Unexplained Infertility – What the Semen Analysis Does Not Tell Us!
Infertility evaluations often fail to identify the precise cause of infertility. While currently utilized standard infertility testing procedures may not find the precise explanation for the delay in conceiving, it is logical to assume that there is a defect in either the female or male leading to the delay in conception. The complete semen analysis is the current standard of care for evaluation of the male and includes an evaluation of the count (number of sperm/ml of semen), motility (percentage of moving sperm), and morphology (percentage of microscopically normal appearing sperm). The World Health Organization (WHO) has established standards for a normal semen analysis based on fertile men. These standards are accepted throughout the world allowing for comparisons across laboratories in different geographical locations. However, it is important to recognize that the standard semen analysis does not provide a complete evaluation of the “function “ of sperm.
Spermatozoa must undergo many changes before fertilization can occur. We must keep in mind that in order to fertilize the egg, sperm must swim with enough velocity to penetrate the cumulus cells that surround the egg, bind to the zona pellucida (the membrane that surrounds the egg), and eventually penetrate the zona pellucida. This process of sperm penetration of the cumulus cells and binding with the zona pellucida requires the individual sperm cell has appropriate energy supplies in the form of adenosine triphosphate (ATP). Under normal conditions, during transit of the female reproductive trace, sperm undergo a process called capacitation. This process involves generation of a compound called adenyl cyclase, which activates an enzyme (protein kinase A). This chemical reaction results in a change in sperm protein (tyrosine phosphorylation), enabling spermatozoa to become capable of fertilizing. The important thing to point out here is that there is no current method of evaluating these intra-cellular processes (capacitation) in the woman’s body while they are going on.
After capacitation, sperm must undergo acrosome reaction and hyperactivation while in contact with the zona pellucida before they can gain entrance into the cytoplasm of the egg. For this process to occur, sperm must be coated with a specific surface protein.
The standard semen analysis does not assess capacitation of spermatozoa in the female reproductive tract, the acquisition of sperm surface proteins required for zona pellucida binding and penetration, and the ability to fertilize the egg.
Many sperm function tests exist, including the sperm oocyte penetration test, hemizona assay, stimulation of the acrosome reaction, hyperactivated motility assessment using computer assisted semen analysis, and in-vitro capacitation tests. However, these tests are usually not done at the present time because the clinical usefulness in terms of predicting pregnancy has not been clearly shown to be superior to the sperm concentration and morphology. Additionally, health insurers are often reluctant to cover these procedures even when infertility coverage is in place.
When men are found to have severe reductions in the sperm count, they are often referred for intra-cytoplasmic sperm injection (ICSI) and IVF if intrauterine insemination fails. The difficulty arises in men who have normal sperm counts and morphology, but have deficiencies in capacitation, acrosome reaction, or actual fertilization that are not diagnosed. These “undiagnosed” or sometimes referred to as “occult” male factors are encountered from time to time when complete fertilization failure occurs in an IVF treatment cycle in which insemination has been utilized rather than ICSI. While routine performance of sperm function tests might alert clinicians to the possibility of the occasional “occult” male factor, the reality is that this approach leads to the performance of many tests on men with normal semen parameters in order to identify the occasional patient with an “occult” male factor who would clearly benefit from use of ICSI at the time of IVF. One approach that has been used in some clinics is to consider the possibility of an occult male factor in any couple in whom with unexplained infertility. When these patients become candidates for IVF because of failed simpler treatments, ICSI is performed on all or in some cases half of the eggs retrieved. Inseminating half of the eggs and performing ICSI on the other half, allows for a comparison of the fertilization rates for each group of eggs and may clarify whether a couple’s infertility is due to a male factor. This information can be useful for determining the direction of future treatment should it be necessary.
New sperm function tests need to be developed to allow accurate prediction of fertilization in vitro, and to help determine whether progeny will be healthy. Detailed genetic studies may help identify genetic abnormalities of sperm that impact the ability of sperm to fertilize and the outcome of progeny.
Source: Wang C, Swerdloff, RS “Limitations of semen analysis as a test of male fertility and anticipated needs from newer tests”, Fertility and Sterility 2014 Vol. 102, No. 6. pp. 1502-1507.