Conditions that cause infertility that act at the testicular level are listed in

Table 42-12. Unlike most pretesticular conditions, which are treatable with hormone manipulation, testicular effects are, at present, largely irreversible. If sperm are observed, however, assisted reproductive technology can provide biological children for affected men.

Chromosomal Causes

Abnormalities in chromosomal constitution are well-recognized causes of male infertility. In a study of 1263 infertile couples, a 6.2% overall incidence of chromosomal abnormalities was detected. Among men whose sperm count was < 10 million/mL, the incidence was 11%. In azoospermic men, 21% had significant chromosomal abnormalities. For this reason, cytogenetic analysis (karyotype) of autosomal and sex chromosomal anomalies should be considered in men with severe oligospermia and azoospermia.

A. Klinefelter syndrome (

Figure 42-7)
Klinefelter syndrome is the most common genetic reason for azoospermia, accounting for 14% of cases (overall incidence 1:500 males). It has a classic triad: small, firm testes; gynecomastia; and azoospermia. This syndrome may present with delayed sexual maturation, increased height, decreased intelligence, varicosities, obesity, diabetes, leukemia, increased likelihood of extragonadal germ cell tumors, and breast cancer (20-fold higher than in normal males). In this abnormality of chromosomal number, 90% of men carry an extra X chromosome (47,XXY) and 10% are mosaic, with a combination of XXY/XY chromosomes. Paternity with this syndrome is rare but more likely in the mosaic or milder form of the disease. The testes are usually < 2.0 cm in length and always < 3.5 cm; biopsies show sclerosis and hyalinization of the seminiferous tubules with normal numbers of Leydig cells. Hormones usually demonstrate decreased testosterone and frankly elevated LH and FSH levels. Serum estradiol levels are commonly elevated. Since testosterone tends to decrease with age, these men will require androgen replacement therapy both for virilization and for normal sexual function.

B. XX Male Syndrome
XX male syndrome is a structural and numerical chromosomal condition, a variant of Klinefelter syndrome, that presents as gynecomastia at puberty or as azoospermia in adults. Average height is below normal, and hypospadias is common. Male external and internal genitalia are otherwise normal. The incidence of mental deficiency is not increased. Hormone evaluation shows elevated FSH and LH and low or normal testosterone levels. Testis biopsy reveals absent spermatogenesis with fibrosis and Leydig cell clumping. The most obvious explanation is that SRY, or the testis-determining region, is translocated from the Y to the X chromosome. Thus, testis differentiation is present; however, the genes that control spermatogenesis on the Y chromosome are not similarly translocated, resulting in azoospermia.

C. XYY Syndrome
The incidence of XYY syndrome is similar to that of Klinefelter, but the clinical presentation is more variable. Typically, men with 47,XYY are tall, and 2% exhibit aggressive or antisocial behavior. Hormone evaluation reveals elevated FSH and normal testosterone and LH levels. Semen analyses show either oligospermia or azoospermia. Testis biopsies vary but usually demonstrate arrest of maturation or Sertoli-cell-only syndrome.