrus full reversibility regarding estrus and fertility For short-term treatment: treatment into umbilical area instead of neck. Repeated treatments possible for long-term/permanent contraception. GnRH agonist implants offer a suitable alternative for contraception in male dogs and male and female cats!

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Thank you for your attention!

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