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US20120046518A1 - Estrus Synchronization Preparations & Effective CIDR-Less Protocols - Google Patents

Estrus Synchronization Preparations & Effective CIDR-Less Protocols Download PDF

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US20120046518A1
US20120046518A1 US13/203,020 US201013203020A US2012046518A1 US 20120046518 A1 US20120046518 A1 US 20120046518A1 US 201013203020 A US201013203020 A US 201013203020A US 2012046518 A1 US2012046518 A1 US 2012046518A1
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preparation
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progestin
estrus
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Jennifer Yoakum
Hal Witt
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis

Definitions

  • the present invention generally relates to the fields of artificial insemination and embryo transfer in animals that undergo estrus and, more particularly, to the protocols and pharmaceuticals used to facilitate, manage, and control estrus synchronization in such animals.
  • estrous synchronization traditionally refers to artificially synchronizing the estrous cycle throughout a group of female animals using hormone manipulation and supporting protocols.
  • the animals may include such mammals as ruminants or non-menstruating placental females such as female cattle.
  • estrus synchronization can reduce the number of days after a cow calves before she can begin a new pregnancy. This shortened interval increases the number of offspring a cow can produce in her lifetime.
  • Cows that do not conceive during the regular breeding period require additional interventions at the producer's expense.
  • cows that conceive early in the breeding season will produce calves that weigh more at weaning because the calves are older.
  • cows that calve early will have more days postpartum before the beginning of the next breeding season, which serves to improve the cow's overall health.
  • estrus synchronization also allows the producer to synchronize the feed, supplements, immunizations, and treatments for all the cows in the herd, which allows for more efficient management and greater opportunities for profit. Additionally, estrus synchronization allows producers to breed virgin heifers three weeks before inseminating the main herd, which gives the heifers additional recovery time after their first calving before the next breeding season begins.
  • producers attempt to coordinate the onset of estrus in their animals, which, without intervention, is typically asynchronous across a group of animals. To achieve a synchronized onset of estrus, producers use hormones and supporting protocols to intervene in their animals' estrous cycles.
  • the estrous cycle comprises recurring physiologic changes that are induced by mammalian reproductive hormones.
  • the mammalian reproductive system includes the hypothalamic system which releases gonadotropin releasing hormone (GnRH), as well as the pituitary system that secretes follicle stimulating hormone (FSH) and luteinizing hormone (LH).
  • GnRH gonadotropin releasing hormone
  • FSH follicle stimulating hormone
  • LH luteinizing hormone
  • the mammalian ovaries release hormones that include estrogens and progesterone.
  • Species that have estrous cycles characterized by non-menstruating placental females reabsorb the endometrium if fertilization and conception does not occur during that particular cycle. In such species, females are generally only sexually active during the estrus phase of their cycle, a condition commonly referred to as being “in heat.” Therefore, an animal may be described as “in estrus” when it is in that particular part of “the estrous cycle.”
  • the estrous cycle there are four basic phases to the estrous cycle in mammals and, therefore, in all female cattle (including genus Bos of the taurine and zebu species), ewes, does, cows, nannies, mares, and female ruminants.
  • the proestrus phase one or more follicles of the ovary begin to grow. Typically this phase can be as short as one day, or as long as three weeks, depending upon the mammalian species.
  • the lining of the uterus develops.
  • estrus proper refers to the days when the animal is “in heat.” In this phase, under regulation by gonadotropic hormones, ovarian follicles mature and estrogen secretions begin to influence the reproductive system. In female cattle, ovulation may occur spontaneously during this phase. Estrus may continue for a number of days, followed by interestrus. During the third phase, metestrus, the indications of estrogen stimulation diminish and the corpus luteum begins to form. The corpus luteum is essential for establishing and maintaining a pregnancy.
  • the corpus luteum produces progesterone which: (a) prepares the uterus for pregnancy by thickening and developing the endometrium, (b) maintains the pregnancy if fertilization occurs, and (c) inhibits the cattle from showing signs of standing estrus and ovulating.
  • progesterone which: (a) prepares the uterus for pregnancy by thickening and developing the endometrium, (b) maintains the pregnancy if fertilization occurs, and (c) inhibits the cattle from showing signs of standing estrus and ovulating.
  • the corpus luteum secretions inhibit LH and FSH.
  • the uterine lining begins to secrete progesterone. This third phase is generally short and may last one to five days.
  • the final stage of the estrous cycle is diestrus, which is characterized by the production of progesterone by the corpus luteum. In the absence of a pregnancy, the diestrus phase terminates with the regression of the corpus luteum. The lining in the uterus is not shed (as in menstruating mammalian species) but is reconfigured for the next cycle.
  • estrus synchronization also encompasses a wide variety of hormonal manipulation techniques that attempt to control the date(s) on which a particular female can either be successfully inseminated or otherwise impregnated.
  • One of the most reliable synchronization techniques uses a controlled intravaginal drug release (CIDR®) device that is inserted vaginally and left in place to introduce hormones into the animal.
  • CIDR® devices are marketed under the CIDR® trademark by InterAg of Hamilton, New Zealand, although we use the term in our descriptions to refer generically to such vaginal inserts.
  • FIGS. 1 and 2 show two typical protocols for using the CIDR® product. There are many different protocols that require a CIDR® product; the two examples shown in FIGS. 1 and 2 are not an exhaustive list.
  • FIG. 1 (Prior Art) depicts a CIDR® protocol that requires heat detection before artificial insemination (AI).
  • FIG. 2 depicts a CIDR® protocol with timed artificial insemination (TAI) not dependent upon detection of estrus.
  • TAI timed artificial insemination
  • CIDR® cattle inserts typically contain 1.38 grams of progesterone in elastic rubber molded over a nylon spine. The devices are typically packaged in a plastic pouch and are inserted using a special applicator device. CIDR® cattle inserts are administered intravaginally, one per animal, in beef cows and heifers. The CIDR® cattle insert releases progesterone during a seven day treatment period. CIDRs® typically allow for sustained release of hormones to delay estrus for five to fourteen days while the cow's corpus luteum is hopefully held intact to allow proper development of the cow's follicles until full estrus is allowed to proceed, often under the influence of a prostaglandin injection.
  • Lutalyse® sterile solution (dinoprost tromethamine) that is typically given to all synchronized cattle either at the time of, or within one day before, CIDR® removal. Removal of the insert on treatment Day Six or Seven results in a drop in plasma progesterone, ideally triggering estrus within three days.
  • a CIDR® insert is shown to extend from Day Zero to Day Seven of the protocol. Associated with placement of the insert on Day Zero is the administration of an injectable gonadotropin releasing hormone (GnRH). On Day Six or Seven, with removal of the CIDR® insert, prostaglandin (such as Lutalyse®) is typically administered by injection.
  • GnRH injectable gonadotropin releasing hormone
  • prostaglandin such as Lutalyse®
  • AI artificial insemination
  • FIG. 2 depicts another CIDR® protocol that is similar in most respects to the protocol described in FIG. 1 .
  • this second protocol calls for a time period of 60-66 hours after Day Seven (and the removal of the CIDR® insert) for a further administration of a dose of GnRH and subsequent AI. As indicated in FIG. 2 , this typically results in a Day Ten artificial insemination of the animal.
  • CIDR®-based synchronization protocols there are also “CIDR®-less” synchronization protocols—meaning methods that do not require the use of a CIDR® or any intravaginal device to administer hormones.
  • the present invention includes both unique preparations and protocols that, among other benefits, (1) dramatically improve estrus synchronization rates in healthy, mature, cycling female cattle as well as in virgin heifers, (2) help preserve the corpus luteum, (3) improve the success rate of embryo transfer (transplantation), and (4) enable CIDR®-less estrus synchronization, thereby avoiding the infections, vaginitis, and animal discomfort that occur with CIDR devices.
  • the present invention is embodied in an injectable preparation for promoting CIDR-less estrus synchronization in non-menstruating placental females, which includes: (a) a steroidal estrogenic compound such as estradiol 17- ⁇ (E2), estradiol benzoate, or the like in an amount effective to induce estrus in healthy, mature, cycling female cattle; and (b) a steroidal progestin such as progesterone, hydroxyprogesterone, medroxyprogesterone, altrenogest, norgestomet, levonorgestrel, or other progestogenic compound or any derivatives, analogs, or agonists thereof, and any combinations thereof, for preserving the corpus luteum intact for a period of at least five days after its injection; and (c) an excipient compounded with an estrogenic compound and a progestin to produce an injectable compound.
  • a steroidal estrogenic compound such as estradiol 17- ⁇ (E2), estradiol benzo
  • One embodiment of the preparation is made where the estrogenic compound, the progestin, and the excipient are combined in quantities such that the estrogenic compound is in concentrations from 0.05% to 1.0% by volume relative to the overall injectable preparation, preferably from 0.06 to 0.125%, and the combination is in a form suitable for intramuscular delivery.
  • Another embodiment of the present invention includes a preparation which, when compounded, obtains progestogenic concentrations of at least 30 mg/mL.
  • the present invention is also embodied in protocols for improving estrus synchronization and fertilization rates in non-menstruating female animals without utilizing an intravaginal hormone dispensing device.
  • the protocols are based on four ordered steps: (1) injecting intramuscularly one or more healthy, cycling females with a first steroidal hormone preparation to prepare such females to induce estrus; (2) administering a second preparation principally prostaglandin, or its biologically functional, to actually initiate estrus; (3) administering a third preparation of an estrogenic compound to force ovulation; and (4) impregnating each female animal, either through artificial insemination or otherwise.
  • the first preparation is administered by intramuscular injection within the first twelve hours of Day Zero.
  • the second preparation is administered by intramuscular injection no sooner than the beginning of Day Five but no later than the end of Day Eight.
  • the third preparation is administered about one day after the second preparation, and the animals are artificially inseminated or naturally bred about one day after the administration of the third preparation.
  • the first step is to administer to each female animal by intramuscular injection approximately 2 cm 3 of a first steroidal hormone preparation combining an estrogenic compound with a progestin.
  • a first steroidal hormone preparation combining an estrogenic compound with a progestin.
  • each female receives an intramuscular injection of a second preparation, namely prostaglandin, or its biologically functional equivalent, in an amount to initiate estrus and ovulation.
  • the final step in the typical process is the further step of impregnating the female animals, preferably through artificial insemination.
  • a related preparation and protocol is involved in an alternative embodiment that is used to synchronize donor cows.
  • Such embodiments include a base protocol the DonorSyncTM Protocol, to use the preparation of the foregoing embodiments to prepare donor cows for embryo transfer (ET).
  • ET practice donor cows are often treated with a hormone protocol to facilitate embryo production. The donor cow is inseminated at the appropriate time, and the embryos are collected about 6-8 days after breeding. When the donor cow's embryos are collected, they need to be immediately transplanted into recipient cows. For the embryo to survive and become a live pregnancy, each recipient cow's estrous cycle must be in the same state as the donor cow's cycle so that the recipient cow's uterus is prepared to receive the embryo.
  • the present invention protocol using DonorSyncTM, with its higher concentration of progestin than in the SuperSyncTM preparation, has been shown to be highly affective in resetting the follicular wave.
  • DonorSyncTM yields excellent results in producing transferable embryos.
  • kits for example, it can be appreciated that aspects of the present invention allow for a kit that contains both preparations and protocols to be followed to achieve estrus synchronization. Still other embodiments of the invention relate to products made by the described protocols as well as apparatuses and systems for performing all or part of such protocols.
  • the teachings of the present inventions are preferably embodied as injectable hormonal preparations and as protocols that use such preparations in order to improve estrus synchronization and achieve a much higher percentage of estrus synchronization as well as the desired preservation of larger corpus luteum sizes.
  • the protocols and administered preparations described below in conjunction with the present invention are further facilitated by other techniques known to optimize the benefits of estrus synchronization. These other techniques include the maintenance of adequate nutrition as well as efforts to maintain sufficient overall body scores for the cows and heifers.
  • Those skilled in the art will also recognize alternative applications of the compounds and methods of the present invention that may include the preparation of recipient cows for implantation of embryos.
  • SuperSyncTM a preferred formulation for a steroidal hormonal preparation that Applicant expects to commercialize under the designation “SuperSyncTM.”
  • the formulation of the SuperSyncTM preparation is a combination of an estrogenic compound, a progestin, and appropriate excipients to achieve an injectable form.
  • an “estrogenic” compound we mean an artificial or synthetic estrogen (i.e., a steroidal estrogenic compound) or derivatives, analogs, or agonists thereof, and any combinations thereof.
  • progestin we mean an artificial or synthetic progesterone (i.e., a steroidal progestogenic compound), such as, for example, progesterone, hydroxyprogesterone, medroxyprogesterone, altrenogest, norgestomet, levonorgestrel, or other progestogenic compound, or derivatives, analogs, or agonists thereof, and any combinations thereof.
  • the estrogenic compound is selected from the group of estradiol 17- ⁇ or estradiol benzoate, or their derivatives, analogs, agonists and the like.
  • the estrogenic compound and the progestin are compounded with an excipient that preferably combines an anhydrous carrier base (such as sesame seed oil, cotton seed oil, olive oil) with one or more excipient solvents.
  • the excipient solvents are phenylmethanol (approximately 10% of the final volume) and a co-solvent benzoic acid phenylmethyl ester (approximately 10% of the final volume).
  • the excimer is compounded with at least 1 mg/mL estrogenic compound (preferably 1.25 mg/mL).
  • estradiol 17- ⁇ For a 2 cm 3 dose, preferred preparations provide from 2 to 3 mg estradiol 17- ⁇ , which is an amount effective to initiate estrus or, in other words, to reset the follicular wave in a heifer or a cow (including a non-bovine cow), and at least 30 mg/mL progestogenic compound (preferably more than 40 mg/mL and approximately 60 mg/mL), which has been found to be effective at preserving the corpus luteum intact for five or more days from the date of injection.
  • the maximum amount of estradiol 17- ⁇ should not ever exceed 5 mg per dose.
  • FIG. 3 depicts the methodology of a SuperSyncTM Protocol according to the processes of the present invention.
  • FIG. 4 provides a flow chart describing in a step-by-step manner the methodology of the protocol of the present invention. Initially (Step 402 in FIG. 4 ), it is necessary to identify a Day Zero for the protocol by determining a time period of 45-60 days postpartum. Starting the protocol no earlier than this time period ensures an involuted uterus. On Day Zero (Step 404 ), 2 cm 3 of the proprietary formulation (SuperSyncTM) is administered by intramuscular (IM) injection, preferably in the neck of the animal.
  • IM intramuscular
  • the formulation of the proprietary preparation may vary moderately, but in the preferred embodiment includes progesterone and estradiol in a ratio of 60 mg/mL progesterone to 1.25 mg/mL estradiol. This proprietary preparation should be administered in the first twelve hours of Day Zero.
  • the administered preparations described above in the protocol generally carry out the following functions in the process of estrus synchronization.
  • the proprietary preparation of progestin and estradiol provides a unique simultaneous combination of effects.
  • the progestin component keeps a cow or heifer out of heat and extends the estrous cycle.
  • the progestin/estradiol combination when administered at Day Zero, resets the follicular wave in the animal.
  • the prostaglandin (PG) prepares for initiation of heat in the animal.
  • Estradiol, administered subsequent to prostaglandin further facilitates ovulation.
  • Gonadotropin releasing hormone is a hormone that triggers ovulation or starts development of a new follicular wave.
  • Lutenizing hormone (LH) also triggers ovulation and follicle stimulating hormone (FSH) promotes follicular formation.
  • FSH follicle stimulating hormone
  • Progestin mimics natural progesterone produced by the corpus luteum after ovulation which prepares the uterus for pregnancy and serves to keep the cow or heifer from coming back into heat.
  • Estradiol is the most common, and generally considered to be the most effective estrogen hormone.
  • Estradiol 17- ⁇ is a naturally occurring hormone that tends to result in the quickest reaction in cows.
  • Estradiol benzoate is a possible alternative to estradiol 17- ⁇ .
  • the progestin helps to preserve the corpus luteum in good condition by shutting down the pituitary function. In essence the progestin ensures that the corpus luteum remains intact.
  • the estradiol functions to reset the follicular wave.
  • estradiol 17- ⁇ knocks off the dominant follicle, thereby releasing the ovacyte (ovulation), which becomes the egg (once fertilized).
  • the ruptured follicle also either becomes the corpus luteum or adds to it (presuming that a corpus luteum was pre-existing).
  • the second action step of the SuperSyncTM Protocol takes place on Day X, where Day X is any day from 5 to 8 days after Day Zero, although it may start as soon as the corpus luteum has adequately redeveloped.
  • Day X On Day X, therefore, 5 cm 3 of prostaglandin (PG) is administered by intramuscular injection, preferably in the neck of the animal, and preferably within four hours of 8:00 am and optimally within one hour of 9:00 am.
  • the prostaglandin (PG) utilized may be a product marketed as Lutalyse® (a Registered Trademark of Pharmacia & Upjohn Co. of Michigan) which contains the naturally occurring prostaglandin F2 ⁇ (dinoprost) as the tromethamine salt.
  • each milliliter contains dinoprost tromethamine equivalent to 5 mg dinoprost.
  • the prostaglandin (PG) may be a product marketed as Estrumate® (a Registered Trademark of Schering-Plough of New Jersey) which is a synthetic prostaglandin analogue structurally related to prostaglandin F2 ⁇ .
  • Estrumate® a Registered Trademark of Schering-Plough of New Jersey
  • Each milliliter of the colorless, aqueous solution contains 263 mcg of cloprostenol sodium (equivalent to 250 mcg of cloprostenol).
  • the prostaglandin functions to put a heifer or cow into heat, thereby disrupting the yellow tissue that makes up the corpus luteum, causing the release of scent and other signs of heat. This process thereby forces ovulation which is the start of complete estrus.
  • the third action step typically occurs on Day Y, which is the day immediately following Day X, but should occur within 12 to 36 hours after administering the second preparation wherein 1 cm 3 of estradiol is administered, sometime on Day Y, preferably within four hours of 1:00 pm, and optimally within one hour of 1:00 pm.
  • This administration of estradiol functions to stimulate the pituitary to release hormones causing ovulation (i.e., ovacyte to drop, vulva to swell, etc.).
  • estradiol used here and elsewhere in the preferred protocols is preferably estradiol 17- ⁇ (E2) or estradiol benzoate, although it should be appreciated that various other natural or synthetic estrogenic compounds, or their derivatives, analogs, or agonists, and any combinations thereof, may be used as less preferred alternatives. It will also be appreciated that, at the risk of marginalizing the benefits of the dosing in the preferred embodiments, alternate concentrations and/or volumes may also be used. For instance, it is appreciated that certain aspects of the invention can be accomplished through administration of other concentrations of the estrogen compound, so long as at least one milligram of estradiol 17- ⁇ , or the biologically functional equivalent dose of an alternate steroidal estrogenic compound, is administered.
  • the final action step (Step 410 ) in the SuperSyncTM Protocol is carried out on Day Z, which is the day immediately following Day Y, wherein insemination is effected on Day Z, preferably within four hours of 2:00 pm, and optimally within one hour of 2:00 pm. Insemination may be carried out with frozen or thawed semen, with actual fertilization typically occurring 4-6 hours after insemination.
  • the protocol of the present invention is less labor intensive than those protocols associated with the use of the CIDR® device and may be used on female animals that are genetically ill-suited to CIDR® use (e.g., Beefmaster cows that typically cannot retain a CIDR® in place) or individual females that do not tolerate the CIDR® (e.g., vaginal scarring from previous pregnancies).
  • the present invention's protocol is less traumatic for the cows and heifers, and may be expected to generally maintain better overall health during administration of the protocol than with the CIDR® system.
  • an alternative embodiment of the present invention involves use of a form of the first preparation (and in a higher dose) in donor cows to achieve successful estrus synchronization in preparation for embryo production, collection, and transfer into recipient cows.
  • This embodiment is effective in taurine cows but is especially effective in Brahman or other zebu cows.
  • FIG. 5 depicts the methodology of a DonorSyncTM Protocol according to the processes of the present invention.
  • one or more of the preferred variations of the Day Zero preparation from the previous embodiments is used to prepare the donor cow.
  • the injected amount of such preparations is increased—preferably from 30% to 150% more than in the prior description.
  • the donor cow is injected with the first preparation in a dose of from 3.0 to 4.5 cm 3 and, beginning four days later, a multi-day course of follicle-stimulating hormone (FSH) administered intramuscularly twice daily to produce more ovacytes, concluding with injections of prostaglandin to rupture all of the developed follicles.
  • FSH follicle-stimulating hormone
  • the donor cow is inseminated, usually several times in over a 12 to 24 hour period. Thereafter, on Day T, typically Day 7, the embryos are collected from the donors and transferred either to the recipients or preserved by freezing.

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WO2010085363A1 (en) 2010-07-29
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