Defective protein in sperm could be responsible for many cases
Scientists in Hong Kong and China have identified for the first time a protein in sperm from humans and from mice that could be responsible for many unexplained cases of male infertility.
Defective versions of the protein, called epithelial ion channel, have previously been reported to be responsible for female infertility.
Writing in the latest issue of the Proceedings of National Academy of Sciences journal, the researchers said they detected the protein in sperm samples from mice and human subjects
"(The protein) is involved in the transport of bicarbonate, which is required for sperm activation in order to fertilize the egg. If you have a defect in this (protein), then fertilization capacity of the sperm will be impaired or reduced," Chan Hsiao Chang, physiology professor at the Chinese University in Hong Kong, said in a telephone interview on Thursday.
Experiments showed that sperm taken from mutant mice with defective versions of the protein had far lower fertility than sperm taken from normal mice, the researchers said.
The discovery would help doctors more accurately diagnose and explain many cases of male infertility that have so far gone unexplained.
"For many people, they are infertile, but they don't know why, so diagnosis would be the immediate advantage," Chan said.
Between 8 percent and 12 percent of couples with women of childbearing age - or between 50 and 80 million people - are infertile globally, according to the World Health Organization.
Half of infertile couples fail to reproduce because of problems with male fertility.
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Management of Male Infertility
General Considerations
While 85% of couples are able to conceive after one year of protected intercourse, approximately 15% of couples are unable to initiate a pregnancy without some form of assistance or therapy. These patients are said to be "primarily infertile." In approximately one-third of these couples, a male factor appears to be singularly responsible, and in an additional 20% both a male and a female factor can be identified. Therefore, a male factor is at least partly responsible for difficulties in conception in roughly 50% of these couples.
It has been shown that the longer a couple remains subfertile, the worse their chance for an effective cure. In addition, many couples experience significant apprehension and anxiety after only a few months of failure to conceive. For these reasons, unduly prolonged unprotected intercourse should not be advocated before workup of the male is instituted. Although it has often been recommended that clinical evaluation be delayed until 12 months of unprotected intercourse has passed, we believe that the initial screening of the male should be considered whenever the patient presents with the chief complaint of infertility. This initial evaluation, however, should be rapid, noninvasive, and cost-effective. The most important part of the management of male infertility is the correct diagnosis. The use of standard techniques for evaluating medical problems in general, such as complete history, physical examination, and laboratory tests is essential for this purpose.
Initial Evaluation
1. History
A detailed history should address the duration of the couple's infertility, and also previous pregnancies with the present or previous partners. In addition, previous difficulty in achieving conception and any previous evaluation and treatment should be documented (Table 1).
(a) Sexual Habits
One of the most common problems encountered in this patient population is either too-frequent or too-infrequent intercourse. Often, neither the husband nor the wife understands her menstrual cycle. They do not realize that the optimal time for intercourse is midcycle and that the most effective frequency of intercourse is every 48 hours. This is based on the fact that sperm survival in normal cervical mucus and within the cervical crypts is approximately 2 days. Thus, this frequency will assure viable spermatozoa concurrently in the 24-hour period during which the egg will be within the fallopian tube and capable of being fertilized.
It is also important to discuss coital techniques with the husband, e.g., the use of lubricants or the frequency of masturbation that can deplete the sperm "reserve." Many lubricants have been tested for in vitro effects on sperm motility.1 Commonly used substances, such as K-Y Jelly, Lubifax, Surgilube, Keri Lotion, petroleum jelly, and saliva result in a deterioration of motility. Others, such as raw egg white, vegetable oil, and the Replens douche, do not impair in vitro motility. Astroglide, a water-soluble, inert vaginal lubricant, contains no petroleum ingredients or detergents that may be toxic to sperm; however, with increasing concentration, there is impairment of sperm motility equivalent to that found with K-Y jelly.
(b) Childhood Illnesses
A history of specific childhood illnesses and disorders may be an important finding in the evaluation of the infertile male. For example, it has been shown that in the male born with a unilaterally undescended testis, regardless of the time of orchiopexy, overall semen quality is considerably less than that found in normal men. Approximately 30% of men with unilateral cryptorchidism and 50% with bilateral cryptorchidism have sperm densities below 12-20 million/mL.2 Despite this impairment in semen parameters, the majority of men with a history of one undescended testis are able to initiate a pregnancy without difficulty.
Testicular trauma or torsion of the testes should be noted, since both can result in atrophic testes. Approximately 30% of men with history of testicular torsion will have abnormal results on semen analysis.3
A history of postpubertal mumps orchitis is also important. Mumps does not appear to affect the testes when experienced prepubertally. However after the age of 11 or 12, unilateral mumps orchitis is seen in 30% of males affected and bilateral orchitis in approximately 10%.4 Furthermore, the testicular damage can be quite severe and should be readily appreciated on physical examination, since the involved gonads will be markedly atrophic.
Patients who have had operative correction (Y-V plasty) of their bladder neck during childhood often suffer from retrograde ejaculation due to ablation of the internal sphincter. Bladder neck reconstruction at the time of ureteral reimplantation surgery was common in the early 1960s; this patient population has now entered an age group when pregnancy will most likely be attempted. Retrograde ejaculation should be suspected in the man who gives a history of bladder surgery and whose ejaculate volume is less than 1 cc, severely oligospermic, and abnormally alkaline. The correct diagnosis can be made by finding large numbers of sperm in the postejaculate urine. Children born with congenital anomalies involving the male reproductive system, such as bladder exstrophy/epispadias, can also exhibit abnormalities of ejaculation because of difficulties with both intromission and ejaculation. Spermatogenesis is usually normal; however, the ejaculatory ducts may be obstructed, or retrograde ejaculation may occur. Also, a history of herniorrhaphy suggests the possibility of iatrogenic vasal injury.
(c) Exogenous Agents That Interfere With Spermatogenesis
The history should also include a detailed inquiry into exposure to environmental toxins and medications that may interfere with spermatogenesis, either directly or through alterations in the endocrine system. For agents such as heat, ionizing radiation, heavy metals, and some organic solvents, there are many studies that support these associations. Recent publications have also reported the effect of specific pesticides (i.e., dibromochloropropane) on gonadal function.5 Furthermore, reversibility has been substantiated when the oligospermic patient has been removed from this toxic environment.6 However, once azoospermia has occurred, return to a normal pre-exposure state is highly unlikely.
Medications, such as sulfasalazine and cimetidine, or ingestants, such as caffeine, nicotine, alcohol, or marijuana, have also been implicated as gonadotoxic agents. Withdrawal from these substances should enable return of normal spermatogenesis if they are acting adversely. Also, calcium ion channel blockers may interfere with sperm membrane function and fertilization ability.7
The use of androgenic steroids by athletes is a potentially significant cause of infertility in both adults and adolescents, and the problem is becoming more commonplace.8 The incidence of steroid abuse has been reported to be as high as 30%-75% among professional athletes or body builders. Androgenic steroids exert their deleterious effect by depressing gonadotropin secretion and interfering with normal spermatogenesis. Consequently, if a person is taking any of these medications at the time of initial interview, the medication should be stopped and the patient's semen reevaluated at a later date.
Elevated temperatures, as in the routine use of saunas and hot tubs, may interfere with spermatogenesis.9
(d) Surgical History
Retroperitoneal Lymph Node Dissection: Approximately 75% of all testicular cancer patients will retain the potential for fertility.10 Retroperitoneal lymph node dissection can involve excision of portions of the sympathetic chain necessary for ejaculation. Some patients will retain seminal emission, but many will have retrograde ejaculation or lose the ability to emit semen altogether.
Prostatectomy: Patients who have had transurethral or open prostatectomy also have a high incidence of retrograde ejaculation. This incidence is reported to range from 40%-90%.
2. Physical Examination (Table 2)
Physical examination of the infertile man should include a generalized and complete evaluation. Any factor that affects overall health can theoretically be responsible for abnormalities in sperm production. For that reason, the physical examination should be thorough, with emphasis placed on the genitalia.
(a) Body Habitus
If the patient appears to be inadequately virilized (androgen-deficient), as evidenced by decreased body hair, gynecomastia, eunuchoid proportions, etc., the diagnosis of delayed maturation due to an endocrine abnormality should be considered and evaluated.
(b) Phallus
Penile curvature or angulation should be assessed, as should the location of the urethral meatus, i.e., for presence of hypospadias. Abnormalities can result in improper placement of the ejaculate within the vaginal vault.
(c) Scrotum
The scrotal contents should also be carefully palpated with the patient standing. Testicular size and consistency must be noted and the volume of the testis estimated either with an orchidometer or by measuring the long and wide diameter of the testes to the nearest millimeter. It has been shown that a decrease in testicular size is often associated with impaired spermatogenesis. Standard values of testicular size have been recorded for the normal population.11 These data document that in the normospermic male, the length of the testis should be greater than 4 cm and the volume greater than 20 mL.
Examination of the peritesticular area is also essential. Epididymal induration, irregularity, and cystic changes should be noted, as should the presence absence of the vas deferens and any nodularity along its course. Certainly, engorgement of the pampiniform plexus should be identified, since a varicocele can cause abnormalities of gonadal function.12 Ideally, the patient should be examined in a warm room after standing for several minutes. Palpation for asymmetry of the spermatic cords, followed by a Valsalva maneuver with re-palpation of the spermatic cords, should be routinely performed. An "impulse" can often be felt with the increase in intra-abdominal pressure.
(d) Digital Rectal Examination (DRE)
DRE is necessary to assess prostatic size, as well as to rule out prostatic and/or seminal vesicular induration, masses, or cysts.
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