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Cancer and fertility

If you are given a cancer diagnosis today, your chances of recovery are often much more favourable than ten or twenty years ago. Many cancers can now be cured efficiently by means of chemotherapy, whether or not combined with surgery or radiation. This is due, among other things, to new medical techniques, which allow for more aggressive forms of chemotherapy and radiotherapy to be applied.
Unfortunately many types of cancer treatment have a negative and often irreversible effect on your fertility (see gonadal toxicity). At UZ Brussel, the Oncofertility team strives to mitigate the damage inflicted by cancer treatment.

What is oncofertility?

Oncofertility is the medical discipline at the crossroads between cancer treatment and reproductive medicine. It aims to preserve the fertility of cancer patients who are at risk of becoming infertile due to chemotherapy or radiotherapy.

The negative effect of a cancer treatment on human fertility is called gonadal toxicity. This is a combination of the term ‘gonads’ (reproductive organs) and ‘toxicity’ (harmfulness).

Most cancer treatments have a – direct or indirect – negative impact on fertility.
The treatment is aimed at destroying cancer cells: by removing them during a surgical procedure, by destroying them by means of radiation or by stopping there development with the help of chemotherapy.
But a treatment with chemotherapy or radiotherapy is not selective and will also impact on other cells apart from the cancer cells. Besides, the reproductive organs can also be damaged directly by radiation or surgery.

A cancer treatment will usually result in the – temporary or permanent – disappearance of the menstrual cycle in women, and the production of sperm cells in men.
For children a cancer treatment before their puberty can be just as harmful to their future fertility. The chemotherapy also affects the germ cells.

With girls and women
In the context of a cancer treatment especially one (biological) fact is important: the fertility of women is largely defined by the (remaining) stock of egg cells, often referred to as the ovarian reserve.
Egg cells are stored in small follicles (vesicles) in the ovaries. When you are born you have a few hundred thousands or even up to one million or more of them, but that is it for the rest of your life. As opposed to what happens to men during sperm production, women do not produce new reproductive cells once they are born. And opposed to most other cells in our body, egg cells cannot recover from damage.
Immediately after your birth the number of egg cells starts to go down with advancing age. By the time you reach puberty only 200,000 to 400,000 egg cells are left. From puberty onwards, about a dozen of eggs mature in each menstrual cycle, one of which reaches full maturity. In other words: during your fertile years you ‘loose’ about five hundred egg cells in the menstrual cycles, through ovulation
Normally, your entire stock will be depleted by the time you reach fifty, when menopause occurs.
  
The effect of radiation
The effect of chemotherapy
The consequences of surgery

The effect of radiation   

Radiation aims for the local destruction of cancer cells. Unfortunately, radiotherapy is not selective for cancer cells: it causes the damage of all cells in the irradiated body area. If your lower abdomen is irradiated, the ovaries (containing the egg cells) and the womb will also become damaged.
Unfortunately, immature egg cells are also affected by radiation. The higher the dose, the bigger the effect and the more immature egg cells are destroyed. The remaining stock after a cancer treatment is, in other words, linked to the administered dose. Because the ovarian reserve of egg cells determines the duration of your fertile period as a woman, a serious reduction of the stock can result in early menopause.
The further you are advanced in your 'reproductive age', the higher the chance that infertility occurs. A girl or a young woman have the best chances of getting pregnant naturally after cancer therapy. A woman aged thirty will usually have a temporary period of amenorrhoea (the absence of menstrual period), a woman aged forty will often become permanently infertile.
Also when total body irradiation (TBI) is performed for a bone marrow transplantation, the ovaries will be affected. The seriousness of the damage depends on the radiation dose on the ovaries.

The effect of chemotherapy   

During chemotherapy a medicine is administered which stops the division of cancer cells. It is an non-specific treatment which mainly affects cells which are dividing quickly. This means that not only cancer cells are destroyed but e.g. also cells covering the gastrointestinal tract, the cells in the bone marrow and the cells generating one's hair (that is why the hair loss occurs).
The toxic effect on the ovarian reserve is closely related to the age at which chemotherapy is administered. Also the types, combinations and doses of medication, either or not in combination with other radiation, will define the final damage. Egg cell damage mainly occurs when alkylating agents are used. For many types of medication the effect is actually not yet sufficiently known. In the past couple of years attempts have been made to reduce the adverse effect on egg cells by means of dose adjustments and new combinations.

The consequences of surgery   

The impact of cancer on your fertility is obviously very direct when a tumour has developed in your womb or in an ovary. An ovarian tumour is usually treated by surgical removal of the ovary.
If it is just one ovary, the removal does not necessarily result in reduced fertility, at least if the procedure is not combined with radiation or chemotherapy.
If, on the other hand, both ovaries have to be removed, this will be the end of your natural fertility. Besides, the production of the ovarian hormones will also cease. In that case, if you want to have children, you will have to rely on assisted reproduction with the use of donor material (see What to do if you want children?)
If the tumour results in removal of the womb (which is the case for some cervix carcinomas) the desire to have children can only be fulfilled through surrogate motherhood or adoption of a child.

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With boys and men
In order to understand how cancer treatment affects your fertility, you must know the following details about the male reproductive organs.
The testicle contains the seminiferous tubules, which contain the feeding cells (Sertoli cells) and seminiferous cells or stem cells. Between the seminiferous tubules are the Leydig cells, which are responsible for the production of the male hormone testosterone. The rest of the testicle is made out of cells of the supporting tissue.
During childhood, no mature sperm cells are produced. The testicles only contain stem cells. Their number remains more or less constant; this is the result of a continuous renewal through cell multiplication.
From puberty onwards – which is usually around the age of 12 for boys – the number of stem cells rises strongly, which will also increase the volume of the testicles. At the same time testicular hormones ensure that boys develop male sex characteristics and the production of sperm can start. This will continue for the rest of your life.
Mature sperm is created from the stem cells according to a complex division process in which the stem cells go through different maturation stages. The entire process – from stem cells to mature sperm cells or spermatozoa – takes 90 to 120 days. The maturation process occurs in the thousands of seminiferous tubules in different phases, making sure that different maturation stages are always present in the testicle.
   
The effect of radiation
The effect of chemotherapy

The effect of radiation  

Radiation is usually aimed at local destruction of (cancer) cells, but also causes damage to all cells in the irradiated area of the body. The negative effect on fertility mainly occurs when radiation is applied on the testicle or in the groin area.
Unfortunately, the stem cells – which are present since your birth and which you need to produce sperm cells when you become an adolescent – are also susceptible to radiation. Depending on the doses of radiation they can therefore partially or entirely disappear from the testicle.
The later maturation stages of the stem cells (i.e. the mature sperm cells), which are present in the testicle from puberty onwards, are less susceptible to radiation. If someone is exposed to a massive radiation dose, e.g. after an accident in a nuclear plant, the stem cells may disappear completely, but sperm cells may be present in the ejaculate for up to one or two months after the accident. Those were produced from the later maturation stages, which are more resistance against the negative radiation effect. After some months, however, no more new sperm cells are produced because the stem cells, which form the basis for sperm production, have been destroyed. This phenomenon is called maturation depletion: the exhaustion of the stock of maturing sperm cells which were already in production in the testicle.
The sperm cells that can still be found in the ejaculate can – without being destroyed – have suffered radiation damage resulting in errors in their genetic programming. That is why, in case of fertilization using this sperm and subsequent pregnancy, there is an increased risk of miscarriage or congenital abnormalities.

The effect of chemotherapy  

Many chemotherapeutic drugs act through blockage of cancer cell division. This is an aspecific action mainly affecting cells that are dividing quickly. This means that not only cancer cells are affected but e.g. also cells covering the gastrointestinal tract, the cells in the bone marrow and the cells generating one's hair (that is why hair loss occurs) and the seminiferous cells in the testicle. Just like in case of radiation the early stem cell stages are the most vulnerable ones; the later maturation stages are less susceptible.
The Sertoli and Leydig cells (see above) are also less susceptible to chemotherapy. That is why they remain in function and the Leydig cells can continue to produce testosterone.

In summary, chemotherapy can have the following effects:
  • arrest of sperm cell production. After your treatment the production can resume, sometimes after several years;
  • stem cell renewal may no longer occur. Chemotherapy may cause the number of stem cells in the testicle to be reduced, or disappear altogether. In that case, the long-term result will be a reduced or failing production of sperm cells;
  • due to the reduction or disappearance of the stem cells a permanent increase of the hormone (FSH) stimulating the sperm cell production will occur. Circulating levels of the male hormone testosterone, which is produced by the Leydig cells, usually remain normal. Even though some patients may experience reduced libido, the potency will usually remain good in the long term.

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