Partial androgen insensitivity syndrome

Overview

Partial androgen insensitivity syndrome (PAIS) is a rare genetic condition that affects the development of the male reproductive system. It is part of a spectrum of androgen insensitivity syndromes, where the body's ability to respond to androgens—male sex hormones such as testosterone—is impaired. Individuals with PAIS have a 46,XY karyotype (typically male), but their physical characteristics can vary widely depending on the degree of androgen resistance. This can result in genitalia that are ambiguous, undervirilized, or appear predominantly female despite the presence of male chromosomes. PAIS lies between complete androgen insensitivity syndrome (CAIS), where individuals are entirely resistant to androgens, and mild forms where masculinization occurs but with fertility or pubertal issues.

Causes

PAIS is caused by mutations in the AR (androgen receptor) gene, located on the X chromosome. This gene is responsible for producing androgen receptors—proteins that bind to androgens and trigger the expression of male-specific genes. When these receptors are faulty due to a mutation, the body cannot fully respond to male hormones, leading to incomplete masculinization of external genitalia and other reproductive features. The condition is inherited in an X-linked recessive manner, which means it is usually passed from mothers to their sons, although spontaneous mutations can also occur.

Symptoms

The symptoms of PAIS vary significantly among individuals and may include:

• Ambiguous genitalia at birth, such as a small penis, enlarged clitoris, or fused labia

• Micropenis or hypospadias (urethral opening on the underside of the penis)

• Undescended testes (cryptorchidism)

• Gynecomastia (breast development during puberty)

• Reduced body hair or lack of virilization during puberty

• Infertility due to impaired testicular function

• Normal or female gender identity in some cases, depending on upbringing and phenotype

In some individuals, the external genitalia may appear predominantly male or female, making diagnosis difficult without genetic testing.

Diagnosis

Diagnosis of PAIS involves a combination of physical examination, hormone level testing, imaging studies, and genetic analysis. Key diagnostic steps include:

• Karyotyping: to confirm a 46,XY chromosomal pattern

• Hormonal evaluation: to measure levels of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH)

• Androgen receptor gene sequencing: to identify mutations in the AR gene

• Pelvic ultrasound or MRI: to assess internal reproductive structures (e.g., absence of uterus, presence of testes)

• Human chorionic gonadotropin (hCG) stimulation test: to evaluate testicular response to hormonal signals

Diagnosis often occurs in infancy due to ambiguous genitalia or later in adolescence when puberty does not proceed as expected.

Treatment

Treatment for PAIS is highly individualized and often involves a multidisciplinary team of endocrinologists, geneticists, surgeons, and mental health professionals. Key aspects of treatment include:

• Gender assignment and counseling: Based on phenotype, genetic findings, and family input, with psychological support for both patient and family

• Hormone therapy: May include testosterone supplementation in individuals raised as male or estrogen in those raised as female, depending on pubertal development

• Surgical management: Includes genital reconstruction, hypospadias repair, or gonadectomy (removal of testes) if there is an increased risk of malignancy

• Fertility counseling: Infertility is common; options may include sperm banking if viable sperm are present or discussions of assisted reproduction

• Psychological support: To address issues of gender identity, body image, and psychosocial well-being throughout development

Prognosis

The long-term outlook for individuals with PAIS depends on the degree of androgen insensitivity, timing of diagnosis, and the appropriateness of the treatment plan. With early diagnosis and supportive care, most individuals can lead fulfilling lives. However, challenges may include infertility, psychological distress related to gender identity, and social acceptance. Regular monitoring for testicular malignancies is essential in individuals who retain undescended testes. Psychosocial support and gender-affirming care play a critical role in optimizing outcomes and quality of life.