Five things to know about Fertility Preservation in women with Cancer

The incidence of cancers among young people is increasing due to changing lifestyles, deteriorating dietary patterns and many other yet unknown factors. And, at the same time newer techniques and technologies allow for early detection and treatment of cancers. A combined effect of these two factors is that more and more women of reproductive age group are now receiving anticancer treatment. While this helps many women lead a longer life, this does not always translate into a high quality reproductive life. Fertility preservation has therefore become very important for such women and they need to know what all options are available for them. This article explains various methods of fertility preservation available for women diagnosed with cancer.

Question 1- What is fertility preservation?

Fertility preservation essentially means preserving the ability of an individual woman or couple to conceive at a later date. These days, women are going for fertility preservation for a number of reasons. These include –

a) Women diagnosed with cancers and being planned for cancer treatment

b) Women undergoing treatment for Rheumatic diseases like Rheumatoid Arthritis and SLE and Myelodysplasia, which require them to take medications which can harm their fertility

c) Social indications – women not wanting to conceive at a young age for reasons such as career aspirations or if they are still looking for a suitable partner

This article discusses fertility preservation for women who are diagnosed with cancers and are going for cancer treatment. Fertility preservation carried out prior to the cancer treatment plays an important role in improving the quality of life of women surviving cancers. We counsel all women of reproductive age group, who are planned for cancer treatment and offer this option to all women who wish to preserve their fertility.

Question 2 – Why should a woman diagnosed with cancer worry about her fertility?

According to the National Cancer Registry of India, the number of newly diagnosed cases of cancer in India will cross the figure of 11 Lakh by year 2020, more than half of whom will likely be women. Of these, approximately two Lakh will be in adult patients within their reproductive years, i.e. up to age of 45 years.

Abdominal surgeries, especially the ones performed for treatment of cancers of reproductive organs – ovaries and uterus can cause permanent damage to the reproductive organs. Similarly, chemo and radiotherapy for cancers also affect the reproductive potential of women, as they have potential to cause genetic and structural damage to the reproductive organs. According to estimates, approximately 40-80% of women receiving cancer treatment are at risk of infertility resulting from cancer treatments in form of chemotherapy, radiation therapy and surgery.

Question 3 – How does cancer chemotherapy affect fertility of a woman?

Chemotherapeutic drugs kill cancer cells by interrupting critical cellular processes and stopping cellular growth and multiplication. But, these drugs can also cause DNA abnormalities and oxidative damage to the normal germ cells (cells which produce eggs) of a woman, leading to death and deformities of developing oocytes. The degree of damage to oocytes depends upon the specific drug that is used and its dose and also on age of the patient receiving this treatment. Older women with relatively lower ovarian reserves are more likely to be affected by the drugs, which can actually lead to premature ovarian failure (POF). The resulting damage to the ovaries can manifest in form of either temporary amenorrhea or premature menopause, both resulting in infertility.

Question 4 – How does radiation therapy affect fertility of a woman?

Radiation therapy can affect both ovary and uterus, thus impacting the fertility potential of the woman. Radiation induced damage to reproductive organs can cause infertility, miscarriage, preterm labor, intrauterine growth retardation and low birth weight. Radiations damage myometrium (inner lining of the uterus), and reduce its blood supply, which cause uterine fibrosis and hormone dependent endometrial insufficiency. The amount of damage caused to the ovaries by radiations depends upon age of the patient and amount of radiation exposure to the ovaries. Over 90% of patients undergoing total body irradiation or total abdominal irradiation eventually end up with ovarian failure.

Question 5 – What are various methods of preserving fertility among women?

There are multiple techniques, which can help women preserve their fertile potential for future and there are some other techniques, which are still emerging. The five main fertility preservation methods are explained below.

1. Embryo cryopreservation

Embryo cryopreservation means freezing embryos for implantation at a later (more suitable) occasion. This requires the patient to undergo IVF before starting the treatment for cancer. The embryos thus formed are then frozen. Embryo freezing is a proven and established technique and offers good results, which of course depend on the number and quality of embryos frozen.

Limitations of embryo cryopreservation:

a) Controlled ovarian stimulation in order to procure the eggs can take between 2-4 weeks’ time, depending on when the patient consults for fertility preservation. This means that the treatment for cancer has to be delayed by that many days, which may not always be in the best interest of the patient.

b) High Serum E2 levels resulting from hormonal stimulation of ovaries may have a negative effect on estrogen-sensitive tumors. We always seek an expert opinion from an oncologist before starting the stimulation.

c) IVF may not be possible in/ preferred by unmarried women, as it required sperms at the time of the procedure, and some women may not want to limit their reproductive autonomy in the future.

d) There are serious ethical and legal implications regarding disposal of the embryos, in case patient dies before she can use the embryos.

e) IVF cannot be used a fertility preservation technique for pre-pubertal girls undergoing treatment for cancers.

2. Mature oocyte cryopreservation

Oocyte cryopreservation (commonly referred to as Egg Freezing) is a preferred method of preserving fertility, especially among unmarried women as it allows the women to maintain their reproductive autonomy in future. However, egg freezing also required the patient to undergo controlled ovarian stimulation and, therefore, suffers from some of the same disadvantages as embryo freezing.

Just like embryo cryopreservation, egg cryopreservation can also not be used to preserve fertility potential among pre-pubertal girls. Also, since only a limited number of eggs/ embryos can be frozen is one cycle, the patient can take only as many attempts at pregnancy in future.

We recommend only one single attempt at stimulation and egg retrieval in order not to delay start of cancer treatment. We also take extreme care during stimulation so as to minimize the chance of ovarian hyper stimulation. The patients undergoing stimulation for fertility preservation are monitored very closely for ovarian response and dose of stimulation is titrated accordingly.

3. Ovarian tissue cryopreservation (OTC)

Ovarian tissue cryopreservation or tissue freezing is the process of harvesting ovarian cortical tissue (containing primordial follicles), dissecting the tissue into small pieces and freezing them for use later on. In most of the cases, this procedure can be performed laparoscopically (key hole surgery) and is done before starting any treatment for cancer. The frozen ovarian tissue can be re-transplanted into the patient on completion of cancer treatment, either into the pelvis (called orthotopic transplant) or in abdominal wall or forearm (called heterotopic transplant).

There is possibility of natural conception with orthotopic pelvic transplant of the ovarian tissue, but the patient definitely needs IVF treatment to conceive after heterotopic transplant of ovarian tissue. We always suggest orthotopic transplantation as a preferred method, as it is more biological and has better success rates.

Indications of Ovarian tissue cryopreservation-

a) Patient age less than 37 years

b) Good ovarian function – S FSH, AFC, AMH

c) Pre-pubertal girls where egg/ embryo freezing is ruled out

d) High risk for Permanent ovarian failure as a result of cancer treatment

Advantages of OTC over egg/ embryo freezing-

a) There is no need to delay cancer treatment in order to do OTC

b) There is no risk of ovarian hyper-stimulation and negative effect of progesterone on cancer

c) Partner or donor sperm is not required at the time of performing OTC, thus woman’s reproductive autonomy is maintained.

d) OTC helps preserve a larger number of follicles and technically allows for the resumption of ovarian function, which may last then many years.

However, OTC is still not a common fertility preserving method, especially for systemic cancers like leukemia, wherein cancer cells may be present in the frozen ovarian tissue. We consider OTC as a fertility preservation technique only in cases where egg/ embryo freezing is not indicated, namely when delaying start of cancer treatment not an option acceptable or controlled ovarian stimulation using hormones is contraindicated or IVF is not possible. OTC does not work for women over 40 years of age, as their ovarian reserve is relatively poor.

4. Fertility-sparing surgery – Ovarian transposition

Patients needing radiation treatment can benefit by fertility sparing surgeries. But, ovarian transposition is not an option for patients needing combined radiation- chemotherapy, which is a case in majority of patients. This procedure involves surgically moving the ovaries away from the field of radiation. For example-

a) Lateral fixation of ovaries in patients needing craniospinal irradiation

b) Moving ovaries out of the pelvis or into the anterior abdominal wall in patients who require radiation therapy to the pelvis

Disadvantages of ovarian transposition-

a) Risk of cyst formation in ovary and postoperative adhesions leading to chronic pelvic pain

b) Some patients may be harboring metastatic cancer in the ovaries, which may skip the radiation treatment

c) Transvaginal ovum pickup is not a viable option if the ovaries have been transposed and the patient may need laparoscopic egg pick up for IVF.

5. In vitro maturation

In vitro maturation (IVM) is another technique of fertility preservation for patients with cancers, but the success rate of IVM remains lower than egg/ embryo freezing. IVM involves aspiration of immature follicles (with/ out hormonal stimulation) for maturation outside of the body. The mature oocytes or embryos thus generated are then frozen for use at a later occasion.

Does infertility treatment put women at higher risk of cancers?

Many patients ask me if IVF treatment leads to a higher risk of cancers, especially in breasts and ovaries. As per the latest published scientific literature on this subject, there is no real evidence to link IVF with higher risk of cancers among these women.

As an infertility specialist, I am required to counsel mcancery patients about potential complications of fertility treatment. One of the most often asked question is if infertility treatments put the women at a higher risk of cancers.

Fertility drugs like clomiphene citrate and hormones used for ovarian stimulation & assisted reproductive technologies like IVF and ICSI have all been implicated to causes various cancers among women, including not only cancers of cervix, uterus, ovaries and breast, but also melanoma and cancers of the central nervous system.

A simple answer to this question is that as per the latest studies, there is no conclusive evidence to suggest a higher risk of invasive cancers in women receiving infertility treatment.

Why has infertility treatment been linked with higher risk of cancers?

There are multiple theories as to why fertility treatment may increases the risk of cancer in women.

  1. Hormonal treatment with Clomiphene and Gonadotropins causes cancers because elevated levels of estrogen and progesterone hormones can trigger carcinogenic activity in the ovarian , uterine and breast tissues
  2. Ovarian enlargement due to development of multiple follicles causes trauma to the ovaries, which may result in carcinogenesis.
  3. Injury to ovaries resulting from multiple needle punctures made during egg retrieval has also been suggested to cause cancers of ovaries.

However, at the same time, it has also been suggested that infertile and nulliparous women are inherently at an increased risk of certain cancers so actually infertility treatment may not be the cause of cancers in these women.

What does the scientific evidence tell us?

Extensive research has been conducted on this subject, but the results so far have been pretty inconclusive. We need to appreciate that it is indeed difficult to study direct relationship between cancers in women and infertility treatment because many of these cancers appear many years after the treatment/ causative injury. Therefore, large populations have to be studied over a long period of time in order to arrive at any meaningful conclusions regarding the relationship between fertility treatment and cancers.

Of all the cancers suspected to be associated with infertility treatment, cancers in ovaries are most often linked to the infertility treatment. The overall evidence in this regard is mixed. While some studies have found the risk of ovarian cancers to be higher in women with a history of fertility treatment, others have ruled any such association out.

A research group from Israel retrospectively studied possibility of such an association in over 106,000 women, who had delivered between 1998 and 2013.1 The researchers found that women with conceived with IVF treatment had a significantly increased risk of being diagnosed with ovarian and uterine cancers as compared to women who had conceived either naturally or using ovulation induction. However, another study of over 87,000 women from Israel only conducted around the same time did not find any significant relationship between IVF exposure and risks of breast, endometrial, or ovarian cancers.2

In a population based cohort study of 812,986 women from Norway, who had delivered between 1984 and 2010, the researchers tried to assess the overall risk of cancers and specifically of cancers of cervix, uterus, ovary, thyroid, the central nervous system and melanoma among the women who had conceived using ART. 3 They found that the overall risk of cancers was not higher among the women conceiving using ART and delivering at least one baby. Although there was a hint of higher incidence of some cancers among women undergoing IVF, this could not be statistically proven owing to the weak nature of this kind of population based study.

A Cochrane review of 25 studies (consisting of 11 case-control studies and 14 cohort studies) covering 182,972 women did not find any convincing evidence supporting an increased risk of invasive ovarian tumors with fertility drug treatment. However, the researchers concluded that there may be an increased risk of borderline ovarian tumors in subfertile women treated with IVF.4

Cancer of the breast is the second most commonly discussed cancer that is assumed to be linked with hormonal treatment for infertility. Large studies and meta-analyses have not found any significant correlation between treatment for infertility and breast cancer. 5,6 While some studies have suggested that the risk of breast cancer increases after exposure to ovulation inducing agents (especially clomiphene citrate)6, many other studies do not support such an association.5 Therefore, I don’t advocate long term administration of Clomiphene, as the risk of breast cancer is not fully ruled out with its long term use.

Conclusion

Overall we can say that on the basis of existing scientific evidence, there is no conclusive proof of a causal link between ovarian and breast cancers and fertility treatment. Therefore, treatment of infertility using hormones and ART is by and large safe. The cancers of ovary and breast detected among women with history of treatment for infertility are more likely to be related to their infertile status than to the effect of fertility drugs. However, we must keep in mind that majority of the available studies on this subject suffer from methodological limitations and therefore cannot be fully relied upon. Further research on this subject will certainly enlighten us more on the possibility of any such association.

References

1.       The risk of female malignancies after fertility treatments: a cohort study with 25-year follow-up. Kessous et al. J Cancer Res Clin Oncol. 2016 Jan;142(1):287-93.

2.       In vitro fertilization and risk of breast and gynecologic cancers: a retrospective cohort study within the Israeli Maccabi Healthcare Services. Brinton et al. Fertil Steril. 2013 Apr;99(5):1189-96.

3.       Cancer risk among parous women following assisted reproductive technology. Reigstad et al. Hum Reprod. 2015 Aug;30(8):1952-63.

4.       Risk of ovarian cancer in women treated with ovarian stimulating drugs for infertility. Rizzuto I, Behrens RF, Smith LA. Cochrane Database Syst Rev. 2013 Aug 13;8:CD008215.

5.       IVF and breast cancer: a systematic review and meta-analysis. Sergentanis et al. Hum Reprod Update. Sergentanis et al. 2014 Jan-Feb;20(1):106-23.

6.       Breast cancer incidence after hormonal treatments for infertility: systematic review and meta-analysis of population-based studies. Gennari et al. Breast Cancer Res Treat. 2015 Apr;150(2):405-13.

For further information or queries on this subject, please write to me at ivfgurgaon@gmail.com.

Dr Parul Katiyar