Chemotherapy can cause premature ovarian failure (POF). This is the cessation or inhibition of any physiological activity in the ovary. There is no established definition of chemotherapy induced POF but Molina et al (2005) suggest ’irreversible amenorrhoea lasting for several months following chemotherapy and a FSH level of ≥ 30 MIU/mL’ (2)

Chemotherapy can cause fibrosis of the ovary with destruction of the follicles resulting in failure of ovulation, amenorrhoea (absence of regular periods) and sterility.(3) There may also be a reduction in the hormones produced by the ovary which can lead to menopausal symptoms such as hot flushes and vaginal dryness. The effects of chemotherapy may be temporary but are often permanent.

With temporary ovarian failure, the normal menstrual cycle may not resume for 6–12 months after treatment is completed.(4) Ovarian function may be erratic and may include months of amenorrhoea interspersed with normal menstrual periods. If there is continuous amenorrhoea for more than 12 months this is usually associated with menopausal symptoms.

Because we can't predict exactly how each person's fertility will be affected, it is important that women who could potentially become pregnant while having chemotherapy use contraception.

Contraception should be used throughout the course of the chemotherapy treatment (even if periods have stopped) as there is a potential risk of damage to the developing foetus from the chemotherapy drugs. The oral contraceptive pill is not recommended for women with breast cancer due to the possible risk of hormonal stimulation of the cancer.

For both men and women having chemotherapy, it is recommended that a barrier form of contraception (such as a condom) is used for a few days after treatment. This is because tiny traces of chemo may (theoretically) get into the cervical fluid or sperm and cause irritation to partners.

Menopause occurs when the number of primordial follicles (these contain immature eggs in the ovary) falls below a certain level. There is a change in the balance of the sex hormones in the body and this causes menopausal symptoms such as hot flushes and vaginal dryness. Many women also report emotional changes for example, mood swings and poor concentration. These may be a consequence of the physical symptoms rather than directly related to the hormone changes themselves. If both ovulation and menstruation have stopped, a woman is considered to be menopausal. The normal age for a natural menopause is between the mid-40s and mid-50s.

Chemotherapy related menopause may be due either to direct injury to the ovary or to indirect injury resulting from the loss of follicular cells. The eggs die or become non-functional. There is a range of ages at which the menopause occurs naturally and it is likely that chemotherapy brings this forward.

Age

Fertility in women naturally decreases with age. It begins to decline in the late 20s, but the rate of decline becomes more rapid at about the age of 38.

Schulz et al (1979) found that the ovaries of premenopausal women with normal menstrual cycles appear to be far more resistant to chemotherapy drugs than those of peri-menopausal women, since amenorrhoea occurred more frequently, more quickly and with smaller doses in the latter group.(5)  Women who have chemotherapy treatment when they are premenopausal are therefore more likely to recover ovulation and menstruation than those who are peri-menopausal.

Most studies have tended to group people into ‘old’ (>40 years) and ‘young’ (<40 years). Generally, for patients less than 40 years old, far higher doses of chemotherapy are tolerated before ovarian function is affected, and the likelihood of normal periods returning after treatment is far greater than for older women.(6) One study has reported an increased risk of menopause from the age of 35 in premenopausal women being given adjuvant treatment for breast cancer.(7) In women under 30 years old, the risk of ovarian dysfunction resulting in menstrual changes is very low.

It has been reported that women treated with chemotherapy, who have a normal menstrual cycle and even go on to have children, may experience menopause at an earlier age than the normal female population.(8)  Even women treated in their teenage years have a higher likelihood of experiencing premature menopause in their 30s. This suggests that damage incurred at the time of treatment reduces the number of follicles enough to reach the menopausal threshold early.(9)

There is some suggestion that temporarily suppressing ovarian function using an LHRH analogue such as Zoladex may protect future ovarian function. However, the evidence for this is somewhat controversial. Studies so far have been small and there have been conflicting results. Larger randomised trials are in progress and more data is needed before conclusions can be drawn.(10), (11)

Ovarian suppression with the oral contraceptive has not been shown to be effective in preventing radiotherapy or chemotherapy induced damage.(3)

Published studies regarding the gonadal effects of chemotherapy given to pre-pubescent girls suggest varying toxicity, depending to some extent on the drug, its dose and the length of treatment. Much of the data refers to children treated for childhood leukaemia and brain tumours.(9)

Females are generally less susceptible to the negative effects of chemotherapy than males. However, ovarian failure is a well-established consequence of certain treatment regimens. The larger number of surviving primordial follicles available after treatment may explain the apparent resistance of the pre-pubertal ovary.(12)

Most girls treated with procarbazine or nitrosoureas for brain tumours show evidence of ovarian dysfunction, but essentially all enter and progress normally through puberty.(9)

The use of cyclophosphamide can have an adverse effect on the ovaries. Himelstein-Braw et al looked at ovaries from 1 week to 4 years after diagnosis of ALL (acute lymphoblastic leukaemia) and showed inhibition of follicular development in all cases treated with cyclophosphamide, which was related to the duration of chemotherapy.(13)

In ALL, the use of multi-agent chemotherapy [vincristine, prednisolone, daunorubicin, asparaginase, methotrexate, 6-mercaptopurine] as first-line therapy results in little significant impairment of ovarian function (i.e. hormonal output or fertility potential).(14)

People who have relapsed however, will require more intensive chemotherapy, and often high-dose treatment; therefore long-term fertility is far more likely to be compromised.(14)

The higher the dose of the cytotoxic drug the more likely it is to affect the ovary. Younger women (those under 40 years old) are more able to tolerate higher doses of chemotherapy of the same regimen with less toxicity to the ovary than older women.

In combination regimens which include alkylating agents, over half of women will develop amenorrhoea. Cyclophosphamide is the drug with the best documented ovarian toxicity. Regimens containing cyclophosphamide are four times more likely to induce short-term ovarian failure compared to other combination chemotherapies.(15)  The effect of the taxanes has not been thoroughly evaluated.(16)

The possibility of menstruation returning is much greater in women aged less than 40 years old. Most of the documented data refers to women being treated for Hodgkin lymphoma. Younger women are more likely to recover ovarian function and be able to have children. Recovery time varies a great deal, however, and may take up to one year.

The ability to return stem cells or bone marrow to the patient means that much higher doses of cytotoxic drugs can be given. This may be with the aim of curing a disease such as leukaemia, or treating a disease that is showing resistance to more standard doses of chemotherapy.

Treatment may involve high-dose chemotherapy alone or in combination with total body irradiation (TBI) i.e radiotherapy given to the whole body.

In girls who have bone marrow transplants (without TBI) before puberty, fertility chances remain quite high. This is likely to be because the ovaries in younger females contain a greater number of eggs. Many published reports of young women conceiving and delivering normal children attest to the possibility of recovery of some degree of ovarian function after high-intensity therapy. But few document the total number of women treated or desiring fertility, so the probability of fertility remains difficult to clarify.(9)

In terms of fertility rates following treatment, women treated for aplastic anaemia appear to have better results than women treated for leukaemia. Age at treatment is important; with women younger than age 26 more likely to see the return of menstrual function. If TBI is part of the conditioning programme, however, no woman older than 25 is likely to recover menstrual function.

In pre-pubertal girls treated using TBI as part of the conditioning regimen, there is more likelihood of fertility in adult life. In very young but post-pubertal females, ovarian recovery is seen in 10– 25% at 2 to 7 years following bone marrow transplant.(17)

One large retrospective study of pregnancy outcomes following high dose treatment showed that only 0.6% of women conceived after autologous or allogenic stem cell transplantation, but the pregnancies had a successful outcome.(18)  However, other data has found that for women who received a bone marrow transplant and went on to become pregnant, the risk of miscarriage, pre-term labour or low birth weight babies (particularly if TBI was included in the conditioning regimen) increased.(19)