Gonavet Veyx. Depherelin GnRH-Analogue. Application in pigs. Ovulation synchronization for fixed-time insemination

Transcription

1 Gonavet Veyx GnRH-Analogue Application in pigs Ovulation synchronization for fixed-time insemination Optimization of reproductive performance

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3 Gonavet Veyx facilitates control of ovulation in both adult sows and gilts following oestrus synchronization, so that insemination of individual animals and groups can be planned ahead of time down to the precise day and hour (fixed-time insemination). Ovulation synchronization in groups of animals has been an effective tool in reproduction control for many years now. The resulting advantages - in production engineering, hygiene and division of labour increase both the management efficiency and earnings of piglet production operations. Basic physiological principles Intact reproductive function in the breeding animals is an essential condition of herd productivity and the economic success of operations in the field of animal husbandry. Neurohormonal regulation of the ovarian cycle plays a central role in animal reproduction. Attempts to influence the relevant regulatory complexes presuppose a highly detailed knowledge of the physiological processes involved. These processes take place in complex steps involving different, but highly integrated, organic planes (see fig. 1), among them: The extrahypothalamic structures of the central nervous system, by way of which exogenous and endogenous stimuli influence the secretion of GnRH (gonadotropin releasing hormone) as mediated by neurotransmitters, peptides and prostaglandins The hypothalamus as the main centre of GnRH production The adenohypophysis, where FSH (follicle stimulating hormone), LH (luteinizing hormone), and prolactin are produced The ovary as the target organ of the gonadotropins and production location of oestrogens, androgens, gestagens and folliculostatin The uterus, both an important effector of the ovarian hormones and an organ that directly influences the ovarian cycle by means of prostaglandin F 2.

4 Fig. 1. Physiological regulation of reproduction in the female animal (acc. to DÖCKE, simplified presentation) Gonadotropin releasing hormone (GnRH) plays a central role in the regulation of female sexual function. It is formed by the hypothalamic neurones and released pulsatilely. The GnRH enters the hypophysis (pituitary gland) by way of a special vascular system (the hypothalamopituitary-portal vein system). The pituitary effect of GnRH leads to synthesis and release of the gonadotropic hormones. Its efficiency in this function depends on a number of factors. For instance, LH release induced by GnRH also depends on the concentration of ovarian sexual steroids in the organism. GnRH is rapidly catabolized and inactivated, making its biological halflife very short. In heifers, the highest blood levels were measured five minutes after intravenous injection of 2.5 mg GnRH and the pre-injection level was reached again after only 1.5 hours. Elimination of the metabolites is mainly renal. The pituitary gonadotropins LH and in a smaller amount FSH enter the bloodstream discontinuously, reflecting the secretion impulses mediated by GnRH, by which route they reach the ovary, where they stimulate the growth of the follicles and maturation of the oocytes. In the follicular epithelium they induce formation of gonadotropin receptors, and initiate synthesis of the ovarian steroids. FSH controls oestrogen production. FSH secretion is in turn regulated in reaction to the blood oestrogen level. When the oestrogen level exceeds a certain level, FSH production is reduced. A high oestrogen level initiates the oestrus and induces, by means of positive feedback, the LH peak, which in turn leads to follicle maturation and ovulation.

5 The ovulation-inducing LH peak is quickly catabolized. In the subsequent phase, the pituitary gland is not receptive to further GnRH stimulation. This is particularly important in practical application of GnRH or its derivatives to induce ovulation, since it prevents an endogenous LH peak from occurring in addition to the induced one and disturbing the ovarian and hormonal processes. Following ovulation, a corpus luteum begins to form from the follicle and to produce increasing amounts of progesterone. In animals that are not gravid, the function of the corpus luteum is interrupted by the action of prostaglandin F 2. The corpus luteum then regresses and the progesterone level drops off. Reduction of the progesterone effect is then followed by increased release of FSH, preparing the way for the beginning of a new oestrous cycle. In addition to the stimulation of pituitary gonadotropin secretion, further effects of GnRH on the organism have come to light in recent years, for instance an intensification of sexual behaviour, probably induced by way of extrahypothalamic brain structures. GnRH also acts upon the gonads directly, i. e. without the intermediary function of the gonadotropins. To date, observations in female animals have revealed mainly an accelerating effect on oocyte maturation, luteinization and accumulation of progesterone, the hormone that maintains pregnancy, in the granulosa cells of mature follicles. Based on a knowledge of these correlations, GnRH or its analogues can be administered in cycling animals to achieve the desired effect: a single, high-dose hormone injection can induce LH release, which in turn initiates ovulation. Chemistry Gonavet Veyx contains a synthetic derivative of the physiological gonadotropin releasing hormone GnRH. In chemical terms, the substance is D-Phe 6 -LHRH (D-Phe 6 -luteinizing hormone releasing hormone, gonadorelin[6-d-phe]), a highly potent peptide hormone (decapeptide) with the empirical formula C 62 H 80 N 17 O 13 x CH 3 COOH (x = 1 to 2), a molar mass of 1,271.4 g/mol (acetate-free substance) and the sequence: PyroGlu-His-Trp-Ser-Tyr-D-Phe-Leu-Arg-Pro-GlyNH 2. The difference between native GnRH and the synthetic derivative consists in the replacement of glycine at position 6 in the amino acid sequence by D-phenylalanine. GnRH analogues produced in this way are characterized by a longer duration of action and a much greater affinity to the GnRH receptors in the pituitary gland. They also show greater resistance to peptidases.

6 As a result Gonavet Veyx shows approximately ten times the level of efficacy of physiological GnRH. The preparation Gonavet Veyx is a clear, nearly colourless, aqueous solution with a weak, but characteristic odour of acetic acid and a ph of 5.0 to 6.0. Methyl 4-hydroxybenzoate is added as a preservative agent. Pharmacology The LH secretion induced by exogenously administered Gonavet Veyx commences immediately after the injection and develops into an LH peak within 1 2 hours. Pre-injection levels are not reached until about 7 8 hours after injection. A pre-condition for reproduction control with this agent is application during pre-oestrus or early oestrus so as to utilize the high levels of reactivity in the pituitary and ovary in this stage of the cycle to enhance treatment success. Its efficacy is compromised in the absence of reactivity, for instance in acyclical, postoestral or metoestral female animals. LH blood levels depend primarily on the stage of neuroendocrinal development reached by the individual animal, which determines the hormone release potential of the adenohypophysis. The gonadotropins released reach the ovarian follicle via the bloodstream. In the gonadotropin receptive cells of the Theca granulosa and interna follicle maturation is then terminated and ovulation is induced. Single-dose administration of Gonavet Veyx results in temporary LH secretion. Administration of Gonavet Veyx repeated at short intervals over a longer period increases the level of LH release and leads to an imitation of the pulsatile basal secretion of the hypothalamus. In physiological terms, the enhanced GnRH effect is probably induced by the oestrogens via formation of additional GnRH receptors in the gonadotropic cells. This process, combined in equal measure with repeated administration of small amounts of Gonavet Veyx over a longer period, then leads to the increased release of LH and in a smaller amount of FSH from the pituitary, which substances are in turn responsible for the initiation of a new wave of follicle maturation and thence onset of ovulation. A constantly high GnRH level is an unphysiological state producing a desensitization of the gonadotropic cells due to a reduction of the number of GnRH receptors in the cell membrane. Gonadorelin[6-D-Phe] is well tolerated and has a low toxicity level. The calculated LD 50 following intravenous application is 15.4 mg/kg body weight in rats. In subacute toxicity testing in rats (28-day application period), Gonavet Veyx proved harmless in an application range equivalent to 50 times the therapeutic dosage level. Gonadorelin[6-D-Phe] is completely metabolized within 10 hours after injection. The active agent cannot cause intoxications, although exact dosage is necessary for precise timing of the desired effect. There are no relevent effects from biological residues, for which reason no withdrawal period is necessary.

7 Pharmacotherapy Gonavet Veyx was clinically tested on a large number of sows with various indications. Extensive field tests and many years of experience with routine applications are on file, mainly in the area of ovulation synchronization. Ovulation synchronization represents a further development of the oestrus synchronization procedure. The aim of this method is to synchronize onset of ovulation in a group of oestrussynchronized gilts or adult sows so that insemination can be carried out at predetermined times. Reliable fixed-time insemination means that oestrus checks are practically a thing of the past and sperm can be ordered on a pre-planned basis. Control of repeat breeders is also simplified. The group of inseminated adult sows go through the subsequent stages of gravidity together, then farrow within a few days of one another, whereby the gravidity period can also be reliably pre-planned. Using PGF 2 (PGF Veyx ) and Depotocin, it is possible to compress the onset of farrowing within this group of sows down to brief intervals, compressing farrowing controls, which otherwise occupy a number of days and nights, to brief intervals. Piglet care (e. g. administration of iron, vaccinations) can then be carried out at predetermined times for large groups of piglets. This makes it easier to meet basic hygienic standards in pig keeping and pig nursery. Use of reproduction control methods has the following advantages for the sow breeder: Potentially simultaneous occupation and clearance of stall units (all-in-all-out-principle) Better organization of work and production steps Production of uniform piglet lots with the same genetic structure and the resulting market advantages Reduction of expenses for keeping of teaser and breeding boars Reliable groupwise integration of replacement sows in periodic farrowing systems More efficient planning and control of gilt stock management. The main conditions for efficient use of the reproduction control system include on-time provision of groups of breeding animals in good health, with good responses and willing to breed combined with quality feeding and husbandry. Substitutive compensation of deficiencies in these areas is only possible within narrow limits. As is the case with all hormone preparations, Gonavet Veyx only compensates disturbances when there is no grave damage, caused for example by problems with feeding, husbandry or disease. The particular ovulation synchronization procedure with Gonavet Veyx depends on whether the reproduction control program is to involve adult sows or gilts. Figure 2 illustrates methods of ovulation synchronization with subsequent insemination scheduling that have been used successfully for years. The procedures listed here for herds of adult sows and gilts

8 24 42 h Fig. 2. Methods of ovulation synchronization with subsequent fixed-time insemination in adult sows and gilts with simultaneous servicing and farrowing within the group in a set production rhythm can readily be adapted to the requirements of particular operations (e. g. selection of a different day of the week for weaning or servicing). Ovulation synchronization in adult sows At first, hcg was used for biological synchronization of ovulation in groups of adult sows, whereby the antigenic and immunogenic properties of hcg represented a specific disadvantage of this substance. With the aim of replacing hcg, Gonavet Veyx was tested and found to be suitable for use as an ovulation stimulant in pigs. The initial evidence was collected for adult sows. Following simultaneous groupwise separation from the piglets, the animals were first treated with PMSG (pregnant mare serum gonadotropin). PMSG induces oestrus, stimulates follicle growth and thus creates favourable endocrinological conditions for a fixed-time ovulation. Administered at a time interval following the PMSG dose that allows for reestablishment of a physiological balance, Gonavet Veyx contributes to a better synchronization of ovulation within groups of adult sows than other agents. Group concentration of the ovulation

9 process is an essential pre-condition for good fertilization and fertility results in sows. It also provides a basis for fixed-time insemination. As a rule, this proven method requires two sperm portions per inseminated sow. The first insemination (AI 1 ) should be carried out 24 to 26 hours after the induction of ovulation. Repeat insemination (AI 2 ) should be concluded by a maximum of 16 hours after AI 1. This is the basis of the treatment scheme sketched out in figure 3. It applies to sows with a four-week lactation period. Best results are obtained with animals showing a pronounced standing reflex during both insemination procedures. Evaluation of the standing behaviour can contribute to optimization of ovulation synchronization and adaptation to the relevant parameters of a particular breeding operation. In sows with longer oestrus, a third insemination (AI 3 ) about 6 hours after AI 2 is recommended. Fig. 3. Treatment scheme for ovulation synchronization and fixed-time insemination in adult sows with a 4-week suckling period In operations with a suckling period exceeding 4 weeks, it makes sense to shorten the interval between the PMSG and Gonavet Veyx treatments from the 72 hours listed figure 3 to hours. On the other hand, the time interval is to be extended to hours for a suckling period of 3 weeks. The preferred dose for adult sows is 1 ml Gonavet Veyx (equivalent to 50 µg gonadorelin[6-d-phe]). In clinical field studies, the lower dosage level of 0.5 ml (equivalent to 25 µg of active agent) only proved sufficient to achieve the desired effect under certain conditions. This applied to sows beginning with parity number 3 and for the insemination period from September to May. On the other hand, the higher dosage level of 1 ml provided better performance during the fertility-sensitive summer period as well as in primiparous and heavily suckled sows. In extensive studies with adult sows, results with Gonavet Veyx were superior to those of control treatments with hcg or combinations of hcg and GnRH in terms of the synchronization and farrowing results (see tabs. 1 and 2).

10 Tab 1. Fertility results in ovulation-synchronized gilts and adult sows with hcg or GnRH (Gonavet Veyx ; HÜHN and BRÜSSOW 1997, BRÜSSOW and WÄHNER 2005) Group Number of animals (n) Pregnancy rate (%) Piglets born alive per litter Gilts hcg 1, a a Gonavet Veyx 1, b b Adult sows hcg 30, a a Gonavet Veyx 20, b b a, b : p < 0.05 Piglet index Tab. 2. Fertility performance results in ovulation-synchronized adult sows depending on variations in breeding condition (according to STAHL et al., 1989) Evaluation of sows Treatment Inseminated sows Pregnancy rate % Piglets born alive per litter Piglet index Normal 500 IE hcg 2, ml Gonavet 2, Veyx 1 ml Gonavet Veyx 2, Heavily suckled 500 IE hcg ml Gonavet Veyx 1 ml Gonavet Veyx

11 Ovulation synchronization in gilts At first the sexual cycle is medically suppressed in sexually mature gilts (in heat at least once prior to synchronization treatment, recommended minimum age 220 days, minimum weight 115 kg) for 18 days with Altrenogest (Regumate ). To initiate simultaneous onset of oestrus, PMSG treatment follows 24 hours, according to recent studies by SCHNURRBUSCH (2002/2003) 36 to 42 hours, after the last Altrenogest-application then the Gonavet Veyx injection hours later. A dosage of 1 ml (equivalent to 50 µg gonadorelin[6-d-phe]) has proved effective. This results in a concentrated onset of ovulation in the gilts within a timespan of approximately 40 hours after the Gonavet Veyx -application. Fixed-time insemination can then take place during the times as listed in figure 4. In one-year field tests, use of Gonavet Veyx significantly improved both the gravidity rate in gilts with fixed-time insemination as compared to hcg (+ 4.4 %) and the piglet index (+ 51). As shown by table 3, this superiority was in evidence in all seasons tested (insemination quarters). Numerous tests performed subsequently on gilts confirmed that Gonavet Veyx is a highly suitable agent for ovulation synchronization. 18 s 5 at least 24 h Fig. 4. Treatment scheme for ovulation synchronization followed by fixed-time insemination in gilts

12 Tab. 3. Fertility results in ovulation-synchronized gilts in a one-year field test (HÜHN et al., 1991) Insemination quater Treatment group Number of animals Pregnancy rate % Piglets born alive per litter Piglet index III/ IU hcg ml Gonavet Veyx IV/ IU hcg ml Gonavet Veyx I/ IU hcg ml Gonavet Veyx II/ IU hcg ml Gonavet Veyx Summary As the result of the clinical test program and subsequent field studies as well as years of experience with the product in livestock practice, Gonavet Veyx can be said to be well-suited for use in ovulation synchronization in adult sows and gilts subjected to PMSG pre-treatment and planned for fixed-time insemination. Following PMSG administration, Gonavet Veyx improves the synchronization effect compared with other agents (hcg or combination of hcg and GnRH). The result is a significant improvement in groups of artificially inseminated sows (e. g. higher pregnancy rate, higher count of piglets born alive per 100 first inseminations).

13 Brief product information Active ingredient: Gonadorelin[6-D-Phe]acetate Composition: 1 ml of the injection solution contains: Active substance: 52.4 µg gonadorelin[6-d-phe]acetate (equivalent to 50 µg gonadorelin[6-d-phe]) Excipients: 1.0 mg methyl 4-hydroxybenzoate (Ph. Eur.) Sodium hydroxide, acetic acid 99 %, water for injection purposes Pharmaceutical form and contents: 10 ml, 6 x 10 ml and 50 ml injection solution for intramuscular and subcutaneous use Substance or indication group: Gonadotropin releasing hormone agonist Indications: Control and induction procedures in cattle and pig reproduction. Therapy of ovarian infertility disorders or, dysfunctions of the reproductive organs, in cattle and horses. Cattle: Ovulation induction in cases of delayed ovulation due to LH deficiency Ovulation induction/synchronization as part of a fixed-time insemination program Stimulation of the ovaries from the 12 th day post partum during the puerperium Ovarian cysts (due to a LH deficiency) Pigs: Ovulation induction/synchronization within a program of fixed-time insemination and synchronized batch farrowing Horses: Centrally dependent LH deficit induced insufficiency of the reproductive cycle (anoestrus, acyclic oestrus) Contraindications: Application commencing on day 12 p. p. in cows with tertiary follicles ripe for ovulation. Infectious diseases and other significant disorders affecting the health status. Advice on correct administration: None

14 Interactions with other medicinal products: A synergistic effect is observed for a combination therapy with FSH, especially in animals with a puerperal disorder. Concurrent application of human or equine chorionic gonadotropin may lead to excess ovarian reactions. Warnings: None Dosage, method and route(s) of administration: Given as ml of Gonavet Veyx per animal Cattle: Induction of ovulation in cases of ovulation delay due to a LH deficiency 2.0 ml i.m. Induction/synchronization of ovulation as part of a fixed-time insemination procedure 1.0 ml i.m. Stimulation of the ovaries beginning on day 12 post partum during the puerperium 1.0 ml i.m. Ovarian cysts (due to a LH deficiency) 2.0 ml i.m. Pigs: Adult sows ml i.m. or s.c. Gilts ml i.m. or s.c. Mares: 2.0 ml i.m. Gonavet Veyx is generally applied as a single dose. Overdose: None. Undesirable effects: Disorders of the oestrous cycle. If you notice any other side effects, please inform your veterinary surgeon or pharmacist. Withdrawal period: Cattle, horses, pigs Edible tissues Cattle, horses Milk 0 days 0 days

15 Special storage precautions: Store in a cool place at 2 8 C and protect from light, keeping it in its outer container. The medicine can be used for a period of 28 days after opening the container and when stored in a refrigerator. After this expiry date, any medicine remaining in the container is to be disposed of. Do not use after the expiry date stated on the label and the outer carton. Keep out of the reach and sight of children. Advice: Concerning the use in cattle and horses there are separate brochures.

16 Authors: Priv. Doz. Dr. Dr. habil. Wolfgang Zaremba Prof. Dr. habil. Uwe Hühn Veyx-Pharma GmbH Söhreweg 6 D Schwarzenborn Germany Phone Fax zentrale@veyx.de