Sex Determination
Why Do Doctors Want to Mess with
My Hormones? "XX Male" and "XY Female" aka
Swyer Syndrome Persistent Mullerian Duct
(Differences in Sexual Development) Androgen Insensitivity
(Differences in Sexual Development) 5a-Reductase Deficiency
(Differences in Sexual Development) XX or XY || Male or Female ||
100% Correct Gender estimation on
Ultrasound * You can't assume someone's
biological sex just based on their external anatomy
When
a Person Is Neither XX nor XY: A Q&A with Geneticist
Eric Vilain 5/30/07 About one in 4,500 babies show ambiguous genitalia at birth, such as a clitoris that looks like a penis, or vice versa. For the Insights story, "Going Beyond X and Y," appearing in the June 2007 issue of Scientific American, Sally Lehrman talked with noted geneticist Eric Vilain of the University of California, Los Angeles, about the biology of sex determination, gender identity and the psychology and politics behind both. Here is an expanded interview. When did you first discover your interest in intersex individuals and the biology of sex development? I started in Paris as a medical student, and my first assignment was to a unit of pediatric endocrinology in a Paris hospital, and it was the center of reference for all of France for babies born with ambiguous genitals. And I was actually literally shocked by the way decisions were made on these patients. I felt it didn't rely on solid scientific evidence. I mean, I'm a scientist, I'm a big believer of you can't just do things without being supported by evidence. In this case it was more like people would say it was just common sense—if the clitoris sticks out this much, you have to fix it. Or if the penis is really too small, it has to be bigger. Otherwise what life is this child going to have? And you know, I was never convinced by common sense. I kept asking, "How do you know?" There was no good answer to that. There were a lot of patients and it was always the same discussions. And it was mainly about clitoral reduction. So there were sexual politics there, too? Yes. I was reading at the time this book by Michel Foucault. He has book that's called Herculine Barbin. He basically tells the story of this girl who clearly has a large clitoris. She goes and gets sexually aroused as she sleeps in the bed of other girls, as it was normal for girls to do. She goes to this religious institution for girls until eventually someone finds out, and then it's a big scandal. She becomes a pariah, and she ends up committing suicide. I was reading that, I was pretty young, I was like 18. Defining normality has always been an obsession of mine. How do you define what's abnormal versus normal? I guess it's the philosophical roots of the French educational system. But why choose to study intersex questions for the rest of your career? My scientific inclination was excited by this because not only was it understanding a rare condition that makes people different, all of these social aspects, but also it has scientific implications in the basic biology of developing male or female. Always in biology, you want to look at the exception to understand the general. So understanding intersex individuals makes us understand how typical males and typical females do develop. So what has your research overall been able to say about sex development? We've identified new molecular mechanisms of sex determination. In particular we've discovered genes, such as WNT4, that's female-specific and not present in males, and that's sort of shifted the paradigm of making a male as just activation of a bunch of male genes. In fact it's probably more complicated. What we've shown is that making a male, yes, is activating some male genes, but it's also inhibiting some antimale genes. It's a much more complex network, a delicate dance between pro-male and antimale molecules. And these antimale molecules may be pro-female, though that's harder to prove. It sounds as if you are describing a shift from the prevailing view that female development is a default molecular pathway to active pro-male and antimale pathways. Are there also pro-female and antifemale pathways? Modern sex determination started at the end of the 1940s—1947—when the French physiologist Alfred Jost said it's the testis that is determining sex. Having a testis determines maleness, not having a testis determines femaleness. The ovary is not sex-determining. It will not influence the development of the external genitalia. Now in 1959 when the karyotype of Klinefelter [a male who is XXY] and Turner [a female who has one X] syndromes was discovered, it became clear that in humans it was the presence or the absence of the Y chromosome that's sex determining. Because all Klinefelters that have a Y are male, whereas Turners, who have no Y, are females. So it's not a dosage or the number of X's, it's really the presence or absence of the Y. So if you combine those two paradigms, you end up having a molecular basis that's likely to be a factor, a gene, that's a testis-determining factor, and that's the sex-determining gene. So the field based on that is really oriented towards findingtestis-determining factors. What we discovered, though, was not just pro-testis determining factors. There are a number of factors that are there, like WNT4, like DAX1, whose function is to counterbalance the male pathway. Why are genes such as WNT4 and others necessary for sex development? I don't know why it's necessary, but if they're doing this then probably they're here to do some fine-tuning at the molecular level. But these antimale genes may be responsible for the development of the ovary. And WNT4 is likely to be such a factor. It's an ovarian marker now, we know. But if you have an excess of WNT4, too much WNT4 in an XY, you're going to feminize the XY individual. Is the conceptual framework for sex determination changing, then, because of these discoveries? I think the frame has slightly changed in the sense that even though it's still considered that the ovary is the default pathway, it's not seen as the passive pathway. It's still "default" in the sense that if you don't have the Y chromosome, if you don't haveSRY, the ovary will develop. [SRY, or sex-determining region Y, encodes the so-called testis determining factor.] That's probably the new thing in the past 10 years, that there are genes that are essential to make a functioning ovary. That really has changed, and WNT4 is one of the reasons for it. What do you feel are your group's most important contributions to the sex biology field so far? The two things that we contributed was, one, to find the genes that are antimale, and reframing the view of the female pathway from passive to active. And the second thing is in the brain. We're the first ones to show that there were genes involved in brain sexual differentiation, making the brain either male or female, that were active completely independently from hormones. Those were probably our two main contributions. Do you think this difference in gene expression in the brain explains anything about gender identity? About identity, it says nothing [yet]. It might say something. So those genes are differentially expressed between males and females early during development. They're certainly good candidates to look at to be influencing gender identity, but they're just goodcandidates. At a recent international meeting to discuss management of people with genital and gonadal abnormalities, you successfully pushed for a change in nomenclature. Instead of using terms such as "hermaphrodite" or even "intersex," you recommended that the field use specific diagnoses under the term, "disorders of sex development." Why did you and other geneticists feel a nomenclature change was necessary? For the past 15 to 16 years now, there really has been an explosion in the genetic knowledge of sex determination. And the question being, how can we translate this genetic knowledge into clinical practice? So we said maybe we should have a fresh approach to this. The initial agenda was to have a nomenclature that was robust but flexible enough to incorporate new genetic knowledge. Then we realized there were other problems that were in fact not really genetic, but that genetics could actually answer them. Ultimately individuals who are intersex will each have their diagnosis with a genetic name. It's not going to be some big, all-encompassing category, like "male hermaphrodites." And that's much more scientific, it's much more individualized, if you will. It's much more medical. How did the conference participants respond to the proposal? The majority of health care professionals were very happy with it. There were some, there was a conservative side that said, "Why change something that was working?" There was significant minority dissent that was saying, "Why do we care?" Because it was working, for us it's an intellectual frame that has worked. So it required a little bit of education, saying, you know, it's important not only because it's more precise and it's more scientific, but also the patients would benefit from it by removing the word "hermaphrodite" and so forth. About the change to disorders of sex development, there was no issue at all in the group. Why is the medical emphasis of this new term problematic for some? The one piece in the nomenclature that remains highly controversial is the replacement of "intersex" with "disorders of sex development." And I'll say a few things about that. One is that intersex was big. Sometimes we wouldn't know who to include and who not to include. "Intersex" was vague and "disorders of sex development" at least is a very medical definition, so we know exactly what we're talking about. For instance, if there are chromosomal abnormalities, if you have a patient who is missing one X chromosome—Turner syndrome—or having an extra X—Klinefelter's syndrome—both those, now wedo include them in "disorders of sexual development." They're not ambiguous. They do belong in this large category of people with "medical problems," quote-unquote, of the reproductive system. So intersex was vague, DSD is not vague. What were some of the social issues you were trying to address? There was another issue with the old nomenclature, which was the actual word, "hermaphrodite." "Hermaphrodite" was perceived by adult intersex individuals as demeaning. It also had some sexual connotation that would attract a flurry of people who have all sorts of fetishes, and so the intersex community really wanted to get rid of the term. Cheryl Chase, executive director of the Intersex Society of North America (ISNA), said she has been promoting a nomenclature change for some time. Why? People like Cheryl would say intersex issues are not issues of gender identity, they are just issues of quality of life—whether early genital surgery was performed appropriately or not, and that's really what has impaired our quality of life. She and others at ISNA do support the change because of an interesting side effect—because it becomes a very medicalized definition, the medical science should apply. It should apply strongly. That means it's not as if now we're talking about something that's not a disorder, that is just a normal variant, a condition. If it's just a condition that's a normal condition, then there is no need for medical attention. So basically my point of view is really, let's separate the political from the medical, the science. There's a whole psychology to this, you know, the surgeons often are under the impression that there is this tiny, vocal minority of activists who just want to destroy their work. Intersex individuals are really distinct from, for instance, the gay and lesbian community that does not have any a priori medical issue, there is no difference in the development of any of the organs, or they don't need to see a doctor when they're a newborn. I think it's quite different. Sure, some intersex are gay or lesbians, but not all are. Why was it necessary for intersex individuals to take an activist stance at one time? Because otherwise nothing would have changed in the practice. Otherwise this consensus conference would just not have happened. It was really in response to activism. They put the problem on the table and it required, it really forced the medical community to address an issue that was rare enough not to be addressed. Some have called the new term a political setback, because it pathologizes what could be seen as normal human variation. First of all, we can call normal variants everything; we can call cancer a normal variant. Of course, it kills you in the end, but it is a normal variant. We can play with words like that, but for practical purposes these "normal variants" have a lot of health risks that require lots of visits to the doctor for a bunch of issues that intersex patients have: fertility issues, cancer issues (the testis inside the body can increase the risk of cancer), sexual health issues. So if you're to start going to the doctor a lot for your condition, you can call it a normal variant, but that's not really useful. You're calling it a normal variant for political purposes. I'm calling it a disorder because I want all the rules and the wisdom of modern medical practices to be applied to the intersex field. I don't want intersex to be an exception: To say, "Um, you know, it's not really a disease," so therefore [physicians] can do whatever they want. That's what has been driving this field, people saying, well, you know, we can experiment, it's a normal variant. There has been considerable controversy over whether surgeons should immediately make a decision about an infant's sex and quickly correct ambiguous genitalia. The consensus statement seems to promote a more cautious approach to surgery, while still assigning gender rapidly. What is your view? I'm saying intervene [with surgery] only if you've proven that intervention is actually of benefit to the patient. Not of benefit to the parent. Because you know that surgery is used a lot to help the parent psychologically. It's a quick fix, if you will. The child looks different, it's very distressing for everyone, and one way to make it go away is just to make the kid look like everyone else. And that's really psychological help for the parents. But that should not be a parameter for surgery. We're talking about psychological distress to the parents, and that should be treated appropriately by a psychologist or psychiatrist, but not by surgery of the child. Do you think this consensus statement will change the common practice of performing sex-assignment surgery early on? (laughing) Well, yes. See, the consensus statement is a house of cards. You build it once, and there's no one that really inhabits it; it can be destroyed. They're not guidelines. I think it will change, but it will require some additional work. One of the things I think should happen next is to have a few leading clinics actually apply all the consensus recommendations and then do studies showing whether they actually impact the health and the well-being of the patient. It's not easy to do, because some of the recommendations require money. Like saying, "We need a psychologist"—that's easier said than done. There's no funding for having a psychologist in all these clinics. So I think it will influence some things. For instance, the nomenclature will change. I get a lot of phone calls and e-mails from authors of major textbooks, they're going to change. Also from editors of journals who publish articles about intersex, so that's going to change. But will that change the general outcome of patients? I don't know. I hope so. I think it's a step in the right direction. Many physicians and geneticists look at intersex simply as a medical condition that should be addressed. You seem to take patients' social and political concerns very seriously, too. Why? I've always been interested in the fact that medicine is very normative, and reductionist—it reduces people to their pathologies….'' Medicine should be in the business of making people as a whole better, rather than just curing the disease. And anyway, I'm not the only one saying that. Actually, I always use cancer as an example. A lot of cancer doctors are very well aware of this. They're offering options that sometimes do not include treatment just because they're aware of the fact that the treatment would ruin the quality of life so much that it's just not worth it. How do you handle working in a field that is so volatile socially and politically? Everything that you do, people jump on and make claims about sexuality or gender. I interpret everything conservatively. You have to not make the mistake of overinterpreting anything. That's my way of trying to navigate that. You also have to be aware of the social sensibilities. You can't just have an autistic approach to it and say, I'm just going to ignore it completely. If you're aware of the social sensibilities, and if you don't overinterpret your data, you're in good shape. How do you stay aware and informed? Being part of ISNA is one way [as
a member of its medical advisory board]. It forces me to
listen to what the patients have to say, which is really not
part of the medical culture, at least in this field. The way
to assess the well-being of a patient is to really listen to
what the patient has to say. Differences
in sex development Sometimes the term Disorders of Sex Development is used, as is Variations in Sex Characteristics (VSC) or Diverse Sex Development. Some adults and young people with DSD prefer to use the term intersex. Why does DSD happen? You or your child may have sex chromosomes (bundles of genes) usually associated with being female (XX chromosomes) or usually associated with being male (XY chromosomes), but reproductive organs and genitals that may look different from usual. This happens because of a difference with your genes or how you respond to the sex hormones in your body, or both. It can be inherited, but there is often no clear reason why it happens. The most common times to find out that a person has a DSD are around the time of their birth or when they're a teenager. Types of DSDs There are many different types of DSD. Some examples are: Usual female pattern genes with genitals that look different to girls' genitals Some people have XX (usual female) chromosomes with ovaries and a womb, but their genitals may not look the same as many females. For example, they may have a more developed clitoris and their vagina may be closed. Doctors refer to this condition as 46,XX DSD. The most common cause is congenital adrenal hyperplasia (CAH). A person who has CAH lacks an enzyme (chemical substance) that their body needs to make the hormones cortisol and aldosterone. Without these hormones, their body produces more androgens (sex hormones that are naturally higher in males). If the child is female, the raised androgen levels before birth can cause their genitals to look different, such as a larger clitoris and a vagina that is not open in the usual place. CAH can also cause serious health issues, such as life-threatening kidney problems that need to be treated as soon as possible. Find more information and advice from the CAH support group. Genes usually seen in males with genitals that look the same as most girls' and some internal male structures Some people have XY (male) chromosomes, but their external genitals may develop in the usual way for girls or boys. Sometimes it's difficult at first to know whether their genitals are more similar to girls' or boys'. A person may have a womb and may also have testicles inside their body. Sometimes the testicles might not work properly. Doctors refer to this condition as 46,XY DSD. Many people with 46,XY DSD are boys born with the opening to pass urine towards the bottom of their penis or below it. For some, the scrotum appears separated into two smaller sacs, one on either side. Doctors call this peno-scrotal hypospadias and boys and men with this DSD can have either fully developed or partially developed testes. There are several causes of 46,XY DSD. One possible cause is androgen insensitivity syndrome (AIS), where the body "ignores" androgens or is insensitive to them. Sometimes a person's body does not respond at all or only partly responds to androgens. Complete insensitivity to androgens makes a person with XY chromosomes female. Partial insensitivity to androgens can mean that some people are male and others are female. Find support and more information about AIS from DSD Families or the AIS Support Group. Ordinary looking genitals but different sex development Some people have a chromosome pattern other than the usual XY or XX. They may have one X chromosome (XO), or they may have an extra chromosome (XXY). Their internal and external sex organs can be either male or female, but they may not go through a full physical development at puberty. For example, a child with female sex organs may not start having periods. Doctors call this sex chromosome DSD. One type is Klinefelter syndrome, which is where a boy is born with an extra X chromosome (XXY). This can mean they do not produce the usual level of testosterone, the sex hormone responsible for the development of male characteristics, such as the testes and body hair. Testosterone is also important for bone strength and fertility in men. Find more information and support about Klinefelter syndrome. Another example of this type of DSD is Turner syndrome, which is where a girl is born with a missing X chromosome. Girls and women with Turner syndrome are often infertile and their height may be shorter than average. Find support and more information about Turner Syndrome. Female with usual external genitals, but without a womb Some females are born with an underdeveloped womb or without a womb, cervix and upper vagina. The ovaries and external genitalia look the same as most girls and women and they develop breasts and pubic hair as they get older. This is called Rokitansky syndrome. It's also known as Mayer-Rokitansky-Küster-Hauser (MRKH syndrome). The cause is not clear, but girls and women with Rokitansky syndrome/MRKH have XX chromosomes. Often the first sign of Rokitansky syndrome is that a girl does not start having periods. Sex involving the vagina may also be difficult because the vagina may be shorter than most women's. Not having a womb means that a woman cannot become pregnant, but it's sometimes possible to take eggs from their ovaries, fertilise them, and implant them in another woman's womb (surrogacy). For support and more information about Rokitansky syndrome at: Sex characteristics usually seen in males or females Some people with a very rare type of DSD have both ovarian and testicular tissue (sometimes one ovary and one testis). Their genitals may appear female or male or could look different from either. Most people with this type of DSD have XX (female) chromosomes. The cause is not usually clear, but some people with the condition have been found to have genetic material that's usually seen on the Y chromosome appearing on their X chromosome. Doctors refer to this condition as 46,XX ovotesticular DSD. What happens after the birth of a baby Sometimes doctors check a baby for DSD soon after birth because of signs such as undescended testicles or if a baby's genitals look different. Tests may be done to help get a clear diagnosis and find out whether any immediate treatment is needed. Tests may include:
Your care team may advise you to delay registering your child's birth for a few days until the tests are complete, you have discussed the results with your child's care team and the sex of your baby is established or decided. Many forms of DSD do not require any medical care other than understanding the baby's development and knowing what to expect as they grow older. A specialist nurse in your care team can help you learn about DSD and a psychologist will help you address any concerns you have. You can find more information about what happens when your baby is born with genitals that look different in the First Days leaflet from DSD Families. Advice for parents of older children Sometimes a DSD may be diagnosed if an older child does not go through puberty properly. For example, your child may not start showing the changes linked with puberty, or they may start puberty but not have periods. Speak to a GP if you have any concerns about your child's development at puberty. They can refer your child to a specialist. This will usually be a consultant paediatric endocrinologist, who specialises in hormones, or an adolescent gynaecologist. A team of specialist healthcare professionals will work with you to understand your child's condition and offer you and your child support and advice. A psychologist in the team can talk with you or your child about sexuality, relationships and body image among other subjects. Some people with DSD may need hormone therapy and psychological support. Some may want to think about altering their existing genitals, for example by using vaginal stretch techniques. Some people with DSD consider altering the appearance of their genitals by having surgery. If you think you have a DSD If you think or know you have a DSD, information and support is available. Speak to a GP, as they'll be able to refer you to a team of specialist healthcare professionals. They can answer your questions, help you stay healthy and put you in touch with others with DSD if that's something you're interested in. Most people with a DSD stay with the gender linked to their sex at birth, which is the sex on their birth certificate. But if your legal sex does not represent who you are or how you identify, you may want to discuss your options with your care team. If you have a DSD and want to explore parenthood, you can also discuss this with your specialist care team. Where to get support If you have a DSD or you're the parent of a child with a DSD, you may find it useful to contact a group involving others with the same or similar experiences. These groups can often offer more information and advice about living with a DSD, and may be able to put you in contact with others who've been in a similar situation to you. You are welcome to ask your care team about people with experience of your diagnosis in your local area who are happy to be contacted. Information: National DSD support groups include: Congenital Adrenal Hyperplasia Support Group Source: www.nhs.uk/conditions/differences-in-sex-development/ Ambiguous genitalia is a rare condition in which an infant's external genitals don't appear to be clearly either male or female. In a baby with ambiguous genitalia, the genitals may be incompletely developed or the baby may have characteristics of both sexes. The external sex organs may not match the internal sex organs or genetic sex. Ambiguous genitalia isn't a disease, it's a disorder of sex development. Usually, ambiguous genitalia is obvious at or shortly after birth, and it can be very distressing for families. Your medical team will look for the cause of ambiguous genitalia and provide information and counseling that can help guide decisions about your baby's gender and any necessary treatment. Symptoms Your medical team will likely be the first to recognize ambiguous genitalia soon after your baby is born. Occasionally, ambiguous genitalia may be suspected before birth (prenatally). Characteristics can vary in severity, depending on when during genital development the problem occurred and the cause of the disorder. Babies who are genetically female (with two X chromosomes) may have:
Babies who are genetically male (with one X and one Y chromosome) may have:
Causes Ambiguous genitalia primarily occurs when hormone abnormalities during pregnancy interrupt or disturb the fetus's developing sex organs. How sex organs form in the womb A baby's genetic sex is established at conception, based on the sex chromosomes. The mother's egg contains an X chromosome, and the father's sperm contains either an X or a Y chromosome. A baby who inherits the X chromosome from the father is a genetic female (two X chromosomes). A baby who inherits the Y chromosome from the father is a genetic male (one X and one Y chromosome). Male and female sex organs develop from the same tissue. Whether this tissue becomes male organs or female organs depends on the chromosomes and the presence or absence of male hormones.
Occasionally, a chromosomal abnormality may make determination of genetic sex complex. How ambiguous genitalia occurs A disruption of the steps that determine sex can result in a mismatch between the appearance of the external genitals and the internal sex organs or the genetic sex (XX or XY).
Possible causes in genetic females Causes of ambiguous genitalia in a genetic female may include:
Possible causes in genetic males Causes of ambiguous genitalia in a genetic male may include:
Ambiguous genitalia can also be a feature of certain rare, complex syndromes that affect many organ systems. Risk factors Family history may play a role in the development of ambiguous genitalia, because many disorders of sex development result from genetic abnormalities that can be inherited. Possible risk factors for ambiguous genitalia include a family history of:
If your family has a history of these risk factors, consider seeking medical advice before trying to conceive. You may also benefit from genetic counseling. Complications Complications of ambiguous genitalia may include: Infertility. Whether people with ambiguous genitalia can have children depends on the specific diagnosis. For example, genetic females with congenital adrenal hyperplasia usually can get pregnant if they so choose. Increased risk of certain cancers.
Some disorders of sex development are associated with an
increased risk of certain types of cancer. When Your Baby’s Sex Is
Determined For some parents, it’s one of the most exciting parts of being pregnant: finding out your baby’s sex. But what, exactly, decides a baby’s sex, and how does it all develop? Here’s your primer to what’s known as fetal sexual differentiation during pregnancy. When is baby’s sex determined? Sex is determined at conception by the combination of X and Y sex chromosomes a baby receives from the egg and the sperm. All eggs contain one X chromosome, while sperm contain either an X chromosome or a Y chromosome. Embryos with XY chromosomes develop male sex organs, while those with XX chromosomes develop female sex organs. That means the sperm determines a baby’s sex! There are 70 different genes located on the sex chromosomes that define a baby’s sex. Throughout pregnancy, exposure to hormones decided by your baby’s genes affect a baby’s anatomy, physiology and even behavior. What sex do you start as in the womb? Up until about week 7 to week 8 of pregnancy, both sexes have what’s known as a “genital ridge” — i.e. an identical preliminary set of genitalia that will eventually differentiate to become either male or female sex organs. That means that our sex organs come from the same foundations: The testes in men are equivalent to labia and ovaries in women, and the penis is the equivalent of the clitoris. When does an embryo become male or female? Between week 7 and week 12 of pregnancy, the foundations of your baby’s sex organs develop. Male sex If it weren’t for the male hormone testosterone, all babies would develop female sex organs. At around week 7, male genitalia begin to develop when the Y chromosome signals for the start of testosterone production. At about week 9, a baby boy’s genitals begin the process of becoming male. The genital ridge starts lengthening to form the penis. The penis and clitoris, however, actually remain the same size until about 14 weeks. In a baby boy, buds that will become the prostate appear at around 10 weeks, and his urinary system is fully formed by about 14 weeks. Peak concentrations of testosterone in your baby boy’s body are comparable to the amounts found in adult men at around week 16 of pregnancy! Between 16 and 20 weeks, testosterone levels fall until they reach the range found in early puberty by about 24 weeks. The testicles will begin descending in week 26, while baby’s penis grows the most during the third trimester. Female sex In girls, the ovaries will first appear around weeks 11 to 12 of pregnancy. And by about week 20, a baby girl will have somewhere near 7 million primitive eggs. That eye-popping number will eventually whittle down to about 2 million by the time she’s born. At 22 weeks, the vagina opens on the surface of the perineum. When can you tell the sex of a baby? At around 18 to 22 weeks of pregnancy, a level 2 anatomy ultrasound can commonly determine whether a baby is male or female by looking for a penis, although technicians do occasionally make the wrong call. They can mistake an umbilical cord for a penis, or sometimes a penis isn’t visible because it’s pushed between the baby’s closed legs. An ultrasound done at 13 weeks — usually as part of the nuchal translucency screening — can also give a very good clue as to your baby's sex. You can find out even earlier at around week 10 of pregnancy if your practitioner recommends noninvasive prenatal testing (NIPT), a screening that analyzes fetal DNA from your baby’s placenta floating in your blood. It can very accurately determine a baby’s sex, though it’s not 100 percent precise. The only way to know your baby’s sex for sure before birth is with a more intensive diagnostic test like amniocentesis or chorionic villus sampling (CVS), which look at your baby’s own DNA. How many people are born intersex (male and female sex characteristics)? About one in every 1,000 babies are born with noticeably atypical genitalia that’s considered “intersex.” An intersex baby may appear female on the outside with mostly male anatomy in the inside, or with genitals that are mix of male and female types (for example, a girl born with a very large clitoris or a boy with a very small penis). Intersexuality can stem from a range of factors, and in some cases the cause is unknown. The most common cause is not having a clear pair of XY or XX chromosomes. Rare disorders such as Turner syndrome, Klinefelter syndrome and androgen insensitivity syndrome are among numerous other causes. NIPT, amniocentesis and CVS can detect common genetic sex chromosome conditions like these in utero. Some research suggests that more babies — about 1.7 percent — are born with one or more intersex traits, meaning they have hormones, sex chromosomes or genitalia that don’t fit the precise definition of male or female. This uses a much wider definition that incorporates the wide biological diversity seen in the sexes. Most variations are found at birth, but because they can be very subtle, people can discover they’re intersex during puberty (when they develop differently than expected) or even much later in life. Asking about your baby’s sex is one of the top queries you’ll get from family and friends throughout your pregnancy. It might be one of the answers you’d most like to know yourself — or maybe you don’t really care! Either way, if you’re only a few weeks into your pregnancy, you can tell them that it’s all the same in that region … at least for now. From the What to Expect editorial team
and Heidi Murkoff, author of What to Expect When You're
Expecting. What to Expect follows strict reporting
guidelines and uses only credible sources, such as
peer-reviewed studies, academic research institutions and
highly respected health organizations. Learn how we keep our
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Women Than Expected Are Genetically Men -
10/25/16 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 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.” 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. Gender:
When the body and brain disagree - 7/31/15 First of two parts In November 2014, Zoë MacGregor celebrated her 13th birthday. Like any teen might, she invited a friend to her house for a sleepover. They ordered pizza, had brownies and ice cream for dessert, then watched a movie. The Seattle-native’s journey to becoming a teen had been very different from that of many of her friends, however. Until she was 9, the girl had lived as Ian — a boy. But by spring 2011, Zoë recalls, “I was starting to feel more and more like I was not quite boy, but sort of both.” Eventually it hit Zoë that she was neither a boy nor a hybrid of two genders. “No,” she realized, “I’m a girl.” Doctors refer to people who feel that they belong to the opposite sex from the one they were assigned at birth as transgender individuals. (The term comes from the Latin, where trans- means “on the far side.”) One week before the end of third grade, Zoë announced her social transition at school. In this case, transition described the start of a process to make outward signs of gender match one’s inner identity. For transgender children and youth, this social transition usually involves changing one’s name, hairstyle and choice of clothes. As a first big step in this process, Zoë reintroduced herself to her classmates. “I didn’t ask them to start calling me Zoë. It was more like I said: ‘Now my name is Zoë.’” Roughly a year later, her parents legally changed her name. At 13, she now has a hard time recalling what life was like before her transition. But her identification as a girl started much earlier. Zoë was 4 when she first asked for a dress. Her mom, Carolyn MacGregor, remembers agreeing — hesitantly — but didn’t promise to buy one right away. “It was the third time she asked when I thought, ‘I really need to not put this off.’” The next day, the two went to a store and picked out a few dresses. Zoë put one on as soon as she got home. Within a few minutes, a sitter arrived to watch Zoë and her younger sister. Before Carolyn knew it, her two kids and the sitter headed out the door to a park. Zoë was still wearing the dress. “At that moment, I realized it wasn’t just for dress-up. She wanted a dress as part of her clothing,” Carolyn says of Zoë. Looking back, she adds, “It was something [Zoë] quickly integrated into her everyday life. It wasn’t, ‘I’m going to go play dress-up.’ I never felt like it was something that was just a role.” Today, Zoë is an otherwise typical eighth-grader. The teen loves to read and she plays percussion. At school, her favorite subject is art. She enjoys an after-school club where she plays the popular video game Minecraft. Outspoken and confident, she says it’s important that people understand that being transgender isn’t really a “choice.” Instead, she explains, “It’s more like a realization that you are that different gender.” Sex. Gender. What’s the difference? Although many people use the terms sex and gender interchangeably, they mean quite different things. Indeed, sex and gender don’t necessarily agree. That’s how it is in Zoë’s case. Gender is based on culturally accepted norms — attitudes or behaviors that are typical for males or females. Gender identity has to do instead with our inner sense of who we are. People often express their gender identity by how they dress or behave. Meanwhile, sex is determined at conception by the genes each of us inherits from mom and dad. It may become visible by ultrasound several months into pregnancy. Chromosomes hold genes. They’re the tiny pieces of DNA that tell our cells what to do. Humans have 23 pairs of chromosomes. One pair consists of sex chromosomes . They come in two forms: X’s and Y’s. Women have two X’s. So when they share half of each pair of chromosomes with their offspring, the sex chromosome they offer will always be an X. Men have an X and a Y. So if dad shares an X chromosome with his child, it will make a girl (XX). If he shares a Y chromosome, the child will be male (XY). Or at least, that’s usually the case. When it comes to sex, researchers have learned that biology can be more complicated than just ‘boy’ or ‘girl.’ For instance, some people carry two X chromosomes mixed with a fragment of a Y chromosome. These people develop into what look to be males. That happens even though the presence of two X chromosomes means that they are female, at least biologically. It gets even more complicated when gender identity enters the picture. For more than 99 percent of the world’s population, gender identity and biological sex will agree. Such a person is called cisgender. (The Latin prefix cis- means “on the same side.”) But a small share of people experiences a mismatch between sex and gender. Some of these people grow up feeling like they aren’t the gender the rest of the world — including their parents and doctors — sees them as. This experience is called transgender. The term transgender is distinct from one’s sexual orientation, meaning whether a person is attracted to males or females. Transgender individuals may outwardly appear male or female. But for reasons that are still unclear, they feel like — and, eventually report knowing themselves to be — the opposite gender. Some may even identify a little bit with both genders. Untangling sex and gender During pregnancy, genetic factors influence the development of the embryo as it grows into a fetus. An XX person (girl) usually develops ovaries. An XY person (boy) will usually develop testes. In individuals with XY chromosomes, there is a gene on the arm of the Y chromosome, called SRY. This gene signals the development of testes. When an SRY is not present, an ovary will develop. That will then lead to development of the female anatomy. If testes develop, they will go on to produce the male hormone called testosterone (tess-TOSS-ter-own). This hormone instructs the body to make male genitals. It also leads to the development of bigger bones, a brain structure unique to males and other male physical characteristics. The basic biology behind how chromosomes and genes signal the body to take on a female or male anatomy has been known for a long time. Still, researchers are learning a great deal about how much more complex this sex determination is than they had originally thought. And researchers know far less about what drives gender. “To my knowledge, no studies have conclusively demonstrated where our sense of gender identity comes from,” says Kristina Olson. She works at the University of Washington in Seattle. As a developmental psychologist, Olson studies how people develop and change as they grow from infancy into adulthood. Some people have speculated that genes, the environment or hormone levels might play a role in influencing gender, Olson says. In fact, she says, “I know of no study showing one, the other or which combination makes gender.” For thousands of years, careful observers — namely, parents — have noticed that children at an early stage begin to strongly express a preference for certain toys, colors and clothing. Around this same early age, children also begin to express their gender identity. “What we know from typical gender development is that kids generally know and can say whether they’re a boy or a girl around age 2 or 3,” says Olson. By that same age, many transgender children also will express their gender identity. But in their case, it will differ from the expected, Olson says. “Most people find it shocking that a transgender kid could ‘know’ that they are or are not a particular gender so early,” she says. However, Olson’s research tells her that it makes complete sense that gender identity can show up at the same age in transgender and cisgender children. To better understand transgender kids In 2013, Olson and her colleagues launched the TransYouth Project. This long-term national program is studying the development of up to 200 transgender children between the ages of 3 and 12. The goal is to learn how their gender identity develops. For every transgender child, Olson’s team is including a cisgender child. That second child is called a control. Each pair of participants will be as alike as possible. For instance, if the transgender participant identifies as a boy, the control will be a boy. Both will be the same age. And both will come from families with similar incomes. When possible, the study also enrolls brothers and sisters. This will allow the researchers to compare how a family’s support and belief systems might affect the siblings. In an earlier study, Olson and her colleagues found that transgender children as young as 5 identified just as strongly with their expressed gender as cisgender kids did. That study also asked the participants, all aged 5 to 12, to link concepts related to their gender. For example, when given a list of words on a computer screen, someone might pair “me” and “female.” Findings from that study appeared April 5 in Psychological Science. Some research has suggested that transgender children may simply be confused about their gender identity, or wrong. New data imply this is not the case, Olson and her colleagues say. Nor are transgender children just engaging in imaginative play, her team adds. Boys, for instance, are not simply pretending to be girls, as other children might pretend to be a dinosaur or superhero. Olson plans to track kids taking part in the TransYouth Project through at least puberty — and, if funding continues, into adulthood. Along the way, her team’s data should uncover much about how transgender youth find their way through important stages in their development, from puberty to parenthood. Few good long-term data exist on transgender children, Olson says. That’s especially true for those who are fully supported by their family and community in expressing their identity. To fill in those missing data, Olson explains, “is a huge part of why I’m doing this study.” A complicated soup Researchers know little about how transgender people differ in their biological development, if at all, from cisgender individuals. Nor, as mentioned earlier, do scientists know where our sense of gender comes from. Studies of children who have been allowed to transition to the opposite gender are providing clues. As it turns out, the brain appears to play a bigger role in our identity than does anything else, says William Reiner. He is a child and adolescent psychiatrist. He works at the University of Oklahoma Health Sciences Center in Oklahoma City. Reiner studies young children and teens who transition to the opposite gender of what doctors had assigned them at birth (based on their apparent biological sex). Some of these children are transgender. Others may have experienced conditions in the womb that led their genitals to develop abnormally (see explainer below). This second situation can lead doctors to incorrectly interpret an individual’s biological sex. (This condition should not, however, be confused with transgender identity). If a boy is born with the genitals of a girl, for instance, a doctor may by accident assign the child to the wrong sex. As this boy grows up, his parents and doctor may realize the mistake. But just telling this child that he’s a girl won’t convince him that this is who he is. That’s because identity is determined internally, within the complex interactions among the 100 billion cells in his brain. The brain is a complicated soup of chemicals, Reiner points out. Somehow, he says, these chemicals add up to something whose “total is much larger than the sum of its parts.” Part of that sum is who we see ourselves as. Our identity. “And part of that,” he adds, “is whether we’re male and female.” The gender assigned to a newborn is based on what that baby’s body looks like. Yet that outward identity, while important, “is not the only part,” he says. By looking at someone’s body, or even mapping that person’s genes, “We can’t really answer the question of what identity is.” That, he says, remains hidden within the inner workings of our brain. A wide spectrum in animals Transgenderism is unique to humans. Yet research has turned up lots of variety within the sexual development and behavior of animals. Like people, animals exhibit behaviors typical of males and females. Still, many social and other behaviors in animals do not fit neatly into those categories, notes Paul Vasey. He works at the University of Lethbridge in Alberta, Canada. As a comparative psychologist, he studies how behaviors in humans and animals differ or appear the same. With such a wide range of differences
in sexual development and behaviors in the animal kingdom
(see Explainer: Male-female plasticity in animals), Vasey
says that it’s not surprising to see similar variation
among people too. “There’s a continuum,” he
concludes “— in both the animal kingdom and in
humans.”
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