MManagement of the gonads

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Martine Cools, paediatric endocrinologist, and Piet Hoebeke, paediatric urologist, University Hospital Ghent, Belgium

Sten Drop, paediatric endocrinologist, Katja Wolffenbuttel, paediatric urologist and Leendert Looijenga, pathologist, Erasmus MC Rotterdam, The Netherlands

As a person affected by DSD, or a parent, you may be informed that in DSD, there is an increased risk for the development of a cancer in the gonads. This cancer risk is related to the Y chromosome (people with 46,XX DSD have no increased cancer risk) and to the abnormal development or maturation of the gonads.

If present, the cancer may remain silent, meaning only located within the gonad, for a very long time. In this stage, the cancer is not dangerous for your body, and when the gonad is taken out, the cancer is gone and you don’t need any additional treatment. The procedure to take the gonads out is called a gonadectomy. Only when the cancer becomes invasive, meaning that it also affects organs outside of the gonads, you need additional chemotherapy and/or radiotherapy to be cured.

For many years it used to be common to take both gonads out at a young age in all children with an increased risk. However, recent research has shown that the risk to develop gonadal cancer, and the age at which these cancers develop, can be very different between the various forms of DSD. Therefore, when doctors now give advice on whether or not and when a gonadectomy has to be done, they take into account many different elements, such as:

  • What is the underlying condition that led to the DSD (e.g. complete or partial AIS, 45,X/46,XY mosaicism,…)?
  • What are the risks vs the benefits to the body of the sex hormones produced by the gonads?

Do the gonads have “good” (desired) or eventually “bad” (unwanted) effects in this patient?

In complete AIS, the gonads produce male hormones, which have no effects as such but are transformed by the body itself into female hormones. These female hormones will help for the development of breasts and strong bones during puberty, which is clearly a “good” effect. However, whether an effect is “good” or “bad”, can be different depending on the sex of rearing: e.g. in a girl with partial AIS, the male hormones will have at least some effects on the body, causing (partial) male sexual development during puberty, which is then a “bad” effect. However, when the child is raised as a boy, he will be happy with these male effects.

  • What is the age of the patient, as the risk of cancer may increase with age?

In some conditions, e.g. in complete AIS or disorders of testosterone biosynthesis, the risk is low before puberty, and probably higher thereafter. In other conditions, such as girls with 46,XY complete gonadal dysgenesis (sometimes called “Swyer syndrome”), the risk is already high in childhood. If it is possible to postpone the decision with regard to gonadectomy until adolescence, for example if tumor risk only rises after puberty, then this has the advantage that the affected person, together with the medical team, can take decisions regarding the gonads for him- or herself. If not, parents have to decide for their child, which is not an easy task!

  • Where are the gonads? In DSD patients, gonads that are in the abdomen or in the inguinal region (the groin) have a higher cancer risk than gonads that are in the labia or the scrotum.

Because the decision on how best to manage the gonads can be very different depending on the underlying condition, we will discuss some conditions separately now. Of course we can only give some general information here, and the pros and cons of a decision with regard to gonadectomy should always be taken on an individual basis and be discussed with your treating physician.

THE GIRL WITH COMPLETE ANDROGEN INSENSITIVITY SYNDROME

The gonads have differentiated as testes, but the male hormones (testosterone) that they produce cannot perform any action. Testosterone is transformed by the body itself into female hormones(estrogens). Estrogens can act normally in girls with complete AIS, therefore, breast development starts at a normal age, which is a relief for many affected girls. Additionally, bones need hormones to become strong, and estrogens will also help in this.

The cancer risk is low (probably less than 1%) during childhood in complete AIS, but after puberty, it becomes higher (probably between 5 and 10%). Therefore, most doctors will now recommend leaving the gonads in place until puberty has been completed.

This also means that the decision whether or not to perform gonadectomy can be discussed with and taken by the adolescent or young adult patient. After puberty some women prefer to keep their gonads, others may want to have them removed, and take hormone pills to maintain their general well-being and bone health. Unfortunately, there are no reliable medical or technical examinations (such as ultrasound, MRI) to detect a cancer in an early stage..

THE GIRL WITH PARTIAL ANDROGEN INSENSITIVITY SYNDROME OR TESTOSTERONE BIOSYNTHESIS DISORDERS

The gonads have differentiated as testes. In testosterone biosynthesis disorders, the amount of testosterone that is produced is severely reduced. In partial AIS, the produced testosterone performs some, but less than normal action. A cancer is not likely to arise before puberty, but to avoid the development of male sex characteristics during puberty, the doctors will advise to remove the gonads sometime during childhood/before puberty. However, if there are doubts about gender identity, this issue has to be addressed first before gonadectomy is performed.

THE BOY WITH PARTIAL ANDROGEN INSENSITIVITY SYNDROME OR TESTOSTERONE BIOSYNTHESIS DISORDERS

The gonads have differentiated as testes. In testosterone biosynthesis disorders, the amount of testosterone that is produced is severely reduced. In partial AIS, the produced testosterone performs some, but less than normal action. Although less than normal, testosterone has a “good” effect, inducing the development of male sex characteristics and strong bones during puberty. Cancer risk can be minimized by bringing the gonads in the normal scrotal position in early childhood.

Therefore, when the gonads are not in the scrotum at birth but in the abdomen or in the groin region, doctors will suggest performing an operation called orchidopexy in early childhood, to bring the testes into the scrotum. When this is not possible, taking out the testes might be the safest option.

After puberty, the cancer risk becomes higher (maybe around 10%, as in complete AIS after puberty). By having the testes in the scrotum, the cancer can be detected at an early stage by self-examination and ultrasound. Therefore it is safer to leave the testes in place in these boys/young men than for example in girls/young women with complete AIS. Most doctors will suggest regular follow-up of the testes by regular self-examination and ultrasound; sometimes, taking a sample (biopsy) is recommended after puberty. A biopsy is a short surgical procedure in day clinic performed under local or general anaesthesia in which a very small part of the testis is removed and examined under the microscope. Cancer cells can be detected under the microscope at a much earlier stage than with ultrasound or other imaging techniques.

THE GIRL WITH 46,XY GONADAL DYSGENESIS OR 45,X/46,XY GONADAL DYSGENESIS

Gonadal dysgenesis means that the gonad has not developed into a normal testis or a normal ovary.

Except for the very rare case of an XX/XY karyotype, the production of female hormone (estrogen) is very unlikely in dysgenetic gonads, but sometimes, male hormone (testosterone) is produced before birth (in that case, an enlarged clitoris is often noticed at birth or in the first months of life) and during puberty. Cancer risk can be very high (30% or more) in some persons with gonadal dysgenesis, and the cancer can develop at an early age, even in childhood. For these reasons, gonadectomy during childhood is generally recommended in girls with gonadal dysgenesis.

THE BOY WITH 46,XY GONADAL DYSGENESIS OR 45,X/46,XY GONADAL DYSGENESIS

Gonadal dysgenesis means that the gonad has not developed into a normal testis. However, the gonad produces (less than normal) male hormone (testosterone), which is of course of benefit for the affected boy. Sometimes, the testes are found in the normal scrotal position, but more often, they are in the abdomen or groin region at birth. Cancer risk can be very high (30% or more) and is difficult to estimate. Very generally speaking, the more the genitalia look like that of an unaffected boy, the lower the cancer risk. The risk also increases if the testes are not in the scrotum Cancers are most likely to develop after puberty, but can already occur in childhood.

Because the gonad produces testosterone which is important for boys during puberty as well as afterwards, doctors will try to avoid gonadectomy if possible. Therefore, they will suggest performing a small operation called orchidopexy in early childhood, to bring the testes into the scrotum. When this is not possible, taking out the gonads might be the safest option. During the orchidopexy, or at another occasion, a testis biopsy (a small sample) can be collected and examined under the microscope. This procedure can then provide extra information with regard to cancer risk; cancer cells can be detected under the microscope at a much earlier stage than with ultrasound or other imaging techniques. If no cancer cells are detected in the biopsy and the testes can stay in the scrotum, the doctors most often will suggest regular follow-up of the testes by regular self-examination and ultrasound. Sometimes an additional testis biopsy after puberty and/or later in life may be necessary.

WHAT ARE THE REPRODUCTIVE OPTIONS?

Germ cells –the cells that can develop into sperm or eggs- are usually absent or severely reduced in numbers for all the conditions described above. If they are present, they have developed abnormally (i.e. eggs or sperm are likely to be of too ‘poor quality’ to be used). With current medical knowledge it is technically very difficult and ethically controversial to use them for assisted reproductive techniques.

HOW CAN WE MONITOR GONADS?

  • Boys with DSD and scrotal testes are advised to perform self-examination by palpation of their testes once a month from puberty onwards. In case of any abnormal finding, an ultrasound is the next step.
  • Testes that cannot be brought into the scrotum are either removed or placed in the groin (inguinal region). A biopsy is recommended to assess the cancer risk. Testes that are located in the inguinal region might be difficult to palpate; in these cases an annual ultrasound might be justified, especially when the result of the biopsy showed a high cancer risk.
  • For gonads in the abdomen, ultrasound and MRI are not reliable enough to monitor early cancer development. Similarly, blood tests are also not reliable for monitoring the very early stages.

PRACTICALITIES OF THE GONADECTOMY AND GONADAL BIOPSY PROCEDURES

Gonadal structures can be located either inside the abdomen or they can be descended and be found in the groin area or within the labia or scrotal sacs. The position determines the way a biopsy or gonadectomy is done.

  • If the gonad is in the abdomen, the surgeon will choose to do a laparoscopy. In this minimally invasive approach, instruments are introduced in the abdomen through very small openings (< 1 cm), one in the umbilicus and most often two in the lateral side of the lower abdomen. With these instruments, including a camera, a small part of the gonad can be taken. The capsule of the gonad is incised and a small part of the gonadal tissue is excised and sent to the laboratory for further examination. The capsule of the gonad can be repaired with a suture and the gonad is left in the abdomen. The result of the biopsy will determine what will happen with the gonad in the future. If a gonadectomy needs to be done, this can be done with the same laparoscopic procedure. The blood vessels of the gonad are identified and clipped and the gonad can then be removed. Most often the small opening for the instruments is large enough to allow removal of the gonad. If the gonad is too big, the largest of these openings can be enlarged. Laparoscopic procedures are most often performed in day clinic.
  • If the gonad is outside the abdomen, the biopsy and gonadectomy are performed through a groin incision. The procedures are similar to the laparoscopic procedures. If the gonad will be preserved, in boys, most often it will be descended to a full scrotal position in the same procedure. The groin incision can be small (2 cm) and most of these procedures are also done as day cases.

The risks of these procedures are the typical risks associated with general anaesthesia which in otherwise healthy children are extremely low. In experienced hands, the surgical risks are also minimal. Recovery time is also minimal: in general, school or work can be restarted the day after laparoscopy and some days after groin incision.