The use of a 4.7 mg deslorelin slow release implant in male dogs in the field.

OBJECTIVE: Slow-release GnRH agonist implants (SRI) are used for reversible medical downregulation of testicular function in male dogs as an alternative to surgery. The 4.7 mg deslorelin SRI should reduce testosterone after 6-8 weeks and induce castration-like effects for 6 months (mon). However, some individual variation is described in the field in regard to onset and duration of effect. For this reason, we aimed to study the effects of the 4.7 mg deslorelin SRI in a larger cohort. MATERIAL AND METHODS: In total 50 intact, healthy male dogs (12-48 months, mon; 9-40 kg) were treated with a 4.7 mg deslorelin SRI into the umbilical area (TG, n=45) or served as untreated controls (CG, n=5). CG dogs were surgically castrated after measurement of testicular dimensions and blood sampling for testosterone. In TG, SRIs remained for 5 mon in place and subsequently 3-7 male dogs were surgically castrated at removal (week, W 0) or 1, 2, 3, 4, 5, 6, 7, 8 or 10 weeks later. Examination parameters were testicular dimensions (before treatment, at 4, 8, 12 W, 5 mon, weekly until castration), testosterone (before treatment, at 8 W, 5 mon, castration) and testicular histology (castration). RESULTS: Whereas examination parameters did not differ between CG and TG before treatment, testicular volume and testosterone was significantly reduced at all time points during treatment. In all but 3 (8 W) and 2 male dogs (5 mon) testosterone was basal during treatment before removal, whereas the parameters were significantly reduced compared to pre-treatment in the respective dogs. After implant removal, testosterone and testicular volumes increased. However, different to earlier studies, the "restart" was more variable with individual basal testosterone until W7, but also physiological testosterone concentrations in W2. Similarly, histological testicular findings at castration were quite variable: besides an arrest on spermatogonia and spermatocytes, elongated spermatids with normal spermatogenesis were found in individual dogs. CONCLUSION: Our study confirms the efficacy of the deslorelin SRI, but also individual variation especially regarding reversibility of effects on endocrine and germinative testicular function. CLINICAL RELEVANCE: Deslorelin SRIs offer a suitable alternative to surgical castration with individual variation to be considered when used in clinical practice.

Anti-Müllerian Hormone Concentrations for Determining Resumption of Sertoli Cell Function following Removal of a 4.7 mg Deslorelin Implant in Tomcats.

Background: Deslorelin implant use in cats is a medical alternative to surgical sterilization, and due to its prolonged efficacy, its use has shown growing interest in the veterinary community. In the case of breeding facilities, its removal is often requested for the early restoration of testicular function. As anti-Müllerian hormones (AMH) in males is dependent of testosterone secretion, its assay may determine the restoration of testicular steroid secretion. An average of 3 weeks has been already described for tomcats' testicular function resumption after implant removal, but information about AMH concentrations in deslorelin-treated tomcats is lacking. Methods: Fourteen tomcats were treated for temporary suppression of fertility with a 4.7 mg deslorelin implant, which was surgically removed after 3, 6 or 9 months (n = 6, 4 and 4 tomcats, respectively). A general clinical and reproductive check with a gonadorelin stimulation test for testosterone determination was performed before deslorelin implant administration. After implant removal, tomcats' testicles were ultrasonographically checked for volume determination every 1-2 weeks with observation of the glans penis (presence or absence of spikes) and blood collection to assay both testosterone and AMH concentrations. Results: AMH concentrations increased significantly during the deslorelin treatment from 20.95 ± 4.97 ng/mL to 82.41 ± 14.59 ng/mL (p < 0.05). Following implant removal, AMH concentrations progressively decreased to pre-treatment levels, with a value of 28.42 ± 7.98 ng/mL on the third week post-removal where testosterone secretion was again detected. Conclusions: Even if a big variability of AMH concentrations exists between male individuals, resumption of tomcats' testicular function following a deslorelin treatment can be determined by AMH assay.

Efficacy and Safety of 4.7 mg Deslorelin Acetate Implants as a Neutering Option in Male Cats: A Large-Scale Multicentre Randomised Controlled Study.

This multicenter-controlled, double-masked randomized European study was conduc-ted to confirm both the efficacy and safety of a deslorelin implant in controlling fertility and sexual behavior in a large population of tom cats over a 12-month period. Among the 225 screened individuals, a total of 205 privately owned indoor intact male cats, aged 3 months of age or older, were randomly allocated to a deslorelin implant (n = 154) or to a negative control group (n = 51). After the screening visit performed between day (D)-14 and D-7, six additional visits were sche-duled on D0, D45, D93, D186, D279 and D372. Effects on testosterone, sexual behaviors, penile spines, testicular volume and intact male cat urine odor were assessed at every visit under masked conditions as regards to the treatment group. In addition, phone calls from the investigators to the owners were scheduled on D7 and then on a monthly basis whenever no visit was scheduled. Success was defined as an individual serum testosterone concentration below or equal to 0.10 ng/mL and was 77.9% at D45, 83.1% at D93, 84.4% at D186 and D279, and 61.7% at D372 in the deslorelin group, and 3.9% at D45, 5.9% at D93, 3.9% at D186, 7.8% at D279 and 3.9% at D372 in the negative control group. Testing for superiority was made stepwise from D45 to D372 upwards; the difference in success rates was significant from D45 to D372 (p < 0.001 for each time point). The mean testosterone concentration dropped from baseline in the deslorelin group, remaining below the set threshold of 0.1 ng/mL until D372. From D7 onwards, the mean sum score for sexual behaviors (including vocalization, urine marking, aggression and intact male cat urine odor) was significantly lower at each observation time point in the deslorelin group compared to the control group, where no decrease in scores was observed. The mean percent change to baseline of the testicular volume and the percentage of cats with a decreased visibility and adult appearance of penile spines were significantly lower in the deslorelin group as soon as D45. No relevant safety concerns were reported during the course of the study. The deslorelin implant Suprelorin® 4.7 mg (Virbac, Carros, France) is a safe and effective neutering option, inducing infertility over a 12-month period when administered to intact male cats aged between 3 months of age and 11 years of age. The implants also successfully reduced sexual behaviors (i.e., vocalization, urine marking, aggression), intact male cat urine odor, testicular volume and penile spine score for 1 year (372 ± 5 days).

Chronic Use of Deslorelin in Dogs: Six Cases (2005-2022).

Deslorelin is currently registered for the induction of temporary infertility in male dogs, male cats, male ferrets, and also prepubertal female dogs, but research has shown its usefulness for other conditions requiring chronic treatment. This paper presents six cases of dogs chronically treated with deslorelin for indications such as benign prostatic hyperplasia, control of fertility, abnormal reproductive behavior and urinary incontinence. All animals were in good health during treatment. Treatment duration was 2-9 years. No short-term side effects were observed except for flare-up reactions, which were observed only in 1/4 intact males. Two dogs developed a neoplasia: a spayed bitch treated for urinary incontinence developed a pituitary carcinoma, and an intact male dog implanted for control of fertility developed a bladder carcinoma. While the pituitary carcinoma seems unlikely to be related to deslorelin, the bladder carcinoma could be due to the neutered condition of the dog (which was treated for 9 years) as urinary tract neoplasia is more common in dogs following gonadectomy. Chronic treatment with deslorelin is regarded as safe when an animal is being treated for life. The possibility that a pause in the treatment might be helpful for the animal should be investigated.

Efficacy and Safety of 4.7 mg Deslorelin Acetate Implants in Suppressing Oestrus Cycle in Prepubertal Female Dogs.

Our multicentric, masked, controlled and randomised study aimed to assess the efficacy and safety of Suprelorin® 4.7 mg (Virbac, Carros, France) regarding oestrus prevention in prepubertal intact bitches. Twelve- to eighteen-week-old females (n = 83) were allocated either a deslorelin implant (n = 62) or 0.9% sodium chloride (n = 21) group. Clinical assessment (heat signs), 17ß oestradiol and progesterone assays, and vaginal cytology were performed at day (D)0, D7, D21, month (M)3 and M6 after product administration, and were then performed every other month until reaching puberty. Trained owners assessed heat signs between each veterinary visit. All bitches (n = 83) reached puberty before M30. Deslorelin significantly extended the median time to sexual maturity when compared to the control group (377 days versus 217 days after D0, p < 0.0001). Three females, implanted between 16 and 18 weeks of age, expressed an induced oestrus. Additional descriptive data, collected over a 24 month-period, showed functional reproductive abilities in both deslorelin (n = 52) and control (n = 21) groups once puberty was achieved. In conclusion, Suprelorin® 4.7 mg seems to be an effective and safe option for postponing the onset of oestrus when administered to prepubertal female dogs aged from 12 to 16 weeks.

A Comparative Study of the Effects of Osaterone Acetate and Deslorelin Acetate on Sperm Kinematics and Morpho-Functional Parameters in Dogs.

Benign prostatic hyperplasia (BPH) is one of the most common problems in older male dogs that often has a huge impact on their health and welfare. This article presents a comparison between osaterone acetate (Ypozane®; Virbac®)(OA) and deslorelin acetate (Suprelorin®; Virbac®)(DA), medications that are the main therapeutic alternative to castration in dogs with BPH. Forty dogs were divided into four groups: I-negative control (five dogs without BPH); II-positive control (10 individuals diagnosed with BPH); III-15 dogs treated with DA, and IV-10 individuals treated with OA. Semen fractions were collected on days 0 (day of treatment), 7, 14, and 21, and weeks 8, 12, 16, and 20. Macroscopic, microscopic and CASA analyses were performed. Both DA and OA significantly affected the properties of the canine ejaculate. The DA lead to the lack of libido and had lesser effects to the sperm function before it caused azoospermia, whereas OA had no effect on libido and only temporary reduction in seminal plasma volume was observed, which resulted in temporary deterioration in the percentage of motile and progressive spermatozoa.

Double-Blind, Placebo-Controlled Trial of Cyproterone Acetate to Prevent Flare-Up Effect on Dogs Implanted With Deslorelin.

Deslorelin slow-released implants are registered in Europe for the reversible suppression of fertility in male dogs. After administration, a time-limited increase in sex hormones concentration and related behavioral problems may be observed. The aim of this work was to assess whether cyproterone acetate, a synthetic progestogen, can prevent this flare-up effect. Eighteen privately-owned entire male dogs were enrolled in this double-blind, placebo-controlled, randomized clinical trial. All subjects received a 4.7 mg deslorelin implant by SC route and 1-3 capsules containing either cyproterone acetate 2 mg/kg (N = 9) or a placebo (N = 9), by oral route BID for 14 days, depending on the dog's weight. The dogs were followed for 28 days. An increase in the blood testosterone concentration was observed in respectively 9/9 and 7/9 dogs of the control and cyproterone groups (p = 0.47). However, a worsening of the sex hormone related problems (i.e., urinary marking, mounting, aggressiveness toward other dogs and/or escape) was only observed in the placebo group, in 56 or 66% of the dogs as measured by respectively the veterinarian and the owners. Our study suggests that cyproterone acetate is effective and safe to supress the deslorelin induced behavioral flare-up effect, but not the rise in testosterone.

B-Mode and Doppler Ultrasonographic Findings of Prostate Gland and Testes in Dogs Receiving Deslorelin Acetate or Osaterone Acetate.

This article presents B-mode and color Doppler imaging of the prostate and testes in dogs suffering from benign prostate hyperplasia (BPH), and receiving deslorelin acetate (SuprelorinTM) or osaterone acetate (YpozaneTM). The study was planned as a controlled clinical trial, dogs were divided into negative control (healthy dogs, n = 10), positive control (dogs with BPH, n = 10), and study groups, III (n = 15), receiving deslorelin acetate (DA), and IV (n = 10), receiving osaterone acetate (OA). The B-mode appearance of the prostate parenchyma improved in all investigated dogs from the DA group, and in 60% of OA dogs. Prostate volume was reduced more quickly with OA (from D14), but lasting for a shorter time (on average up to week 20), compared to DA that reduced the prostate volume more slowly (>8 weeks), but the reduction remained longer (>24 weeks). The systolic peak velocity (SPV) and mean velocity (Vmean) were higher in all dogs diagnosed with BPH, compared to Control Group I. The indices did not change in both Control Groups I and II, whereas in study Groups III and IV they decreased throughout the study period compared to day 0 and Control Group II. In Group III the highest reduction was noted from day 21 to week 8, whereas in Group IV the lowest Vmean was recorded before day 21. Testicular parenchyma and volume changed significantly in Group III receiving DA, and the velocity of blood flow in the testicular artery correlated positively with testicular volume only in this group (III). The present study proved the usefulness of B-mode and color Doppler US imaging techniques for diagnosis and progress assessment of dogs suffering from BPH. The blood flow kinetics (mainly SPV) demonstrated a time association between the blood flow changes registered in the prostatic artery, and the subsequent volumetric and sonographic improvement of the prostate parenchyma. The reduction in flow indices was noted prior to the reduction in prostate volume, suggesting that the sonographic recovery of the prostate tissue, occurs secondarily to the regression of the prostate vascular system. Both investigated medications (osaterone acetate and deslorelin acetate) led to a significant sonographic improvement. Deslorelin acetate reduced prostate volume more slowly, but its effect lasted longer than for osaterone acetate.

Comparison of Clinical Effectiveness of Deslorelin Acetate and Osaterone Acetate in Dogs with Benign Prostatic Hyperplasia.

This article presents the results of a randomized clinical trial, designed to compare the efficacy and therapeutic profiles of YpozaneTM (osaterone acetate-OA) or SuprelorinTM (deslorelin acetate-DA) in male dogs with clinical signs of benign prostate hyperplasia (BPH). Forty-five intact male dogs were used in the study. The Group I (negative control) included 10 healthy dogs, the Group II (positive control) included 10 dogs with confirmed BPH and no treatment, whereas Group III and IV consisted of dogs with BPH and treated either with DA (15 dogs) or OA (10 dogs). The clinical response, testosterone and estradiol levels, hematology, biochemistry, and adverse effects incidence were evaluated. Both OA and DA proved to be effective for BPH treatment in dogs, as they allowed for the clinical remission in all treated dogs. The complete alleviation of BPH symptoms was noticed sooner with the use of OA (in 80% of dogs from day 7) compared to DA (in 40% of dogs within the first 21 days). The recurrence of clinical signs related to BPH was observed from week 24 in dogs treated with OA, whereas no relapse was noticed in dogs treated with DA at the end of the 36 weeks of the observation period. In 5 dogs (33%) treated with DA, a flare-up effect (increase in the clinical signs associated with BPH) was noticed on day 7. Despite individual differences in the clinical action, both medications were effective and safe options for the treatment of symptoms related to BPH in dogs.

Serological detection of anti-leptospiral antibodies in outdoor cats in Switzerland.

Leptospirosis is endemic in Switzerland affecting a broad range of hosts. The aim of this study was to estimate the exposure of cats to Leptospira in Switzerland. Plasma samples from 107 outdoor cats with an array of clinical problems were tested via microscopic agglutination test for the presence of anti-leptospiral antibodies against 12 serovars of 9 serogroups. Using a reciprocal cut-off titre of 1:100, an overall seroprevalence of 10.3% (95%CI 5.2-17.7) was observed. Seroreactivity against serovars Bratislava (n = 6), Australis (2), Pomona (3) and Copenhageni (1) was detected with reciprocal titres ranging from 1:100 to 1:800. The serologic status of the cats was independent of the disease group (p = 0.62). These results show that cats in Switzerland are commonly exposed to Leptospira and confirm the importance of serogroup Australis in this region.

Length of efficacy and effect of implant location in adult tom cats treated with a 9.4 mg deslorelin subcutaneous implant.

OBJECTIVES: The objective of this study was to assess duration of efficacy, side effects and return to fertility following use of the 9.4 mg deslorelin implant (Suprelorin 12; Virbac) in cats, and test whether efficacy and duration of action are influenced by implantation site (interscapular vs periumbilical). METHODS: Sixteen healthy adult tom cats were checked with (1) reproductive examination, (2) gonadotropin-releasing hormone stimulation test and (3) semen collection until achievement of sterility, then with (1) and (2) only at 2, 4, 6 and 12 months, and every 6 months thereafter until treatment effect disappeared. RESULTS: Serum testosterone reached basal levels by 7 days post-treatment. Semen quality improved initially then started to worsen by 1 month post-treatment and after 70 days post-treatment all cats were sterile. Early in the third month post-treatment there was a significant decrease in testicular volume and penile spikes. Testicular histology was normal upon neutering performed after resumption of fertility. No injection site lesions or treatment-related side effects were observed. There was no difference between periumbilical and interscapular placement for all criteria, but there was a trend for the decrease in testicular volume to last longer and for the regression of penile spikes to start sooner after interscapular administration. One of 16 cats did not respond to treatment. Six cats were lost at variable times during the study while fully responding to treatment. In the cats that completed the study, normal fertility was regained after 805 days, on average, but with a variable duration of effect from 750-850 days. CONCLUSIONS AND RELEVANCE: Treatment with a 9.4 mg deslorelin implant in male cats was effective for a period of 750-850 days, which is 1.5-2 times longer than the effect of the 4.7 mg deslorelin implant. Fertility (based on serum testosterone production and the presence of penile spikes) was regained at the end of the study. Placing implants in the intrascapular vs periumbilical location did not affect duration of suppression of testosterone production. The interscapular location may be characterised by a better efficacy, although further studies are needed to clarify this issue.

Reestablishment of sperm quality after long-term deslorelin suppression in tomcats.

The aim of the study was to determine the time after treatment with a 4.7 mg deslorelin implant until Tomcat spermatogenesis activity was restored, and seminal parameters reached pre-implant values. Tomcats (n = 6) were randomly assigned to one of two treatments. Three cats (n = 3) received a deslorelin implant (4.7 mG; Suprelorin®, Virbac, France) in the interscapular subcutaneous region whereas three (n = 3) received no implant and served as control group. Semen samples were collected by electroejaculation every 4 wk from 3 mo before treatment (pretreatment samples) until reestablishment of pre-treatment sperm quality, 32 mo post-implant insertion (PI). Each semen sample was assessed for motility, velocity, concentration, total sperm count, viability, acrosome integrity, plasma membrane integrity and sperm morphology. After semen collection, testicular volume and presence/absence of penile spines were recorded. Additionally, blood samples were taken to measure testosterone concentration. An increase in sperm concentration and total sperm count was present 1 mo PI despite of an abrupt decrease in serum testosterone concentrations after 2-4 weeks. This initial stimulatory effect was followed by a decrease in seminal parameters, reduction of testicular volume and disappearance of penile spines 2 mo PI. A single Suprelorin® 4.7 mg implant suppressed sperm production for 22-25 months. No clinically side effect was observed during the study period. All toms returned to their initial seminal quality 23-28 months after treatment. Therefore, we conclude that Suprelorin® 4.7 mg is a safe option for reversible reproduction control during long periods in tomcats.

Host cell protein testing strategy for hepatitis B antigen in Hexavalent vaccine - Towards a general testing strategy for recombinant vaccines.

BACKGROUND: Recombinant proteins expressed in host cell systems may contain host cell proteins (HCP) as impurities. While there is no clear evidence of clinical adverse events attributable to HCP, HCP levels and profiles must be documented to meet regulatory requirements and to understand the consistency of the biological product and manufacturing process. We present a general strategy for HCP characterization applied to a recombinant protein antigen, Hepatitis B surface antigen (HBsAg) used in a multivalent vaccine. METHODS: Polyclonal antisera raised against HCPs in process fractions from a mock preparation of the HBsAg yeast expression host, Hansenula polymorpha, were used to develop a quantitative sandwich ELISA to measure HCP content in batches of purified recombinant HBsAg. Batches were also subjected to SDS-PAGE and LC-MS/MS to identify detectable proteins. Batch consistency was further assessed by SDS-PAGE/densitometry purity analysis and by the ratio of specific HBsAg content (by ELISA) to total protein. RESULTS: Using the quantitative HCP ELISA, the HCP content showed no discernable trend in multiple HBsAg batches manufactured over a 5-year period. All batches were ≥95% pure by SDS-PAGE/densitometry, with consistent HBsAg/total protein ratios. In addition to the expected HBsAg antigen protein, LC-MS/MS analysis of three HBsAg batches identified several yeast proteins, none of which are known to cause adverse reactions in humans. CONCLUSIONS: Analysis of multiple HBsAg batches showed consistent HCP content and identification profiles, as well as product purity and specific antigen content, demonstrating consistent manufacturing process. Recombinant vaccines, unlike therapeutic products, are administered infrequently with only small amounts of protein injected at a time. With limited potential for adverse reactions to small quantities of HCPs in purified recombinant vaccine antigens, and considering the relevant regulatory guidelines, we conclude that once consistent manufacturing process has been demonstrated, routine HCP testing in recombinant vaccine antigens is no longer required.

Postponement of puberty in queens treated with deslorelin.

Objectives The purpose of this study was to assess efficacy of deslorelin, a gonadotropin-releasing hormone (GnRH) agonist marketed in Europe for the control of male dog reproduction, for the postponement of puberty in queens. Methods Nine prepubertal queens aged 3-9 months were selected for this study; their general and reproductive health was checked through clinical, haematological, vaginal cytology and hormonal tests. Following treatment with a 4.7 mg deslorelin implant, each cat received a monthly clinical examination and blood was collected for hormonal assay every third month. Cats were monitored for 14.1 ± 5.2 (range 7-23) months. Results All cats were in good body condition and normal health prior to treatment. Their health status remained unchanged throughout the study and no significant variation was observed with regard to serum progesterone or oestradiol. Seven days post-treatment, 1/9 queens showed signs of heat, and one other queen showed complete vaginal keratinisation. No other signs of heat were subsequently observed in any other queen. Five queens were lost during the study after 7, 7, 16, 17 and 18 months of observation (during which time they did not show signs of heat). By the end of the study, no sign of puberty was observed in the four remaining queens at 21-36 months of age. Conclusions and relevance A 4.7 mg deslorelin implant was able to suppress the feline pituitary-gonadal axis, leading to postponement of puberty for up to 21-36 months in the four queens that completed the study. Deslorelin can be considered as a safe method to postpone puberty in queens.

Long-term contraception in a small implant: A review of Suprelorin (deslorelin) studies in cats.

RATIONALE: Deslorelin (Suprelorin®; Virbac) is a gonadotropin-releasing hormone (GnRH) agonist licensed in select countries for the long-term suppression of fertility in adult male dogs and male ferrets. This article summarizes studies investigating the use of deslorelin implants for the long-term suppression of fertility in male and female domestic cats. EVIDENCE BASE: Slow-release deslorelin implants have been shown to generate effective, safe and reversible long-term contraception in male and female cats. In pubertal cats, a 4.7 mg deslorelin implant suppressed steroid sex hormones for an average of approximately 20 months (range 15-25 months) in males and an average of approximately 24 months (range 16-37 months) in females. Reversibility has been demonstrated by fertile matings approximately 2 years post-treatment in both male and female adult cats. In prepubertal female cats of approximately 4 months of age, puberty was postponed to an average of approximately 10 months of age (range 6-15 months) by a 4.7 mg deslorelin implant. CHALLENGES: The large variability in the duration of suppression of gonadal activity makes the definition of the optimal time for reimplantation quite challenging. In addition, the temporary stimulation phase occurring in the weeks following deslorelin implantation can induce in adult female cats a fertile estrus that needs to be managed to avoid unwanted pregnancy. Longer duration and larger scale controlled field studies implementing blinding, a negative control group and a carefully controlled randomization to each group are needed. Furthermore, the effects of repeated treatment need to be investigated. Finally, the effect of treatment on growth and bone quality of prepubertal cats needs to be assessed. However, the ease of use, long-lasting effects and reversibility of deslorelin implants are strong positive points supporting their use for controlling feline reproduction.

The road to sustainability must bridge three great divides.

The world's large and rapidly growing human population is exhausting Earth's natural capital at ever-faster rates, and yet appears mostly oblivious to the fact that these resources are limited. This is dangerous for our well-being and perhaps for our survival, as documented by numerous studies over many years. Why are we not moving instead toward sustainable levels of use? We argue here that this disconnection between our knowledge and our actions is largely caused by three "great divides": an ideological divide between economists and ecologists; an economic development divide between the rich and the poor; and an information divide, which obstructs communications between scientists, public opinion, and policy makers. These divides prevent our economies from responding effectively to urgent signals of environmental and ecological stress. The restoration of natural capital (RNC) can be an important strategy in bridging all of these divides. RNC projects and programs make explicit the multiple and mutually reinforcing linkages between environmental and economic well-being, while opening up a promising policy road in the search for a sustainable and desirable future for global society. The bridge-building capacity of RNC derives from its double focus: on the ecological restoration of degraded, overexploited natural ecosystems, and on the full socio-economic and ecological interface between people and their environments.