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      Use of Propylene-Glycol as a Cosolvent for GnRH in Synchronization of Estrus and Ovulation in Sheep

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          Abstract

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          The foreseeable shortage of equine chorionic gonadotrophin (eCG) for estrus synchronization in sheep will have a huge impact on breeders using out-of-season breeding, artificial insemination, or embryo transfer because there is no other product with similar activity. Hence, there is a strong need for alternative protocols. The aim of the present work was to evaluate the reproductive response of sheep in breeding season to the administration of gonadotrophin-releasing hormone (GnRH) using propylene-glycol as a cosolvent, as well as the most adequate timing for such administration. From the results obtained, protocols based on a short-term treatment with a Controlled Internal Drug Release (CIDR) device and a single dose of GnRH in propylene-glycol at 36 h after CIDR removal may constitute an alternative to traditional protocols based on the administration of a single dose of eCG at CIDR removal.

          Abstract

          The foreseen shortage of eCG for estrus synchronization in sheep makes necessary the development of alternative protocols. The aim of the present work was to evaluate the reproductive response of sheep in breeding season to the administration of GnRH using propylene-glycol as a cosolvent and the subcutaneous route for slowing and extending the release of GnRH, as well as the most adequate timing for such administration. In the present study, protocols based on a short-term CIDR treatment and a single subcutaneous dose of GnRH in propylene-glycol at 36 h after CIDR removal induced a similar ovarian response to protocols based on administration of eCG at CIDR removal or intramuscular GnRH in distilled water at 56 h after. In such protocol, 80% of the animals developed estrus in a narrow timing (75% between 36 and 48 h after CIDR removal), and all of them also ovulated in a narrow window (87.5% between 72 and 76 h after CIDR removal, with 62.5% between 72 and 76 h) and showed a similar ovulation rate and plasma progesterone concentrations at the induced estrous cycle. Hence, administration of GnRH in propylene-glycol may constitute an alternative to traditional protocols based on the administration of eCG.

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          Solubilizing excipients in oral and injectable formulations.

          A review of commercially available oral and injectable solution formulations reveals that the solubilizing excipients include water-soluble organic solvents (polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide), non-ionic surfactants (Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-alpha-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS 15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44/14, Softigen 767, and mono- and di-fatty acid esters of PEG 300, 400, or 1750), water-insoluble lipids (castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil and palm seed oil), organic liquids/semi-solids (beeswax, d-alpha-tocopherol, oleic acid, medium-chain mono- and diglycerides), various cyclodextrins (alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, and sulfobutylether-beta-cyclodextrin), and phospholipids (hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, L-alpha-dimyristoylphosphatidylcholine, L-alpha-dimyristoylphosphatidylglycerol). The chemical techniques to solubilize water-insoluble drugs for oral and injection administration include pH adjustment, cosolvents, complexation, microemulsions, self-emulsifying drug delivery systems, micelles, liposomes, and emulsions.
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            Hormonal control of reproduction in small ruminants

            Reproduction of small ruminants can be controlled by several methods developed in recent decades. Some of these involve administration of hormones that modify the physiological chain of events involved in the sexual cycle. Methods which utilise progesterone or its analogues are based on their effects in the luteal phase of the cycle, simulating the action of natural progesterone produced by the corpus luteum after ovulation, which is responsible for controlling LH secretion from the pituitary. Use of prostaglandins is an alternative method for controlling reproduction by eliminating the corpus luteum and inducing a subsequent follicular phase with ovulation. Finally, the discovery of the properties of melatonin in photoperiod-dependent breeding animals opened up a new methodology to control reproduction in these species, inducing changes in the perception of photoperiod and the annual pattern of reproduction. Use of hormones to induce oestrus has allowed increased use of artificial insemination in small ruminants, a very useful management tool, considering the difficulty of detecting oestrus in these species. At commercial level, synchronisation of oestrus allows control of lambing and kidding, with subsequent synchronisation of weaning of young animals for slaughter. Also, it allows more efficient use of labour and animal facilities. Multiple ovulation and embryo transfer programmes are also possible with the use of oestrus synchronisation and artificial insemination. Finally, hormonal treatments have also been used to induce puberty in ewe-lambs and doelings.
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              Gonadotropin-releasing hormone analogs: Understanding advantages and limitations

              Pituitary stimulation with pulsatile gonadotropin-releasing hormone (GnRH) analogs induces both follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Pituitary gonadotropin secretions are blocked upon desensitization when a continuous GnRH stimulus is provided by means of an agonist or when the pituitary receptors are occupied with a competitive antagonist. GnRH antagonists were not available originally; therefore, prolonged daily injections of agonist with its desensitizing effect were used. Today, single- and multiple-dose injectable antagonists are also available to block the LH surge and thus to cause desensitization. This review provides an overview of the use of GnRH analogs which is potent therapeutic agents that are considerably useful in a variety of clinical indications from the past to the future with some limitations. These indications include management of endometriosis, uterine leiomyomas, hirsutism, dysfunctional uterine bleeding, premenstrual syndrome, assisted reproduction, and some hormone-dependent tumours, other than ovulation induction.
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                Author and article information

                Journal
                Animals (Basel)
                Animals (Basel)
                animals
                Animals : an Open Access Journal from MDPI
                MDPI
                2076-2615
                21 May 2020
                May 2020
                : 10
                : 5
                : 897
                Affiliations
                [1 ]Departamento de Farmacologia y Toxicologia Facultad de Veterinaria, UCM, Ciudad Universitaria s/n, 28040 Madrid, Spain; mvz_zusan@ 123456hotmail.com (Z.S.-J.); tencinas@ 123456ucm.es (T.E.); bulnes@ 123456inia.es (A.G.-B.)
                [2 ]Universidad Autónoma Agraria Antonio Narro, Torreón, Coahuila 25315, Mexico; velizderas@ 123456gmail.com
                [3 ]Departamento de Produccion y Sanidad Animal, Facultad de Veterinaria, Universidad Cardenal Herrera-CEU, CEU Universities, C/ Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain; guigarsar@ 123456alumnos.uchceu.es
                [4 ]Dipartamento di Medicina Veterinaria, Università degli Studi di Sassari, Via Vienna 2, 07100 Sassari, Italy; berling@ 123456uniss.it
                [5 ]Departamento de Reproduccion Animal, INIA, Avda. Puerta de Hierro s/n, 28040 Madrid, Spain
                Author notes
                [* ]Correspondence: paula.martinez@ 123456uchceu.es ; Tel.: +34961369000
                Author information
                https://orcid.org/0000-0002-2500-8063
                https://orcid.org/0000-0002-0917-4475
                Article
                animals-10-00897
                10.3390/ani10050897
                7278457
                32455785
                2611c217-c696-4b40-9b1b-553ad0c748eb
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 29 April 2020
                : 19 May 2020
                Categories
                Article

                ecg,estrus synchronization,gnrh,propylene-glycol,sheep
                ecg, estrus synchronization, gnrh, propylene-glycol, sheep

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