• View in gallery

    Mean weekly rates of egg production from Japanese quail (Coturnix coturnix japonica) that received a 4.7-mg deslorelin acetate implant (treatment group [circles]; n = 10 at the start of the study) or an identically sized placebo implant (control group [squares]; 10) on day 0. Egg production was recorded daily for 180 consecutive days. One bird from the treatment group died on day 29, and 1 bird from the control group died on day 65. Mean rate of egg production (total number of eggs laid/group divided by the number of birds in the group) was calculated on a daily basis and included antemortem egg production data from deceased birds. Mean daily rate of egg production was then calculated for each week and plotted for each group. Rates were significantly (P < 0.05) different (shaded area) between groups from weeks 2 through 12.

  • View in gallery

    Mean and SD plasma concentrations of androstenedione for the same quail as in Figure 1. Blood samples were obtained between 7 am and 8 am on days 0, 14, 29, 62, 90, 120, 150, and 180, and plasma was stored at −70°C until analysis. *Value is significantly (P < 0.05) different between treatment and control groups. See Figure 1 for remainder of key.

  • View in gallery

    Mean and SD plasma concentrations of 17β-estradiol for the same quail as in Figure 1 (A) and for the same groups after exclusion of 4 birds in the treatment group that continued to lay eggs following injection of the deslorelin acetate implant were excluded from the analysis (B). See Figures 1 and 2 for remainder of key.

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Evaluation of the efficacy and safety of single administration of 4.7-mg deslorelin acetate implants on egg production and plasma sex hormones in Japanese quail (Coturnix coturnix japonica)

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  • 1 William R. Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.
  • | 2 Department of Veterinary Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.
  • | 3 Department of Veterinary Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.
  • | 4 Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996.
  • | 5 California Animal Health and Food Safety Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.
  • | 6 Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.
  • | 7 Department of Veterinary Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.

Abstract

Objective—To evaluate the effects of 4.7-mg deslorelin acetate implants on egg production and plasma concentrations of 17β-estradiol and androstenedione in Japanese quail (Coturnix coturnix japonica) over 180 days and assess safety of the implants in quail via gross and histologic examination.

Animals—20 female Japanese quail.

Procedures—Following a 7-day period of consistent egg laying, quail were anesthetized and received a 4.7-mg deslorelin implant (treatment group; n = 10) or identical placebo implant (control group; 10) SC between the scapulae. Egg production was monitored daily. Plasma concentrations of 17β-estradiol and androstenedione were measured on days 0 (immediately prior to implant injection), 14, 29, 62, 90, 120, 150, and 180 via radioimmunoassay. Birds were weighed periodically and euthanized at day 180 for complete necropsy.

Results—Egg production was significantly decreased in the treatment group, compared with the control group, from 2 to 12 weeks after implant injection. Egg production ceased in 6 of 10 quail in the treatment group (mean duration of cessation, 70 days). Plasma androstenedione and 17β-estradiol concentrations were significantly lower on day 29 in the treatment group than in the control group. Plama androstenedione and 17β-estradiol concentrations were significantly lower on day 29 in the treatment group then in the control group.

Conclusions and Clinical Relevance—4.7-mg deslorelin acetate implants reversibly decreased egg laying for approximately 70 days in most of the Japanese quail evaluated. Further studies evaluating implants containing different concentrations of the drug are needed in quail and other avian species.

Diseases associated with the reproductive tract are common in birds; dystocia, chronic egg laying, and egg yolk peritonitis are among the most common reproductive disorders reported in companion avian species.1,2 Definitive treatment often includes surgical removal of the reproductive tract, which carries a higher risk and cost than medical treatment. Therefore, many of these reproductive disorders are managed medically. Numerous treatments have been used; however, leuprolide acetate, a GnRH agonist, is the current therapeutic drug of choice.3,4 This synthetic GnRH agonist was designed as a depot formulation to provide long-term treatment for reproductive diseases in humans.5 Gonadotropin-releasing hormone agonists initially stimulate release of LH and FSH from the anterior pituitary gland.6 This stimulation is short-lived because persistence of these agonists will cause downregulation of GnRH receptors in cells that produce LH and FSH via negative feedback mechanisms.7 Despite the benefits of leuprolide acetate, it is an expensive drug and has a short duration of action in birds; it has been reported to significantly decrease plasma sex hormone concentrations for approximately 2 weeks in Hispaniolan Amazon parrots.8

Deslorelin acetate is another synthetic GnRH agonist that is formulated in a controlled-release implant designed for SC administration in dogs as a reversible contraceptive; it is currently not FDA approved in the United States for use in dogs. In a previous study,9 56 sexually intact male dogs (body weight, 3.8 to 44 kg) received a single 4.7-mg deslorelin implant, which resulted in decreased circulating concentrations of reproductive hormones for 6 months. An additional 10 sexually intact male dogs (body weight, 7 to 36 kg) were administered a 9.4-mg deslorelin implant, which suppressed testosterone for approximately 12 months. The effect on reproduction was reversible in all dogs studied. Very recently, 4.7-mg deslorelin implants have been legally marketed in the United States as an FDA Indexed Minor Use/Minor Species product under MIF 900-013 for the management of adrenal gland cortical disease in male and female domestic ferrets. Deslorelin acetate has been used to modulate reproductive hormones in many species,10–20 and there is an anecdotal report21 on the use of deslorelin acetate implants in various avian species. However, to our knowledge, no controlled clinical trials have described the efficacy and safety of this product in birds. The objectives of the study reported here were to evaluate the effects of a 4.7-mg deslorelin acetate implant on egg production and plasma concentrations of 17β-estradiol and androstenedione in young female Japanese quail (Coturnix coturnix japonica) over a 180-day period and to evaluate the safety of the implants through gross and histologic examination at the end of the study. We hypothesized that the 4.7-mg deslorelin implant would significantly and reversibly decrease egg production and plasma sex hormone concentrations, compared with values for the control group, and would not cause any important pathological changes in quail.

Materials and Methods

Birds—Twenty 8-week-old female Japanese quail with a mean ± SD body weight of 137.5 ± 11.5 g were used for the study. The birds were individually housed indoors with a constant photoperiod (16 hours of light and 8 hours of dark) via nonfluorescent lighting and were fed a commercial diet for egg-laying poultry ad libitum.a Prior to inclusion in the study, birds were determined to be healthy on the basis of the results of a physical examination, PCV, WBC count estimate, and fecal examination for parasites. Birds were randomly assigned to either the control (n = 10) or treatment (10) group by an automated computer software program.b The study protocol was approved by the University of California-Davis Institutional Animal Care and Use Committee.

Drug implantation and monitoring of birds and egg production—The birds were monitored for 7 days prior to the start of the study to ensure that each was laying eggs regularly at a rate of approximately 1 egg/24 h. Anesthesia was induced for placement of the implants in all birds by administration of 2% to 4% isoflurane in O2 with a flow rate of 1 L/min delivered via face mask. The deslorelin and placebo implants were obtained directly from the manufacturer, and each were from the same lot. The reported release rate is > 1 μg/d for periods of > 1 year for dogs22; the release rate is unknown for avian species.

Each bird received a 4.7-mg deslorelin implantc or an identical placebo implant (containing no deslorelin) between the scapulae with a sterile, disposable applicator syringe and 14-gauge needle provided by the drug manufacturer. The skin defect was closed with tissue adhesive.d Doses of deslorelin acetate in the implants ranged from 31.5 to 37.3 mg/kg when calculated on the basis of the body weight of the birds. The implant is commercially available in 2 doses, and the smaller dose was selected for this initial study.

Egg production was recorded for all birds every morning between 7 am and 9 am for 180 days after implantation. Subjective assessments of the eggs, including color and shell quality, were performed daily. Basic health assessments (observations of eating, drinking, and fecal consistency and output) were also performed daily. The birds were weighed weekly for the first 6 weeks and then monthly for the remainder of the 180-day study period. The presence of the deslorelin or placebo implant was confirmed via palpation or direct inspection weekly for the first 6 weeks and again at necropsy. The investigators monitoring egg production and health assessments were blinded to treatment groups of birds.

Plasma sex hormone evaluation—Blood samples (1.0 to 1.3 mL) were collected immediately before implantation (day 0) from a jugular vein with a 3-mL syringe and 25-gauge needle and placed into heparinized tubes.e The samples were immediately centrifuged to separate the plasma, which was stored at −70°C until analysis. Venipuncture and sample handling were repeated in the same manner on days 14, 29, 62, 90, 120, 150, and 180. Venipuncture was performed between 7 am and 8 am at each collection.

Plasma samples were analyzed for 17β-estradiol and androstenedione concentrations via commercially available radioimmunoassay kitsf at the College of Veterinary Medicine Clinical Endocrinology Laboratory, University of Tennessee. All samples were run simultaneously to avoid interassay variation, and laboratory personnel were blinded to the treatment groups of birds. Performance characteristics for the 17β-estradiol and androstenedione assays were determined with pooled plasma from 5 healthy female Japanese quail. The intra-assay coefficient of variation for estradiol and androstenedione was 6.54% and 5.56%, respectively. The interassay coefficient of variation for estradiol and androstenedione was 10.34% and 11.38%, respectively. Mean recovery of known amounts of estradiol standards added to quail plasma was 111.50%. Mean recovery of known amounts of androstenedione standards added to quail plasma was 91.50%. The analytic sensitivity of the estradiol and androstenedione assays was 7.2 pg/mL and 0.05 ng/mL, respectively, on the basis of information provided by the manufacturer.

Gross and histologic evaluation—All birds were euthanized on day 180 via CO2 chamber, and a complete necropsy was performed. The entire reproductive tract was removed, and the weight of the ovary, size of the ova, oviduct length, and presence of eggs were recorded for each bird. Aerobic bacteriologic culture was performed on liver samples from birds with subtle multifocal pallor in the parenchyma detected on gross observation; swabs were inoculated on a combination blood and McConkey agar plate, followed by incubation at 37°C with 5% to 10% CO2. The complete reproductive tract (ovary, infundibulum, magnum, isthmus, uterus, and vagina) as well as samples of the brain, peripheral nerves, air sacs, heart, lung, liver, spleen, kidney, crop, intestines, and skin and subcutaneous tissues at the implant site were immersed in neutral-buffered 10% formalin solution, embedded in paraffin wax, sectioned at 4 μm, and stained with H&E. The histologic examination was performed by an ACVP board-certified pathologist (AM) who was blinded to the treatment groups of birds, and changes in the reproductive tract as well as ancillary lesions in the remaining organs were noted. In birds that had liver disease detected on histologic examination, portal hepatitis was scored as follows: multifocal, small infiltrates (mild); multifocal, larger infiltrates occasionally extending into the parenchyma (moderate); and extensive, multifocal to diffuse infiltrates with evidence of hepatocellular damage (severe). All sections of liver with moderate or severe portal hepatitis lesions were additionally stained with Masson trichrome for collagen. Kidney sections of birds with evidence of glomerulopathy were stained with phosphotungstic acid haematoxylin for fibrin. Immunohistochemical analysis for Chlamydophila sppg (1:50 dilution) was performed on the liver sections from one of the birds with severe hepatitis.

Statistical analysis—Differences in oviductal and ovary weights between the treatment and control groups were evaluated with a Student t test. Egg production data were analyzed by calculating egg-laying rate (total number of eggs laid/group divided by the number of birds per group) for each day. Mean daily egg-laying rates for each group were determined for each week of the study, and a Student t test was used to evaluate differences between the treatment and control groups. Plasma androstenedione and 17β-estradiol concentrations were evaluated for normal distribution via a Shapiro-Wilk test and reported as mean and SD. Two-way repeated-measures ANOVA was performed on plasma androstenedione and 17β-estradiol concentrations to examine secular changes, group differences, and time-by-group interactions with commercially available software.h For all analyses, values of P ≤ 0.05 were considered significant.

Results

Birds and egg production—Mean rates of egg production (eggs/group/wk) for the treatment and control groups were summarized on a weekly basis throughout the 180-day study period (Figure 1). Mean rate of egg production was significantly (P = 0.004) decreased in the treatment group, compared with the control group, by week 2 (0.4 vs 1.0 eggs/group/wk, respectively), and this persisted through week 12 (0.4 vs 0.9 eggs/group/wk, respectively; P = 0.013). At week 13, no significant (P = 0.18) difference was detected between the 2 groups for this variable, and this persisted for the remainder of the study.

Figure 1—
Figure 1—

Mean weekly rates of egg production from Japanese quail (Coturnix coturnix japonica) that received a 4.7-mg deslorelin acetate implant (treatment group [circles]; n = 10 at the start of the study) or an identically sized placebo implant (control group [squares]; 10) on day 0. Egg production was recorded daily for 180 consecutive days. One bird from the treatment group died on day 29, and 1 bird from the control group died on day 65. Mean rate of egg production (total number of eggs laid/group divided by the number of birds in the group) was calculated on a daily basis and included antemortem egg production data from deceased birds. Mean daily rate of egg production was then calculated for each week and plotted for each group. Rates were significantly (P < 0.05) different (shaded area) between groups from weeks 2 through 12.

Citation: American Journal of Veterinary Research 74, 2; 10.2460/ajvr.74.2.316

Six of 10 birds in the treatment group stopped producing eggs 3 to 9 days after implant injection. Mean duration of cessation of egg laying in these birds was 70 days. The remaining 4 birds in this group continued to lay eggs regularly throughout the 180-day study period. One bird in the control group stopped laying eggs after approximately 30 days, and this persisted for the duration of the study. On day 2, birds in the treatment group laid more eggs (n = 13) than did birds in the control group (8); however, the difference was not significant. Also on day 2, 3 birds in the treatment group laid eggs with atypical color patterns (these were either completely white in appearance [2 eggs from 2 birds] or were small, uniformly brown, and thin shelled [1 egg from 1 bird]).

Two birds died during the course of the study, 1 from each group. Necropsies were performed on both birds. The bird from the treatment group had no evidence of systemic disease or injury. The cause of death in the bird from the control group was self-trauma to the neck. Neither bird had evidence of reproductive tract disease. All other birds had normal appetites and behavior and maintained their body weights for the duration of the study. No signs of illness associated with the implant were detected at any time during the study.

Plasma sex hormones—Mean and SD plasma concentrations of androstenedione (Figure 2) and 17β-estradiol (Figure 3) were plotted. Mean androstenedione concentration was significantly (P = 0.026) lower on day 29 in the treatment group (0.36 ng/mL) than in the control group (0.79 ng/mL), but there were no significant differences at any other time point. Plasma 17β-estradiol concentrations were significantly (P = 0.026) lower in the treatment group than in the control group on day 29 (118.07 vs 211.34 pg/mL, respectively). A significant (P = 0.036) difference was also detected on day 180 (206.69 vs 151.13 pg/mL in the treatment and control groups, respectively). When birds in the treatment group that continued to lay eggs (n = 4) were removed from analysis for both hormones, 17β-estradiol concentrations were significantly lower in the remaining treatment group birds, compared with birds in the control group, on days 14 (68.8 vs 222.93 pg/mL; P = 0.018), 29 (60.5 vs 211.34 pg/mL; P = 0.001), 62 (85.1 vs 203.27 pg/mL; P = 0.019), and 90 (128 vs 236.78 pg/mL; P = 0.027). No significant group-by-time interaction was detected in the androstenedione group after the 4 apparently unaffected birds were removed from analysis.

Figure 2—
Figure 2—

Mean and SD plasma concentrations of androstenedione for the same quail as in Figure 1. Blood samples were obtained between 7 am and 8 am on days 0, 14, 29, 62, 90, 120, 150, and 180, and plasma was stored at −70°C until analysis. *Value is significantly (P < 0.05) different between treatment and control groups. See Figure 1 for remainder of key.

Citation: American Journal of Veterinary Research 74, 2; 10.2460/ajvr.74.2.316

Figure 3—
Figure 3—

Mean and SD plasma concentrations of 17β-estradiol for the same quail as in Figure 1 (A) and for the same groups after exclusion of 4 birds in the treatment group that continued to lay eggs following injection of the deslorelin acetate implant were excluded from the analysis (B). See Figures 1 and 2 for remainder of key.

Citation: American Journal of Veterinary Research 74, 2; 10.2460/ajvr.74.2.316

Gross and histologic evaluation—The deslorelin and placebo implants were found intact at the original implantation site in all birds during gross necropsy. Gross inspection of the birds revealed no abnormalities except for 1 bird from the control group that had a severely atrophied reproductive tract detected on histologic examination. This bird stopped laying eggs several weeks into the study and was the only bird that was not laying by day 180.

The reproductive tracts from all birds had subjectively minimal histopathologic changes, and these were evenly distributed among the control and treatment groups. Changes in the magnum consisted of few discrete foci of pallor due to loss of densely eosinophilic secretory granules in the tubular glands of 3 birds (2 from the control group and 1 from the treatment group) and a more extensive pallor and vacuolar changes in another 3 birds (2 from the control group and 1 from the treatment group). There were minimal focal lymphoplasmacytic infiltrates in the magnum and isthmus of 1 bird from the treatment group, in the infundibulum of 2 birds (1 from each group), and in the vagina of all birds. Mean ± SD weight of the oviducts (9.63 ± 3.54 g vs 9.51 ± 4.28 g for the treatment and control groups, respectively; P = 0.95) and ovaries (5.16 ± 1.13 g vs 4.81 ± 1.87 g, respectively; P = 0.63) did not differ significantly between groups. The implant site was grossly unremarkable in all birds and was composed of a well-circumscribed granuloma located in the panniculus with central blue-gray tinged foreign material on microscopy. One bird in the control group had mild multifocal lymphoplasmacytic myositis deep to the implant site. Additional findings were crop candidiasis in 3 birds (1 from the control group and 2 from the treatment group) and mild splenic hyperplasia and mild to moderate vacuolar hepatopathy in all birds. In 3 birds of the control group and 4 birds of the treatment group, there were acute and chronic inflammatory changes in the liver, with evidence of early collagen deposition in the chronic cases. The lesions were acute multifocal random necrosis or nonsuppurative portal hepatitis with hepatic cord disarray, anisokaryosis, and anisocytosis. Aerobic bacterial culture was performed for liver swabs from 2 birds (1 bird with extensive nonsuppurative hepatitis and 1 in which no lesion was identified on histologic examination); there was no bacterial growth after incubation for 48 hours. Results of immunohistochemistry for Chlamydophila spp in the tested bird were negative. In the kidneys of 3 birds in the treatment group, multiple glomeruli had deeply eosinophilic material within the mesangial capillaries that was multifocally positive for fibrin via phosphotungstic acid haematoxylin staining. No other remarkable lesions were noted in any of the remaining organs examined.

Discussion

In the present study, Japanese quail in the treatment group that received a 4.7-mg deslorelin acetate implant had significantly decreased mean egg production detected 2 weeks after implant injection, and this persisted through the 12-week time point. This suggests a total duration of action of approximately 70 days. However, 4 of 10 birds in the treatment group continued to lay eggs regularly throughout the 180-day study. On day 2 of the study, a greater number of eggs were laid by the treatment group, compared with the control group; however, the difference was not significant. An initial increase in egg laying can be explained by the initial stimulatory effect of a GnRH agonist on FSH and LH.7 Also on day 2, several birds in the treatment group laid eggs with atypical color patterns. Several of those eggs were completely white, and another lacked the typical spotted brown pigmentation of Japanese quail eggs.23 In other poultry species, increased transit time has been reported to have the opposite effect on egg color, with increased pigment deposition on egg shells.24 No such changes in shell color were noted when affected birds in the treatment group began to lay eggs regularly again, at approximately day 70.

Deslorelin acetate is a GnRH agonist that, similar to the naturally occurring hypothalamic decapeptide GnRH, initially stimulates secretion of LH and FSH from the pituitary gland. Ultimately, the excessive amount of GnRH produced in an animal will lead to downregulation of GnRH receptors via negative feedback mechanisms. This receptor deficiency will eventually result in decreased production and release of the gonadotropins FSH and LH.25 With this lack of LH and FSH, the reproductive tract becomes quiescent. Overall, the function of GnRH in birds is similar to that of mammals; however, some texts refer to this hormone as LH-releasing hormone because the mechanisms dictating pituitary release of FSH in birds are not clear.26 Three forms of avian GnRH have been identified.2 This physiologic difference in avian versus mammalian GnRH may explain the decreased efficacy (egg laying ceased for only 6/10 birds in the treatment group) and decreased duration of effect of deslorelin acetate implants in Japanese quail in the present study, compared with dogs (70 days vs 6 months, respectively).9 Drug or implant failure is a less likely possibility for the discrepancy in efficacy among quail in the treatment group, considering that all implants were obtained simultaneously from the manufacturer and were from the same lot. The efficacy and duration of deslorelin in quail were disproportionate to the dose, considering the dose contained in implants of the present study was substantially higher (31.5 to 37.3 mg/kg) than doses used in previous studies of dogs (0.15 to 0.76 mg/kg)9 and ferrets (3.0 to 4.41 mg/kg).10

Although originally developed for use in domestic dogs, deslorelin acetate implants have been used for contraception in many mammalian species, such as ferrets,12,27 domestic cats,28,29 nondomestic cats,15,16 rats,17 flying foxes,18 boars,14 and tammar wallabies.20 In addition to contraception, deslorelin acetate has been used to enhance uterine involution in dairy cattle30 and to decrease sex hormones in ferrets with adrenocortical disease.10 Withdrawal times for deslorelin for quail and their eggs have not been established. Recently, this drug has become available in the United States for the treatment of adrenal cortical disease in ferrets. However, the product is still not FDA-approved for other species or for any animals intended for use as food. Deslorelin in avian species could also be useful for the treatment of diseases and unwanted associated reproductive behaviors. Definitive treatment for many reproductive disorders is salpingohysterectomy, which involves removal of the left oviduct, given that the right ovary and reproductive tract are absent or vestigial in most avian species.31 Because of its proximity to the aorta, the ovary is rarely removed at the time of surgery because of the possibility of fatal hemorrhage. Continued ovarian activity and associated reproductive behaviors (aggression, feather-destructive behavior, and masturbation) may still occur following surgery.1,32 Because of the risks inherent in surgical intervention, there are obvious benefits for a long-term medical treatment of reproductive disease in birds.

Egg production is a variable used to objectively monitor avian reproductive tract activity over an extended period of time and has been used in another study32 to quantify the effects of various contraceptives. Young female Japanese quail were chosen for use in the study reported here because they lay eggs on a consistent basis, approximately 1 egg every 24.5 hours when provided with an appropriate light-dark cycle.33 Egg production in our study was reported as a mean weekly rate to allow inclusion of data from the 2 birds that died during the study. The effects of deslorelin acetate egg production were reversible, and all the birds in the treatment group were producing eggs regularly by the end of the study.

Mean plasma concentrations of the hormones androstenedione and 17β-estradiol were significantly lower in the treatment group than in the control group in the present study on day 29, which was consistent with the egg production data. Decreased concentrations of these hormones have also been reported following administration of other GnRH agonists in other avian species.8,34,35 However, a significant difference in 17β-estradiol concentration between groups was also seen at day 180 in the present study, which was not consistent with the egg production data. This discrepancy may have been attributable to differences in the number of birds in each group that were actively laying eggs. By day 180, there were 9 birds in each group, with all 9 birds in the treatment group laying eggs regularly and only 8 birds in the control group laying consistently. Also, the SDs of both groups were large for both hormones measured. A second statistical analysis was performed to determine whether the correlation of either hormone with egg production would improve when the 4 birds in the treatment group that continued to lay eggs throughout the study were excluded, with the result that mean 17β-estradiol concentrations were significantly lower in the treatment group than in the control group from days 14 to 90. This finding was more consistent with egg production data; however, large SDs were still detected. Androstenedione concentrations were similar regardless of exclusion of the same 4 egg-laying birds from the treatment group in the second analysis. Androstenedione and 17β-estradiol concentrations differ during the ovulation-oviposition cycle of avian species.26 A study36 has shown that ovulation occurs approximately 15 to 90 minutes following egg laying in Japanese quail hens. Specific ovulation and oviposition times were not known for our study birds; therefore, venipuncture procedures could not be correlated with individual birds' oviposition. Despite performing venipuncture within the same hour on each sample collection day, substantial SDs were noted within each group for these sex hormones.

Androstenedione and 17β-estradiol concentrations were evaluated in a study8 examining the effects of a different GnRH agonist (leuprolide acetate) in non-breeding psittacine birds; in the study reported here, evaluation of these hormone concentrations did not contribute any additional information regarding the efficacy of deslorelin acetate in Japanese quail. Luteinizing hormone has been examined in Japanese quail to monitor reproductive activity.37–39 Unfortunately, the authors were unable to identify a commercially available assay or a laboratory that is currently performing avian LH and FSH plasma concentration measurements. Progesterone has been shown to follow a more predictable pattern in relationship to ovulation and is found in lower concentrations in nonovulating Japanese quail.37 Therefore, plasma progesterone concentration may be a more accurate measure of reproductive activity in this species. Increased frequency of sampling may have improved determination of the onset and duration of deslorelin acetate. However, the small size of our study subjects precluded more frequent venipuncture. If larger avian species were examined in future studies, additional hormone measurements may prove useful in this regard.

Reports of adverse effects of GnRH agonists are uncommon in the literature.40 Injection site discomfort and lameness have been described for a small number of California sea lions and California sea otters,41 and suspected anaphylaxis and death following leuprolide acetate administration have been described in 2 elf owls.42 Recently, a dog treated for 3 months with a 4.7-mg deslorelin implant was reported to develop signs of prolonged estrus due to follicular cysts.43 Weight gain and mild edema around the implant sites have been reported in female cats that received deslorelin implants.28 In that study, continued ovarian suppression was noted in 8 of 10 cats beyond the 14-month study period, which brought into question the reversibility of deslorelin acetate in felids. No adverse effects were noted in any Japanese quail during the present study, and body weights remained steady in all birds.

No clinically important pathological changes of the reproductive tract were detected in treated birds of the present study. The changes noted in the tubular glands of the magnum, loss of secretory granules, and vacuolar changes were found in both groups. Similar changes have been noted in quail of similar age in association with cessation of egg laying.44 Japanese quail age more rapidly than do the larger gallinaceous species; subsequently, their rate of egg laying decreases sharply after hens are 26 weeks old if they are housed under stimulatory lighting conditions.45 Therefore, the mild lesions noted in the reproductive tract of birds from both groups were likely age related. Hepatic lesions were identified in both groups of birds during complete pathological examination. These lesions were considered incidental background changes because an infectious etiology was not identified, and all birds remained free of clinical signs of disease throughout the course of study. The renal glomeruli contained fibrinlike depositions reminiscent of fibrin thrombi in 3 birds of the treatment group. One of these birds also had liver changes; however, the others had no other changes indicative of a systemic infectious or inflammatory process. In humans, orally administered contraceptives have been shown to have a net prothrombotic effect, likely due to increased levels of estrogens and, to a lesser extent, progestins.46 However, GnRH agonists cause a dramatic decrease in circulating concentrations of estrogens and progestins after a brief initial stimulatory effect. Therefore, these contraceptives are not expected to cause the thrombotic complications that have been associated with orally administered contraceptives containing a combination of estrogens and progestins. In addition, these were incidental findings at necropsy; the clinical importance of these lesions in the 3 treatment birds and potential effects of GnRH agonists on hemostasis remains unknown.

The decreased duration of effect of the 4.7-mg deslorelin acetate implant (approx 70 days) in Japanese quail of the present study, compared with dogs that received 4.7-mg implants containing the same agent (6 months),9 may represent an inherent difference in drug metabolism for this particular species or avian species in general when compared with mammals. In the study reported here, we evaluated a single administration of a 4.7-mg deslorelin implant, and multiple or repeated dose administrations could have a different efficacy or may potentially result in pathological changes. Japanese quail were used as a representative small avian species, but responses may differ among these.

Further investigations are needed to determine the pharmacokinetics of this drug and whether implants containing higher doses of deslorelin acetate than those used in the present study have greater efficacy, longer duration of action, or both and are safe for use in Japanese quail. The effects and safety of the 4.7-mg implants used in the present study or implants that provide larger doses of deslorelin acetate should be evaluated in other avian species in which this drug may be considered for clinical use, such as those commonly kept in zoological institutions or by private owners. The study of withdrawal times for food-producing avian species should also be evaluated in conjunction with its clinical effects.

ABBREVIATIONS

FSH

Follicle-stimulating hormone

GnRH

Gonadotropin-releasing hormone

LH

Luteinizing hormone

a.

Layena, Land O' Lakes Purina Feed LLC, Turlock, Calif.

b.

Randomizer.org. Research randomizer, version 4.0, Available at: www.randomizer.org/form.htm. Accessed Mar 4, 2011.

c.

Suprelorin, Peptech Animal Health Pty Ltd, Macquarie Park, NSW, Australia.

d.

Surgi-lock 2oc, Meridian Animal Health, Omaha, Neb.

e.

BD Microtainer, Becton, Dickinson and Co, Franklin Lakes, NJ.

f.

ImmuChem Double Antibody, MP Biomedicals, Solon, Ohio.

g.

Chlamdophilia spp antibody, Virostat, Portland, Me.

h.

Stata/IC, version 12.0, StataCorp LP, College Station, Tex.

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Contributor Notes

Supported by a grant from the Center for Companion Animal Health, School of Veterinary Medicine, University of California-Davis.

Peptech Inc donated the deslorelin and placebo implants.

Presented in abstract form at the 43rd Annual Conference of the American Association of Zoo Veterinarians, Kansas City, Mo, October 2011.

The authors thank Steven Petritz and Thea Lambert for technical assistance.

Address correspondence to Dr. Hawkins (mghawkins@ucdavis.edu).