Epidemiology, causes, work-up (history, physical, lab tests)

Defining infertility
Infertility is defined as the inability of a sexually active, non-contracepting couple to achieve pregnancy in one year, the time in which about 90% of couples succeed. When a female is in her 20s, the average time to pregnancy is six months. This time frame reflects not only the limited few days in the middle of a woman's menstrual cycle when she ovulates and conception is possible, but also the fact that most conceptions do not survive beyond early embryonic development and are lost before a woman's next menstrual period. In addition, about 15% of couples with a clinical pregnancy go on to a spontaneous miscarriage. The female partner's reproductive age is also an important determinant of the man's ability to initiate pregnancy since the length of time required to establish pregnancy increases progressively with advancing maternal age. Fertilization of the egg is more difficult and early pregnancy loss is more frequent as a woman becomes older. As demonstrated from abortuses, chromosomal abnormalities from aging eggs are frequent among women with advancing maternal age, but there may also be uterine factors that contribute to early pregnancy loss.

Among couples of reproductive age, about 10% are involuntarily infertile. Of such couples, about 30-50% are infertile because of male reproductive dysfunction and, not uncommonly, both partners have reproductive problems. An additional 40% of reproductive-age couples are infertile because of medically or surgically acquired problems, including voluntary sterilization. Thus, only about half of reproductive-age couples can easily achieve pregnancy.

Causes of male infertility
Male infertility is a multifactorial syndrome encompassing a wide variety of disorders. In more than half of infertile men, the cause of their infertility is unknown and could be congenital or acquired. Recognition of a male reproductive component in an infertile partnership is often delayed because, traditionally, women have been the primary focus of the infertility evaluation and have ready access to gynecological care; men are much more reluctant to seek advice. Men are also more apt to confuse fertility with sexual potency (the ability to have an erection), ejaculation and ability to perform sexually, and they assume that if they produce seminal fluid at orgasm then they also produce sperm.

The known causes of male infertility are quite numerous but can be grouped into a moderate number of major categories (Table 1). In addition, a man may be mistakenly labelled as infertile because of failure to recognize subtle abnormalities in his sexual performance or in his partner's gynecologic function (Table 2).

Clinical evaluation
Considering all of the above issues, infertility requires a detailed evaluation of both partners. Meticulous attention to potential risk factors in the history plus a careful physical examination of the man can provide important clues to the origin of the problem(s) and guide the selection of laboratory tests and methods for subsequent treatment. In addition to assessing the state of virilization, presence of gynecomastia and phallic competence, the physician should also specifically document testicular size, presence of epididymis and vas deferens, prostate status, and whether a varicocele can be palpated and/or becomes evident following valsalva. With regard to testicular size, a calibrated orchidometer is recommended, rather than just length and width, as the volume of a sphere is a cubic function of the radius and a more accurate and convenient estimate of testicular mass. Decreased testicular volume and turgor (atrophy) provide important clinical clues to reduced testicular germ cell content.

Laboratory evaluation
Laboratory testing provides additional insight into both the extent and mechanism of testicular dysfunction (Fig.1). The hormonal profile is essential in differentiating gonadotropin deficiency from primary testicular dysfunction. Regardless of cause, as the testicle fails, the serum follicle-stimulating hormone (FSH) level rises in proportion to the amount of spermatogenic tissue lost, while the serum luteinizing hormone (LH) level increases only when testicular dysfunction is severe. The testosterone level is maintained within the normal range, even in many men with clinical hypogonadism, because sex hormone binding globulin levels become markedly elevated in response to decreased androgen production and increased estrogen concentrations. However, the free or unbound testosterone level decreases. In contrast, disorders due to gonadotropin deficiency are characterized by a profound fall in testosterone level and a failure of reciprocal increases in FSH and LH. While prolactin concentration is elevated in the presence of a prolactin producing pituitary adenoma, and in some men with acromegaly, the production of this hormone remains unchanged in other testicular disorders.

Obstruction of the excurrent ducts (epididymis, vas deferens and ejaculatory ducts) is characterized by the triad of azoospermia, normal testicular size and a normal serum FSH level. In this setting, a testicular biopsy is essential in order to demonstrate complete spermatogenic progression. The anatomical site of the obstruction can then be determined using a combination of procedures such as vasogram, scrotal and rectal ultrasound, and scrotal exploration with sampling of ductal fluids. In the special case of congenital absence of the vas deferens, seminal vesicles and ejaculatory ducts, semen is uniquely characterized by a small volume of non-coagulating seminal fluid which lacks fructose.

In the majority of infertile men, detailed semen analyses are required to fully characterize their reproductive dysfunction. Several important caveats are worthy of note. Semen should be collected with a consistent controlled abstinence interval (36 to 48 hours are recommended). Sperm count, motility and other characteristics change with prolonged abstinence, making comparison between samples and between different men misleading. Statistically, three semen samples are required to establish a stable estimate of values because of inherent variability of this excretory function. In addition, some noxious influences on testicular function (hot baths, viral illnesses, and toxicants) may produce transient effects on semen quality which can last for 1 to 2 sperm cycles (3 to 6 months) necessitating a moderately long term basal evaluation, especially when contemplating a therapeutic intervention.

Conventionally, semen analysis includes measurement of sperm concentration, semen volume, percent of motile sperm, quality of forward progression of these motile sperm, viability and morphology (Table 3). Recently, computer-assisted sperm analysis (CASA) has become available, providing more sophisticated measures of sperm motion, such as velocity, linearity and lateral head displacement. This automated method requires considerable technical attention to semen dilution and randomized cell sampling to avoid selection bias. With regard to the various semen parameters, there is clearly a progressive increase in the frequency of male infertility as values for sperm concentration, motility and morphology deteriorate. However, there are many exceptions. Some men with oligospermia (low count) can easily impregnate their partner, and other men with normal semen parameters are infertile.

The above paradox has stimulated the development of a number of specialized sperm function tests which provide considerable information beyond the traditional semen parameters (Table 4). Sperm count and motility are primarily bulk parameters, while newer measures address cell membrane integrity, sperm capacitation and ability to acrosome react as well as sperm-egg interaction. With the advent of in vitro fertilization, we can now directly assess sperm fertilizing ability. We have come to recognize that male fertility involves a complex series of events, wherein abnormalities in one or more steps block the ability of that man to initiate a viable pregnancy (Table 5).

Suggested Reading

Liu, DY and Baker HWG. Tests of human sperm function and fertilization in vitro. Fertil Steril 1992;58:465-483.

Clark RV, Sherins RJ. Male infertility. In: K.L. Becker, ed. Principles and Practice of Endocrinology and Metabolism. Philadelphia: J.B. Lippincott Co.; 1990:985-991.

Burris AS, Clark RV, Vantman DJ, Sherins RJ. A low sperm concentration does not preclude fertility in men with isolated hypogonadotropic hypogonadism after gonadotropin therapy. Fertil Steril 1988;50:343-347.

Calvo L, Dennison-Lagos L, Banks SM, Dorfmann A, Thorsell LP, Bustillo M, Schulman JD and Sherins RJ. Acrosome reaction inducibility predicts fertilization success at IVF. Hum Reprod 1994;9:1880-1886.

Sherins RJ. Clinical use and misuse of automated semen analysis. New York Academy of Science 1991;637:424-435.