The use of intrauterine insemination (IUI) has become a very frequently used tool in treating infertility. Proper use of IUI can significantly improve pregnancy rates, but probably it is an overused procedure.
One of the obvious needs for IUI is to overcome a cervical factor problem. Scant, thick cellular mucus may be secondary to previous surgery to the cervix, e.g., conization, previous cervical infections, or intrauterine exposure to diethylstilbestrol (which is becoming far more uncommon). However, the most common cause of hostile cervical mucus is related to the antiestrogen effect of clomiphene citrate when used for improving follicular maturation. Occasionally supplementing estrogen therapy after stopping the drug can improve the mucus but if this fails, then IUI has been very successful.
Intrauterine insemination has several theoretical advantages over intercourse or intracervical insemination (ICI) for male factor problems. In a recent study by Check et al., accurate timing of IUI with properly prepared semen may be an effective therapy for male factor since the pregnancy rates were similar for male factor and cervical factor cases. Sperm separation techniques allow an increased concentration of the best quality sperm in the ejaculate, while removing harmful white blood cells and other debris. Motile sperm should be separated from the rest of the semen using a sperm wash separation procedure, then they can be concentrated for insemination. Many studies have shown that pelleting of the semen, prior to separation of the motile sperm, can release reactive oxygen species which may harm the whole sperm population.
Percoll density gradient centrifugation appears to be the most popular sperm separation method today. It has the advantage over other methods by recovering a higher percentage of motile sperm as well as removing seminal debris and non-motile cells. Percoll is made of a colloidal silica coated with polyvinylpyrrolidone (PVP). Centrifugation of the columns, allow for the motile sperm to swim down through the Percoll and pellet at the bottom of the centrifuge tube. All non-motile cells and debris should remain above the Percoll layer. A one layer procedure is performed by diluting the raw semen with an equal part of modified human tubal fluid (HTF) (Irvine Scientific #9963) supplemented with 0.5% HSA. Up to 2mL of the semen mixture was overlayed onto 1mL columns of 90% Percoll, made isotonic using modified human tubal fluid (modified HTF-HEPES 10x, Irvine Scientific #99141) and centrifuged for 20 minutes at 300g. The top semen layer is discarded and the sperm pellet placed into a new tube. The pellet is then washed and resuspended in HTF for insemination. If the motile sperm population is low, then the remaining 90% layer can be washed and possibly used for insemination.
A Mini-Percoll procedure can be used for severely oligospermic samples. However, the original procedure does call for an initial centrifugation step to pellet the sperm and concentrated to 0.3mL prior to layering onto a three layer column.
When sperm reaches the cervical mucus there is a reservoir and sperm can be released to the tubes over a period of several days. However, weak sperm may not be able to have longevity of survival, and for this reason timing the IUI very close to ovulation may improve fertility outcome. The mucus, 12 hours before ovulation, begins to regress and may not support survival of sperm after intercourse or ICI. After ovulation, the mucus is even worse even though the oocyte is viable in the fallopian tube for at least 8 hours. Placing the sperm intrauterine 4 hours before or within 8-12 hours after ovulation eliminates the burden of sperm longevity, thus allowing fertilization to occur.
Some clinicians try superovulation with IUI for "unexplained" infertility. Controlled studies have shown that the pregnancy rate is higher if gonadotropins are used with the IUI versus IUI alone. I personally think that this approach is very costly to patients and increases their risk of ovarian hyperstimulation syndrome and multiple births and thus may not be necessary. Meticulous and careful evaluation of the process of ovulation including follicular maturation defects, checking for oocyte release from the follicle, and judicious use of progesterone (P) support in the luteal phase will eliminate the need for this "shotgun" approach. There are no data proving that IUI improves pregnancy rates when the postcoital test is normal.
When males have antisperm antibodies attach to their sperm, but the postcoital test is normal, IUI may not be necessary. However, if the postcoital test is poor, simply bypassing the mucus by performing IUI is not that effective because the attached antibodies may also interfere with fertilization. Pretreatment of the sperm with an enzyme call chymotrypsin may neutralize some of the harmful effects of the antibodies and thus markedly improved pregnancy rates following IUI.
Chymotrypsin-galactose treatment of sperm prior to IUI also improves pregnancy rates in another circumstance where a male has a subnormal (<50%) hypo-osmotic swelling (HOS) test score. Interestingly, this defect does not impair fertilization but apparently releases a toxic factor that damages the oocyte in such a way that despite normal cleavage, implantation is impaired. Sixty percent of patients will improve the HOS score to >50% following chymotrypsin treatment and in this group a normal PR following IUI may be achieved. The reagents used for chymotrypsin/galactose treatment were: Earle's balanced salt solution (EBSS) (Irvine Scientific 9208), chymotrypsin type IV-s, 5mg (Sigma CHY-5s), D(+)-galactose (Sigma G5388) and bovine albumin fraction V powder, low endotoxin BSA (Irvine Scientific 1092). The chymotrypsin/galactose pre-treatment protocol was as follows: to 5 ml of EBSS, 0.1 M galactose was added and the solution incubated at 37oC, sterilized by filtration using a 0.2um filter, and added to 5mg chymotrypsin just prior to semen production. Semen was collected directly into chymotrypsin/galactose in a specimen cup and immediately disrupted with a transfer pipette until the coagulum was liquefied (30-60's). Rapid addition of 30mg/mL BSA stopped the enzymatic reaction, and when this was fully dissolved (~5 min), the specimen was layered onto a Percoll column.
When sperm is cryopreserved and then thawed, poor pregnancy rates ensue following ICI even with donor quality sperm. This is probably due to a lack of longevity of survival caused by a reduction in sperm motility occurring during freezing and thawing. A population of vigorously motile sperm must penetrate the cervical mucus, transcend to the site of fertilization and then penetrate the oocyte. A perfectly timed IUI can bypass the cervix and place a highly motile concentration of sperm close to the oocyte, thus allowing a normal pregnancy rate.
It should be noted that success with IUI requires perfect timing because of the narrow time window that sperm placed intrauterine can achieve fertilization. Ovulation will typically occur 36 hours after the luteinizing hormone (LH) surge. Our protocol begins monitoring 16 days before expected menses by pelvic sonography for follicular maturation and serum estradiol levels. Once a mature sized follicle of 18-24 mm is obtained the woman will monitor urinary LH every 4-5 hours. Intrauterine insemination is timed 36-40 hours from the LH surge and will be repeated within 12 hours if the oocyte had not released as yet. Frequently, an ultrasound will be performed first and if the follicle is still intact, the IUI will be delayed a few hours.
Early reports with the use of IUI had a very poor outcome. This may have been related to improper preparation techniques that led to release of harmful reactive oxygen species and improper timing. However, when used properly and for the correct indications, pregnancy rates with IUI now approach those of normal fertile couples.
December
1996
Copyright 1996. The
American Surrogacy Center, Inc.(TASC), Marietta, GA
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