Androgen Insensitivity Syndrome: Symptoms, Types, Causes and Treatment

Androgen Insensitivity Syndrome (AIS) is a complex condition that challenges our traditional understanding of sex and gender, blending genetics, endocrinology, and psychology. Affecting individuals with a 46,XY karyotype, AIS occurs when the body cannot respond to androgens, the hormones responsible for male sexual development. This results in a spectrum of physical traits, ranging from typical female appearance to ambiguous genitalia or mild male infertility. Understanding AIS is crucial—not only for those directly impacted, but also for healthcare providers, families, and society at large.

Symptoms of Androgen Insensitivity Syndrome

AIS can present with a wide variety of symptoms, often making diagnosis challenging. The symptoms depend on the degree of androgen resistance, the specific genetic mutation, and the individual's developmental stage. Early recognition of these signs is essential for timely diagnosis and personalized care.

Symptom	Presentation	Typical Age Range	Source(s)
Primary amenorrhea	Absence of menstruation	Adolescence	1 2 3 4
Inguinal/labial swellings	Testes found in labia or groin	Infancy/adolescence	1 2 4
Ambiguous genitalia	Genital appearance not clearly male or female	Birth	3 4 5
Gynecomastia	Breast development in males	Puberty	4 6
Sparse or absent pubic/axillary hair	Lack of typical body hair	Adolescence	1 5
Infertility	Inability to conceive or father children	Adulthood	4 6 8
Mild undervirilization	Subtle male genital differences	Childhood/adulthood	6 9

Table 1: Key Symptoms

Overview of Symptoms

AIS symptoms are diverse and vary by individual and syndrome type.

Primary Amenorrhea

One of the hallmark signs, particularly in complete AIS (CAIS), is primary amenorrhea—the absence of menstruation in someone with otherwise normal female secondary sexual characteristics. This often prompts investigation in adolescence, leading to diagnosis 1 2 4.

Inguinal/Labial Swellings

Some individuals present with inguinal or labial masses, which are usually undescended testes. This is a classic sign in infants or young girls with CAIS, and may be found during a hernia repair or routine examination 1 4.

Ambiguous Genitalia

Partial AIS (PAIS) is frequently associated with ambiguous genitalia at birth. This can manifest as a micropenis, hypospadias, or a bifid (split) scrotum, necessitating careful evaluation and sex assignment 3 4 5.

Gynecomastia

An increase in breast tissue, or gynecomastia, is common in PAIS or mild AIS (MAIS) during puberty. This is due to an imbalance between androgen and estrogen effects 4 6.

Sparse or Absent Body Hair

Sparse or absent pubic and axillary hair is a subtle but important sign, particularly in CAIS, where affected individuals often have less body hair than typical females 1 5.

Infertility and Mild Undervirilization

Infertility is a common issue, especially in MAIS, where outwardly typical males may have reduced sperm production or other fertility problems. Mild undervirilization may also be seen, sometimes only detected during a fertility work-up or genetic analysis 6 8 9.

Types of Androgen Insensitivity Syndrome

AIS does not present as a single, uniform condition. Instead, it exists along a spectrum, with three main recognized types. Understanding these types is essential for accurate diagnosis, management, and counseling.

Type	Phenotype Description	Key Features	Source(s)
CAIS	Complete female phenotype	Normal breast development, absent or sparse body hair, absent uterus and ovaries, presence of testes	1 2 4 5
PAIS	Ambiguous genitalia	Partial virilization, variable genital appearance, gynecomastia, possible fertility issues	2 4 5 6
MAIS	Mild male phenotype	Normal male genitalia, mild undervirilization, spermatogenic defects, possible gynecomastia	4 6 8 9

Table 2: AIS Types and Phenotypes

Complete Androgen Insensitivity Syndrome (CAIS)

CAIS is the most severe form. Individuals have a 46,XY karyotype and testes, but their bodies are completely unresponsive to androgens. As a result, they develop a typical female external phenotype, including normal breast development. However, they lack a uterus and ovaries, and may have sparse or absent pubic and axillary hair. CAIS is often discovered when an adolescent girl fails to start menstruation (primary amenorrhea) 1 2 4 5.

Partial Androgen Insensitivity Syndrome (PAIS)

PAIS is characterized by partial responsiveness to androgens. This leads to a spectrum of genital ambiguity, such as micropenis, hypospadias, bifid scrotum, or partially fused labia. The degree of masculinization can range widely—even within the same family. Some individuals may be raised as males, others as females, depending on the appearance of the genitalia 2 4 5 6. Gynecomastia during puberty is common, and fertility can be affected.

Mild Androgen Insensitivity Syndrome (MAIS)

MAIS is the mildest form and may go undiagnosed until adulthood. Individuals have typical male genitalia but may experience infertility due to impaired spermatogenesis. Pubertal gynecomastia can also occur. These individuals are often raised as males and may seek medical advice for fertility issues or subtle differences in pubertal development 4 6 8 9.

Causes of Androgen Insensitivity Syndrome

AIS is rooted in genetics, but the relationship between genotype and phenotype is complex. It is primarily caused by mutations in the androgen receptor (AR) gene, though other molecular mechanisms may also play a role.

Cause	Mechanism/Impact	Variability	Source(s)
AR gene mutations	Disrupt androgen receptor function	800+ known mutations	1 2 3 4 9
Ligand binding domain defects	Prevent androgen binding	Common in CAIS/PAIS	9 10
Splice-site or frameshift mutations	Affect receptor structure/function	Variable	5 10
Non-AR gene mechanisms	Disrupt androgen signaling	Possible, under study	7

Table 3: Underlying Causes of AIS

Androgen Receptor (AR) Gene Mutations

The AR gene, located on the X chromosome, encodes the androgen receptor—a protein that binds androgens and initiates male sexual differentiation. Mutations in this gene disrupt receptor function, preventing normal androgen action and leading to AIS. Over 800 mutations have been identified, affecting all domains of the receptor. Most are point mutations, but deletions, frameshifts, and splice-site changes also occur 1 2 3 4 9 10.

Ligand Binding Domain Defects

The ligand binding domain is crucial for the receptor's ability to bind androgens. Mutations here are a frequent cause of both CAIS and PAIS, as they prevent androgen binding or proper receptor activation 9 10.

Splice-Site and Frameshift Mutations

Some mutations disrupt the structure of the androgen receptor protein itself, either by altering the amino acid sequence (frameshift) or affecting how the gene is processed (splicing). These changes can have variable effects, sometimes altering receptor function only partially, which may explain the variability seen in PAIS and MAIS 5 10.

Non-AR Gene Mechanisms

Recent research has identified cases of AIS-like symptoms in individuals who do not have detectable AR gene mutations. This suggests the presence of other factors—such as defects in cellular pathways involved in androgen signaling—that can lead to androgen resistance. These are under active investigation and may be classified as a new type of AIS in the future 7.

Genotype-Phenotype Correlation

One of the challenges in AIS is predicting the clinical presentation based on the specific genetic mutation. While some mutations are strongly associated with CAIS, others may lead to a spectrum of phenotypes even within the same family. Environmental factors, ligand concentrations during fetal development, and somatic (post-zygotic) mutations further complicate this relationship 5 10.

Treatment of Androgen Insensitivity Syndrome

AIS treatment requires a personalized, multidisciplinary approach that goes beyond medical management to include psychological and social support. The goals are to address the individual's physical health, optimize quality of life, and support psychosocial well-being.

Treatment	Purpose/Goal	Key Considerations	Source(s)
Gonadectomy	Prevent gonadal tumors	Timing (after puberty for CAIS), lifelong hormone therapy	1 2 3 4
Hormone replacement	Induce/maintain secondary sexual characteristics, bone health	Estrogen (most common), testosterone (rare)	1 2 3 11 12
Surgical interventions	Address genital ambiguity, vaginal depth	Cosmetic/reconstructive, individualized	2 5
Psychological support	Coping, disclosure, sex assignment	Ongoing, multidisciplinary	2 3 4 8
Genetic counseling	Family risk, fertility options	Inheritance, support	4 5 8

Table 4: AIS Treatment Strategies

Gonadectomy

Individuals with AIS have undescended testes, which carry a risk of developing germ cell tumors. In CAIS, the risk is considered low before puberty but increases in adulthood. Therefore, gonadectomy (removal of the testes) is usually recommended after puberty to allow for natural estrogen-driven breast development. In PAIS, the timing is individualized based on the degree of androgen sensitivity, sex of rearing, and risk assessment 1 2 3 4.

Hormone Replacement Therapy

After gonadectomy, hormone replacement therapy is essential. Estrogen is the standard for those raised as females, supporting secondary sexual characteristics and bone health. Testosterone may be considered in rare cases, especially for those raised as males, but its use is not well-established 1 2 3 11 12. The optimal formulation and dose are areas of ongoing research, particularly regarding long-term bone health.

Surgical and Reconstructive Interventions

Some individuals with PAIS may require surgical procedures to address ambiguous genitalia or to create or lengthen a vagina for sexual function. Surgical intervention is individualized, and non-surgical options such as vaginal dilation may suffice in many cases 2 5.

Psychological and Social Support

AIS can cause significant psychosocial stress, stemming from issues surrounding sex assignment, identity, disclosure, and fertility. Expert psychological support is crucial throughout life, not just at diagnosis. Family counseling and engagement with patient advocacy groups provide additional support 2 3 4 8.

Genetic Counseling

Given the X-linked inheritance pattern, genetic counseling is important for affected families. It informs them about recurrence risk, implications for siblings, and options for family planning 4 5 8.

Conclusion

Androgen Insensitivity Syndrome is a multifaceted condition that bridges genetics, endocrinology, and psychosocial care. A nuanced understanding is essential for compassionate and effective management.

Main Points:

• AIS symptoms are variable and depend on the degree of androgen resistance, ranging from female phenotype with primary amenorrhea to mild male infertility.
• There are three main types: complete (CAIS), partial (PAIS), and mild (MAIS), each with distinct clinical features.
• The primary cause is mutation in the androgen receptor gene, though other mechanisms are emerging.
• Treatment requires a multidisciplinary approach, including gonadectomy, hormone therapy, possible surgery, and strong psychological support.
• Ongoing research is refining our understanding of genetic causes, optimal hormone management, and long-term outcomes for individuals with AIS.

AIS is a testament to the diversity of human biology and the importance of personalized, holistic care.