by L. L. Penney, M.D.

Mid-Missouri Reproductive Medicine & Surgery, Inc.
1502 East Broadway, Suite 106
Columbia, MO 65201
(573) 443-4511

Just a few years ago, unexplained infertility was reported in up to 60% of patients in studies from the medical literature. Even as recently as the last few years, authors have continued to report its prevalence as high as 20% to 25%. A recent textbook summarized several studies dating back to 1950 and quoted an average percent of unexplained infertility of 16.7%. Of note, some recent authors report their percent unexplained between 0% and 6%.

How can such wide discrepancies in the percentage of unexplained infertility be explained?

Obviously, if one considers, as has been proposed, a semen analysis, evaluation of ovulatory function, a post coital exam, a hysterosalpingogram, and a laparoscopy a complete initial assessment in any couple not conceiving in one year of attempting, a larger number of patients will be diagnosed as unexplained infertility than if additional tests are included or a longer period of infertility is required before making the diagnosis. If one accepts an abnormal parameter as an explanation, expanding the diagnostic tests only slightly reduces "unexplained" infertility dramatically as shown, for illustrative purposes, in the attached table from my own practice.

Apart from the definition of infertility itself, an additional consideration would be the definition of test normals in any given practice or clinic. For example, if one uses 60% sperm motility of grade three plus as the lower limits of normal and accepts that any lower value may be associated with infertility, many otherwise "unexplained" male infertility problems become "explained".

We also know, as with smoking, excess caffeine intake, or alcohol use, or can deduce numerous causes of infertility which are not precisely evaluated by currently available tests. For example, consider success rates with gamete intrafallopian transfer in couples with unexplained infertility. These success rates on average in this country will be 26% to 28% in terms of a live birth per oocyte retrieval. This is strikingly increased over controlled ovarian hyperstimulation combined with intrauterine insemination with washed husband's semen success rates. Other than simply increasing the number of gametes available, what does GIFT accomplish? It obviates the need for sperm transport through the fallopian tube, for oocyte release from the ovary, and for oocyte pickup by the fallopian tube. So, as alluded to above, one can deduce, in all probability, defects must exist in one or more of those mechanisms in at least a percentage of couples with unexplained infertility.

IVF data clearly indicate, even in the most successful programs, low implantation rates relative to the number of embryos transferred. Defects which lead to problems with implantation are probably much more common than we realize and constitute another area of unexplained infertility for which testing is currently being investigated. Assaying implantation factors such as integrins may, in fact, lower the percentage of patients identified with unexplained infertility, but do not assist in the initial deliberations regarding therapy.

Some authorities would suggest that there is an overlap between certain causes of recurrent pregnancy loss and infertility. In other words, infertility and early recurrent pregnancy loss represent just points of a spectrum. For instance, these physicians might evaluate for the antiphospholipid syndrome, ordering tests usually performed for recurrent pregnancy loss patients, in couples presenting with infertility. If one accepts this as a cause of infertility, then failure to test would place a certain percentage of patients into the unexplained infertility category while, in another office, they would be considered explained infertility.

If one believes that laparoscopic management of endometriosis does not improve pregnancy rates then, of course, laparoscopy would not be performed. Although a large, prospective, randomized trial has not been performed, most available data suggest that pregnancy rates are significantly improved by surgical treatment, even if mild or minimal endometriosis exists. So, here is another circumstance where one subscribing to the former position might find unexplained infertility, while one subscribing to the latter position would find explained fertility.

One of the common questions when a patient doesn't conceive during a treatment cycle, regardless of the therapeutic regimen, is "What went wrong, Doctor?" Part of the answer also relates to the concept of unexplained infertility. That is, part of one's response is to point out healthy young couples experiencing intercourse in a random fashion conceive in only 20% or 25% of cycles. This means normal couples fail to conceive in 75% of cycles. One cannot ascertain "what went wrong" with those cycles any more than one can precisely identify a single etiology or even a group of etiologies responsible for the failure to conceive in any one treatment cycle. So, once again, the concept of unexplained infertility can be quite broad.

A couple who has attempted to conceive for three years without success in a sense has already tried thirty-six months; so, assuming they don't conceive in the next cycle or two, they've already demonstrated their chances of conception on a per cycle basis are 3% or less. In fact, those numbers are borne out by more sophisticated studies which indicate that the probability of conception without treatment in such couples is actually in the range of 1% to 3% per month. Therefore, couples need to consider not only the female partner's age, but the duration of infertility in determining whether to proceed to empiric therapy; that is, therapy which is not being addressed to a particular diagnosis which has been established.

Therapies which are probably successful in treating unexplained infertility include clomiphene ovulation induction or human menopausal gonadotropin ovulation induction, either of which may be combined with intrauterine insemination, which may itself improve the pregnancy rates in unexplained infertility. More controversial therapies include glucocorticoids, baby aspirin, and heparin. Generally, any treatment regimen extended beyond six months will enter the point of diminishing returns. As a practical point, most patients don't proceed beyond six cycles of clomiphene or three or four cycles of human menopausal gonadotropin before considering assisted reproduction technology such as IVF or GIFT.

That this problem is not approaching resolution or clearly defined borders is attested to by the fact a rapid file search for the past ten years retrieved approximately 290 articles addressing in some manner unexplained infertility. Consensus as to the extent of testing required before one can conclude that unexplained infertility exists, or treatment if it does, will not be forthcoming soon.

"Explained" Infertility

587 Consecutive Patients
L. L. Penney, M.D.