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Diagnosing and Treating Male Factor Infertility

by Dr. Geoffrey Sher on July 2, 2017

About 1/3 of infertility is caused by a male factor, one third by a female factor and another third is due to a combination of both male and female factors. Thus, in more than 50% of cases, a male factor causes or contributes to the problem. Today, with very few exceptions, in the case of moderate or severe male infertility (unless it can be reversed medically or surgically) in vitro fertilization (IVF) with intracytoplasmic sperm injection is the treatment of choice. In such cases, intrauterine insemination (IUI) will, in my opinion, not improve the chance of pregnancy over no treatment at all and accordingly is contraindicated.

  1. DIAGNOSIS:

The diagnosis of male factor infertility is often based on the results of a simple semen analysis which today, is largely conducted by computer analysis which has replaced the old convention, morbid microscopic, visual evaluation using a Coulter counter. However, while computerized semen analysis has vastly improved the accuracy of assessing sperm count and motility, it is not reliable in evaluating structural sperm defects. To do the latter, we use a grading system known as the Kruger classification. A normal sperm count is one where after several days of abstinence, more than 20 million sperm are present per milliliter of ejaculate. While the sperm count is a helpful tool, it is not the most important parameter. Rather sperm motility and morphology are far more significant measures. When more than 50% of motile sperm are motile and especially if most are moving linearly and purposefully, augers well for male fertility, but a motility of  more than 40% is also compatible with adequate male fertility potential. When it comes to the potential to initiate pregnancy through intercourse, a Kruger score of over 14% points to optimal male fertility but when it comes to requirements for optimal IVF outcome, a score of more than 4% is adequate.

While a semen analysis is the most widely used method for assessing male fertility, it lacks both specificity and sensitivity. There are other tests that can augment its reliability. Some of these include sperm chromosomal analyses to look for structural and numerical chromosomal defects; sperm cultures for infection; hormonal testing to determine whether the cause of sperm dysfunction is due to testicular insufficiency is the result of inadequate brain-pituitary stimulation of sperm production, testicular biopsy; testing the ability of sperm to attach to eggs or penetrate its envelopment (the zona pellucida) sperm antibody testing, biochemical testing of the semen, measurement of sperm antibodies (see below) and importantly, the relatively recent introduction of the sperm chromatin structure assay-SCSA (see below).

In cases of absent sperm in the ejaculate (azoospermia) or very low sperm parameters, measurement of blood FSH, LH, testosterone, TSH and prolactin is needed. If the FSH/LH is high (much over 12MIU/ml) then it is likely that this is a testicular failure and probably little could be done to improve matters. On the other hand, if the FSH/LH level is in the normal range, the cause of absent sperm in the ejaculate (azoospermia) could be obstruction of both sperm ducts (vasa deferentia). Confirmation would require a thorough urological exam).

The Chromatin Structure Assay (SCSA):

SCSA is a tool for measuring clinically important properties of sperm nuclear chromatin integrity. The results correlate well with the potential of sperm from a given male to produce embryos that would be sufficiently “competent to produce a live birth. The SCSA utilizes the metachromatic features of acridine orange (AO), a DNA probe, and the principles of flow cytometry (FCM).

SCSA data are not well correlated with classical sperm quality parameters and have been solidly shown to predict sub/infertility and poor reproductive performance. The SCSA measures DNA damage. The degree of abnormalities in the genetic material of the sperm is expressed numerically as the DNA Fragmentation Index (DFI). DNA damage may be present in sperm from both fertile and infertile men. Therefore, this sperm DNA damage analysis may reveal a hidden abnormality of sperm DNA in infertile men classified as unexplained based on apparently normal standard sperm parameters. Infertile men with abnormal sperm characteristics exhibit increased levels of DNA damage in their sperm. Sperm from infertile men with normal-appearing sperm may have DNA damage to a degree comparable to that of infertile men with abnormal-appearing sperm. The data suggests that an abnormal SCSA assay is more likely to occur in cases of abnormal semen parameters. Thus the assay is ideally suited to fertility clinics to assess male sperm DNA integrity as related to fertility potential and embryo development as well as effects of reproductive toxicants. Since SCSA parameters are independent of conventional semen parameters, results may allow physicians to identify male patients for whom IVF and intracytoplasmic sperm injection (ICSI) will be far less likely to result in initiation of viable (>12 weeks) pregnancy

Cancer treatments are well known to adversely affect male fertility. Reduction of sperm output arises from the cytotoxic effects of chemo-or radiotherapy upon the spermatogenic epithelium. However, even if the epithelium survives there is a hazard to reproduction as the transgenerational in expression and present with effects ranging from “infertility to miscarriage and there is an association with infertility and reproductive performance. Optimal sperm chromatin packaging seems necessary for full expression of the male fertility potential. SCSA emerges as predictors of the probability to conceive and carry the pregnancy to viability The most important component of the SCSA is the DNA Fragmentation Index (DFI). Values of <15% are almost always suggestive of normal fertility. Fifteen to thirty percent (15-30%) represents a transitional value but >30% is accompanied by a significant increase in male infertility.

The improvement seen in sperm motility after sperm separation and Percol processing is not associated with a similar improvement in sperm DNA integrity (SCSA) assay results). These data suggest that sperm processing techniques will not minimize sperm DNA damage and the potential transmission of genetic mutations in assisted reproductive cycles.

It is important to add that most current data available on the significance of  abnormal SCSA results in infertile couples seeking treatment has emanated from non-IVF pregnancies. Available data suggests the following:

The viable IVF pregnancy rate (and thus presumably also the birth rate) could be as much as 2 times lower in women under 35yrs of age, whose husbands have abnormal SCSA assays, with a DNA Fragmentation Index (DFI) of >30%. Results become progressively worse with advancing maternal age such that at 35 yrs+, the viable pregnancy rate could be as much as 3-4 times lower.

Although it is possible for abnormal SCSA results to sometimes spontaneously revert back to normal, this probably occurs quite infrequently.

Although abnormal SCSA results are detected in men with apparently normal semen analyses, abnormal results are more commonly seen in cases of men who have abnormal sperm parameters (abnormal sperm count, motility and/or morphology)

Antisperm antibodies:

Sperm antibodies occur in about 7% of infertile women and are even more common in men, especially those who have previously undergone reproductive surgery such as vasectomy or vasectomy reversal. In fact, when vasectomy was performed more than ten years prior was, more than was >70% of such men will have high concentrations of sperm antibodies representing a severe form of male infertility. Autoimmunity to sperm does not invariably preclude spontaneous pregnancy conception. Rather, the effects are graduated; i.e., the larger the immunologic response, the less likely it is that a pregnancy will occur.

Like any other kind of antibody manufactured by the body, sperm antibodies are formed in response to antigens. These antigens are proteins, which appear on the outer sperm membranes as the young sperm cells, develop within the male testes. Antigens can only stimulate antibody production when they come in contact with components of the blood. Under normal conditions, blood and sperm do not mix. Direct contact between the two is prevented by a cellular structure in the testes called the blood/testis barrier. This barrier is formed by Sertoli cells, which abut very closely against each other, forming tight junctions that separate the developing sperm cells from the blood and prevent immunologic stimulation. However, the blood/testis barrier can be broken by physical or chemical injury or by infection. When this barrier is breached, sperm antigens escape from their immunologically protected environment and come in direct contact with blood elements that launch an immunologic attack.

In the female’s body, deposited sperm are regarded as foreign invader cells and as such would normally be targeted for attack and destruction by circulating antibodies. Yet sperm, which are immunologic aliens to the woman, do not usually cause an antibody response. Although usually exposed to billions of sperm during her lifetime, few women develop sperm antibodies. Why this is so is not well understood. It is known that the cellular construction of the vagina provides a physical barricade somewhat similar to the blood: testis barrier in the male. Here, too, physical damage or infection will increase the likelihood of sperm and blood mixing and subsequent antibody production.

Once sperm and blood come in contact, whether in the male or female, specific antibodies are produced against them by specialized blood cells called T- and B-lymphocytes. The three main types of sperm antibodies produced are Immunoglobulin G (IgG), Immunoglobulin A (IgA) and Immunoglobulin M (IgM). These antibodies bind to the proteins (antigens) on the sperm head, mid piece or tail. The antibodies formed may be of the circulatory type (in the blood serum) or secretory type (in the tissue). This is important because high levels of antibodies in the blood do not always antibodies will find their way to the semen where they can affect the sperm. For example, the concentration of IgG is much lower in secretions of the reproductive tract that it is in the blood. Conversely, the local level of IgA is higher in the reproductive secretions than in the blood. This is an important point, which we will return to later.

Once sperm antibodies have formed, they can affect sperm in several different ways. Some antibodies will cause sperm to stick together (agglutinating antibodies). Agglutinated sperm clump together in huge masses and are unable to migrate through the cervix and uterus. Other antibodies mark the sperm for attack by Natural killer (NK) cells of the body’s immune system (opsonizing antibodies). Some antibodies cause reactions between the sperm membrane and the cervical mucus preventing the sperm from swimming through the cervix (immobilizing antibodies). Antibodies can also block the sperm’s ability to bind to the zona pellucida of the egg, a prerequisite for fertilization. Finally, there is evidence that the fertilized egg shares some of the same antigens that are found on the sperm. It is possible that sperm antibodies present in the mother can react with the early embryo, resulting in its destruction by phagocytic cells.

 

There are a number of diagnostic tests available to detect the presence of sperm antibodies. These are flow cytometry and the ELISA (enzyme-linked immunoabsorbent assay), the Franklin-Dukes sperm agglutination assay or the Immunobead Binding Test (IBT), to name a few. At the Sher-IVF, the Indirect Immunobead Binding Test (IBT) is used selectively to detect antibodies present in the blood of both male and females.

IgA is the most common antibody in secretions of the cervix, uterus and fallopian tubes. IgG might also be present, but IgM is found only rarely. In the male, IgA and IgG are found in the semen although there is controversy as to whether they originate locally (secreted by testicular cells) or cross over from the circulation. Antibodies of the IgM class are not found in semen.

Like the source of some antibodies, the question of the critical levels of sperm antibodies is also hotly debated among clinicians. There seems to be general agreement that blood serum levels above 40% by the IBT are associated with significant fertility problems.

  1. TREATMENT:

The treatment of male factor infertility is one of the true success stories in the field of reproductive medicine. It is important to emphasize that while intrauterine insemination of washed sperm (IUI), a procedure that we first introduced into the field about 35years ago, is widely advocated as a treatment for male infertility, with the exception of very mild cases, it is in my opinion ineffective for cases of moderate or severe male infertility. The first line of attack with sperm dysfunction should be to try to reverse the underlying cause (medically or surgically) and if this is unsuccessful, go directly to IVF/ intracytoplasmic sperm injection (ICSI). In summary, some important treatments of Male Infertility include:

  • Hormonal Therapy (Clomiphene, Letrozole; gonadotropins, corticosteroids, thyroid hormone)
  • Non-Hormonal/surgical Drug therapy (bromocriptine, antioxidant therapy, antibiotics)
  • Surgery (varicocelectomy, vasectomy reversal, surgical treatment of undescended testes etc.)
  • IVF-Related procedures (intracytoplasmic sperm injection (ICSI), Testicular sperm extraction (TESE)

Simply stated moderate or severe male infertility that cannot be reversed in the man’s body, by simple medical or surgical treatment, mandates/IVF ICSI. Intrauterine insemination is in my opinion, not an effective treatment. 

Hormonal Therapy:

In a relatively small number of cases of male infertility, the failure to produce an adequate quality of sperm relates to reduce secretion by the pituitary gland of those hormones necessary to stimulate sperm production. The pituitary gland in the man produces two important hormones with regard to testicular function. The first is called follicle-stimulating hormone (FSH), and the second is luteinizing hormone (LH). Luteinizing hormone’s predominant function is to act on a particular variety of cells in the testicles that produces the male hormone testosterone. These cells are referred to as Leydig cells. A sustained reduction in FSH production, therefore, is capable of resulting in male infertility. Usually, if there is a reduction in either one of the components, LH or FSH, the other one will also be low. In other words, if a man produces a normal amount of LH and has a normal blood male hormone (e.g. testosterone, androstenedione, dehydroepiandrosterone) level, it is very unlikely that he will have a reduced FSH production, and, accordingly, if his sperm function is reduced, it is unlikely to be the result of reduced FSH production by the pituitary gland.

The woman’s cycle usually lasts about 28 days, and under normal circumstances, she releases one egg per menstrual cycle. In the man there exists an a cyclical production of spermatozoa In fact the entire spermatogenic cycle, from initiation to the production of the most mature forms of spermatozoa, takes 90-100 days. Accordingly, any treatment administered to the man in order to improve sperm production can only be properly assessed after waiting for a period of approximately 100 days. In the man, as with the woman, the pituitary gland releases FSH and LH in response to need. In other words, if there is an abundance of male hormone being produced? Then, the pituitary gland, through messages received from higher centers in the brain, reduces its production of LH. This push-pull mechanism is referred to as a feedback response, helps the body regulate exactly how much stimulation is needed to keep normal testicular function going both with regard to the production of male hormones and with regard to the production of spermatozoa.

In order to assess the potential of a male to respond to fertility drugs aimed at stimulating the testicles to produce more spermatozoa and/or male hormone, it is therefore necessary to first measure both FSH and LH which are produced by the pituitary gland, as well as prolactin and the male hormones testosterone, androstenedione, dehydroepiandrosterone, Measurement of these hormones gives an indication as to the likelihood of the man responding to treatment aimed at: 1) inducing increased production of FSH or FSH/LH (e.g.; clomiphene citrate or Letrozole) or, 2) the direct administration of gonadotropins which comprise of FSH, LH or HCG [e.g.  Menopur, Bravelle, Follistim, Puregon, Gonal F and/ or hCG.

  1. Clomiphene Citrate (The first approach) Clomiphene citrate is a hormone which, through its central action in the brain, stimulates the pituitary gland to produce natural FSH in large amounts. The FSH, in turn, as mentioned above, stimulates spermatogenesis. The treatment is very simple, and involves the administration of 1/2 (25 mg.) of Clomiphene citrate every alternate day for a period of 100 days, to perform a baseline semen analysis, FSH, LH, and male hormone measurements immediately prior to initiating therapy, and then to serially repeat all of these tests throughout the treatment with Clomiphene. The final assessment of response can only be made approximately 100 days after initiating therapy. This administration of Clomiphene is essentially harmless to the man. He may experience some minor side effects such as spots in front of the eyes, dryness of the mouth, headaches, slight changes in mood, and, rarely, hot flashes. These side effects are all reversible upon discontinuation of therapy.

 

  1. Gonadotropin Therapy. In cases where Clomiphene therapy fails to be successful, or in certain situations where it is not possible for Clomiphene to stimulate the pituitary gland into action, it is possible to administer FSH alone or in combination with LH in the hope of stimulating the testicles directly. This therapy, in certain cases of male infertility, might be combined with the administration of the hormone human chorionic gonadotropin (HCG), which is also a natural hormone, which has a function similar to that of LH>. The basis upon which hCG would be administered would be in order to further stimulate the production of male hormones in cases where failed masculinization is associated with reduced sperm production. Administration of these drugs is usually carried out 3 times per week, again for a period of about 100 days, and the same hormonal and sperm assessments as stipulated for Clomiphene therapy would apply. The treatment is, again, relatively harmless, and the minor side effects which might occur are all reversible upon discontinuation of therapy.

 

  1. Other hormonal therapies: There is very little evidence that the administration of vitamin preparations or specific male hormone administration would be of benefit in the treatment of male infertility. In some cases, there may be systemic conditions affecting other areas of the body which indirectly might impact upon the pituitary gland’s ability to produce the hormones necessary to stimulate testicular function. Rare examples include administration of Thyroid Hormone in cases of involvement of the thyroid gland, severe diabetes mellitus, and collagen diseases amongst others. Sometimes the pituitary gland produces too much prolactin, which in turn inhibits the ability of FSH and LH to act on the testicles. In such cases, it may be necessary to administer a drug called Parlodel and Cabergoline (Bromocriptine) to suppress prolactin production, and thereby remove the restraining effect that prolactin might have on the action of FSH upon the testicles. There are, of course, many other such examples of where treatment of unrelated conditions might improve overall male fertility, The recent introduction of Letrozole (Femara) provides a possible alternative to clomiphene.

*Testosterone is only mentioned because it is prescribed so often to try and improve sperm function. Such treatment is in fact contraindicated because prolonged use (more than 2-3 months) of testosterone will almost always have the reversed effect, compromising sperm count, motility and even morphology.

If the man is fortunate enough to respond to one of the above treatment modalities for enhancement of sperm production, then it is possible for a number of masturbation specimens of sperm to be collected and frozen in liquid nitrogen in order to be kept for a number of years so that there will always be relatively good quality sperm on hand, even if the fertility treatment is discontinued, and you revert back to a relatively poor production of sperm subsequently. It is, of course, not practical to permanently treat an individual on potent medications such as Clomiphene, or gonadotropins.

Intracytoplasmic Sperm Injection (ICSI):

Although always a treatment of choice for moderate and severe male infertility, it was not until the introduction of ICSI in the mid 1990’s that IVF became more successful when applied in cases of male infertility than for female related causes. ICSI is a procedure where fertilization is achieved through the direct injection of a single sperm into the substance of each mature egg. Even high concentrations of anti-sperm antibodies attached to the sperm ( see below) or severe sperm defects such as absence or abnormalities of the acrosome ( the enzyme-rich attachment at the top of the sperm-head, that enables the sperm to penetrate the zona pellucida [“ the envelopment of the egg”], are offset by ICSI.

The performance of ICSI in cases of “male factor infertility” has been shown to slightly increase the risk of  certain embryo chromosome deletions (leading to a slight increase in early miscarriages) as well as the potential for a resulting male offspring to have male infertility in later life. However, there is no evidence of any significant increase in the incidence of serious birth defects in   ICSI-offspring. More relevant is the fact that when ICSI is performed for indications OTHER THAN male infertility there is no reported increase in the risk of subsequent embryo chromosome deletions, miscarriages or in the incidence of subsequent male factor infertility in the offspring.”

Surgery:

Varicocele:

There are two approaches to treating varicoceles:

  • Traditional treatment of a varicocele is through ligation (under general anesthesia) of one or both spermatic veins that carry blood from the pampiniform venous plexus (“varicocelectomy”). While surgery is in most cases curative, post-surgical recurrence is not uncommon.
  • Another approach is interventional radiological obliteration of one or both the spermatic veins. This approach involves passing a balloon catheter via a groin blood vessel, under radiological view, into the spermatic vein and inflating the balloon in that position. This causes the spermatic vein to permanently occlude. Sometime later, the catheter is withdrawn and the vein remains occluded causing the varicocele to collapse and the pampiniform plexus to shrink. Disappear. This radiological approach is often more effective, far less costly, less traumatic and less likely to, result in a recurrence than is spermatic vein, surgical ligation. It is also conducted under local anesthesia and as an out-patient procedure. In my opinion this approach has become the preferred method for treating varicoceles.

Regardless of whether surgical or interventional radiological treatment is contemplated, it is in my opinion, advisable for the patient to take a male fertility blend that is rich in antioxidants such as Proceptin (which is not currently sold at Drug Stores and requires online purchase). This will sometimes result in an improvement in the DFI within 3-6 months. It should be taken for at least 12 weeks whereupon the SCSA should be repeated.

It is important to bear in mind that both surgical and radiological treatment will only improve sperm function in about 35% of men who have varicocele.. Understandably, it is tempting to attribute a cause and effect relationship to fertility problem and a varicocele. But, the truth is that the existence of a varicocele is often coincidental (unrelated) to the underlying cause of the infertility

Testicular Sperm Extraction (TESE)

TESE is a procedure involving the introduction of a thin needle directly into the testicle(s), under local anesthesia, without making a skin incision. Hair-thin specimens of testicular tissue are removed (usually under local anesthesia) in the space of 15 to 30 minutes. Sperm are extracted from the tissue and each egg is injected with a single sperm using the ICSI technique. It is most commonly done in cases of spermatic duct (vas definers) occlusion or absence but can also be performed in cases of ejaculatory dysfunction, such as might occur following spinal cord injuries, after prostatectomy, or in cases of intractable male impotency. TESE is simple, relatively low-cost, safe, and virtually pain-free. Most men can literally take off a few hours for the procedure and return to normal activity straight away. Aside from the remarkable success rates with TESE/ICSI is the fact that, unlike vasectomy reversal, the procedure allows the man to retain his vasectomy for future contraception.

Treating an abnormal SCSA:

There is some suggestion that the use of an antioxidant/vitamin blend such as Proxeed or Proceptin (www.proceptin.com) taken for 8-12 weeks, can cause the DFI to revert to normal in many cases. Also, there is also evidence that men who have varicoceles ( a collection of distended veins in the scrotum) associated with an abnormal SDI assay may experience a reversion of the DFI assay back to normal, 2-6 months following surgical or radiological ablation of the varicocele.

In summary, an abnormal SCSA augers poorly for the outcome of fertility treatment in general and IVF/ICSI in specific. In such cases, the fertilization rate and pregnancy rates are reduced and the chance of early pregnancy loss appears to be increased significantly. However, an abnormal SCSA result does not totally preclude a successful pregnancy. In fact, I have seen cases where viable ICSI pregnancies resulted when the DFI was >75%. However, it would seem that the prognosis worsens progressively as the age of the egg provider advances beyond 33yrs.

Although an abnormal SCSA results rarely revert to normal spontaneously this can and does happen on occasion. Selective surgical ligation or radiologic ablation of a varicocele as well as medical anti-oxidant treatment may be effective in restoring the SCSA to normal.

Treatment of Antisperm antibodies: 

Once an antibody problem (whether the male or the female harbors them) has been identified, the best option is a form of in vitro fertilization (IVF) known as intracytoplasmic sperm injection (ICSI) where each egg is injected with a single sperm), high pregnancy and birth rates have been reported. In fact, ICSI, has optimized IVF pregnancy in cases of male immunologic infertility, to the point that success rates are virtually unaffected by the presence or concentration of antisperm antibodies.

Sperm donation:

Some cases of male factor infertility are so profound and intractable as to preclude using male partner’s sperm. In such cases, there is still hope by using donor sperm (DS) The use of donor sperm is both safe and effective. In addition to meeting medical and matching requirements all DS should (with some exceptions) be cryopreserved (frozen) and quarantined for about 6 months, whereupon the sperm donor should be re-tested for viral sexually transmitted diseases such as HIV and hepatitis C which can lie dormant and be undetectable for this period of time. Thereupon the sperm can be dispensed for use. The freezing process weakens DS. Thus thawed DS should not be used for intra-vaginal insemination. Rather its use should be confined to dispensation by IUI or ICSI.

 

 

 

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