Recovery of Oocytes Using Transvaginal Ultrasound in the Mare:
Abstract Introduction In-vitro fertilisation (IVF) programmes are well established in human medicine and a key part of the process is ultrasound-guided transvaginal oocyte aspiration (Cohen et al 1986; Kemeter and Feichtinger 1986) and this technique has superseded the more invasive laparoscopic techniques. In animals, including the mare, oocytes have traditionally been obtained from follicle aspiration of slaughterhouse ovaries or via a flank laparotomy technique (Vogelsang et al 1988). Slaughterhouse material has the obvious disadvantage of lack of repeatability and there is often considerable delay in the time between oocyte collection and placement in culture medium. Surgical laparotomy techniques have obvious disadvantages in terms of ease and repeatability. Consequently it was an important finding when Pieterse and his co-workers at Utrecht University (Pieterse et al 1988), using cattle, were the first to describe the technique of oocyte aspiration during transvaginal ultrasound ovarian scanning in domestic animals. They coined the term 'ovum pick-up' (OPU) for the collection of the oocytes and OPU offered a repeatable, less invasive and less traumatic system to provide a source of oocytes. These oocytes could then be used in invitro maturation (IVM)/IVF programmes or gamete intrafallopian transfer (GIFT) studies. The ability to perform non-surgical repeated OPU to obtain equine oocytes was an important step to allow progress in the horse. The first report of the technique in the horse was by Bruck et al (1992), although only four follicles were punctured in this report. More widespread use of the technique was reported by Cook et al (1992 & 1993) and Bracher et al (1993). Both groups of workers reported that the procedure was safe and well tolerated and the technique allowed for repeated collection of oocytes in vivo. Since then there have been few reports of workers using the technique to obtain equine oocytes (Parlevliet et al 1993; Dippert et al 1994; Meintjes et al 1994) although at the recent International Equine Reproduction Symposium in Brazil, six papers from four groups of workers involved transvaginal aspiration of oocytes (Carnevale and Ginther 1995; Kanitz et al 1995; DuChamp et al 1995; Bezard et al 1995; Meintjes et al 1995; Li et al 1995) Despite this current interest in oocyte aspiration, there are probably less than 10 groups of workers repeatedly aspirating equine oocytes using transvaginal ultrasound world-wide. It is, therefore, not surprising that gamete manipulation techniques in the horse are poorly advanced compared with other species. This not only reflects the relatively new stage of the techniques, but also certain difficulties innate to the horse as well as the economic structure of the equine breeding industry. Some of the difficulties such as in vitro oocyte maturation and sperm capacitation are outside the scope of this paper which will concentrate on technical aspects of transvaginal guided-ultrasound follicle aspiration. The actual technique of ovum pick-up represents the key first step in whatever the aspirated oocytes are to be used for. Manipulating the equine ovary in vivo has many technical difficulties and this may be partly responsible for the generally low (20-30%) recovery rates found in the mare (Bracher et al 1993; Cook et al 1993). However, many factors such as size of follicle punctured (Kanitz et al 1995; DuChamp et al 1995) and stage of cycle/ pregnancy status of the mare (Meintjes et al 1995) affect recovery rate and so it is difficult to compare recovery rates between different groups of workers. This point will be addressed in more detail subsequently.
Follicle Aspiration in the Mare: Technique and Equipment Used Mare Preparation and Restraint
The mare should be restrained in a set of stocks/crush which limit her movement. It is particularly important to limit lateral movement as this can make fixation of the ovary against the ultrasound transducer difficult. Bladder catheterisation and epidural anaesthetic, as commonly used in the cow (Pieterse et al 1988) are not generally used in the mare. Ultrasound Equipment Once experienced in the orientation of the sector transducer, the author's preference is for a 7.5 MHz sector transducer as this allows more possibility to manipulate the ovary to allow for more complete puncturing of all follicles. Our recent follicle puncturing studies have been done using a Scanner 200 Vet (Pie Medical Ltd; Maastricht, The Netherlands) with a 7.5 MHz mechanical sector annular array system with a multi angle transducer (150 / 90 / 60 scan- angles) (Pie Medical Ltd; Maastricht, The Netherlands). During 1995 the 90 or 150 scan- angle was used and this expanded ultrasound field facilitates the positioning of follicles within the puncture line. Carnevale and Ginther (1993) point out that the advantage of their method using a linear- array transducer is that this is the commonest transducer used for routine mare gynaecological work. However, sector transducers have many applications in equine veterinary medicine and most facilities likely to be performing transvaginal follicle aspiration would be likely to have a sector transducer in the author's opinion. Needle Guidance System
Ovum Pick-Up Needle and
Collection Systems There are basically two types of ovum pick-up needle systems: double or single lumen needles with the double lumen needle design allowing both flushing and aspirations simultaneously. Some workers have used both single and double lumen needles (Bracher et al 1993; Cook et al 1993; DuChamp et al 1995) whilst others have used either single-lumen needles (Meintjes et al 1995) or double-lumen needles (Kanitz et al 1995). It was agreed by the three groups of workers using both single and double lumen needles ((Bracher et al 1993; Cook et al 1993; DuChamp et al 1995) that the double lumen system provided better recovery rates. However, Meintjes et al (1995) using single-lumen needles reported a recovery rate of 75.8% which is higher than that reported by Bracher et al (1993), DuChamp et al (1995) and Kanitz et al (1995) all of whom used double lumen needles. However, Meintjes et al (1995) are the only group of workers to have aspirated oocytes from pregnant mares and this recovery rate of 75.8% was better that the 42.9% these workers obtained when puncturing pre-ovulatory follicles. It is clear that recovery rate is a confusing term as it depends how it is assessed and is also affected by many factors, not simply whether a single or double lumen needle is used (see later). The length of the needle has varied from 50 Cm (Bruck et al 1992; Meintjes et al 1995) to the more usual 60 Cm (DuChamp et al 1995) with 60 Cm being the standard length supplied by Cook Veterinary Products, probably the main supplier of equine ovum pick-up needles. The gauge of the needle has varied from as thick as 12 gauge (Cook et al 1993; Meintjes et al 1995) to 15 gauge (Bracher et al 1993) or 16 gauge (Carnevale and Ginther 1993). Throughout the repeated follicle puncturing attempts in our laboratory during 1995, a new disposable needle guidance system, based on that described by Bols et al (1995) in the cow, was used. In the system we used in 1995, an 18-gauge luer-lock disposable needle is attached via a stainless steel connector to sterile teflon tubing. The tubing was inside a hollow stainless steel tube and was then connected to a flushing syringe and a suction pump with a variable vacuum pressure normally set at 200 mm Hg. The stainless steel tube with the needle at the end is inserted into a guidance tube incorporated into the top of the OPU device. Care must be taken when inserting the needle into the guidance system that the needle goes smoothly through the hole at the end of the OPU device otherwise a rough edge may develop which can cause extra trauma during the puncture session. A marker on the metal needle guide indicates the extent the metallic needle guide and needle should be passed along the needle guide corridor.
Suction apparatus
Puncture technique
On the instruction of the operator manipulating the ovary, the needle is then advanced beyond the needle guide, through the vaginal wall and into the follicle to be punctured. The instruction to advance the needle should only be given when the follicle has been steadily positioned on the puncture line. A distinct 'popping' sensation is felt when the follicle is entered and the echoic needle can be visualised within the follicle. As soon as the tip of the needle has been seen to enter the follicle, suction is immediately applied and the follicle, as imaged on the ultrasound screen, begins to collapse. Suction should be continued until the follicle appears to have completely collapsed. If flushing of the collapsed follicle is being performed, the flushing fluid can be visualised on the ultrasound screen re-filling the follicle and confirming the needle is still located in the correct place. During and after aspiration of the follicle fluid, the needle should be slowly and gently rotated in an attempt to curette the follicle wall. In addition the follicle can be gently manipulated per rectum. This should help dislodge any oocyte tightly attached to the follicle wall. This is important in the mare as recent work has shown considerable differences in equine and bovine oocyte-cumulus morphology within the ovarian follicle (Hawley et al 1995) including the presence of a 'thecal pad' in the mare which may at least partly explain the poorer recovery rates of the mare as compared with the cow. In any case, it makes thorough aspiration of the follicle important in the mare. If a second follicle is seen adjacent to the punctured follicle, the direction of the transducer can be slightly adjusted so that the puncture line crosses the new follicle. Then the second follicle can be punctured and aspirated without withdrawing the needle from the ovary. This procedure should be repeated until all visible follicles have been aspirated. At the time of puncture, the size of the follicle can be estimated from the ultrasound screen. If information about recovery rates from different sized follicles is required, separate sterile plastic collection tubes should be used for each selected category of follicle. If significant blood (enough to be clearly visually obvious) the needle should be withdrawn and a new collection tube selected. When puncturing a large follicle it is probably better to puncture the follicle through the ovarian stroma rather than puncturing from the outside of the follicle. The later approach would seem to offer more potential for failure to recover the oocyte.
Flushing of Follicle The number of times the follicle is flushed depends on the size of the follicle: during dioestrus Cook et al (1992) simply aspirated follicles 5 mm. Larger follicles are flushed between 3 and 10 times using from 10-250 ml of flushing medium again depending on the size of the follicle (Bracher et al 1993; Cook et al 1992; DuChamp et al 1995; Kanitz et al 1995; Meintjes et al 1995).
After-care of mares
Recovery and identification of oocytes Recovery Rate Stage of Oestrous Cycle Aspiration technique including flushing The use of a 12 gauge double-lumen needle rather than a 12 gauge single-lumen needle resulted in an increased recovery rate from pre-ovulatory follicles (84% versus 51%) (Cook et al 1993). Bracher et al (1993) reported a similar pattern, although overall lower, in recovery rate between follicles aspirated using a single-lumen (12.3%) or double-lumen (24.4%) needle. The lower overall recovery rate for these latter workers may be a reflection of the different follicles for puncture: the recovery rates for Cook et al (1993) where based on aspirating pre- ovulatory follicles whereas Bracher et al (1993) performed follicle aspiration as long as more than 3 follicles (size not specified) were seen at an ultrasound examination of the ovaries. DuChamp et al (1995) also reported that recovery rate was higher with a two-way needle system then a one-way system (29% versus 22%). However both of these figures are lower than those reported by Meintjes et al (1995) using a single-lumen ; they reported recovery rates of 75.8% in pregnant mares. The value of flushing has been evaluated for human IVF procedures and whilst some papers report no improvement in oocyte recovery rate with flushing (Scott et al 1989; Haines et al 1989) others suggest that flushing follicles with a double-channel needle can result in an increased recovery rate of oocytes (Waterstone and Parsons 1992). Vacuum pressure. Follicle Size To further complicate the situation others report no effect of follicle size on recovery rate (Bracher et al 1993; DuChamp et al 1995). Hormone pre-treatment Needle size In our '95 studies, a disposable 18 gauge needle system was used. The use of the disposable needles rather than the long specifically designed OPU needles has the advantage of always using a sharp needle as if the disposable needle becomes blunt it can easily and cheaply be replaced. Although the long OPU needles are able to be re-sharpened this can be difficult and the needle never regains its original sharpness. It remains to be seen if the recovery rates are as good with the disposable needles. Even if they prove acceptable for bovine work, the different features of the mare ovary means that the results from the bovine cannot be directly transposed. Aspiration only with a disposable needle system has obvious economic and time advantages, but it is not yet possible to say if recovery rates could be improved by using a different system. To investigate this possibility we will be using both a 12 gauge disposable needle system without aspiration and comparing the recovery rates with the use of a double lumen 12 gauge equine OPU needle (Cook Veterinary Products Ltd). It was possible to bore out the existing metallic needle guide which used 18 gauge needles to take 12 gauge needles. The new needle guide can allow use of both disposable short needles and also the long 60 Cm OPU needles and so represents a versatile system. To conclude this discussion of recovery rates, almost all workers reporting use of OPU in the equine have utilised long OPU needles and so the question of whether a disposable needle system can give acceptable recovery rates remains unanswered. There may be information on this based on our recovery rates for this current year (1996) using both systems. In any case, comparison of recovery rates has many difficulties. It is probably accurate to state that at this moment, anyone beginning equine OPU would be best to use a double-lumen 12 gauge needle system, aspirate and flush the follicle. Once acceptable recovery rates have been achieved, use of disposable systems may be tried and recovery rates compared.
Applications of Equine Ovum Pick-Up 1) Improvement of Fertility The non-Thoroughbred breeding population, which represents a large number of competition, show and other valuable animals, will represent the animals from which mares suitable for OPU will be chosen in the near future and until there is any acceptance of the technique by the relevant Thoroughbred authorities. Equine embryo transfer has become widespread in the equine in certain countries such as USA. Within other countries such as the United Kingdom and the Netherlands there are very few foals born from embryo transfer. The reason for this poor uptake of embryo transfer in these countries is multifactorial with both innate equine physiological problems such as difficulty in achieving superovulation and economic reasons being involved. Nonetheless centres such as Colorado State University offering a commercial equine embryo transfer provide an opportunity for problem mares and mares remaining in competition to have foals and good pregnancy rates are obtained. Certain mares, however, can be in embryo transfer programmes for several years with no success. The most likely reasons for this are failure of the embryo to arrive in the uterus or early death of the embryo. For such mare the assisted reproductive techniques of in vitro fertilisation (IVF), gamete intrafallopian transfer (GIFT) and a combination of IVF of in vitro matured (IVM) oocytes, perhaps also involving intracytoplasmic sperm injection (ICSI), may hold the key to the future. While the techniques have been found to work well in the bovine field progress in the equine has been slow. To date there has only been one IVF foal born in the world. However, by the time of this meeting, there will hopefully have been born a foal produced using a combination of IVM, IVF and ICSI techniques by Squires and his co-workers at Colorado State University. OPU has provided the bovine industry with an ideal way of increasing the number of gametes available for maturation, fertilisation and in vitro development which will in turn allow an increased production. The equine breeding industry has different criteria on which it is based and an enormous increase in production from one mare is not a realistic aim. Nonetheless it is possible to envisage that oocyte manipulation may become an option in the clinical situation for the problem, subfertile mare. It is likely that the development of transvaginal ultrasound-needle guided aspiration of oocytes will represent a very important link in this chain of events and the next few years should be exciting times for those of us involved in the field. 2) Research Tool There would appear to be no doubt that refinement and continued development of the technique of OPU in the mare will have a major role in future equine breeding programmes.
References Ball, B.A., Little, T.V., Weber, J.A. and Woods, G.L. (1989) Survival
of Day-4 embryos from young, normal mares and aged. subfertile mares after transfer to
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