What Is Male Pseudohermaphroditism?

Male pseudohermaphroditism is an older medical term for a group of conditions in which a person has XY chromosomes (the typical male karyotype) but develops external genitalia that are partially or fully female in appearance. The medical community has largely retired this label in favor of “46,XY disorders (or differences) of sex development,” commonly abbreviated 46,XY DSD. The renaming reflects both a deeper scientific understanding of these conditions and a recognition that the older terminology was stigmatizing and imprecise. Behind the label sits a surprisingly diverse set of causes, ranging from mutations in a single gene on the Y chromosome to enzyme deficiencies that block testosterone’s effects in the womb.

Why the Terminology Changed

For most of the twentieth century, clinicians sorted atypical genital development into categories using the word “hermaphroditism,” a term borrowed from Greek mythology. A person with XY chromosomes but female-appearing genitalia was classified as a “male pseudohermaphrodite,” while the reverse situation in an XX individual was called “female pseudohermaphroditism.” In 2006, an international consensus conference proposed replacing the entire system. The new framework uses the person’s karyotype as the organizing category, so what was once called male pseudohermaphroditism became “46,XY DSD,” and its counterpart became “46,XX DSD.”¹ You will still see the older terms in textbooks, case reports, and some clinical settings, but major endocrine and pediatric societies have adopted the updated language. Throughout this article, the two terms refer to the same spectrum of conditions.

How Typical Male Development Depends on a Chain of Events

Understanding why these conditions happen requires a quick look at what normally occurs in the womb. Early in embryonic life, the gonads are undifferentiated. In an XY embryo, a gene on the Y chromosome called SRY acts as a master switch that triggers the undifferentiated gonad to become a testis. From there, the testes produce two hormones that do the rest of the heavy lifting: testosterone, which drives the development of internal male structures, and anti-Müllerian hormone (AMH), which causes the female duct system to regress. Testosterone is then converted into a more potent form called dihydrotestosterone (DHT) in certain tissues, and DHT handles the final shaping of external genitalia. A disruption at any step in this chain can produce the spectrum of features grouped under 46,XY DSD.

Gonadal Dysgenesis and the SRY Gene

The most upstream cause is a failure of the gonad itself to form a functional testis. When the SRY gene is mutated or deleted, the gonad may develop as a nonfunctional “streak” of tissue rather than a testis. Researchers have found SRY mutations in a significant share of people with complete gonadal dysgenesis, where the external appearance is entirely female, Müllerian structures like a uterus are present, and the gonads are streaks. In one well-known study, mutations in the DNA-binding region of the SRY protein were identified in three out of five subjects with complete gonadal dysgenesis, confirming that even small changes in SRY can derail the entire cascade.²

SRY is not the only gene involved. Variants in SOX9, MAP3K1, NR5A1, GATA4, and DHX37 have all been linked to 46,XY gonadal dysgenesis, though these account for only a minority of all cases.³ Whole-exome sequencing studies continue to turn up new variants. One recent study identified novel pathogenic variants in GATA4, NR5A1, and DHX37 in patients with gonadal dysgenesis, and noted that over 70% of amino acid changes in GATA4 associated with 46,XY gonadal dysgenesis were clustered in or near a specific zinc-finger domain critical for the protein’s function.⁴ In many individuals, though, the genetic cause remains unidentified, which is one of the frustrations of this field.

Androgen Insensitivity Syndrome

Even when the testes form normally and produce plenty of testosterone, the body’s cells may not be able to respond to it. Androgen insensitivity syndrome (AIS) is an X-linked condition caused by mutations in the androgen receptor gene. More than 900 different mutations have been catalogued, and they produce a wide range of outcomes depending on how much receptor function remains.⁵

In complete AIS, the receptor is essentially nonfunctional. The result is an individual with XY chromosomes and internal testes who develops entirely female external genitalia, often without a uterus. Many people with complete AIS are not diagnosed until puberty, when they fail to menstruate, or during a workup for an inguinal hernia in childhood that turns out to contain a testis. In partial AIS, some receptor activity persists, and the external genitalia may be ambiguous at birth. In mild AIS, the external anatomy looks typically male, but there may be breast development at puberty and reduced sperm production.⁶

The relationship between a specific mutation and the resulting phenotype is not random. Mutations that completely interrupt the receptor’s open reading frame can occur anywhere in the gene and invariably produce complete androgen insensitivity. By contrast, single amino-acid substitutions tend to cluster in the DNA-binding or ligand-binding domains and can produce the full range of severity, depending on how badly the substitution impairs receptor function.⁷ Even deep intronic mutations that do not obviously touch the protein-coding sequence can cause complete AIS by triggering aberrant splicing events that destroy the androgen receptor’s mRNA before a functional protein is ever made.⁸

Enzyme Deficiencies That Block Testosterone or DHT

A separate group of conditions involves enzymes needed either to produce testosterone or to convert it into DHT. These individuals have functioning testes and working androgen receptors, but the hormonal signal itself is too weak or absent at critical moments during fetal development.

5-alpha reductase type 2 deficiency is probably the best-known example. The enzyme 5-alpha reductase converts testosterone into DHT in certain tissues, and DHT is the androgen responsible for shaping the external genitalia, urethra, and prostate.⁹ Without it, infants are born with ambiguous external genitalia despite having normal internal male structures. This condition drew international attention in the 1970s when researchers described clusters of affected families in the Dominican Republic, where local communities had already recognized the pattern and given it a colloquial name.

Another enzyme deficiency involves 17-beta hydroxysteroid dehydrogenase type 3, which converts a precursor steroid (androstenedione) into testosterone itself. Without this enzyme, testosterone levels are low during fetal development, and external genitalia are undervirilized. Diagnosis can be tricky because the expected hormonal ratios do not always behave as textbooks predict, particularly in prepubertal children.¹⁰

Mutations in the receptor for luteinizing hormone (the LHCGR gene) represent yet another route. Luteinizing hormone normally signals the Leydig cells in the testes to produce testosterone. When the receptor is inactive, the Leydig cells are underdeveloped and testosterone production drops or stops. More than 77 different inactivating mutations of this gene have been described.¹¹

Persistent Müllerian Duct Syndrome

Not every form of 46,XY DSD involves the external genitalia. In persistent Müllerian duct syndrome (PMDS), testosterone production and androgen receptors work normally, so the external genitalia look typically male. The problem is with anti-Müllerian hormone or its receptor. Because AMH fails to do its job, the female internal duct system persists alongside normal male structures. A person with PMDS may have a uterus and fallopian tubes discovered incidentally during surgery for an undescended testis or an inguinal hernia.¹² Serum AMH levels help clinicians distinguish whether the mutation lies in the AMH gene itself (where AMH is very low or undetectable) or in the AMH receptor gene (where AMH levels are normal or high).¹³

How These Conditions Are Diagnosed

The diagnostic workup typically starts with a physical examination, a karyotype to determine chromosomal sex, and hormonal testing. In newborns with ambiguous genitalia, the immediate priorities are ruling out adrenal crises (which can occur in some forms of congenital adrenal hyperplasia, a 46,XX DSD condition) and establishing a baseline hormonal profile. Imaging with ultrasound helps identify whether a uterus, gonads, or both are present.

Beyond these basics, the specific hormone patterns at different stages of life can point toward a diagnosis. A recent study evaluating the diagnostic accuracy of serum steroids and peptides across different age groups found that certain markers performed well at distinguishing specific conditions. For example, high FSH was effective at identifying gonadal dysgenesis in minipuberty, prepuberty, and puberty, with sensitivity and specificity both generally above 75%. The androgen sensitivity index showed the highest accuracy for identifying androgen insensitivity syndrome during puberty.¹⁴ These hormonal clues narrow the field, but genetic testing through sequencing of candidate genes or whole-exome sequencing is often needed for a definitive molecular diagnosis.

What Happens at Puberty

Puberty can be a turning point for people with certain forms of 46,XY DSD, particularly 5-alpha reductase deficiency and 17-beta HSD3 deficiency. In both conditions, rising testosterone levels at puberty can produce significant virilization: the voice deepens, muscle mass increases, and the phallus may enlarge. This pubertal virilization occurs because testosterone itself (as opposed to DHT) can drive some aspects of masculinization, and the surge of testosterone at puberty partly compensates for the enzyme that was missing during fetal development.

This pubertal shift has profound implications for gender identity. Many individuals with these enzyme deficiencies are raised as girls because their external genitalia looked female or ambiguous at birth. Studies have consistently reported that a substantial proportion change their gender role to male after puberty. One review found that gender role changes occurred in roughly 56 to 63% of cases of 5-alpha reductase deficiency and 39 to 64% of 17-beta HSD3 deficiency when the individuals had been raised as girls.¹⁵ A study of seven Mexican patients with 5-alpha reductase deficiency, all raised unambiguously as female, found that three spontaneously changed their gender identity and role to male after puberty, and a fourth did so during psychotherapy.¹⁶

These figures are not universal, however. A smaller study of six patients over the age of 15 with 5-alpha reductase deficiency who were raised as female found that four identified as female, one as male, and one as both genders. Only the patient who identified as male requested gender reassignment.¹⁷ The variation underscores that there is no single predictable outcome. Cultural context, timing of diagnosis, individual psychology, and the specific severity of the enzyme deficiency all play roles. This is one of the reasons clinicians have moved away from early irreversible surgical decisions.

Gonadal Cancer Risk

One of the most clinically important concerns in 46,XY DSD is the risk of germ cell tumors developing in the gonads. Several forms of DSD carry an elevated risk, and the level of risk varies enormously depending on the underlying condition. The highest risk, estimated at 15 to 60%, is seen in 46,XY gonadal dysgenesis, where the gonads are dysgenic streaks containing Y-chromosomal material. The lowest risk, under 5%, is found in conditions involving defects in androgen action or synthesis, such as complete AIS and 5-alpha reductase deficiency.¹⁸

The presence of Y-chromosomal material in a dysgenetic gonad is the key risk factor. For high-risk conditions like gonadal dysgenesis, prophylactic gonadectomy (surgical removal of the gonads) is often recommended. For lower-risk conditions like complete AIS, the decision is more nuanced. Removing the gonads eliminates cancer risk but also eliminates the body’s natural hormone source, committing the person to lifelong hormone replacement. Newer clinical guidance emphasizes shared decision-making and, when appropriate, gonadal monitoring rather than automatic early removal.¹⁹

Shifting Approaches to Surgery and Gender Assignment

The clinical management of 46,XY DSD has changed dramatically over recent decades. For much of the late twentieth century, the dominant approach was the “optimal gender policy,” which held that early surgical correction and a firm gender assignment in infancy would lead to the best psychological outcomes. In practice, this meant that many infants with ambiguous genitalia underwent feminizing genital surgery and were raised as girls, on the assumption that gender identity would follow the assigned sex if the rearing was consistent.

That policy has eroded. Surveys of North American pediatric endocrinologists and urologists show a clear shift away from recommending early irreversible surgery and toward deferring decisions until the patient can participate.²⁰ The proportion of clinicians who recommended that parents serve as the sole surgical decision-makers declined significantly over successive surveys. This shift was driven partly by the gender-identity data described earlier, which showed that surgical feminization did not reliably predict female gender identity, and partly by growing advocacy from adults with DSD who reported dissatisfaction with surgeries performed on them without their consent.

Lifelong Hormone Replacement

When gonads are removed or are nonfunctional, the body lacks its primary source of sex hormones. Whether a person is living as male or female, puberty will not progress without intervention, and the absence of sex hormones throughout adulthood carries consequences for bone density, cardiovascular health, metabolism, and psychological wellbeing. Hormone replacement with either testosterone or estradiol is needed to initiate and complete pubertal development, and then continues for life.²¹ Long-term outcome data are still being gathered, but it is increasingly clear that insufficient or absent replacement carries real health penalties.

Psychological Wellbeing

Living with a 46,XY DSD involves challenges that go well beyond the medical. A study comparing women living with 46,XY DSD to a control group found that the DSD group were high achievers in education and professional life and reported generally good quality of life. At the same time, they scored higher than controls on measures of depression, anxiety, and both internalizing and externalizing problems. Younger individuals showed better psychosocial adjustment than older ones, which may reflect both better clinical care in recent decades and the benefits of growing up with more openness about the condition.²² These findings are a reminder that even when physical health is well managed, psychological support matters.

Fertility Possibilities

Fertility in 46,XY DSD depends heavily on the specific diagnosis. In complete AIS, there is no functional uterus and no egg production, so biological pregnancy is not possible. In conditions where the testes are present and at least partially functional, sperm production may occur, though it is often impaired. A case series of patients with 5-alpha reductase deficiency who underwent microscopic testicular sperm extraction (micro-TESE) illustrated both the possibilities and the limits. One patient who had early orchidopexy (surgical correction of undescended testes) at age nine had successful sperm retrieval years later, though embryo development subsequently failed. Another patient whose orchidopexy was delayed until age 25 had no sperm retrieved at all, with testicular tissue showing a complete absence of developing sperm cells.²³ The authors emphasized that early orchidopexy and genital correction may be critical for preserving whatever fertility potential exists, making the timing of surgical decisions a genuinely high-stakes balancing act.

Environmental Chemicals and Fetal Masculinization

While most causes of 46,XY DSD are genetic, there is growing evidence that environmental exposures can also disrupt fetal masculinization, though typically in subtler ways than gene mutations. Endocrine-disrupting chemicals (EDCs) are substances that interfere with hormonal signaling, and the fetus is particularly vulnerable during a period in the second to third month after conception known as the masculinization programming window. Androgen action during this window shapes reproductive anatomy, and disruption of it can be reflected in shorter anogenital distance, a physical marker used as a proxy for fetal androgen exposure in both humans and rodents.²⁴

A systematic review and meta-analysis pooling data across multiple studies found that maternal exposure to certain EDCs was associated with a roughly 26% increased risk of hypospadias and a 37% increased risk of cryptorchidism (undescended testes) in male children.²⁵ These conditions are milder forms of undervirilization than what is typically classified as 46,XY DSD, but they sit on the same biological continuum. The rising incidence of hypospadias in some countries has fueled concern that environmental exposures may be contributing to a broader trend in disrupted male reproductive development.

The Legal Landscape Around Intersex Surgery

The question of whether and when to perform genital surgery on children with DSD has spilled into law and policy. A recent analysis found that all U.S. states with legislation restricting gender-affirming medical care for transgender minors contained statutory exceptions that allow physically comparable interventions on children with intersex traits. In other words, surgeries to “normalize” the genitalia of an infant with a DSD are carved out of the same bans that restrict elective procedures for transgender adolescents, despite the two involving similar medical procedures. Twenty-nine of the 30 state bans examined contained such an exception.²⁶ Advocacy groups have argued that this inconsistency highlights the need for legal protections specifically addressing nonvoluntary genital surgery on infants, while others maintain that parents and physicians should retain decision-making authority. The debate remains active and unresolved.

Animal Models and the Genetic Frontier

A persistent problem in 46,XY DSD research is that many patients receive no molecular diagnosis. The known genes explain only a fraction of cases, and whole-exome sequencing often turns up variants of uncertain significance that are difficult to interpret. Researchers have turned to animal models to help sort out which candidate genes actually matter. One approach used a mouse strain in which a specific Y chromosome variant on a particular genetic background produces undervirilization and sex reversal, mirroring many features of human 46,XY DSD. By comparing gene expression between normal and affected mouse gonads early in development, researchers identified over 500 differentially expressed genes, then cross-referenced these with human variants of uncertain significance found in exome-sequenced DSD patients. The overlap yielded 15 novel candidate genes, seven of which were linked to the well-known sex-determining gene Sox9.²⁷ Work like this is slowly filling in the blanks, though translating mouse findings into clinical diagnoses remains a long road.