Leydig cell hypoplasia

Overview

Leydig cell hypoplasia is a rare genetic disorder that affects sexual development due to the underdevelopment or absence of Leydig cells in the testes. Leydig cells are responsible for producing testosterone, the key male sex hormone. The condition leads to impaired or absent testosterone production, resulting in varying degrees of undervirilization in individuals with a 46,XY karyotype (genetically male). Leydig cell hypoplasia is classified into two types: Type I (complete) and Type II (partial) based on the severity of hormone resistance and phenotypic expression.

Causes

Leydig cell hypoplasia is caused by mutations in the LHCGR gene, which encodes the luteinizing hormone/choriogonadotropin receptor. This receptor is critical for the action of luteinizing hormone (LH), which stimulates Leydig cells to produce testosterone. Mutations in LHCGR impair receptor function, leading to insensitivity to LH and subsequent testosterone deficiency. The condition follows an autosomal recessive inheritance pattern, meaning a child must inherit two defective copies of the gene—one from each parent—to develop the disorder.

Symptoms

The symptoms of Leydig cell hypoplasia vary based on the type of the condition and the individual's genetic sex. Key clinical features include:

In 46,XY individuals (genetically male):

• Type I (complete form):

  • Female external genitalia at birth

  • Absent or undescended testes

  • No puberty or secondary sexual characteristics

  • Infertility

• Type II (partial form):

  • Ambiguous genitalia or undervirilized male genitalia

  • Micropenis or hypospadias

  • Delayed or incomplete puberty

  • Reduced facial and body hair

In 46,XX individuals (genetically female):

• Typically unaffected, as Leydig cells and the LHCGR gene are not critical in typical female development

Diagnosis

Diagnosis of Leydig cell hypoplasia involves clinical evaluation, hormonal testing, and genetic analysis. The diagnostic process may include:

• Karyotyping – to determine chromosomal sex (46,XY or 46,XX)

• Hormonal tests – including LH, FSH, testosterone, and AMH levels. Typically, LH is elevated, and testosterone is low or undetectable

• hCG stimulation test – shows little or no increase in testosterone production

• Ultrasound or MRI – to assess the presence and position of gonads and internal reproductive structures

• Genetic testing – confirmation through detection of mutations in the LHCGR gene

Treatment

Treatment of Leydig cell hypoplasia is individualized based on the patient's gender identity, physical findings, and fertility goals. Options may include:

• Hormone replacement therapy (HRT) – testosterone therapy for individuals raised male to promote secondary sexual characteristics and support puberty

• Estrogen therapy – for individuals raised female, if ovariectomy or gonadectomy is performed

• Surgical management – correction of ambiguous genitalia, cryptorchidism, or hypospadias, if applicable

• Psychological counseling – for gender identity support and coping with the diagnosis

• Fertility counseling – although fertility is typically absent in affected males, options can be discussed

Prognosis

The prognosis of Leydig cell hypoplasia depends on the severity of the condition, the timing of diagnosis, and the support provided. With appropriate hormonal and psychological treatment, individuals can develop secondary sexual characteristics in line with their identified gender and lead healthy, fulfilling lives. Fertility is generally not achievable in affected 46,XY individuals due to impaired testicular function. Lifelong hormone replacement and regular medical follow-up are essential for optimal long-term outcomes.