Battle of the sexes
According to some scientists, that balance can shift long after development is over. Studies in mice suggest that the gonad teeters between being male and female throughout life, its identity requiring constant maintenance. In 2009, researchers reported deactivating an ovarian gene called Foxl2 in adult female mice; they found that the granulosa cells that support the development of eggs transformed into Sertoli cells, which support sperm development. Two years later, a separate team showed the opposite: that inactivating a gene called Dmrt1 could turn adult testicular cells into ovarian ones. “That was the big shock, the fact that it was going on post-natally,” says Vincent Harley, a geneticist who studies gonad development at the MIMR-PHI Institute for Medical Research in Melbourne.
The gonad is not the only source of diversity in sex. A number of DSDs are caused by changes in the machinery that responds to hormonal signals from the gonads and other glands. Complete androgen insensitivity syndrome, or CAIS, for example, arises when a person's cells are deaf to male sex hormones, usually because the receptors that respond to the hormones are not working. People with CAIS have Y chromosomes and internal testes, but their external genitalia are female, and they develop as females at puberty.
Conditions such as these meet the medical definition of DSDs, in which an individual's anatomical sex seems to be at odds with their chromosomal or gonadal sex. But they are rare—affecting about 1 in 4,500 people. Some researchers now say that the definition should be widened to include subtle variations of anatomy such as mild hypospadias, in which a man's urethral opening is on the underside of his penis rather than at the tip. The most inclusive definitions point to the figure of 1 in 100 people having some form of DSD, says Vilain.
But beyond this, there could be even more variation. Since the 1990s, researchers have identified more than 25 genes involved in DSDs, and next-generation DNA sequencing in the past few years has uncovered a wide range of variations in these genes that have mild effects on individuals, rather than causing DSDs. “Biologically, it's a spectrum,” says Vilain.
A DSD called congenital adrenal hyperplasia (CAH), for example, causes the body to produce excessive amounts of male sex hormones; XX individuals with this condition are born with ambiguous genitalia (an enlarged clitoris and fused labia that resemble a scrotum). It is usually caused by a severe deficiency in an enzyme called 21-hydroxylase. But women carrying mutations that result in a milder deficiency develop a 'non-classical' form of CAH, which affects about 1 in 1,000 individuals; they may have male-like facial and body hair, irregular periods or fertility problems—or they might have no obvious symptoms at all. Another gene, NR5A1, is currently fascinating researchers because variations in it cause a wide range of effects, from underdeveloped gonads to mild hypospadias in men, and premature menopause in women.
Many people never discover their condition unless they seek help for infertility, or discover it through some other brush with medicine. Last year, for example, surgeons reported that they had been operating on a hernia in a man, when they discovered that he had a womb. The man was 70, and had fathered four children.
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