Disorders of sex development

Definition

Intersex is a group of conditions where there is a discrepancy between the external genitals and the internal genitals (the testes and ovaries).

The older term for this condition, hermaphroditism, came from joining the names of a Greek god and goddess, Hermes and Aphrodite. Hermes was a god of male sexuality (among other things) and Aphrodite a goddess of female sexuality, love, and beauty.

Although the older terms are still included in this article for reference, they have been replaced by most experts (and patients and families) because they are misleading, confusing, and insensitive. Increasingly this group of conditions is being called disorders of sex development (DSDs).

Alternative Names

Causes

Intersex can be divided into four categories:

• 46, XX Intersex
• 46, XY Intersex
• True Gonadal Intersex
• Complex or Undetermined Intersex

Each one is discussed in more detail below. NOTE: In many kids the cause of intersex may remain undetermined, even with modern diagnostic techniques.

46, XX Intersex. The person has the chromosomes of a woman, the ovaries of a woman, but external (outside) genitals that appear male. This usually is the result of a female fetus having been exposed to excess male hormones before birth. The labia ("lips" or folds of skin of the external female genitals) fuse, and the clitoris enlarges to appear like a penis. Usually this person has a normal uterus and Fallopian tubes. This condition is also called 46, XX with virilization. It used to be called female pseudohermaphroditism. There are several possible causes:

• Congenital adrenal hyperplasia (the most common cause).
• Male hormones (such as testosterone) taken or encountered by the mother during pregnancy.
• Male hormone-producing tumors in the mother. These are most often ovarian tumors. Mothers who have children with 46, XX intersex should be checked unless there is another clear cause.
• Aromatase deficiency. This one may not be noticeable until puberty. Aromatase is an enzyme that normally converts male hormones to female hormones. Too much aromatase activity can lead to excess estrogen (female hormone); too little to 46, XX intersex. At puberty these XX children, who had been raised as girls, may begin to take on male characteristics.

46, XY Intersex. The person has the chromosomes of a man, but the external genitals are incompletely formed, ambiguous, or clearly female. Internally, testes may be normal, malformed, or absent. This condition is also called 46, XY with undervirilization. It used to be called male pseudohermaphroditism. Forming normal male external genitals depends on the appropriate balance between male and female hormones; therefore, enough requires the adequate production and function of male hormones. 46, XY intersex has many possible causes:

• Problems with the testes. The testes normally produce male hormones. If the testes do not form properly, it will lead to undervirilization. There are a number of possible causes for this, including XY pure gonadal dysgenesis.
• Problems with testosterone formation. Testosterone is formed through a series of steps where each requires a different enzyme. Deficiencies in any of these enzymes can result in inadequate testosterone and produce a different syndrome of 46 XY, intersex. Different types of congenital adrenal hyperplasia can fall in this category.
• Problems with using testosterone. Some people have normal testes, make adequate amounts of testosterone, but still have 46, XY intersex.
  • 5-alpha-reductase deficiency. People with 5-alpha-reductase deficiency lack the enzyme needed to convert testosterone to dihydrotestosterone (DHT). There are at least 5 different types of 5-alpha-reductase deficiency. Some of the babies have normal male genitalia, some have normal female genitalia, and many have something in between. Most change to external male genitalia around the time of puberty.
  • Androgen insensitivity syndrome (AIS). This is the most common cause of 46, XY intersex. Here the hormones are all normal, but the receptors to male hormones don't function properly. There are over 150 different defects that have been identified so far, that each cause a different type of AIS. AIS has also been called testicular feminization.

True Gonadal Intersex. Here the person must have both ovarian and testicular tissue. This might be in the same gonad (an ovotestis) or the person might have one ovary and one testis. The person may have XX chromosomes, XY chromosomes, or both. The external genitals may be ambiguous, or may appear to be female or male. This condition used to be called true hermaphroditism. In most people with true gonadal intersex, the underlying cause is unknown, although in some animal studies it has been linked to exposure to common agricultural pesticides.

Complex or Undetermined Intersex. Many chromosome configurations other than simple 46, XX or 46, XY can result in disorders of sex development. These include 45, XO (only one X chromosome), and 47, XXY, 47, XXX -- both cases have an extra sex chromosome, either an X or a Y.

Symptoms

The symptoms associated with intersex will depend on the underlying cause, but may include:

• Ambiguous genitalia at birth
• Micropenis
• Clitoromegaly (an enlarged clitoris)
• Partial labial fusion
• Apparently undescended testes (which may turn out to be ovaries) in boys
• Labial or inguinal (groin) masses -- which may turn out to be testes -- in girls
• Hypospadias (the opening of the penis is somewhere other than at the tip; in females, the urethra [urine canal] opens into the vagina)
• Otherwise unusual appearing genitalia at birth
• Electrolyte abnormalities
• Delayed or absent puberty
• Unexpected changes at puberty

Exams and Tests

• Chromosome analysis
• Hormone levels (for example, testosterone level)
• Hormone stimulation tests
• Electrolyte tests
• Specific molecular testing
• Endoscopic examination (to verify the absence or presence of a vagina or cervix)
• Ultrasound or MRI  to evaluate whether internal sex organs are present (for example, a uterus)

Treatment

Ideally, a team of healthcare professionals with expertise in intersex should work together to understand and treat the child with intersex - and to understand, counsel, and support the entire family.

Parents should understand controversies and changes in treating intersex in recent years. In the past, the prevailing opinion was that it was generally best to assign a gender as quickly as possible, often based on the external genitals rather than the chromosomal gender, and to instruct the parents to have no ambiguity in their minds as to the gender of the child. Prompt surgery was often recommended.  Ovarian or testicular tissue from the other gender would be removed. In general, it was considered easier to reconstruct female genitalia than functioning male genitalia, so if the 'correct' choice was not clear, the child was often assigned to be a girl.

More recently, the opinion of many experts has shifted. Greater respect for the complexities of female sexual functioning has led them to conclude that suboptimal female genitalia may not be inherently better than suboptimal male genitalia, even if the reconstruction is 'easier'. In addition, other factors may be more important in gender satisfaction than functioning external genitals. Chromosomal, neural, hormonal, psychological, and behavioral factors can all  influence gender identity.

Many experts now urge delaying definitive surgery for as long as healthy, and ideally involving the child in the gender decision.

Clearly, intersex is a complex issue, and its treatment has short and long-term consequences. The best answer will depend on many factors, including the specific cause of the intersex. It is best to take the time to understand the issues before rushing into a decision. An intersex support group may help acquaint families with the latest research, and may provide a community of other families, children, and adult individuals who have faced the same issues.

Support Groups

Support groups are very important for families dealing with intersex.

Different support groups may differ in their thoughts regarding this very sensitive topic. Look for one that supports your thoughts and feelings on the topic.

The following organizations provide further information:

• American Association for Klinefelter Syndrome Information and Support -- www.aaksis.org
• CARES Foundation -- www.caresfoundation.org
• Congenital Adrenal Hyperplasia Education and Support Network -- www.congenitaladrenalhyperplasia.org
• Hypospadias and Epispadias Association -- www.heainfo.org
• Intersex Society of North America -- www.isna.org
• Turner Syndrome Society of the US -- www.turner-syndrome-us.org

Outlook (Prognosis)

Please see information on the individual conditions. The prognosis depends on the specific cause of intersex. With understanding, support, and appropriate treatment, overall outlook is excellent.

When to Contact a Medical Professional

If you notice that your child has unusual  genitalia or sexual development, discuss this with your health care provider.