In 1990, it was found that a gene consisting of 79 amino acids, which is a sex-determining factor, exists in the short arm of the Y chromosome. During the next 20 years, there has been a rapid progress in the understanding of sex differentiation mechanism. A major factor of this progress is the existence of various disorders of sex development. As of today, genetic mutations have been found in more than 70 disorders of sex development.

The progress in gene analysis technology has found gene responsible not only for the disorders of sex development, but also for many other diseases. It is not too much to say that during the last 20 years, understanding the mechanism of sex development has been advanced as a result of medical researchers, including clinicians, making a tremendous effort to track disease-causing genes. As the society has started to think about the QOL (quality of life), people also began to turn their attention toward the QOL of refractory disease patients.

Although specialists have been aware for a long time that there were many problems regarding the QOL of patient with disorders of sex development, these specialists have been conducting their treatments individually based on limited experience, since the cause of the disorders were unknown and they had to seek in the dark. The Japanese Society for Pediatric Endocrinology launched a sex development committee 5 years ago to address this issue head on.

Human sexuality is based on the sex of chromosomes (XX, YY), sex of gonads (ovary, testis), sex of genitals, societal sex (on the family register), and sex of the brain. A typical male has 46 and XY chromosomes, possesses testis, vas deferens and penis, is listed as a male in the family register, and recognizes himself as a male. However, there are various chromosomal karyotypes such as XX/XY mosaic, XO, XXY, and XYY. Gonads are still undifferentiated in the 6th week of embryonic life and can be differentiated either into ovaries or testes, thus there are individuals who have both ovaries and testes. The mullerian duct becomes differentiated into fallopian tubes and uterus to form female internal genitalia, and the wolffian duct becomes differentiated into epidymis, seminal vesicle and vas deferens to form male internal genitalia. An embryo in the 6th week of embryonic life possesses both mullerian and wolffian ducts. In the 8th week of embryonic life, all of the external genitalia resemble the female type.

In such a way, sex is not wholly determined at the time of conception, and both sexes coexist until the 6th week of embryonic life. The differentiation of sex normally begins from the 7th week and progresses, until it is almost completed by the 12th week. Many genes and hormones are at work in a complex way during this process, and differentiation into a typical male or female occur by manifestation of the appropriate genes and secretion of the appropriate hormones at the appropriate period. However, differentiation is impeded if part of the above is incomplete or the manifestation period is different, and turns into disorders of sex development. Rather than being considered as disorders that deviated from male or female, disorders of sex development are considered to be disorders that are in midway between the sexes.

On the other hand, hardly anything is known on the sex differentiation mechanism of the brain. It is thought that in a male fetus, brain virilization occurs when secretion of male hormones increase during the 20th to 25th weeks of fetal life and the brain is exposed to male hormones (androgen shower). However, it can be easily imagined that sex development of the brain is not that simple.

In 2006, an international symposium on sex development abnormalities was held with the participation of pediatric endocrinology specialists from around the world. There, it was proposed that terms such as intersex, intersexuality (hermaphroditism), pseudohermaphroditism, etc. be unified as Disorders of Sex Development (DSD), and DSD were defined as “congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical.” Moreover, the Japanese Society for Pediatric Endocrinology approved the revision of the term “abnormal sexual development” to “disorders of sex development” in 2009.

It should be noted that disorders of sex development do not include those of the brain which do not meet the above definition, in other words, disorders such as gender identity disorders. As you can see from the above history, we are at a stage in which comprehensive support of patient with disorders of sex development will be starting from now.

From a personal point of view, I would like to describe the issues that we must deal with in the future as follows.

Dealing with disorders of sex development starts when the obstetrician or midwife suspects the existence of such disorders at the time of delivery. Even when there are disorders of sex development, the baby’s sex is automatically determined if there are no clear abnormalities in the external genitalia. There are many such disorders of sex development, and they are diagnosed as such during the patients’ childhood/puberty when they are medically examined due to low body height or lack of secondary sex characteristics development.

On the other hand, if disorders of sex development were suspected at birth, it is an emergency, and it must be dealt with in a prompt and proper manner, but there are only a few medical institutions nationwide which are prepared with the support system. The pressing concern will be how it should be explained to the parents, as the determination of the sex will be the biggest interest to the family. The way it is explained could have a significant impact on the patient’s future child-care, nurturing and family life. I believe that it is necessary to make a manual for initial response and a compilation of terms that should not to be used for doctors who are not specialists of sex development.

Basically, I believe that the best way when disorders of sex development are suspected is to consult with specialized facilities promptly to seek directions and in most cases to transport the patient to the specialized facilities for subsequent management. Even if there are no specialized facilities nearby, the patient should be transferred as this should be considered a lifetime issue. This is because the disorders are hard to diagnose, determination of sex must be dealt with separately after diagnosing (sex cannot be decided by the name of the diagnosed disorder), assessment by specialists such as pediatric urologist is needed from the viewpoint of surgical therapy, assessment is needed on the effect of future medical therapy, a staff of specialists is needed to handle the psychological support of the parents, etc. As there isn’t much time legally for the family to determine the sex and the name, and since they are under an enormous psychological burden, it is extremely important that a staff of specialists from various fields deal with the situation under a unified opinion during the initial response.

Moreover, since it is necessary to develop a system to keep supporting the patients with disorders of sex development for a long term, there is a need to build a system by a group of specialists at facilities that meet certain requirements. The Ministry of Health, Labour and Welfare has launched the “Fact-finding and creation of treatment policy for abnormal sex development” team (Lead researcher: Tsutomu Ogata/ deputy chairman of the Japanese Society for Pediatric Endocrinology Sex Development Committee) within this year’s “Refractory disease conquering research project,” and showed interest in this matter. There are many constraints regarding the disclosure of information on disorders of sex development and although difficulties in fact-finding surveys are anticipated, I hope that this turns into the beginning of establishing the support system.

Determination of sex is a mandatory requirement for social life in Japan today, and although a certain period of delay is allowed, it needs to be decided soon after birth. During the subsequent rearing process, there are cases in which the patients develop feelings that their societal sex and sex of their brain do not match or that they don’t belong to either sex, and this brings new questions which turn into huge conflicts. If we think that it is impossible for someone with typical sex and stereotypical feelings to imagine the consciousness toward sexuality of people with atypical sex, it is important for us to try to face the adults who have disorders of sex development and understand their inner feelings in thinking about effective support in the future.

Also, sharing widely the understanding that sexuality (gender) is not something absolute in life is an indispensable condition to overcome the disorders of sex development, and I believe that it is our duty as specialists to conduct awareness campaigns for this purpose.

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