Unexplained Infertility

"Unexplained Infertility" has been described as "a misfortune due to laws of chance or limitations of our knowledge." It is a diagnosis of exclusion, meaning the diagnosis is made after a standard fertility evaluation of a couple fails to provide an explanation for their infertility.

What constitutes a standard evaluation is debatable. However, most experts agree for the female partner it includes a history, exam, assessment of ovulation, hysterosalpingogram (radiological study of the uterine cavity and tubes) and often laparoscopy (surgical visualization of the pelvis by placement of a narrow scope into the abdomen).

For the male partner, evaluation usually includes a history, exam, and semen analysis. About 15% of couples with infertility of at least one year duration will have all normal findings after a standard evaluation. By definition, these couples have unexplained infertility.
Why is their infertility unexplained? The simple answer is there are limitations to our ability to evaluate human fertility. For example, for each of the tests mentioned above there are limitations:

Ovulation/Egg: Assessment of ovulation often involves ultrasound visualization of follicle growth, collapse, and evaluation of the progesterone producing ability of the corpus luteum (the collapsed follicle that released the egg).

However, the egg that is presumably released with follicle collapse is only 0.1 mm in diameter and therefore not apparent to ultrasound. Unless pregnancy occurs or eggs are actually extracted, as with IVF, it must be assumed that a healthy, mature egg is actually released with ovulation. Ovulation as assessed by history (regular periods), temperature charting, urine LH testing, or even serial ultrasounds and progesterone levels provide only indirect evidence of egg release and very little information about egg quality.
Pelvis: A hysterosalpingogram (HSG) when normal indicates the uterine cavity is without filling defects (adhesions, polyps, fibroids, or congenital abnormalities) and that the tubes are open (able to fill with and spill dye). However, the HSG is usually unable to detect filmy adhesions (scar tissue) involving the tubes and ovaries or endometriosis, which can significantly impact a woman's fertility. Laparoscopy can detect and treat these problems.

Yet, even a normal laparoscopic exam does not guarantee normal function of the fallopian tubes. In fact, even the tubes of a fertile woman are not thought to pick up every egg that is released. Capturing the egg is only one of many critical functions of the tube. The tube must also facilitate the transport of the egg and sperm to near its end (ampullary-isthmic junction) where fertilization must then occur.

Finally, the tube must transport and nurture the developing pre embryo to the uterine cavity where implantation will occur. It is necessary for the tube to perform all of these functions successfully in a conception cycle; however our ability to evaluate these critical functions is limited. Typically, if the tube appears normal, it is assumed to function normally.
Sperm: Semen analysis has limitations. A baby results from the union of only one sperm and one egg, yet the average ejaculate contains over 20 million motile sperm per cc. It is even unlikely that intrauterine insemination IUI will result in conception if much less than 1 million motile sperm are placed in the uterus. Semen analysis evaluates numbers, movement, and the appearance of the sperm.

However, the real question is, is it likely that there are sperm present functional enough to make the journey to the end of the tube to penetrate and fertilize an egg. Tests used to assess sperm function include the hamster egg penetration test and Kruger strict morphology. Although helpful, these tests have limitations. Again, like with assessment of ovulation, unless conception occurs or one witnesses fertilization as with IVF, the functionality of sperm is an assumption.

With all the things that must go right for conception to occur, it is easy to understand why there is a critical element of time (chance) to achieve a conception. However, unlike flipping a coin, the chance of conception is not constant. Studies have estimated that a young couple has about a 25% chance of conceiving per month for the first 3 months of trying.

This decreases to about 10% if conception has not occurred by months 9-12. Early on, couples with unexplained infertility may experience spontaneous conceptions. However, couples with unexplained infertility of greater than 3 years duration have a spontaneous conception rate of only 1-2% per month.
Lastly, there is the big factor of age as a major cause unexplained infertility." One in five American women are having their first child over the age of 35. About 1/3 of women deferring pregnancy until their mid to late 30's will have difficulty conceiving. At least ½ of women over 40 will have infertility problems.

Unfortunately, even though most women still ovulate into their mid 40's, at this age it is less common for successful conception to occur. Age is known to affect egg and therefore embryo quality. This in turn negatively affects the likelihood of fertilization, implantation, and miscarriage. Also with time, certain mechanical impediments to fertility such as endometriosis can worsen.

In addition to knowing chronological age, the effect of age on infertility is most popularly assessed by a cycle day 3 FSH and estradiol level. A variant of this assessment is measuring these hormone levels before and after a clomiphene challenge. In one study, 38% of women with unexplained infertility had an abnormal clomiphene challenge test.

Unexplained Infertility - Effective Treatments?

Because these treatments are not specific to a particular cause, (the infertility is "unexplained") they are called empirical. In 1998 a retrospective analysis of 45 studies on unexplained infertility was published. Without treatment, the monthly chance of conception was estimated to be about 2% (1.3-4.1%). Treatment with intrauterine insemination (IUI) alone did not raise this conception rate significantly (3.8%).

Treatment of unexplained infertility with Clomid plus IUI increases chance of conception per cycle 2-3 fold (from 2% to 8.3%). Treatment with gonadotropin injections plus IUI raises the conception rate even further to 17% per treatment cycle. Lastly, IVF conception rates for unexplained infertility are typically among a center's highest, usually at least 50% with the transfer of two embryos. The chance of conception is usually simply determined by a woman's age. As noted above, besides being treatment, IVF is also a diagnostic tool. IVF allows assessment of egg and embryo quality and the fertilization capability of the sperm.

If egg quality is poor, these women may be candidates for our donor egg program.

Unexplained infertility-Why do empirical treatments work?

Fertility drugs may correct unrecognized defects of ovulation or hormone production. Intrauterine insemination places a much larger number of sperm into the upper uterine cavity so that a greater number of capable sperm may reach the egg. Clomiphene combined with IUI and, to a greater extent gonadotropin and IUI, also overcome issues of chance.

In all women a healthy egg is not always released, the tube does not always pick up the egg, the sperm does not always fertilize the egg, and a healthy embryo is not always formed. Increasing the number of eggs released and the number of sperm reaching the ampullary-isthmic junction of the tube to meet the eggs enhances fertility in a given cycle. If a woman's tubes never pick up an egg, IVF will be needed to achieve conception. If a man's sperm is unable to fertilize his partner's eggs, IVF (often with intracytoplasmic sperm injection) will be needed.

In summary, there are a number of possible explanations for "unexplained infertility." Empirical treatment of unexplained infertility is often very successful.