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Dr. Charmian Quigley Writes to Greer

Paediatric endocrinologist, Dr. Charmian Quigley, an advisor to the US branch of our group (who has attended all the US group meetings) emailed Greer as follows:

Dear Professor Greer

I am a pediatric endocrinologist with a long standing interest in the Androgen Insensitivity Syndrome (AIS) and other intersex conditions. I completed 4 years of fellowship at the Laboratories for Reproductive Biology at the University of North Carolina in Chapel Hill, NC, USA, working exclusively on understanding the genetics and molecular biology of AIS. I have published a number of scientific papers and textbook chapters on the subject, including a major review in the most respected endocrinology periodical world-wide - Endocrine Reviews (I will gladly send you a reprint of this). At the present time I am in the process of completing an invited chapter for one of the prenier textbooks of endocrinology, De Groot's 'Endocrinology', on the subject of the genetic basis of sex determination and differentiation. I provide this information not to 'blow my own horn', but simply to preface my thoughts that follow, so that you are aware that I am qualified to discuss this subject with you. I speak as a scientist and clinician, not as a psychobiologist, so I will generally confine my discussion to the facts relating to sexual differentiation, as currently understood (this is a very dynamic field, so 'current' won't be so for long). I apologise in advance if I underestimate your medical and biological knowledge. However, I am assuming that your expertise is in the social sciences, rather than the biological.

In your recently published book 'The Whole Woman' in the chapter with the derogatory title of 'Pantomime Dames' you discuss the issue of whether women with AIS and other chromosomal variations are really entitled to be included as 'women' or regarded as 'female'.

Perhaps I misunderstand, but it appears from your words, although not explicitly stated, that you believe that 'female-ness' or 'womanhood' requires that for an individual to be worthy of this title she must have the following: 2 X chromosomes; no Y chromosome; 2 ovaries; one uterus; 2 fallopian tubes; one full-length vagina and one not-too-large clitoris (not sure of your feelings on breasts and sexual hair). In the following I will dissect these membership requirements, providing some medical examples that I hope will highlight the fallacy of these criteria.

You state: "Doctors are not bothering to establish the chromosomal sex of newborns but are judging according to impressionistic criteria whether the genital they are looking at is a clitoris or a penis and apportioning sex arbitrarily on the basis of this casual assessment. " and (facetiously) "From now on chromosomal sex is irrelevant."

First - chromosomal sex - what is the meaning of 'X'?. You place strong emphasis on the presence of 'normal' (for which I would substitute 'usual') chromosomes - that is 44 autosomes and 2 X chromosomes. But what is an 'X'? And why should 2 Xes be a requirement for membership of the 'female' club? A chromosome is simply a collection of genes strung end-to-end and wound up in a long strand. The chromosome itself has essentially no function, it is simply the structure that is visible under a microscope. Furthermore, the genes carried on the chromosome can move from one chromosome to another by a process known as 'recombination'. Thus, for example, genes that normally inhabit chromosome 9, can 'translocate' with genes that generally reside on chromosome 11. Similarly, genes that usually reside on the X, can switch places with genes that usually reside on the Y, and vice versa. By this means, the gene that is responsible for the development of the testis during fetal develoment (called the SRY gene), can be transposed onto the X chromosome . Thus a fetus with two X chromosomes can develop testes and a penis of 'normal' dimensions and undergo entirely 'normal' male puberty (although he will be sterile, as are many 46,XY males). This condition is referred to as 'XX male'. Indeed these individuals are male and should not be regarded as anything but male. So the presence of two X chromosomes can not be regarded as a priori evidence for 'female-ness'. Indeed I contend, as you stated, that 'chromosomal sex IS irrelevant'.

Next - the genes. In the paragraph above, I referred to the situation in which a male develops despite the fact that there is no Y chromosome. The converse can also occur. Thus, a fetus with a 46,XY chromosome constitution may lose the gene that is responsible for testis development. Since the 'testis-determining' gene is gone (deleted), testes do not develop. (Note also that the testis and the ovary are derived from exactly the same precursor tissues and are identical for the first six weeks of fetal life. It is simply the action of one set of proteins versus another that results in development of one type of gonad or the other, whether or not the fetus has an XX or XY endowment. ) So the individual with an SRY deletion develops (sub-functional) ovaries, normal Fallopian tubes, uterus, vagina and 'normal' female genitalia which show absolutely NO evidence of masculinization. This individual will be infertile (as are many 'normal' 46,XX women), but nevertheless has all the equipment required for 'normal' female sexual function and carriage of a pregnancy. Is this person male? Not in my view. The only feature of this woman's portfolio that would keep her out of the club, is the presence of her Y chromosome, even though that chromosome happens to be missing the one gene that is the hallmark of maleness, the SRY gene. So, perhaps we could make an exception for this woman and allow her membership of the club, since nature fortuitously removed the offending 'maleness' gene. Indeed I contend that this woman is as female as you or I, despite the presence of a Y chromosome.

To carry this one step further, I need to explain a little about genetics (please excuse me if this appears condescending - I am asuming, again, that you do not have a genetics or molecular biology background). The human genome contains 3 million genes which are all made up of arrangements of 4 'bases' as they are known - adenine, guanine, thymidine and cytosine. Like chromosomes, genes themselves don't really have any intrinsic function. They are primarily just the repository for the instructions that the cell machinery needs to make a particular protein. The whole genome is constantly undergoing the process of 'mutation'. Despite the negative connotations, mutation is simply the replacement of one 'base' with another during DNA replication. So a cytosine gets replaced by a thymidine, for example. We all carry many mutations around in our own personal genome, contributing to who we are and how we function. Such things as eye color, height, risk of breast cancer, the way a certain enzyme works etc. are all the result of variations in the arrangement of the bases. As the bases alter, the 'code' for the amino acid sequence of a protein alters, so that the protein contains one different amino acid of the hundreds that make up the protein. This small change can alter the function of the protein either quite subtly, or very drastically. Why is this relevant? The simple change of a base, and thereby alteration of the protein it codes for, can completely wipe out the function of the protein. In the situation above, in which a 46,XY fetus loses the SRY gene and therefore develops as a female, I described a complete loss of the gene. But the exact same outcome can occur simply due to the change of one single base in the SRY gene. I used this example in a lecture I gave to an undergrad biology class, entitled 'Sex and the Single Base Mutation'. The point here is that whether the SRY gene is completely deleted or simply emasculated by a single base change, the outcome is an entirely female individual who just happens to have a Y chromosome.

So, assuming you accept my contention that the chromosomes are indeed irrelevant, what DOES it take to make a female? Or, as you put it . . . . "The possibility that men know as little about how to be a man as she does is worth exploring, more interesting to a feminist is what M_____ thinks being a man involves and how she knows that she is 'being' a woman." Indeed, what does it take to 'be' a man or a woman? I suggest that it is not the chromosome complement, the genes carried on them, the proteins that are encoded by those genes, the anatomy that develops due to the function of those proteins, the type of gonadal tissue, or the levels of hormones. Although I am a clinician and a scientist and have no expertise in psychology or psychobiology, I would contend that 'being' a man or a woman can NOT be simply ascribed to chromosomes or anatomy or hormones, but is the result of the complex interaction of all of these things in the context of family, peers and society as a whole.

Turning specifically to the subject of AIS, I would like to share a number of personal observations, based on my intimate knowledge, as a physician, of the genetics, molecular biology, anatomy, physiology and psychology of the many girls and women with AIS for whom I have cared over the years. You state: "In most cases of AIS the newborn child has been mistakenly identified as female and raised as female", and ". . . AIS as the story of women with men's genes." and "she was not a woman but a failed male who may pass for a female . . . . she was wrongly identified at birth as a female. " and "AIS males ... live as spurious females. "

Infants with AIS are not 'mistakenly' identified as female, and AIS individuals are not "males" living as "spurious females". They are correctly identified and raised as female, and live and function as the females they are in adulthood. I should take a moment to clarify some confusion that may exist. AIS is a condition - or rather - a collection of conditions - that results from mutations in a gene, called the AR gene, carried on that infamous X chromosome. The AR gene codes for a protein called the androgen receptor (AR). This protein is required for cells to be able to respond to male hormones - testosterone and a bunch of others. When the AR is completely missing or non-functional, the individual has absolutely no ability to respond to male hormones, so much so that the clitoris is smaller than usual, and no pubic or axillary hair develop, since these features in 'normal' 46,XX women result from the female body's normal response to normal female levels of male hormones. Women with this condition, called Complete AIS, were originally termed 'superfemale' since they really are physically the farthest from male it is possible to be. You may also be interested to know that the testes of these women also function to support the development of the 'superfemale' body, by producing high levels of the quintessential 'female' hormones - estrogens. There are other degrees of AIS, called partial AIS (or PAIS), in which the receptor protein is able to work to some extent, so some degree of male hormone action is possible, as it is in 'normal' 46,XX women. Most of the girls and women in this group have genital development that is closer to that of the 'normal' woman - i.e. a clitoris develops and pubic and axillary hair grow at puberty. Yes, these women have a Y chromosome, and therefore developed testes during fetal life, but far from believing that "AIS 'females' have no female organs and not a female cell in their bodies." I would assert that indeed every cell in their bodies is female, and probably more so than yours or mine, since their cells basically 'lock out' any male influence, refusing to respond to male hormones.

As a pediatric endocrinologist, I have had the experience of caring for infants with a wide range of variations in sexual development. Let me contrast for you a newborn with AIS and one with a severe form of a condition called congenital adrenal hyperplasia (CAH) in which the fetal adrenal glands produce 'superman' levels of testosterone due to a genetic mutation that alters the function of an enzyme in the adrenal gland. The newborn baby with CAIS has a 46,XY karyotype (chromosome complement) but has labia major and minora that are indistinguishable from those of any other little girl. Her clitoris is small - maybe just a few mm long, her vagina is short and ends blindly, with no uterus attached. In her abdomen or pelvis she has two testes that are pumping out a bucketload of estrogen. In the bed next to her is an infant with severe, virilizing CAH. She has a 46,XX karyotype, but you wouldn't know it to look at her. She has a scrotum and a 5 cm penis with the meatus (opening) right at the end, just like the penis of the infant boy in the next crib. However, internally she has a uterus and tubes and ovaries. But her adrenal glands are massive and are pumping out bucketloads of testosterone. Which child is which? And which "sex" or "gender" should each live in? Your definition of 'female' on the basis of chromosomes and anatomy simply can not hold here.

Lest you gain the impression that I am entirely contrary, I should mention my agreement with your statements:

"This implies a curious attitude to females as simply bodies with clefts in for the accommodation of a penis." and " . . . . the Freudian stereotype of women as incomplete beings defined by their lack of a penis." I agree that in certain cases of intersex, in which the genitalia are partially masculinized (such as in cases of 'mild' Partial AIS) there indeed has been a tendency to follow this line of thinking. The standard practice for sex assignment of infants with severe degrees of undermasulinization has been to rear them as female and surgically 'correct' the genitalia to make them look more 'feminine' . This practice was, I believe, based on a disgraceful premise propagated by a surgeon who shall remain nameless, that states "It's easier to dig a hole than build a pole". Infants with severely ambiguous genitalia are a hugely heart-wrenching and vexing challenge and the worlds of pediatric endocrinology and pediatric urology are currently undergoing a deep crisis as the care of these children is reevaluated. This area is the subject of two recent books which may be of interest to you: Kessler SJ: Lessons from the Intersexed, and Dreger AD: Hermaphrodites and the Medical Invention of Sex. I could write another 4 pages on this subject alone, but will refrain from doing so.

"In the meantime women will probably continue to accept as women all those who wish to be regarded as female, including AIS males and surgically altered males and XXY androgynes and single-X individuals." And why not? Why should we be exclusive, rather than inclusive.? Why should the 'female' club require that we all have the same chromosomes or the same anatomy, any more than we would require that we all have long, blonde hair, blue eyes and Monroesque curves? I do not pretend to know what makes me a woman. I just know that I am one. I have never doubted that for a minute, just as women with AIS or SRY mutations or Turner syndrome also know deep inside that they are women. It just 'is'. As a clinician I am faced with the task of trying to explain to parents or girls with AIS themselves, the nature of their condition in a way that does not erode their fundamental belief in their female-ness, but that nevertheless reveals the truth of their chromosomes and testes. I generally approach this by explaining that although MOST girls and women have 2 X chromosomes, there are some who do not. Although in the minority, they are not alone. So some girls have only one X chromosome, some have one-and-a-bit, and some have an X and a Y (actually, genetically speaking, the Y chromosome is just a degenerate X chromosome that has lost a number of its genes over the millenia. It began as an X in our biological forebears, but just lost bits of itself as time went by. The "Y" designation is just the natural flow-on from "X", but we could equally well call it "mini-X" or some such diminutive term). Similarly, although MOST girls and women have ovaries, there are some who do not. Girls/women with Turner syndrome have a fibrous 'streak' in place of an ovary; girls/women with AIS have a testis in place of an ovary (if it was not removed in infancy). These girls are not freaks or 'damaged males', they are simply part of nature's genetic variation.

I will close by commenting on one further item from your chapter:

"We need to be sure that their being classified as female is not a reflection of a refusal on the part of entire males to recognize these damaged males as belonging to their sex. Cruel and unsympathetic though it may seem, women should not automatically accept all those who do not wish to be male as being ex gratia females." I think it is important to highlight that girls and women with AIS or Turner syndrome or SRY mutations do not 'wish' to be anything, either males or females. They simply 'are' females. There is nothing voluntary about their state. The issue is not one of a 'damaged male' being the same state as being a female. These individuals were never male, not even 'biologically male' (after all, given the above examples, what is the definition of 'biologic maleness' - even I, as a molecular biologist, can not define this). And, most importantly, these girls and women are not 'damaged' in any way. I have many other medical examples and opinions I could share, but feel I have gone on long enough in this initial correspondence. I would be happy to share further thoughts and perspectives if you would be interested to do so.

Respectfully,

Charmian A. Quigley. MBBS, FRACP
Pediatric Endocrinologist


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