Advanced Fertility Services

A New Look at the Diagnosis and Treatment of Subfertility: One Man's Opinion by Dr. Hugh D. Melnick, MD, FACOG

Infertility is not a disease, yet it is usually approached medically as if it were one. We, as physicians, are trained to approach all bodily malfunctions in such a way that an assortment of tests are used to make a diagnosis. More obscure illnesses require more comprehensive and elaborate testing. Once testing suggests a diagnosis, treatment is based solely upon that diagnosis. if the diagnosis is correct a patient will then be cured by the appropriate treatment.

This approach works well with an illness, such as a kidney infection, but not necessarily with infertility. For example, when a patient presents with painful urination, urine tests may identify the presence of bacteria of a certain type along with information regarding the most effective antibiotics. An antibiotic is given to the patient who will usually then recover. In this case, treatment is diagnosis driven.

In the case of infertility, the process that leads to a successful conception is really too complex to dissect diagnostically. There are too many steps prior to, and after, fertilization, that must be in proper alignment for the process to work. I often visualize conception to be like a long line of dominoes. When the system works, all the dominoes fall over, in their turn, until the last one tumbles. Only one domino need be slightly out of line in order to make the system fail, since the process stops at a point prior to its successful completion. Successful conception requires many complex biological steps to complete the process. If one step does not work, the whole system breaks down and does not reach the end point of pregnancy. Unfortunately, most often It is impossible to tell exactly at which point the process fails.

To make matters even more complex, many of the blockages to conception occur on a cellular or molecular level. In fact, even after successful fertilization, most embryos, even those that appear to be perfectly formed, have genetic molecular defects the ultimate cause of implantation failure. Only 25% (or less) of embryos become clinical pregnancies.. The 75% (or more) which do not survive, will have had some type of genetic or chromosomal abnormality.

The reality is that there are only three diagnostic tests, which if unequivocally abnormal, will lead to an accurate diagnosis of sterility. If a test of tubal patency shows that both tubes are blocked, conception is impossible. If tests of ovulation show an absence of egg production, conception will not occur. Finally, if the semen analysis is consistently devoid of motile spermatozoa, pregnancy will not occur. If, however, one tube is open, ovulation occurs on a infrequent basis, or the semen analyses reveal poor specimens, pregnancy frequently can, and does, occur. In these instances, even the most basic of diagnostic tests cannot accurately predict whether conception is possible. Therefore, it is possible to accurately diagnose absolute sterility, but very difficult to establish a causative factor in subfertility.

If a couple who has not conceived in a period of time appropriate for their age is determined to be potentially fertile, there are four possible areas in which factors could reside which would prevent conception.

1. Defective egg production, despite normal ovulation.

2. Open, but nonfunctioning Fallopian tubes.

3. Factors that block fertilization in the body.

4. Biologically nonfunctioning sperm despite a normal semen analysis.

Unfortunately, no tests exist to evaluate potential problems in the above areas. Therefore, infertile couples may benefit more by working toward finding therapy to either augment the natural process or conception or bypasses the problem area, rather than spending too much time on diagnostic testing.

The Approach

Because a diagnostic answer is usually not possible, couples should be grouped into two broad categories: potentially fertile and probably infertile. To be potentially fertile, there should be a normal male component, the possibility of normal ovulation and at least one open Fallopian tube and a negative antichlamydia antibody level. Those in the potentially fertile group will be treated in such a way that would tend to increase their fertility by creating more eggs and placing the sperm in dose proximity in order to facilitate the more mechanical aspects of the fertilization process. Initially, Clomid is used to cause the production of extra eggs, and at the appropriate time, intrauterine insemination (IUI) is performed. This treatment protocol is followed for a maximum of three cycles, as long as the patient responds well to Clomid. Since, the probability of pregnancy occurring is best during the first three months of treatment, if pregnancy does not occur during this period of time, it is time to change treatment. Approximately 25% if couples will conceive during the first treatment level.

For those patients who do not conceive, controlled ovarian hyperstimulation with injectable gonadotropoins (Metrodin, Fertinex) is combined with Intrauterine (IUI) or Intraperitoneal (IPI) inseminations. Multiple eggs and sperm are put near each other and, if all other factors are functioning normally, pregnancy should occur within the first three treatment cycles. Twenty to thirty percent of couples will conceive during this treatment phase. For those couples who do not conceive with the above two treatment strategies, the existence of any one of a number of possible defects in the body is preventing conception from occurring. However, in the cases of women aged 34-40 who produce only 2-3 follicles with controlled ovarian stimulation using gonadotropins, the problem usually relates to the depletion of eggs in the ovary. if pregnancy does not occur with this low level of egg production, this patient is usually not a good candidate for continued treatment.

Couples in whom a tubal or male factor is suspected should proceed direly to an IVF cycle. Of course, IVF is also the final logical step for couples not conceiving despite adequately hyperstimulated cycles and insemination.

An IVF cycle should be considered as both a diagnostic and a therapeutic modality. In couples with unexplained or unresolved infertility, a patient's response during an IVF cycle can suggest the general area in which conception falls. Oocyte abnormalities and fertilization failure are readily demonstrable. if fertilization occurs normally In vitro, the probable defect in vivo was either nonfunctional Fallopian tubes, or a toxic factor blocking fertilization.

If fertilization failure is observed In vitro, the cause may be an egg defect (zona pellucida too thick) or a sperm problem (failure to bind or improper acrosome function). Although, in many cases it is impossible to tell if the defect resides in the sperm or egg, the treatment remains the same: the injection of a sperm directly into the egg (ICSI). Again, the diagnosis is not important, since the treatment is identical for both problems.

For patients in whom a male factor is suspected or fertilization failure is anticipated, the initial IVF procedure should include ICSI in order to maximize the chance for a successful cycle. In borderline cases or in patients with long-standing unexplained infertility, the use of ICSI should be considered with one half of the mature eggs.

If there is complete failure of fertilization the cause of infertility is diagnostically uncovered, but is nevertheless heartbreaking for the patients. When an unanticipated fertilization failure occurs, we will attempt to do ICSI on the second day. Although fertilization can usually be obtained, pregnancy rates are much lower than for normally timed fertilization. Some clinics will not do second day ICSI, but I feel that the 5% pregnancy rate with 2nd day ICSI is worth the effort.

Criticism could be expressed for the overzealous use of ICSI. However, its potential benefits may out weigh its downside, which is its extra expense. Performing ICSI adds $1000-$2500 to the cost of an IVF cycle. However, in borderline cases, performing ICSI is an insurance policy against losing the complete cycle. Moreover, in performing ICSI, the oocytes are stripped of their surrounding cells, which enables the quality and maturity of the eggs to be more accurately assessed. In many cases, eggs which appear to be Metaphase II prior to Stripping, are really in Metaphase I and are not ready to be fertilized. Some eggs never do progress to maturity. This oocyte abnormality cannot be determined with the routine fertilization process. The use of ICSI now allows almost every woman who produces mature eggs to have an embryo transfer. In reality, ICSI is probably the only valid treatment for male infertility.

Factors Blocking Fertilization

When the sperm and egg interact in the body, they do so in a very complex environment made up of many biological and cellular components, some known, most not. If, because of the presence of some indeterminate substance the fertilization process is interfered with, conception will not occur. Any number of biological substances produced by the body, proteins, antibodies, or other complex molecules) could cause fertilization failure. There is no possible way to test an individual for the presence of such substances. Yet in a couple having unexplained infertility, the fact that fertilization occurs In Vitro is a very positive event. It rules out most egg problems and problems of fertilization. It also demonstrates biologically normal sperm function. By process of elimination, the block to conception could have been either due to a tubal problem or to the existence of a blocking factor In Vivo, or even both. The actual cause of infertility cannot be determined, but it can certainly be bypassed.

Biologically Nonfunctioning Sperm

It is well known that even men who have numerically abnormal semen analyses can impregnate their partners. Moreover, not infrequently, a man having a normal semen analysis will fall to fertilize eggs In Vitro. Therefore, the traditional semen analysis based on the World Health Organization (WHO) criteria is not always predictive of male fertility. The biological functions of sperm necessary to actually fertilize an egg are not reflected in a semen analysis, nor are any of the other tests of sperm function infallibly indicative of a man's fertility potential. In the actual fertilization process, the sperm must first have enough energy to penetrate the mass of cumulus cells surrounding the egg, bind on to the egg's outer surface and then burrow through the zona pelludica to reach the center of the cytoplasm to deposit its genetic material. Abnormalities in any of these areas may be present, so the inability to fertilize can occur at many different levels. Consequently, tests of male fertility such as the Hamster Egg Penetration Test lack validity and should be abandoned. The only positive proof of normal sperm function is a fairly recent history of fathering a child or fertilization of eggs In Vitro.

Tubal Problems

Fallopian tubes may appear to be normal and open, yet not function properly to allow the unification of egg and sperm or transport and nourish the embryo. For example, approximately 33-50% of all women after an ectopic (tubal) pregnancy will never again conceive despite the remaining tube being open! In such cases, the Fallopian tubes do not function biologically because of damage to the cellular lining which is crucial for proper function. Uterine and tubal infections, many times asymptomatic, are a possible cause of subtle tubal damage. Unfortunately, there is no accurate way to assess tubal function. Diagnostically, a high level of antibodies to chlamydia in a woman's blood may indicate a past tubal infection, which could only suggest a tubal cause of infertility. Patients having one tube blocked and a positive antichlaymidial antibody level should be considered as having a tubal problem.

Oocyte Problems

In some instances of subfertility a problem exists with a woman's eggs, despite seemingly normal ovulation. One such problem is that the zona pellucida, the "shell" of the egg, may be too thick to be penetrated by spermatozoa. Or, follicles may be produced which either contain no eggs, or abnormally appearing (atretic) ones. It may also be that the oocytes are being released at a time prior to full genetic maturity, thereby preventing them from fertilizing properly.

As a woman ages, her remaining eggs will normally undergo some changes in their DNA structure. Such minute changes in the DNA's molecular structure, called mutations, will radically change biological development. More often than not, mutations, create structural abnormalities which result in the formation of a potentially imperfect offspring. These genetic changes exist in the majority of perfectly formed, normal appearing eggs and embryos. To large extent, the birth of imperfect babies is prevented by the failure of such abnormal embryos to continue to grow in the uterus for more than several days. "Natures" way of preventing the birth of these imperfect offspring is the failure of embryo implantation, a biochemical pregnancy or the miscarriage of a "blighted ovum". This is one of the major reasons that, with increasing age, a woman takes much longer to conceive or cannot conceive at all. Most women who are very fertile at a young age may take 3-5 years to conceive after the age of 35. This means that if a woman has 3 years between her last two children, only one out of 36 eggs was genetically suitable to produce a normal pregnancy! Often times, many years before premenopause, women fail to conceive or have an increased rate of miscarriage due to egg problems of a genetic or chromosomal nature. In my experience, this may be one of the most common and untreatable problems we face in treating infertile couples.

A Possible Solution

Unfortunately, since there are no diagnostic tests capable of identifying problems which may exist in these four areas, treatment cannot be diagnostically driven. Therefore, an alternative approach is to spend minimal time on diagnosis, and if no obvious problems are found, begin a treatment plan that is designed to maximize the chances of conception by either enhancing the natural process or by bypassing potential problem areas.

Necessary testing can be performed during the course of one cycle. Bloods are drawn on day 2 or 3 to check the FSH, LH and estradiol. If elevated, the patient can be advised that no further testing or treatment is necessary, since the prognosis for pregnancy is poor.

After menstrual bleeding is over, a hysterosalpingogram (HSG) if performed to document tubal patency and an antichlamydial antibody (IGG) is drawn. At time of ovulation, a vaginal sonogram is performed to document the production of a normal sized follicle as a test of ovulatory function. Other important information such as ovarian follicular reserve, which helps predict responsiveness to fertility drugs, and evaluation of the endometrium, is also obtained from the transvaginal ultrasound. A post coital test can be performed at the same time.

This completes the female diagnostic evaluation. The diagnostic tests which have been omitted are the endometrial biopsy, diagnostic laparoscopy, and sperm antibody testing. The biopsy is not needed because we check ovulation and the endometrium sonographically. According to the European Society for Human Reproduction and Endocrinology (ESHRE), the presence of antisperm antibodies are not correlated with infertility.

Diagnostic laparoscopy is omitted for several reasons. if the tubes are patent by HSG and the antichlamydial antibody is negative, laparoscopy will show normal findings 95% of the time. In the cases of small endometrial implants, laparoscopic or medical treatment does not significantly alter pregnancy rates. Moreover, ovarian endometriosis, which can severely impair ovarian function, can be seen on ultrasound. In these cases, laparoscopy is needed for therapeutic rather than diagnostic reasons. By eliminating routine diagnostic laparoscopy, the patient avoids a surgical procedure under general anesthesia which does not materially enhance her chances for pregnancy.

Evaluation of the male consists of a computer assisted semen analysis, which, in addition to the usual criteria of count, motility and morphology, measures the velocity at which the sperm swim. After the initial evaluation of the semen, the remainder of the specimen undergoes sperm processing and is again analyzed via computer. The specimens are evaluated on their pre and post "wash" condition. If the post processing specimen is normal to low normal in count and morphology and the sperm velocity is greater than 60 micron/sec, the specimen should be able to cause fertilization both InVivo and lnVitro. If the post process velocity, count, and percentage of normal appearing sperm are low, there will most probably be a fertilization problem. Therefore, males are grouped for treatment according to whether they are potentially fertile in the post process specimen or whether fertilization is unlikely to take place. The post process specimen should have more then five million motile sperm having a velocity of greater than 60 microns/sec. for assignment into the potentially fertile group.

Conclusion

Reproductive medicine should not and cannot be diagnosis driven. The diagnostic approach to the infertile couple must be brief and able to separate those who are absolutely infertile from those who are potentially fertile. Treatment of potentially fertile couples should be aimed at enhancing the natural process of conception in the body. Those patients who are not fortunate enough to conceive by this approach have underlying defects in their reproductive systems that, although not identifiable, render them effectively sterile. These patients, like those who are obviously infertile, should be offered IVF treatment in order to bypass their barrier to conception.