Are there XY females?

“Girls born with XY chromosomes are genetically boys but for a variety of reasons – mutations in genes that determine sexual development – the male characteristics are never expressed. They live their lives as girls and then women, and a few can even give birth.

novonordiskfonden.dk - More Women Than Expected Are Genetically Men

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BY MORTEN BUSCH

Sex chromosomes usually determine whether you are female or male. Women are XX. Men are XY. However, genetically, a few women are actually men. They grow up as women with a woman’s body, and most only discover well into puberty that they are different. Danish researchers map for the first time how many women are genetically men. The proportion was higher than expected. You cannot see it if you do not know what you are looking for. One in 15,000 males is born and grows up as a girl. And neither these girls nor their parents know it. These girls do not discover anything different until puberty. “Girls born with XY chromosomes are genetically boys but for a variety of reasons – mutations in genes that determine sexual development – the male characteristics are never expressed. They live their lives as girls and then women, and a few can even give birth. Our research, which is the first nationwide survey in the world, shows that this group is up to 50% larger than previously assumed. How these girls discover the facts and talk openly about their situation also varies greatly,” explains Claus Højbjerg Gravholt, who led the study and is Clinical Professor in the Department of Clinical Medicine of Aarhus University. Together with colleagues, he is investigating why sex chromosome abnormalities occur and therefore how people with XY chromosomes can become women. Two types of genetic mutations mostly make the difference; these were previously referred to as Morris syndrome and Swyer syndrome but are now collectively referred to as disorders of sex development (DSD). “Morris syndrome is now called 46,XY DSD: androgen insensitivity syndrome. These people have an extremely high level of testosterone and other male sex hormones, but the testosterone does not affect the foetal cells that usually develop into male sexual organs because of a mutation in the androgen receptor gene. These people therefore have male chromosomes but are women socially and in external appearance. They do not have internal female sexual organs, and they form testicles that remain concealed in the abdominal cavity.”

THE HIDDEN MEN

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Typically, most of the girls with androgen insensitivity syndrome discover by puberty that they differ from other girls. They do not menstruate, and most will never be able to give birth. Apart from the discovery that more women have XY chromosomes than previously assumed, the researchers were also surprised about the variation in when these girls and women discover that something is different. The girls with androgen insensitivity syndrome were diagnosed at an average age of 7–8 years old but some 34-year-old women with the syndrome had not yet been diagnosed. “This is surprising, although most of these women know that they cannot give birth and that they are configured slightly differently than other women. They just do not know why. Even more surprising, however, is the fact that the average age of girls being diagnosed with gonadal dysgenesis, previously known as Swyer syndrome, is 17 years.” The reason for this high age at diagnosis is presumably that these women actually develop sexual organs that are almost normal. Women with gonadal dysgenesis have a mutation in the SRY gene of the Y chromosome that encodes for a protein known as the testicular determining factor that normally results in the testicles developing in the early weeks of foetal development. In the absence of the protein, the testicles do not develop and female sexual organs that are almost normal develop instead. “The women do not develop secondary female characteristics such as breasts, but they have a womb, so with appropriate hormone treatment and fertilized egg implantation they can actually become pregnant and give birth. The greatest problem is that their ovaries are not developed, and if the ovaries are not removed they have an increased risk of developing ovarian cancer.”

DENMARK IS UNIQUE

Claus Højbjerg Gravholt’s group focuses intensively on the resulting diseases associated with sex chromosome abnormalities. These are mostly important for the people with the abnormalities but are also important in a wider context for understanding many disease processes at the genetic, molecular, clinical and epidemiological levels. “The idea is that this research can help us to understand major disease groups such as type 2 diabetes and heart disease that are more frequent among people with sex chromosome abnormalities. Since these people have a higher prevalence of the resulting diseases, detecting the patterns is also easier. Ultimately, we hope that this knowledge will benefit these women and other people with diabetes or heart disease.”

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The Danish researchers mainly focus on helping and treating the women and men with sex chromosome abnormalities. These people typically face physical challenges related to their sexuality, their inability to give birth or the diseases resulting from lack of sex hormones. They also face mental challenges. “It is very upsetting for people who have grown up and lived for years believing that they are of a particular sex to suddenly discover that they are actually of the opposite sex. This can be a relief but can also be a loss. For most people it comes as a shock that upends their whole identity. Coping with this can take years,” concludes Claus Højbjerg Gravholt. “Incidence, prevalence, diagnostic delay, and clinical presentation of female 46,XY disorders of sex development” was published in September 2016 in the Journal of Clinical Endocrinology and Metabolism. In 2013–2015, the Novo Nordisk Foundation awarded a grant for research on sex chromosome syndromes to the Claus Højbjerg Gravholt group at the Department of Clinical Medicine of Aarhus University.

novonordiskfonden.dk - More Women Than Expected Are Genetically Men

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