Global Infertility Solutions

            Infertility represents a major problem in gynecology with over 20% of couples of reproductive age suffering from this disease.  However, most couples are not aware of the fact that 40% of the time the reproductive dysfunction will occur in the male partner.  There exists a societal misconception that infertility is a ‘woman’s’ problem.  Actually, from a scientific perspective, it is not clear why infertility is so high in men since many more reproductive events occur in the female than in the male.  The male is responsible for producing sperm and getting it to the female reproductive tract.  Whereas, the female not only has to produce her oocytes (eggs) and ovulate them, she is also responsible for being the site of fertilization and embryo transport to the uterus, as well as, being responsible for preparing the lining of the uterus as a receptive site for embryo implantation, nutriment and development. 

 

            If so much more is happening in the female reproductive tract than in the male then why are we faced with a high incidence of male reproductive dysfunction?  The answer lies in the manner in which sperm are produced.  Sperm are produced at a rate that exceeds almost all other cell types of the body.  Over 30 million sperm are produced every day in the testes through the process of cell division.  That is 10 times more sperm than then number of people who live in Western Pennsylvania.  It turns out that cells are very sensitive to damage from external agents when they are dividing.  During cellular division the genes (DNA) replicate their structure in a fashion that does not tolerate any extremes.  Sperm production is severely altered in the presence of environmental toxins, viruses, physical damage or high temperatures (fevers).  A single childhood event (mumps, fever, football injury, etc.) could permanently impair the capacity of the testes to produce functional sperm.  Unfortunately most adult men will usually not remember or realize that their testes may have suffered a transitory trauma that has induced infertility. 

 

 

Semen Analysis

 

            Currently, the semen analysis is the best method of assessing whether sperm production is normal.  A semen analysis will compare a variety of characteristics of the semen and sperm of the patient to the mean values for fertile men (See Table 1). Unfortunately, the semen analysis is not a full proof measure of the ability of an individual’s sperm to fertilize an egg.  Some sperm samples with below normal characteristics have produced normal babies and, likewise, some sperm that appear to be normal do not have the ability to conceive.  But in most instances below average semen or sperm characteristics would be indicative of male infertility.

 

Throughout the last century several scientists attempted to determine which characteristics of sperm and semen are directly related to fertility.    All of this information was coalesced into a working sperm classification system by the World Health Organization (WHO) in 1980.  The initial classification system suffered from numerous weaknesses and was revised in 1987 and again in 1999.  The current classification system (WHO ’99) assesses a variety of criteria that a sperm sample should contain to be considered ‘normal’ (See Table 1).

 

 

Table 1

Normal Ranges for Semen Analysis

(Adapted from the World Health Organization 1999 Criteria)

 

Characteristics		Normal Range
Sperm Concentration     (Millions/milliliter)		> 10-20 million/ml
% Motile Sperm             (moving/immotile x 100)		> 50% moving
Forward Progression     (4 point scale; 4 = excellent)		Grade of 3-4
Morphology                 (% of total that have a normal shape)		> 14% normal*
Volume (ml)		> 1.0 ml
White Blood Cells        (# of sperm visible at high power)		< 5 per high power field
Crystals		None
Viscosity                      (4 point scale; 4 = thick, 1 = thin)		1
pH		7.5 – 8.5
Liquefaction                (yes if liquid in 15-20 min.)		Yes
Semen Color             (red-brown = blood; yellow = infection)		White to gray
Sperm agglutination  (presence suggests sperm antibodies)		None
Gel clumps		None
Debris                      (3-4 point scale; 1 low, 4 large amount)		Low

* Normal morphology range varies between labs

 

 

 

Of the many criteria found in the WHO’99 semen analysis, the four characteristics that appear to be the most commonly found indicators of potential reproductive problems are:

 

1)     Sperm concentration

2)     Percentage motile sperm (i.e., live vs. dead sperm)

3)     Forward progression

4)     Sperm morphology (i.e., external appearance of the sperm)

 

It should be obvious that sperm concentration is important for normal fecundity (ability to conceive), in that, low numbers of sperm would be detrimental for conception.  But what is not obvious is the fact that 10 million active sperm/milliliter, which sounds like a lot of sperm, is considered too low for normal fecundity.  When sperm are deposited in the vagina, they have to enter the uterus through the small opening of the cervix and then make the long journey across the length of the uterus and the oviducts to meet up with an oocyte.  For every 100 million sperm that are deposited into the vagina, only 10 to 1000 sperm will make it to the oocyte.  With this high level of sperm carnage, the deposition of 10 million sperm in the vagina would yield only 1 to 100 sperm for the process of fertilization.  This is not a sufficient number of sperm for conception since the sperm have several tasks to accomplish prior to fertilization.  The sperm have to first digest away the oocyte’s helper cells (granulosa cells), a process that requires multiple sperm.  After the granulose cells are removed, the remaining sperm have to penetrate the oocyte’s thick protective coating, the zona pellucida.  Many sperm die during their attempt to traverse the zona pellucida.  The bottom line is that many sperm are required before that single lucky sperm can enter an oocyte.

                                                   

In addition to having a sufficient number of sperm, the sperm has to be energetic enough to fertilize the oocyte.  Two good measures of the sperm’s vigor are obtained from calculating the percentage of moving sperm (% motile sperm) and the speed at which they move (forward progression).  Men with semen that contain more dead than live sperm or sperm that are moving slowly have a lower potential for conception even when the sample contains more than 20 million sperm/ml. 

 

Sperm morphology or the appearance of the sperm is also related to the ability of sperm to fertilize an oocyte.  The sperm cell has a very simple design.  It is composed mostly of a head that contains the genes (DNA) and a tail for movement.  With such a simple design it would seem that the body would have no difficulty making perfectly shaped sperm, but this is not the case.  The testes produce many unusually shaped sperm.  As previously mentioned, the sperm are being produced at a high rate (>30 million/day).  As a result of this hectic production rate many of the sperm are malformed during the production process.  Most human samples contain a large proportion of sperm with unusual morphology, however, sperm samples that contain more than the average number of unusual sperm seem to have an inherent problem that prevents even their normal looking sperm to fertilize.

 

Numerous sperm morphology classification systems have been developed over the past 50 years.  The two systems most commonly used are the WHO’99 and the ‘Strict Criteria’ system.  Both systems have established criteria for the normal concentration of abnormally shaped sperm.  The ‘Strict Criteria’ system, as the name implies, is stricter than past classification systems.  The ‘Strict Criteria’ does correlate well with the ability of the sperm to fertilize sperm and has fallen into favor as the system of choice for most IVF (in vitro fertilization) clinics.  In the ‘Strict Criteria’, sperm have to measure up to strict limits of acceptability of head size and shape (Figure 1).  If a sperm does not meet these limits it is considered abnormal.  IVF research has shown that sperm samples with >14% normal forms should fertilize an oocyte and sperm samples with <4% normal forms have difficulty fertilizing an oocyte.  Those samples with 4% to 14% normal forms are in the grey area for fertilizability. 

 

Figure 1.  Using the ‘Strict Criteria’ for sperm appearance, a sperm with normal morphology (shape) should have an oval head that matches the exact dimensions shown above.

 

 

The WHO’99 sperm morphology system does not establish an exact range for normality but most labs use a normal range that is similar to the ‘Strict Criteria’.  The WHO’99 also differs from the ‘strict criteria’ in that it classifies the abnormal forms into distinct sub-categories.  Those sub-categories are divided into abnormal forms that involve the sperm’s head, mid-piece or tail.

 

In addition to what we have discussed, there are several other semen and sperm diagnostic characteristics that are less common.  Although these characteristics rare, when they do occur they can also be devastating on fertility.

 

Semen volume is related to sperm concentration in that it affects the amount of sperm that can reach the female reproductive tract.  However, semen volume also has an added hidden problem.  After intercourse, the semen rests in a small pocket at the back of the vagina, just under the cervix, the entrance to the uterus.  Because of this anatomical design the semen usually baths the cervix with sperm.  If the seminal volume is too low (i.e., less than 1.0 ml) then the semen will settle too far into the back of the vagina and not come in contact with cervix at all; a situation that would prevent any sperm from entering the female reproductive tract.  Because of this anatomical arrangement, semen volumes that are less then 0.5 ml are considered a serious infertility problem.

 

The semen that is deposited in the vagina is initially deposited as a thick semi-solid that melts (liquefies) over time.  A lack of the capacity of the semen to liquefy can interfere with fertility.  To understand what could happen we have review what occurs to the semen during intercourse.   At the time of ejaculation, the sperm is pushed out of a storage area next to the testes, the epididymus, and propelled through the male reproductive tract.  As it makes its way towards the outside world, the sperm pass by two glands, the seminal vesicles and prostate glands, which supply most of the fluid found in semen.  These glands also add special chemicals to the semen to assist in the reproductive process.  One of these chemicals is fibrinogen, the protein that makes blood clots.  As the ejaculate leaves the body, this fibrinogen will cause the semen to thicken into a semi-solid clot.  The purpose of this clotting mechanism is to insure that the semen stays in the vagina after the penis is withdrawn.  If the semen did not clot most of the fluid of the semen would seep out immediately after intercourse.  The clot, however, is short-lived.  In addition to fibrinogen, semen also contains slow acting enzymes that digest clots.  These digestive enzymes will cause the clot that is deposited in the vagina to melt in 15 to 30 minutes after ejaculation.  In this manner as the clot ‘melts’, the sperm can escape to enter the uterus.  However if the clot does not convert from a semi-solid to a liquid then the sperm will be trapped within the clot.  Because of this potential problem the first characteristic that is measured in a semen analysis is liquefaction time.  In the lab, the semen sample should become a liquid in 15-30 minutes after ejaculation.

 

In some instances the semen will undergo liquefaction but the proteins of the seminal fluid will denature and become sticky, making the semen thick.  This thickening is different from liquefaction and is not as major a problem as non-liquefaction.  But if it occurs in a semen specimen that may have marginally low sperm numbers or volume, then it would be a serious problem.  To assess this potential problem, the lab will measure the viscosity (thickness) of the semen by passing the semen through a thin pipette and looking at the shape of the drops that form as they leave the tip of the pipette.  The semen drops after liquefaction should appear as separate, discrete droplets.  If the semen is too viscous the semen will leave a pipette as a continuous series of drops attached to each other by thin strands of semen.

 

Another problem that can influence fertility would be an infection of the male reproductive tract.  An infection can adversely affect sperm quality and numbers. Most infections of the male reproductive tract are easy to diagnose since the semen will contain a large number of white blood cells (WBC).  The WBC is the front line of defense of the immune system and during an infection their job is to secrete antibodies to destroy the infectious agent and to physically ingest any bacteria and cellular debris.  In the absence of an infection, WBCs are normally present in semen to remove any sperm that die.  For a semen analysis the sample is viewed on a microscope at high power (200X) and at this magnification, a normal semen sample will contain less than 5 WBC.   If more than 5 WBC are seen in the field of view than an infection is suspected.  When the man has a severe infection, it is not uncommon to see more than 30 WBCs in the high power field.

 

Severe reproductive tract infections in male patients will also affect the color of the semen.  The normal color of semen is from a white to pale gray color.  In the presence of an infection the semen will have a yellowish color. 

 

The color of the semen can also change if the testes or reproductive tract were physically injured.  If the injury was resent or still present, blood will seep into the semen making the semen sample a pink to red color.  If it is an old injury then the semen will be a pale brown.

 

The final characteristic we need to review is sperm agglutination.  When the semen sample is viewed with a microscope, sometimes the sperm will be observed to be attached to (agglutinated) each other in clumps.  They can be attached head to head, tail to tail or both.  There are two major reasons for this reaction.  The first is the presence of sperm antibodies.  The body will sometimes attack sperm as if it is a foreign material and generate antibodies specifically for sperm.  These antibodies will make the sperm stick to each other.  The second reason for sperm agglutination is not related to antibodies.  When sperm die they develop a static charge and start to stick to each other.  Patients who have sperm agglutination can be tested for sperm antibodies.  Sperm agglutination is worrisome since all of the sperm will be tied up in clumps and not makes it into the reproductive tract.  Furthermore, there is evidence that the presence of sperm antibody on the surface of the sperm impedes fertilization.

 

Now that we have reviewed how to interpret a semen analysis the next question that comes to mind is – How do we correct the problems associated with an abnormal semen analysis?  Drs. Minhas and Ripps, in a recent paper on our web site review some of the current treatments for achieving pregnancy in couples dealing with male fertility problems.