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Clinical Evaluation of Male Infertility This chapter briefly discusses as- sessments that should be included in a detailed medical evaluation. Such evaluations might be used to describe a population or used in conjunction with biologic markers described in later chap- ters. Some of the assessments noted here are discussed in detail in later chapters, notably, organ size and semen analysis. MEDICAL HISTORY Markers used to assess pubertal changes include growth spurt, development of fa- cial hair, time when shaving began and shaving frequency, penile growth, noctur- nal emission, and desire to masturbate. Although delay in puberty is usually the result of exposure to noxious agents either in utero (e.g., in the fetal alcohol syn- drome) or in the neonatal period, chemical exposure somewhat later might delay the onset of puberty in connection with central nervous system damage or (less probably) direct testicular damage. The more likely causes of delay or impairment in puberty are genetic disorders, such as hypogonado- tropic eunuchoidism (an autosomal domi- nant disorder) and Klinefelter's syndrome (typically with XXY sex chromosomal con- figuration) (Matsumoto, 1988~. Appropri- ate laboratory tests can clarify whether a sex chromosomal abnormality exists; and 43 the presence or absence of anosmia or hy- posmia, with a detailed family history, should assist in assessing the presence of hypogonadotropic eunuchoidism (Parks, 1988). Traditionally, detection by medical history of changes in testicular function that occur after puberty have relied on such markers as decrease in libido, de- crease in sexual potency, decrease in fa- cial hair growth, diminution in muscular strength, and postpubertal onset of infer- tility. Large decreases in testosterone production are required before the first four of these markers are manifest (Clark, 1988~. Moreover, alterations in libido and sexual potency are usually related to psychologic or other systemic disor- ders, e.g., coronary insufficiency and organic brain syndrome (Walsh and Wilson, 1987~. But exceptions do exist, such as the reported link between decrease in libi- do and central nervous system damage re- sulting from lead poisoning (Lancranjan et al., 1975; Zenz, 1988) and the associa- tion of alcohol and marijuana abuse with changes in sexuality (Sherins and Howards, 1986; Reich, 1987~. To assess infertility as a marker, care- ful attention should be paid to the spouse's general health and reproductive function. Prior fertility should be noted, and, if there are no young children, the

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44 voluntary or involuntary aspect of that status should be documented. The man's work history should be recorded, including at least current and longest jobs (e.g., he might have worked in a chemical or insec- ticide plant or in a laboratory). Finally, systemic disorders associated with chron- ic negative nitrogen balance can adversely affect spermatogenesis; these disorders include ulcerative colitis, Crohn's dis- ease, and poorly controlled diabetes mel- litus (Jequier, 1986~. A history of viral orchitis, mumps (epidemic parotitis), or infectious mononucleosis should not be ignored (Sherins and Howards, 1986~. The Problem of erectile dysfunction Is considered separately, because it has some unique features. As with other markers of male reproductive function, erectile dysfunction is nonspecific in origin; in fact, many men who have it also have psychologic problems. As to specific etiologic factors, most of the men who seek medical assistance are on antihyperten- s~ve medications, usually in conjunction with diuretic agents. Guanethidine se- verely disrupts the sympathetic nervous system and so-called dry ejaculation (actually, retrograde ejaculation, in which not all the sperm and seminal fluid are ejaculated, but some is taken up into the bladder) is a common complaint (Walsh and Wilson, 1987~. Propranolol and other beta-blocking agents affect the sympathe- tic nervous system to a smaller degree, but still can cause erectile dysfunction (Walsh and Wilson, 1987~. Some patients with diabetes mellitus and neuropathy also report erectile dysfunction (Walsh and Wilson, 1987~. Any chemical that causes nerve damage can affect the erectile and orgasmic responses, such as lead poisoning and dioxin. PHYSICAL EXAMINATION Clinical signs that might be used as markers include eunuchoidal skeletal measurements; pattern of facial, body, and pubic hair; penile growth; size of testes; and size of prostate. When damage to the reproductive system begins before or around puberty, eunuchoidal features might be present, including an abnormal ABLE REPRODUCTIVE TOXICOLOGY ratio of arm span to height (arm span at least 5 cm greater than height and distance from symphysis pubis to floor at least 5 cm greater than distance from symphysis pubis to top of skull). The presence of such features requires a marked impairment in testosterone production, because that permits a delay in epiphyseal closure (Griffin and Wilson, 1987~. Effects on pattern of hair growth are obvious if testicular function failed before puberty. But if puberty occurred normally and Leydig cell function became impaired, it could take 2 years or longer for changes in hair growth, including fre- quency of shaving, to appear (Griffin and Wilson, 1987~. Penile size is normally variable, but is usually greater than 2 cm in diameter and 4 cm in length. The scrotal skin is normally pigmented, and rugal folds are present. The eunuchoidal state is easily detected; but, if testicular function fails after puberty, no discernible change in genitalia occurs. Testicular size is dictated primarily by the volume of seminiferous tubules. The testis normally is 4.6 cm long (range, 3.5-5.5 cm) and 2.6 cm wide (range, 2.1- 3.2 cm) (Griffin and Wilson, 1987~. Even in the adult, there is a noticeable de- crease in testicular size if damage occurs, particularly if it is accompanied by fibrosis. One exception is temporary damage' such as in single-dose ionizing- raa~at~on exposure (Matsumoto, 1988), which damages specific cell types but does not cause a reduction in testis size. Prostatic size generally increases gradually with age. If damage to the repro- ductive system occurs with a sharp decrease in testosterone concentration, the prostate might shrink to almost nonpal- pable dimensions; the lateral lobes can no longer be felt, and there is no median sulcus. Even if testosterone concentra- tion is normal, the prostate might fail to develop normally or might atrophy if Sa-reductase is not functioning; the rea- son is the lack of conversion of testoster- one to dihydrotestosterone, which is the principal androgen for normal prostatic growth.

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CLINIC EVALUATION OF ME INFER TILE SEMEN CHARACTERISTICS It is logical to examine semen for as- sessment of testicular function, because it is easily obtained and contains, in addition to spermatozoa, many biochemical components that can be measured. Moreover if a person has ingested or otherwise been exposed to therapeutic agents, such as tetracycline and various chemicals (e.g., TRIS, a flame retardant that was formerly applied to children's pajamas), they can be concentrated and appear in the semen (Hudec et al., 1981~. Sperm concentration or total sperm count is variable and depends in part on frequency of ejaculation, so the patient should be instructed to abstain from ejacu- lating at least 2 or 3 days before semen collection. The patient might collect his semen by masturbation (without lubri- cants) at home and then submit it to a labor- atory within 4 hours. The sample should be kept at ordinary room temperature and protected from extremes in temperature (but not refrigerated) before and during transport. Because the ordinary daily variation is so large, the patient should submit at least three semen samples at separate times (at least a week apart) before conclusions about his fertility are made. The physician should note wheth- er the patient has been ill and has had a body temperature of over 1 00F during the preceding 3 months. If so, the sperm count might be temporarily decreased by the illness. Ejaculate volume of a healthy man varies between 2.0 and 6.0 ml. If ejaculate volume is less than 1.0 ml, possible loss of some of the sample or retrograde ejacu- lation should be suspected. The motility of sperm can be assessed with a light microscope, but dark-field illumination or phase-contrast illumina- tion provides better discrimination (Sherins and Howards, 1986~. This proce- dure should be carried out at 37C. A drop of semen is used with a coverslip. A 400x microscope objective should be used. There are various ways to classify sperm motili- ty, but it is most important to determine the proportion of sperm that are moving forward in a rapid, apparently purposeful 45 fashion. At least 10 fields should be viewed for the assessment. If more sophis- ticated hardware and software are not available, automated technologies can be obtained commercially, as well as spe- cial counting chambers, to facilitate the determination of motility (Jequier, 1986~. Normally, at least 45% of the sperm should be moving forward rapidly. When the percentage is lower, supravital stain- ing should be used to document the ratio of living to dead sperm (Jequier, 1986~. The concentration and especially the total numbers of sperm in the semen are important markers of the integrity of tes- ticular function, but there are others. If numbers of sperm are small by usual fer- tility standards, but their motility and morphology are excellent, then fer- tility might be normal, especially if the female partner is of high fertility; if numbers of sperm are large, but their mo- tility and morphology are poor, the person might be infertile (WHO, 1980a). The pro- bability of pregnancy is the product of the innate fertility of the male and the female, not the property of either partner. This issue might seem elementary, but many researchers lose sight of it and focus almost exclusively on the concentration or total number of sperm in the ejaculate (WHO, 1987~. In general, sperm concentration in nor- mal men ranges from about 20 x 1 06/ml to 200 x 106/ml. There is large variation among and within people. Moreover, the variation does not have a normal distribution; log transformation is commonly used for sta- tistical analyses (WHO, 1987), but some investigators believe that square-root or cube-root transformation is more use- ful. It is common to obtain one semen sample from each person in a group and then use group data to compare with the frequency distribution in a control population to determine whether there has been a hazar- dous exposure (WHO, 1 980a; 1987~. However, that procedure will reveal an adverse effect only if a large population of the men at risk shows azoospermia or oligospermia or if longitudinal studies show a consistent pattern or a return to normal values.

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46 Priority should be given to developing a battery of valid in vitro tests to deter- mine the fertilizing capacity of human sperm. When the sperm penetration test was developed by Yanagimachi and col- leagues (1976), there were high hopes for its use in this manner. However, pros- MALE REPRODUCTIVE TOMCOLOC;Y pective studies have pointed out its defi- ciencies when it is used as a model. Its accuracy in identifying sperm from fer- tile men is only about 50%. A search for more suitable biochemical markers is need- ed to overcome the problems in this kind of assessment.