The causes underlying male infertility are numerous but are conveniently grouped by effects at one or more of the following levels: pretesticular, testicular, and posttesticular.

Pretesticular

Conditions that cause infertility that act at the pretesticular level tend to be hormonal in nature (

Table 42-11).

Hypothalamic Disease

A. Gonadotropin Deficiency (Kallmann Syndrome)
Kallmann syndrome is a rare (1:50,000 persons), genetically heterogeneous disorder that occurs in familial and sporadic forms. The X-linked form of the disease is a consequence of a single gene deletion (Xp22.3 region, termed KALIG-1). It may also be autosomally transmitted with sex limitation to males. In either case, there is a disturbance of neuron migration from the olfactory placode during development. This neural region contains precursors not only for the olfactory nerves but also the LH-releasing cells of the hypothalamus, which explains the 2 most common clinical deficits in the disorder: anosmia and absence of GnRH. Pituitary function is normal. The clinical features include anosmia, facial asymmetry, color blindness, renal anomalies, microphallus, and cryptorchidism. The hallmark of the syndrome is a delay in pubertal development. The differential diagnosis includes delayed puberty. Patients have severely atrophic testes(< 2 cm) with biopsies showing germ cell arrest and Leydig cell hypoplasia. Hormone evaluation reveals low testosterone, low LH, and low FSH levels. Men can be fertile when given FSH and LH to stimulate sperm production. Virilization can be obtained with testosterone or human chorionic gonadotropin (hCG).

B. Isolated LH Deficiency (“Fertile Eunuch”)
This very rare condition is due to partial gonadotropin deficiency in which there is enough LH produced to stimulate intratesticular testosterone production and spermatogenesis but insufficient testosterone to promote virilization. Affected individuals have eunuchoid body proportions, variable virilization, and often gynecomastia. These men characteristically have normal testis size, but the ejaculate contains reduced numbers of sperm. Plasma FSH levels are normal, but serum LH and testosterone levels are low-normal.

C. Isolated FSH Deficiency
In this extremely rare condition, there is insufficient FSH production by the pituitary. Patients are normally virilized, as LH is present. Testicular size is normal, and LH and testosterone levels are normal. FSH levels are uniformly low and do not respond to stimulation with GnRH. Sperm counts range from azoospermia to severely low numbers (oligospermia).

D. Congenital Hypogonadotropic Syndromes
Several syndromes are associated with secondary hypogonadism. Prader-Willi syndrome (1:20,000 persons) is characterized by genetic obesity, retardation, small hands and feet, and hypogonadism and is caused by a deficiency of hypothalamic GnRH. The single gene deletion associated with this condition is found on chromosome 15. Similar to Kallmann syndrome, spermatogenesis can be induced with exogenous FSH and LH. Bardet-Biedl syndrome is another rare, autosomal recessive form of hypogonadotropic hypogonadism that results from GnRH deficiency. It is characterized by retardation, retinitis pigmentosa, polydactyly, and hypogonadism. The presentation is similar to Kallmann syndrome except it includes genetic obesity. The hypogonadism can be treated with FSH and LH. Cerebellar ataxia can be associated with hypogonadotropic hypogonadism. This rare condition can result from consanguineous unions. Cerebellar involvement includes abnormalities of speech and gait. These patients can be eunuchoid-looking with atrophic testes. Hypothalamic-pituitary dysfunction due to pathologic changes in cerebral white matter is thought to be the reason for infertility.