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New Treatments for Disorders of Sexual Differentiation

This is an individual who has gonadal dysgenesis, by definition, this is gonadal dysgenesis, the gonad has not differentiated into an ovary or a testes, although it certainly looks more like hermaphrodite, testicular feminization syndrome, but because there are no germ cell, there is going to be no hormone production so at the time of puberty, no estrogen will be produced, there will be no formation of the secondary sexual characteristics, obviously this individual will be infertile because there are no germ cells here from which to produce an oocyte.

In addition there is no development of second sexual characteristics, no breast development, no pubic hair, and you can see the somewhat abnormal positioning of the arms as well. Other examples of the phenotype, this is an infant who has neck webbing again residua of the in utero cystic hygroma and there is some edema in the hands that are typical. This is an x-ray of the hand of a 45X individual and what we are pointing at here is the short fourth metacarpal, and I donít know why that is associated with 45X but it is. This is a picture of comparing the fetal gonads of a 45X fetus and a normal fetus, just to show that they both have germ cells at this stage of development, so itís not that the germ cells donít develop normally, but they undergo an accelerated atresia so that by the time of puberty, there are virtually no germ cells left.

The next category are female pseudohermaphrodites which are those individual with a 46XX karyotype that donít differentiate normally as normal females. So one example might be in the nursery, you have a baby and you see ambiguous genitalia, and you canít tell by looking at this whether this is a boy or a girl in terms of the sex you are ultimately want to rear this child in, and you certainly canít predict what the chromosomes are from looking at this genitalia. So the first thing we are always going to do in this situation is draw blood for chromosome studies, and we are also going to start thinking about what could have caused this, what are the possibilities. The most common possibility is a defect in the pathway for production of leukocorticoids, no adrenal hyperplasia syndrome. This is the system that goes from acetating cholesterol.

Another reason why a female fetus might not develop as expected for a normal female might be born with virilization is if she has been exposed to high levels of testosterone or one of the testosterone products. We talked about that earlier this afternoon and in most cases, I think we avoid all these agents, to this is a very infrequent problem. Males pseudohermaphrodites are 46XY individuals who donít develop as expected for normal males. Here again, the fetus or infant may have abnormal genitalia, and again, this is not clearly male or female and there are a variety of different causes for this. One cause is mosaicism 45X, 46XY so that for example, the initial conceptus is 46XY but during the course of cell division, Y chromosome is lost in one of the early cell lines and some of the cells have 45X and some of them have a normal chromosome.

This is a woman who has a 46XY karyotype and in fact the androgen insensitivity syndrome, the old name for it is testicular feminization. As you can see, she is differentiated as a female, she does not have Turner syndrome stigmata. She has development of secondary sexual characteristics, but whatís missing here is pubic and axillary hair. Her tissue that should be responsive to androgen are not responsive to androgen, so she has testes.

Finally, true hermaphrodites are individuals who have both testicular and ovarian tissue and their phenotype is very confusing. They have ambiguous genitalia many times, although the time of puberty, they frequently feminize because their ovarian structure will start producing estrogens and the breast tissue will respond so that they may have been raised as males if their genitalia looked appropriate and yet at puberty, they may start having menstrual bleeding because they frequently have a uterus or of not menstrual bleeding, they may have cyclic hematuria if there is some connection between the müllerian duct structures and the male urethra. This is a picture of the gonadal structures in a true hermaphrodite. By definition, there have to be germ cells from both ovaries and testes. These can be arranged either as a separate ovary and a separate testes on opposite sides of the body or they can be combined as one or two oval testes. Treatment of course involves removal of the wrong type of tissue which in general involves removal of testicular tissue because itís going to be easier to reconstruct as a female than as a functional male. In addition, many of these individuals are able to function as females in terms of having a uterus, having menstrual cycles and in fact, there are a number of pregnancies reported in true hermaphrodite. Gonadal neoplasia is rare but again, unless they are being continued as a male and the testes are being brought down into the inguinal area into a scrotum, they need to have their testicular tissue removed.

The genetic explanation for true hermaphrodite is very hard to come up with because you can see there are a variety of different karyotypes that go along with being a true hermaphrodite and there is not some obvious chromosome abnormality. Most of them look like normal 46XX karyotypes, and yet somehow in the absence of the Y chromosome, they have developed testicular tissue. One reason again may be transfer of the SRY gene onto and X chromosome or to one of autosomes, but for most of them, there is probably some other more complicated explanation related to mutation of one of the other genes that somehow activated itself independently of the presence of SRY and has produced testicular tissue when that gonad should not have.