The term “male hermaphrodite” is outdated and stigmatizing, replaced by the designation: 46,XY Differences in Sex Development (46,XY DSD). This classification describes congenital conditions where an individual’s chromosomal sex (46,XY) does not align with the typical development of their gonadal or anatomical sex. These conditions represent variations in sexual differentiation that begin in the womb.
The core of 46,XY DSD involves a partial or complete failure to produce or respond to the necessary signals for male development. These differences are a spectrum of biological variations in how the body develops from a 46,XY blueprint. Understanding these conditions requires grasping the typical developmental steps that are disrupted.
The Standard Pathway of 46,XY Development
Typical male sexual development is a multi-step process initiated by the Y chromosome. The SRY gene acts as the master switch, causing the undifferentiated embryonic gonads to develop into testes. This process is known as sex determination.
Once formed, the fetal testes contain two main types of hormone-producing cells: Sertoli cells and Leydig cells. Sertoli cells secrete Anti-Müllerian Hormone (AMH), which causes the regression of the Müllerian ducts. These ducts would otherwise develop into female internal reproductive organs.
Simultaneously, Leydig cells produce testosterone, the primary male sex hormone. Testosterone drives the development of the Wolffian ducts into male internal reproductive structures. For the external genitalia to form, testosterone must be converted into dihydrotestosterone (DHT).
The success of this entire process relies on the timely production and proper action of these hormones. Any disruption in the chain can result in a 46,XY DSD phenotype.
Categorizing the Mechanisms of Disruption
The causes of 46,XY DSD are categorized based on the affected stage of the developmental pathway. These mechanisms fall into three groups: problems with gonadal formation, deficiencies in hormone production, and issues with the body’s ability to respond to hormones.
Gonadal Development Failure
This category involves a failure of the undifferentiated gonad to form functional testes. This often stems from mutations in the SRY gene or other necessary genes. If the SRY gene is deleted or non-functional, the gonad defaults to an ovarian path or develops into streaks of tissue.
The resulting condition, 46,XY Complete Gonadal Dysgenesis (Swyer Syndrome), means the testes never develop, and neither AMH nor testosterone is produced. Without AMH, Müllerian structures persist, and without testosterone, the external genitalia develop along the female-typical path.
Androgen Synthesis Failure
In this group, functional testes are present, but Leydig cells cannot produce adequate amounts of testosterone or convert it to DHT. These disruptions are caused by enzyme deficiencies involved in the steroidogenesis pathway.
Enzyme defects causing this failure include those involved in upstream steps of steroid production. A specific example is 5-alpha reductase deficiency (5ARD), where the enzyme converting testosterone to DHT is defective. Since DHT is necessary for full masculinization, this deficiency leads to ambiguous or female-appearing external genitalia at birth, even with normal testosterone production.
Androgen Action/Receptor Failure
This category involves a failure of the body’s cells to respond to androgens, even when hormones are produced in normal or high amounts. This is caused by mutations in the Androgen Receptor (AR) gene, which is located on the X chromosome.
The AR gene provides instructions for making the receptor protein that binds to testosterone and DHT, allowing them to exert effects. If the receptor is non-functional, hormonal signals cannot be transmitted, rendering the body unresponsive to its own androgens. The severity of the AR mutation dictates the degree of insensitivity.
Key Conditions Resulting from 46,XY DSD
The mechanistic failures translate into specific, clinically recognized conditions, each with distinct features. These diagnoses provide examples of how disruption at a specific point in the pathway manifests.
Complete Androgen Insensitivity Syndrome (CAIS)
CAIS is the most widely recognized example of androgen action failure, caused by a complete non-functionality of the androgen receptor. Individuals with CAIS have a 46,XY karyotype and internal testes that produce testosterone and AMH. Since AMH is produced, the Müllerian structures regress, meaning the individual lacks a uterus or fallopian tubes.
Because the cells cannot respond to testosterone or DHT, the external genitalia develop as typically female. These individuals are often raised as female and may present during puberty due to primary amenorrhea. Diagnosis can also occur incidentally during the discovery of undescended testes during an inguinal hernia repair.
Partial Androgen Insensitivity Syndrome (PAIS)
PAIS represents a partial failure of the androgen receptor, meaning the receptor retains some limited function. This partial response leads to a highly variable phenotype, ranging from a predominantly female appearance to ambiguous genitalia, or a male-typical appearance with mild issues like micropenis or hypospadias.
The physical presentation in PAIS is directly related to the residual function of the mutated androgen receptor protein. Like CAIS, PAIS individuals have 46,XY chromosomes and functional testes. The degree of masculinization achieved depends on how well their cells utilized the available androgens.
5-Alpha Reductase Deficiency (5ARD)
This condition is a classic example of androgen synthesis failure, specifically the inability to convert testosterone to DHT due to a deficiency in the 5-alpha reductase enzyme. Since DHT is essential for external genital development, affected individuals are born with ambiguous or predominantly female-appearing external genitalia.
Crucially, the testes are present, producing normal amounts of testosterone, and the internal male Wolffian structures develop normally. At puberty, the large surge of testosterone often leads to dramatic physical changes, including deepening of the voice, muscle development, and significant genital growth. This pubertal virilization can lead to a shift in gender identity.
Phenotype and Clinical Presentation
The clinical presentation of 46,XY DSD spans a broad continuum beyond the simple binary of male or female. The external appearance can range from a fully female phenotype to ambiguous genitalia, or to a male-typical phenotype with subtle internal or functional differences.
A completely female external appearance is characteristic of CAIS and 46,XY Complete Gonadal Dysgenesis. Diagnosis is often delayed until puberty, when the individual presents with a lack of breast development or primary amenorrhea. Internal findings include the absence of a uterus and fallopian tubes, and the presence of testes or streak gonads.
Individuals with conditions like PAIS, 5-alpha reductase deficiency, or partial gonadal dysgenesis are typically born with some degree of genital ambiguity. This ambiguity can include a smaller phallus, a divided scrotum, or the urethra opening in an unusual position (hypospadias). The extent of these differences dictates whether the diagnosis is made at birth or later in childhood.
Diagnosis is sometimes not made until adulthood, often discovered incidentally during an evaluation for infertility or a related endocrine issue. The variety of presentations necessitates a careful, multidisciplinary approach involving endocrinologists, geneticists, surgeons, and mental health professionals. Sex assignment and subsequent medical management prioritize long-term well-being and gender identity development.