Leydig cell hypoplasia

Leydig cell hypoplasia is a condition that negatively affects male sexual development. It is characterized by underdevelopment (hypoplasia) of Leydig cells (Pic. 1) that are responsible for testosterone production in the testes. 

Leydig cell hypoplasia is caused by inactivating mutations (or changes) of the luteinizing hormone (LH)/chorionic gonadotropin (hCG) receptor (LHCGR) gene. Luteinizing hormone (LH) normally acts through the LH/hCG receptor to stimulate the growth of Leydig cells in the testicles and the production of androgens such as testosterone by these cells. In Leydig cell hypoplasia however, there is a reduced capacity for the LH/hCG receptor to respond to LH. It results in hypoplasia or absence of Leydig cells, testicular atrophy, and decresed androgen levels. 

There are two types depending on the severity of symptoms:

• Leydig cell hypoplasia type 2 (LCH type 2) - Affected males may have a small penis (micropenis), the opening of the urethra on the underside of the penis (hypospadias), or a scrotum divided into two lobes (bifid scrotum). Because of these abnormalities, the external genitalia may not look clearly male or clearly female (ambiguous genitalia).
• Leydig cell hypoplasia type 1 (LCH type 1) - In more severe cases of Leydig cell hypoplasia patients have female external genitalia, although Leydig cell hypoplasia does not occur in biological females as they do not have either Leydig cells or testicles. Patients have small testes that are undescended, which means they are abnormally located in the pelvis, abdomen, or groin. People with this form of the disorder do not develop secondary sex characteristics, such as increased body hair, at puberty. 

A diagnosis of Leydig cell hypoplasia is usually made in the neonatal period, following the discovery of ambiguous genitalia, or at puberty, when secondary sex characteristics fail to develop. Puberty is the most common time for Leydig cell hypoplasia to be diagnosed. The diagnosis is confirmed on biopsy of the testes, revealing either absent or underdeveloped Leydig cells. The inside of the testis will be grayish and mucous, displaying arrested spermatogenesis (sperm maturation) and the presence of Sertoli cells that provide support for spermatozoa development within the seminiferous tubule in testes.

There is no cure for patients, but they may need hormone replacement therapy or surgical correction to manage the symptoms.

Associated diseases

Hypogonadism

Male hypogonadism represents an altered testicular function with infertility and decreased testosterone production. The testes are small and osteoporosis (decreased bone density) may be present. The diagnosis is suspected clinically and is confirmed with decreased circulating testosterone concentrations. Leydig cell hypoplasia results in hypergonadotropic hypogonadism, i.e. hypogonadism despite high levels of gonadotropins.

Testicular failure

Testicular failure is the condition of testicles which are unable to produce sperm or testosterone. In Leydig cell hypoplasia, testicular failure is the result of underdeveloped Leydig cells that are responsible for testosterone production.

Complications

Intersex people face stigmatization and discrimination from birth or discovery of an intersex trait such as from puberty. This may include infanticide, abandonment and the stigmatization of families. Globally, some intersex infants and children, such as those with ambiguous outer genitalia, are surgically or hormonally altered to create more socially acceptable sex characteristics. However, this is considered controversial, with no firm evidence of good outcomes.

Risk factors

Epidemiology

Leydig cell hypoplasia is a rare syndrome affecting an estimated 1 in 1,000,000 genetic males.

Leydig cells secrete male sex hormones (androgens,i.e. testosterone) that are important for normal male sexual development before birth and during puberty. Testosterone is the main male sex hormone for spermatogenesis (sperm production) and male characteristics together with controlling the most of the reproductive functions including libido and the activity of accessory sex glands. 

Leydig cell hypoplasia is characterized by impaired Leydig cell differentiation and thus testosterone production. Patients exhibit a wide clinical spectrum, ranging from delayed puberty, complete female external genitalia to male external genital with micropenis, low serum testosterone levels associated with high LH levels. Since testosterone is essential for sperm production, patients may exhibit azoospermia (absence of sperm). 

Patients with partially inactivating mutations may show some early spermatogenesis, with arrest prior to spermiation. Therefore, patients have potential for fertility using assisted reproductive technology. Even very low testosterone level can, in fact, be enough to produce spermatozoa in testicular tissue. The quantity and quality of the testicular spermatozoa may be also enough to survive after freeze/thaw procedure and result in viable embryos leading to live birth.

Genetic test may provide information if there is a risk of having a baby with Leydig cell hypoplasia (Pic. 2).

Affected individuals with a typical male chromosomal pattern may have a range of genital abnormalities. The condition manifests itself as pseudohermaphroditism (partially or fully underdeveloped genitalia), hypergonadotropic hypogonadism (decreased or lack of production of sex steroids by the gonads despite high circulating levels of gonadotropins), reduced or absent puberty (lack of development of secondary sexual characteristics (facial hair and Adam's apple), resulting in sexual infantilism (retention of childish physical qualities in adult life) if left untreated), and infertility.