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Male Factor Infertility

All men should have a semen analysis performed during the initial infertility evaluation. It is frustrating to see couples that have done empiric therapy with Clomid later to find that a male factor is present that lowers the efficacy of this drug. A male factor may be the only factor in about 20 % of couples and is a contributory factor in about 40 % of patients. When a male factor is present the count, motility, and morphology (sperm shape) are abnormal in most cases but not always.

The normal semen parameters (World Health Organization - 2010):
 
Concentration ≥ 15 million /ml
Total Sperm # 39 million/ejaculate
Motility > 32% Progressively Motile
> 40% Progressively Motile + Non-Progressively Motile
Morphology > 4% Normal Forms
Volume 1.5 ml
pH 7.2
WBC < 1.0 x 106 /ml

Many couples wonder if the Ďabnormalí sperm will produce Ďabnormalí children. Abnormal sperm (i.e. two heads, two tails, etc.) probably are unable to fertilize eggs. By the criteria above even a normal semen analysis will have some Ďabnormalí sperm.

The initial infertility consultation will cover important aspects of the male medical history. Medical illnesses such as diabetes or hypertension may affect sperm counts. Surgeries such as varicocele repair, hernia repair, and vasectomy reversal are important. Environmental toxins and smoking may lower the sperm concentration. Medications such as herbals (i.e. St. Johnís Wort, echenacia, and others), antihypertensives, anabolic steroids, or androgens may affect sperm. Some men are treated with decreased libido are given Testosterone therapy. This hormone therapy will suppress the pituitary production of FSH and LH and therefore lead to decreased sperm production by the testes. Given the fact that it takes about 80 days for a mature sperm to be produced, the effect of this therapy may be profound in terms of time to recover. The physical examination will make note of body habitus, hair distribution, secondary sexual characteristics, presence or absence of the vas deferens, and testicular size. Generally, after an abnormal semen analysis is found two times we refer the male to a urologist specifically trained win infertility.

Tests of sperm function

  1. Semen analysis
    See above
     
  2. Post Coital Test (PCT)
    This is a test where sperm and cervical mucus interaction are evaluated. Couples have intercourse several hours before the cervical mucus is examined using a microscope. The test is timed with a positive LH surge using an ovulation predictor kit to assure the mucus is appropriately thin. The stretchibility of the mucus (spinbarkheit), ferning pattern, and motile sperm in the mucus are examined. This test actually correlates poorly with ultimate fertility. Studies have shown that fertile may have no sperm on PCT. Because we often use Intra Uterine Insemination (IUI) as an adjunct to ovulation induction therapy cervical factors may not be relevant.
     
  3. Anti-Sperm Antibodies (ASA)
    The testes are immunologically privileged, that is a system is in place that keeps the immune system from interacting with the sperm. When this blood:testes barrier is compromised (trauma, ductal obstruction, infection, post-vasectomy) the immune cells can enter the testes and recognize the sperm cells as foreign and begin antibody production against them. These antibodies may bind the tail and cause decreased motility, or the head and inhibit fertilization. Treatment may include sperm washing with intra-uterine insemination or in-vitro fertilization with intracytoplasmic sperm injection depending upon the absolute number of sperm.
     
  4. White blood cells (WBCs)
    It is normal to have < 1 million WBCs/ ml of ejaculate. The presence of greater than 1 million WBCs /ml may indicate the presence of an infection in the epididymis, testis, or vas deferens. Treatment with antibiotics is recommended. It is of note that immature sperms cells look like WBCs, so special stains may be done to differentiate these.
     
  5. Hormonal evaluation
    The FSH, LH, and testosterone levels may be evaluated when the semen analysis shows <10 million sperm/ml or if the patient has decreased sexual drive. Some men with low libido are occasionally give testosterone therapy which may help the libido but decrease the sperm count. Testosterone may suppress the pituitary production of FSH and LH which normally stimulate the testes to produce sperm. Sperm need about 80 days to fully mature, so this can lead to profound suppression with a slow recovery of normal sperm numbers. Always consider this issue when contemplating androgen therapy.
     
  6. Ultrasound exam
    Scrotal ultrasound may be used to detect the presence of a varicocele, testicular masses, or the absence of the vas deferens.
     
  7. Post-ejaculatory urine analysis
    A semen analysis with a total volume <1.0ml may indicate the presence of retrograde ejaculation. In retrograde ejaculation the sperm are released into the bladder rather than the urethra. This can be seen in men with diabetes,, neurological diseases, or spinal cord trauma. Also, patients with congenital absence of the vas deferens, hypogonadism, or ejaculatory duct obstruction may have this problem.
     
  8. DNA Integrity Testing
    This tests evaluates the sperm DNA as being single stranded (abnormal) or
    double stranded (abnormal). This test is not run in many labs in the US.
    When this is repeated in many labs, then the test may have more applicability.
    Many sperm samples with grossly abnormal motility, shape, and count may
    have DNA damage, whereas grossly normal sperm may not.

Important Causes of Male Factor Infertility

Azoospermia

The complete lack of sperm is called azoospermia. This can be due to either a lack of production, lack of transport, or a lack of appropriate hormonal stimulation of the testes.
About 15 % of male infertility is due to azoospermia. The evaluation of the man with no sperm includes a complete medical history, FSH and LH level, and testosterone level. It is of interest to know of a childhood history mumps, cryporchidism (undescended testicle), or trauma. Infections such as Chlamydia or Gonorrhea are important. A family history of cystic fibrosis, pregnancy loss, or mental retardation should be ascertained.

Men with obstructive azoospermia commonly have mutations in the gene for cystic fibrosis (CF). CF is the most common fatal autosomal recessive condition in the Caucasian population with 1/25 carrier frequency. CF is found in 1/2500 live births. Gene testing will identify about 70% of patients with CF. In most with CF, the epididymis does not develop resulting in congenital absence of the vas deferens (CAVD). 50% to 80% of men with CAVD without pulmonary or digestive problems have a mutation . Given the high incidence of mutations, the female partner should be tested.

She has a 1:25 chance to be a carrier. Some small studies found mutations in CF with unexplained infertility and non-obstructive azoospermia. Interestingly, if a man had CAVD and renal anomalies, no CF mutations are found. Thus we should evaluate the kidneys.

Some genetic causes of azoospermia can be detected with a chromosome analysis (karyotype). The most common abnormality (10%-15%) is Klinefelterís Syndrome, 47,XXY where the male has an extra X chromosome. The normal male is 46,XY. Some men with Klinefelterís may actually have sperm present when surgical retrieval is done. Other chromosome abnormalities include translocations and inversions. Some studies have shown that as many as 18 % of men with azoospermia may have deletions in the short arm of the Y chromosomes.

Varicocele

The testis functions normally at a temperature normally a few degrees less than body temperature. If the veins surrounding the testes dilate the temperature may be elevated. This may lead to abnormal shape, concentration, or motility. The condition may be detected by physical exam or ultrasound exam. Options for treatment include surgery, intra-uterine insemination, expectant management, or IVF with ICSI depending upon the specific situation.

New Concept: Genetic risks of ICSI - Intra-cytoplasmic sperm injection with IVF

From the above it is clear that our understanding of male infertility is advancing rapidly.
Several years ago intra-cytoplasmic sperm injection was developed as a potential treatment for male infertility, even with the lowest sperm counts.

Several large studies have shown that minor and major malformations were the same with ICSO patients compared to the normal population, about 3%. However, one type of genetic anomaly does appear to be increased; sex-chromosome aneuploidy (abnormal numbers of the sex chromosomes, Y and X). The normal rate is about 0.2 % but with ICSI patients it is about 0.8%. That is 8 abnormal chromosome patients out of 997 total patients. It is important to discuss the genetic implications of ICSI. We should consider karyotype testing, Y chromosome micro-deletion testing, and partner CF mutation testing prior to IVF-ICSI.

Indications for ICSI generally include male factor infertility and prior failed fertilization in IVF. It is debatable if we should do ICSI for unexplained infertility in the presence of normal sperm. The ICSI needle has the potential to damage the spindle apparatus which is the fine filaments that shuttle the dividing chromosomes to either side of the dividing cell. The potential exists for the separation of chromosomes to be abnormal.
 

 

 

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