Ambiguous genitalia is a condition in which an infant’s genitals do not appear male or female. The internal sex organs may be completely normal and fully formed, establishing the genetic gender of the child, but the external genitals may appear indeterminate. Outer tissue may not be easily identifiable as either a scrotum or labia and the clitoris or penis may be difficult to clearly identify.

Some people inaccurately use the term hermaphrodite to refer to individuals with ambiguous genitalia. However, true hermaphrodites (people with the tissue for both male and female sex organs) are extremely rare and only a small percentage of people with ambiguous genitalia are true hermaphrodites. More commonly, these people have the genes and internal sex organs of one gender. The external genitalia for that gender have not developed properly due to a variety of causes. People with ambiguous genitalia are sometimes referred to as having an intersex condition, but sometimes this intersex condition will not become apparent until puberty.

The development of genitalia occurs early in pregnancy, between the seventh and 14^th weeks. The genes received from each parent determine whether the fetus will develop the genitals of a typical boy or a girl. Abnormalities in the genes (the female XX or the male XY) or deficiencies in hormones and enzymes may affect this process and result in the development of abnormal genitalia.

The appearance of ambiguity at birth can be devastating for parents, who expect to know their child’s gender immediately. Diagnostic tests can determine the child’s genetic gender and usually the cause of the ambiguous genitalia. These include blood tests and urine tests to determine genetic markers and hormone levels. X-rays and ultrasounds can be used to view the internal organs. This information may be used to determine the diagnosis as well as aid in treatment of the condition.

For many years, children with ambiguous genitalia were assigned to one gender (usually female) and had surgery in infancy or childhood to make the genitals appear like those of the assigned gender. This early surgery usually removes tissue that cannot be replaced later on. As these children develop, hormones can be given to help them develop other secondary sex characteristics. However, these individuals frequently remain infertile because the physical changes that can be obtained with surgery and/or hormones usually cannot produce physiological changes. Recently, some studies have shown that the assigned gender can affect sexual function or sexual identity. In some cases, the individual does not always agree with the perception of his or her gender. Some physicians now advocate postponing gender assignment and surgery until the child is older and can participate in the decision.

At birth, some babies have external genitals that do not appear specifically male or female. Normally, a female baby is visually identified by the folds of the labia covering the opening of the vagina and a clitoris. A male baby is identified by the presence of a penis and scrotum with testicles. Sometimes, the testicles do not descend from the abdominal cavity into the scrotum and a normal male with a normal penis might have abnormal appearing testes. This is not due to an abnormal development of the male sexual organs, but rather a mechanical problem with the failure of descent into the scrotum. 

Infants with ambiguous genitalia may have tissue that could be a small penis or an enlarged clitoris. Both organs are formed from the same kind of erectile tissue. The urethra may also be in an unusual location along the penis or clitoris, making it more difficult to identify the organ. The other outer tissue may be fused, making it difficult to identify as a scrotum or labia. If the testicles have not descended, the scrotum may appear as fused labia.

Ambiguous external genitalia can make it difficult to determine the child’s gender. But the genetic gender of a child is determined by pairs of chromosomes in each cell. Females typically have two X chromosomes (XX) and males typically have an X and a Y chromosome (XY). At conception, the mother’s egg provides the X chromosome. The father’s sperm can provide an X chromosome, which will form into a female fetus (XX), or a Y chromosome, which will form into a male fetus (XY). Babies can be born with a range of combined chromosomes that result in ambiguous genitalia, and complicate the assignment of gender.

Genes on these chromosomes account for the development of the genitalia. The ovaries or testes (gonads) develop from the same kind of tissue, whether the fetus will eventually become male or female. When this tissue first appears, around seven weeks’ gestation, it resembles the female organs and structures, both internally and externally. Few changes are needed for it to develop into female organs. Major changes must occur when the tissue has to form male organs, aided by the action of male hormones. Thus, the action of male hormones determines when and how male sex organs develop.

The Y chromosome contains a gene (the SRY gene) that causes the gonad tissue to develop into testes. When that gene is absent, as it is in females (who have no Y chromosome), the same gonad tissue develops into ovaries.

This pattern continues throughout the time of genital differentiation, which takes about seven weeks. The testes and other glands in the fetus produce male hormones (androgens), which initiate the growth of other parts of the male genital system (penis, vas deferens, epididymis and seminal vesicle). The action of hormones in females causes the tissue to develop into the uterus, cervix, fallopian tubes and vagina. Any variation or interruption in this process may affect the genital development and result in ambiguous genitalia. The process may not affect the internal organs, meaning a fetus may have well developed testes but does not develop a clear penis. A female fetus may have a uterus and ovaries but fails to develop a vagina with an opening and a clitoris.

Ambiguous genitalia is usually not a life-threatening condition. However, human sexuality is complex and there are profound psychological effects from investigating and determining something that most parents take for granted: the gender of their child. Many conditions that cause ambiguous genitalia can affect sexual function and fertility of the child in adult life.

The appearance of ambiguous genitalia ranges along a spectrum from normal female genitalia to normal male genitalia. There are milder and more severe cases, which may or may not be related to the chromosomal type of the baby. Appearance of ambiguous genitalia usually falls into one of the following types:

• Virilized XX. These are genetic females (XX) who may appear male. They may have a large clitoris that looks like a small penis. Their labia may be fused together. This can obstruct the vaginal opening and may look like a scrotum.
  
  
• Undervirilized XY. These are genetic males (XY) who may appear female. They generally have a very small penis with a misplaced urethra and undescended testicles. Their internal organs are male, but their external genitalia may not be obviously male.
  
  
• Mixed gender/true hermaphrodite. This condition is extremely rare. True hermaphrodites have developed gonads of genders, at least one ovary and one testicle. In many cases, each gonad has some ovarian tissue and some testicular tissue and is called an ovotestis. Other parts of the genitals may also be mixed, such as a vagina that is combined with the urethra.

Ambiguous genitalia may be caused by a number of conditions or abnormalities. There are chromosomal abnormalities that are related to the child’s genetic gender, but may not produce ambiguous genitalia. For example, females with Turner syndrome only have one X chromosome. In later life they will be infertile, but at birth their external genitalia appears female.

Causes of ambiguous genitalia may be grouped into the following areas:

• Hormonal and enzyme action. Much of genital development is guided by hormones and the enzymes that work with them. Numerous conditions that can cause ambiguous genitalia are related to hormones or enzymes that affect hormonal actions. Some of these include:
  
  
• Congenital adrenal hyperplasia (CAH). This is a disorder of the adrenal glands caused by an enzyme deficiency. The adrenal glands should produce the hormones cortisol and aldosterone. Without the enzymes, the glands produce male hormones called androgens. This excess of male hormones in a female baby’s system causes ambiguous genitalia. CAH is the most common cause of ambiguous genitalia in females (virilized XX). In males, CAH does not produce ambiguous genitalia, but may result in early puberty.
  
  Certain forms of CAH can be life-threatening for both genders if not recognized and treated. The missing hormones (cortisol and aldosterone) are necessary to maintain electrolyte levels and blood pressure. They must be taken as supplements for life if the adrenal glands do not produce them.
  
  
• Androgen insensitivity syndromes. In male babies, certain enzymes and receptor cells must be present to react with testosterone so the genitalia can develop. These disorders make the male fetus either completely or partially insensitive to testosterone. If testosterone cannot act, the genitals will appear as an unvirilized XY baby.
  
  
• Enzyme deficiencies in the testes. Other enzyme deficiencies also affect the formation of testosterone or affect its influence on the virilization of cells. When penile development is restricted due to an enzyme deficiency, the resulting tissue may resemble a clitoris rather than a penis.
  
  
• Maternal hormones and enzymes. The conditions in a woman’s body during pregnancy and her hormones and enzymes may affect the developing fetus and its genitalia. These changes usually affect a female fetus (virilized XX). For example, a woman may be taking androgens, which can affect the genitalia. Some women who experienced recurrent miscarriages may have been prescribed progesterone, which in excess amounts may affect the fetal genitals. The mother may have imbalances of her own hormones caused by a tumor. In addition, the absence of an enzyme in the placenta may allow more testosterone to cross the placenta and affect the fetus.
  
  
• Genetic defects. Instead of all cells having the same sex chromosomes (XX or XY), some cells may have different combinations. As a result, sometimes one gonad (ovary or testes) forms correctly and the other remains undeveloped. In cases of complete gonadal dysgenesis, neither gonad develops.
  
  
• Family history. Some of the genetic abnormalities and enzyme deficiencies associated with ambiguous genitalia are hereditary. Parents who are carriers of the gene may have children with the genetic abnormality or may pass on the gene so their children may become carriers as well.
  
  
• Environmental factors. Some cases of ambiguous genitalia may be caused by maternal or paternal exposure to chemicals. Some women whose mothers took the drug diethylstilbestrol (DES) during pregnancy developed a septum, or wall, across the vagina. Other environmental exposures may contribute to ambiguous genitalia, but their influence has not been studied.

Diagnosis of ambiguous genitalia may just involve a brief physical examination of a newborn. In more complicated cases, it may involve multiple physicians and specialists. Diagnosis begins with a complete physical examination. The physician will palpate the baby’s pelvic and genital area to feel for ovaries or testicles. A medical history will be taken to determine if the mother was exposed to anything unusual during pregnancy. The physician will also ask about family history of miscarriage, stillbirth, ambiguous genitalia, infant death or infertility to determine if the abnormality could be hereditary.

Certain common tests can determine the genetic gender of the baby (XX or XY). These include:

• Blood tests. Used for genetic identification and analysis of hormone and endocrine function.
  
  
• Urine tests. Used for analysis of hormone levels and function.
  
  
• Buccal smear. A scraping from the inside of the cheek. Used for chromosome identification.
  
  
• More involved chromosome tests. Used to determine genetic gender or to look for specific chromosomal abnormalities, including some associated with an increased risk of malignant tumors.

Other diagnostic methods can be used to check the internal organs. X-rays and ultrasound can indicate the presence of female or male organs. A genitogram test involves dye injected into the urethra. The dye fills the urethra and vagina (if there is one) so the structures can be identified on an x-ray. In certain cases, a tissue sample (biopsy) is taken from the ovaries or testicles to analyze various elements.

All of these tests should indicate the genetic gender of the child and may help determine the cause of the ambiguous genitalia. With this information, the physicians and parents should be able to consider a treatment plan.

The treatment plans used for ambiguous genitalia for the past several decades have recently come under greater scrutiny. For many years, parents were urged to assign their child’s gender immediately. When necessary, surgery was performed shortly after birth or in early childhood to make the external genitals appear like those of a specific gender. The prevailing belief was that a child raised as a girl and treated as a girl would be a girl, regardless of the child’s chromosomes.

In many cases, babies were raised as females because surgeons could more skillfully create external female genitals and a vagina. At puberty, girls took hormones to appear more female. However, as adults they were infertile because they lacked ovaries and a uterus.

In recent years, several studies have questioned these practices. Some people raised as girls said they felt they should have been raised as boys. Others were comfortable with their gender assignment, but had sexual difficulties as adults. Some theories propose that the hormonal action affects gender identity in the brain, not just in the reproductive organs. Critics question performing surgery before the children can indicate which gender they consider themselves to be.

Today, numerous people contribute to the decision-making process, including physicians, pediatricians, endocrinologists, ethicists and psychologists. Some advocate waiting a few years for surgery until the child can indicate which gender they think they are. Parents must consider whether the child will be able to have any sexual function or fertility if they choose one gender or the other. The American Academy of Pediatrics recommends that parents should refrain from immediately assigning a gender to a newborn with ambiguous genitalia. The group recommends a thorough evaluation of physical examination and laboratory test results for endocrine function and testosterone imprinting before gender is determined.

Regardless of the timing, the treatment options for ambiguous genitalia include:

• Surgery. Surgery may be used to make the external genitalia appear more like those of one gender. It may involve reducing the size of the clitoris or providing an opening for the vagina. Surgery on a penis can require moving the opening of the urethra to its more normal position. This surgery should not affect penile erectile abilities after puberty. Surgery may be used to remove or relocate internal organs such as undescended testicles. Some mild cases of ambiguous genitalia may not need surgery. The long-term effects of the surgery on the sexual function of the organs is difficult to classify, especially when the surgery is performed on sensitive tissue like a clitoris.
  
  
• Hormone treatments. Certain hormonal imbalances treated in infancy can improve ambiguous genitalia. For example, it may be used to reduce the size of an enlarged clitoris. Depending on the cause of ambiguous genitalia, the child may need to take hormones later to produce the outward sexual characteristics of the assigned gender. Hormone treatments usually begin when the child reaches the age for puberty.
  
  
• Counseling. This may be beneficial to the parents and the child when he or she reaches an appropriate age. Counseling may be pertinent both for parents who have assigned a gender to their infant and began the necessary steps, as well as those who choose to wait until the child is older. Each situation is different and can have an enormous impact on the lives of the entire family.
  
  
• Treatment for congenital adrenal hyperplasia (CAH). Infants born with CAH should be diagnosed and have the disorder treated immediately. The absence of necessary adrenal hormones, some of which help regulate important electrolyte levels in the body, can cause death within six weeks if untreated. These infants will require medications for life to maintain these hormone levels. Any ambiguous genitalia associated with the disorder can be treated separately.

Most cases of ambiguous genitalia cannot be prevented. Women should be aware of any family history of genetic disorders and discuss them with their physician before or during pregnancy. Pregnant women should clear all their medications with their physicians and avoid medications with androgens.

Preparing questions in advance can help patients have more meaningful discussions with their physicians regarding their conditions. Patients and parents may wish to ask their doctor or healthcare professional the following questions about ambiguous genitalia:

1. What may have caused ambiguous genitalia in our baby?
   
   
2. Can ambiguous genitalia be detected in a fetus?
   
   
3. Which tests can be used to determine the gender of our baby?
   
   
4. What are the structural problems with the genitalia?
   
   
5. What type of surgery should be performed to correct the condition?
   
   
6. At what age do you recommend the surgery be performed?
   
   
7. What are the risks associated with this surgery?
   
   
8. Do you have experience with surgery for ambiguous genitalia?
   
   
9. How will this affect our child’s sexual function as an adult?
   
   
10. Can our child carry or father a child as an adult?
    
    
11. Will our child need medications or hormones?
    
    
12. Should we let our child decide on his or her gender?
    
    
13. What type of counseling do you suggest for us?
    
    
14. Can you recommend a support group for this condition?