Androgens in Health and Disease.pdf - E Library

Chapter 3/Hypogonadism in Men 49
occur that is sufficient to return testosterone levels to normal under the influence of
increased LH stimulation. These findings confirm that infertile men often possess primary
gonadal failure of a subtle nature. Because there is a fairly high incidence of male
infertility, primary testicular dysfunction in the male population is an important issue.
Klinefelter Syndrome
The chromosomal constitution of 47,XXY epitomizes the classic form of male primary
testicular failure. This abnormality is present in about 1 in 400 men. Klinefelter
syndrome, first described in 1942, was based on nine male patients who, at puberty,
experienced the onset of bilateral gynecomastia, small testes with Leydig cell dysfunction
and azoospermia, and increased urinary gonadotropin excretion (8). Later, it was
shown that Leydig cell failure was variable in its magnitude. In 1956, the X-chromatin
body (Barr body) was found in these individuals, and in 1959, the XXY chromosome
constitution was first described, demonstrating that the disease was the result of an extra
X chromosome (9,10).
PHENOTYPIC MANIFESTATIONS
The phenotypic manifestations of Klinefelter syndrome are characteristic for the
classic form of the disease in which all cells carry the XXY karyotype. Many men with
Klinefelter syndrome have a mosaic form, in which some cell lines are XXY and others
are XY. In these mosaic individuals, all cell lines are from a single zygote, and the XXY
cell lines arise from mitotic nondisjunction after fertilization. Manifestation of the disease
may not be typical or consistent. Before puberty, the only physical findings are the
small testes; in the classic form of Klinefelter syndrome, a gonadal volume of less than
1.5 mL after the age of 6 yr is usual (11,12). A decreased testicular size is the most
diagnostic clinical feature of classic Klinefelter syndrome, even in prepubertal patients
diagnosed with the syndrome. The cause for the small prepubertal testicular size is a loss
of germ cells before puberty; thus, the prepubertal testis is small. In secondary forms of
hypogonadism, the number of germ cells is normal and the prepubertal testicular size is
indistinguishable from that of normal boys.
Microcephaly also has been described in some cases of Klinefelter syndrome. After
puberty, the more characteristic features of the syndrome appear. These include varying
degrees of gynecomastia. The gynecomastia is of interest because it is primarily the
result of an increase in periductal tissue rather than ductal tissue; increased ductal tissue
often is found in gynecomastia of acute onset, whatever the cause. If the gynecomastia
were only the result of the increased estrogen production in Klinefelter syndrome, an
increase in ductal tissue might be expected. Nonetheless, the histopathologic appearance
of the breast tissue is not consistently separable from that of other patients with longstanding
gynecomastia.
After puberty, an abnormality in skeletal proportions becomes manifest. There is an
exaggerated growth of the lower extremities resulting in a decreased crown-to-pubis:
pubis-to-floor ratio, such as that seen in eunuchoid men. Unlike the true eunuchoid
proportions, in which the arm span often is at least 6 cm more than the height, in
Klinefelter syndrome the arm span : height ratio usually is not abnormal. The reason for
the abnormal growth in the lower extremities is unknown. The phenotypic manifestations,
such as the gynecomastia, pattern of hair distribution, muscle mass, and subcutaneous
fat distribution, vary even between patients with classic Klinefelter syndrome.