Dana A. Ohl, M.D.¹ and Alan C. Menge, Ph.D.²

¹ Section of Urology, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-0330

² F4826 Mott Hospital, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0272

Received 07/31/96; Accepted 07/31/96; On-line 09/01/96

5. Selected Clinical Male Infertility Syndromes With Impairment Of Sperm Function

5.1 Antisperm antibodies

Antisperm antibodies may be detected in 8% -21% of infertile males (56-67). Due to initiation of spermatogenesis, sperm-specific antigens first appear at the time of puberty . Since such antigens are not present during development of immunological tolerance, these proteins are potential targets for an immune response and therefore generation of antisperm antibodies.

The specific antigens which are targets against which antisperm antibodies are generated are still being elucidated. Potentially relevant antigens include PH-20, LDH-C₄, SP-10, HSA-63, FA-1, CS-1 and GA-1 (68). The roles of most of these antigens in sperm function are currently unknown. However, FA-1 (fertilization antigen-1) and CS-1 (cleavage signal protein) appear to be respectively important in the fertilization process (69) and in oocyte cleavage (70). Antibodies to sperm antigens may inactivate their functions and therefore lead to infertility. Specific antibodies against FA-1 have been demonstrated in a high percentage of clinical cases of human immunoinfertility (69).

Functional impairments due to antibodies can also be more generalized. Agglutination of sperm may lead to their inability to move through the female reproductive tract. Sperm cytotoxicity may result (71). Sperm with bound antibodies may be unable to penetrate through cervical mucus and there is some suggestion that the Fc region of IgA is responsible for this inhibition (72). Antisperm antibodies on the sperm head may impair development of the acrosome reaction (73). Decreased in vitro fertilization rates have been seen when the man harbors such antibodies (74).

Treatments devised to circumvent infertility related to antisperm antibodies have been disappointing to date (75). Generalized immunosuppression with corticosteroids has had conflicting results, with some studies showing a mild improvement in pregnancy rate and others showing no improvement (76). Laboratory techniques to separate antibodies from sperm by physical means have had little effect (77). In most studies, intrauterine insemination afforded only a slight improvement in the pregnancy rate (78). In vitro fertilization may further improve the pregnancy rate but bypassing the block in fertilization may only reliably be achieved by intracytoplasmic sperm injection (ICSI) (79). Further experience with novel laboratory antibody removal techniques will hopefully yield better results in the future.

5.2 Immotile cilia syndrome

The development of somatic epithelial cilia and sperm flagella is under complex genetic control. When the construction of these structures is changed by a mutation of a crucial gene, the immotile cilia syndrome results (80). Electron microscopic examination of respiratory cilia and sperm tails (Fig 3), shows ultrastructural abnormalities of the microtubular structure.

Figure 3: Transmission electron micrograph of a sperm tail lacking inner and outer dynein arms. This individual had immotile cilia syndrome and despite sperm viability of 60%, shows total absence of sperm motility

The incidence of the immotile cilia syndrome is approximately 1/20,000 (81). Loss of microtubular function is most evident in the respiratory system. The inability to clear mucoid secretions from the lungs results in bronchiectasis and sinusitis (81). Association of these two components of the syndrome with situs inversus (most likely to due lack of normal ciliary function during embryonic development, a 50/50 chance), is called Kartagener's syndrome (82). Situs inversus poses no health hazard and has no clinical implication.

The infertility of men with immotile-cilia syndrome is due to lack of sperm motility (83). There is no specific cure for this sperm defect. However, since the sperm from such individuals demonstrate normal viability, if they enter the oocyte, they should be able to function normally. In fact, intracytoplasmic sperm injection (ICSI) may be used to circumvent this motility problem and to yield fertilized eggs that would undergo normal embryogenesis (84).

5.3 Spinal cord injury/anejaculatory infertility

Spinal cord injury (SCI) may lead to infertility due to erectile and ejaculatory dysfunction (85). There are reliable methods to induce release of semen in SCI men, including stimulation of a reflex ejaculation by penile vibration and electrical stimulation of seminal emission by rectal probe electroejaculation (EEJ). EEJ may also be used for men who have neurogenic anejaculation due to retroperitoneal surgery, diabetic neuropathy, multiple sclerosis and other conditions which affect this reflex. Sperm from induced ejaculation can be harvested and used for artificial insemination. However, the pregnancy rates remain disappointingly low from such endeavors (86).

The functional characteristics of sperm were examined in 32 anejaculatory men who underwent EEJ. Semen analysis showed high sperm counts and poor sperm motility. The average total antegrade sperm count was 448 x 106 and the average retrograde sperm count was 2.3 billion, but the motilities were 10.9% and 6.2%, respectively. Sperm viability very closely paralleled the sperm motility readings, indicating that the absence of motility was due to sperm cell death rather than an isolated motility defect. Further functional testing showed that sperm survived more poorly after overnight incubation, again testifying to their poor longevity. In the cervical mucous penetration test, they performed poorly compared to normal donor sperm. Sperm penetration assay scores were also poor (87). The functional abnormalities in anejaculatory men are not due to the presence of antisperm antibodies (88).

Reasons for poor survival and functional abnormalities in anejaculatory infertility are not known. However, since this heterogeneous clinical group exhibits similar deficiencies, a common neurological factor may be involved. There is experimental evidence to suggest that denervation of the testis can lead to changes in sperm motility in the rat model (89). Further work with this patient population will hopefully yield more clues into the neurological control of spermatogenesis and sperm function.

5.4 Nifedipine-associated Infertility

The acrosome reaction is a complex calcium-dependent process (90). Premature spontaneous acrosome reaction prior to reaching the oocyte may lead to early sperm cell death. On the other hand, the inability of sperm to undergo stimulated acrosome reaction in response to the oocyte investments and/or follicular fluid may lead to failure of sperm to fertilize the ovum.

It has recently been demonstrated that nifedipine, a calcium channel blocker, has the capability of blocking the acrosome reaction (91). A group of men taking nifedipine for hypertension were found to have reversible disordered expression of head-directed mannose-ligand receptors and low rates of acrosome reaction during capacitating conditions. The laboratory was also able to reproduce these findings in vitro by introducing nifedipine in the medium of sperm from normal donors (92). Clinical nifedipine-associated infertility has been reported. Following cessation of the drug, the acrosome reaction status has returned to normal and subsequent pregnancy has been achieved (5)

The fact that problems related to a very common treatment for hypertension went unrecognized for such a long time raises the question of how many other drug-related effects on sperm function may exist. Only through improved understanding of specific biochemical processes involved in human sperm function will enable us to identify and rectify such problems.