The term ‘male pseudohermaphroditism’ is an outdated classification replaced by the more accurate and respectful term 46,XY Disorders of Sex Development (DSD). This updated terminology describes congenital conditions where an individual has the genetic makeup of a male, with 46 chromosomes including one X and one Y, but their reproductive anatomy has not developed along typical lines. While these individuals have internal testes, their external genitalia can appear different from what is expected.
46,XY DSD is not a single diagnosis but a category of conditions that can present in many ways. The shift in language away from ‘pseudohermaphroditism’ reflects a better medical and social understanding. This change aims to reduce stigma and provide clearer communication with individuals and their families.
Understanding Typical Male Development
Typical male development begins at conception with a 46,XY karyotype. The Y chromosome carries the SRY gene (sex-determining region Y), which signals the primitive gonads to develop into testes early in embryonic development. This genetic signal directs the embryo towards a male developmental pathway.
Once formed, the testes produce hormones that shape the reproductive system. One of the first is anti-Müllerian hormone (AMH), which causes the Müllerian ducts to regress and disappear. These ducts are the precursors to female internal structures like the uterus and fallopian tubes.
Simultaneously, the testes start producing testosterone. This hormone acts on the Wolffian ducts, signaling them to develop into the male internal reproductive organs, including the epididymis, vas deferens, and seminal vesicles. These structures are necessary for carrying sperm later in life.
The development of external male genitalia requires another step. Testosterone is converted into a more potent androgen called dihydrotestosterone (DHT) by an enzyme named 5-alpha-reductase. DHT is directly responsible for the masculinization of external structures, leading to the formation of the penis and scrotum from embryonic tissues.
Causes of Atypical Development in 46,XY Individuals
Disruptions at any point in the male hormonal pathway can lead to a 46,XY DSD. These conditions arise from problems with producing androgens or the body’s ability to respond to them, not from an issue with the chromosomes. The specific presentation of a DSD depends on where and how severely this process is interrupted.
A primary cause of 46,XY DSD involves impaired androgen action, where the body produces hormones but the cells cannot use them. The most well-known of these conditions is Androgen Insensitivity Syndrome (AIS). In AIS, androgen receptors are faulty due to a genetic mutation, so while the body makes hormones, target tissues do not get the message to masculinize.
AIS exists on a spectrum. In Complete Androgen Insensitivity Syndrome (CAIS), the androgen receptors are non-functional, so the individual develops external female genitalia despite having a 46,XY karyotype and internal testes. In Partial Androgen Insensitivity Syndrome (PAIS), the receptors have limited function, leading to a wide range of outcomes, often described as ambiguous genitalia.
Other forms of 46,XY DSD are caused by impaired androgen production, where the testes are unable to synthesize sufficient testosterone. Conditions like Leydig cell hypoplasia, where the testosterone-producing cells in the testes are underdeveloped, result in low testosterone levels and incomplete masculinization of both internal and external structures.
Another cause is 5-alpha-reductase deficiency. Individuals with this condition have testes that produce normal levels of testosterone, and their internal Wolffian duct structures develop correctly. However, they lack the 5-alpha-reductase enzyme necessary to convert testosterone into DHT. Without DHT, the external genitalia do not fully masculinize, resulting in ambiguous genitalia at birth.
Diagnosis and Physical Characteristics
The identification of a 46,XY DSD often begins at birth with the observation of atypical genitalia, as physical characteristics vary widely. Common signs include:
- Ambiguous genitalia where it is not immediately clear if the anatomy is male or female
- Hypospadias, where the urethral opening is not at the tip of the penis
- Cryptorchidism, or undescended testes
- A micropenis
In some instances, the condition may not be apparent at birth. In cases of Complete Androgen Insensitivity Syndrome (CAIS), the external anatomy appears female, so the diagnosis is often not made until puberty. The individual may seek medical attention for failing to menstruate, which leads to a workup revealing the 46,XY karyotype and internal testes.
The diagnostic process involves multiple steps to determine the specific cause. It starts with a physical examination of the external anatomy. This is followed by a karyotype analysis, a blood test that confirms the chromosomal makeup is 46,XY, which distinguishes these conditions from DSDs with different chromosomal arrangements.
Hormonal evaluation is another part of the diagnosis. Blood tests measure levels of hormones, including testosterone, dihydrotestosterone (DHT), and luteinizing hormone (LH). The results can point towards whether the issue is with hormone production or hormone action.
Imaging studies, such as a pelvic ultrasound or MRI, are used to visualize the internal reproductive organs and confirm the presence of testes or other structures. Genetic testing may also be performed to identify the specific gene mutation responsible for the condition.
Management and Multidisciplinary Support
The management of 46,XY DSD is a long-term process requiring a coordinated effort from a multidisciplinary team. This team includes pediatric endocrinologists, urologists, surgeons, geneticists, and mental health professionals. The goal is to provide care that addresses the medical, surgical, and psychological needs of the individual and their family.
Hormone replacement therapy (HRT) is a component of management, particularly around puberty. The type of hormone used depends on the gender of rearing. For individuals raised as male, testosterone therapy induces secondary sex characteristics like voice deepening. For those raised as female, such as with CAIS, estrogen therapy promotes breast development.
Surgical intervention may be considered to address specific anatomical features, such as repairing hypospadias or performing an orchiopexy for undescended testes. Historically, cosmetic genital surgeries were often performed on infants. However, there has been an ethical shift to delay non-medically necessary surgeries until the individual is old enough to provide informed consent.
Psychological support is an important part of the management plan. Individuals with DSD and their families often face challenges related to gender identity, body image, and social stigma. Counseling provides a space to navigate these issues, and support groups connect individuals and families with others who have shared experiences.