Fertility preservation is often not foremost in the minds of women who have been diagnosed with cancer, or even after treatment. However, as cancer survival rates for children and young adults improve, the demand for fertility preservation services will increase. General practitioners who see such patients can play an important role in sharing with them the options available.


Women have a finite reproductive lifespan. A baby girl is born with all the follicle-containing oocytes she will have in her lifetime – a finite supply which is depleted with time as the follicles undergo atresia, and is completely exhausted at menopause.

In addition, there is also a known decline in oocyte quality in terms of aneuploidy, related to age-related instability of the oocyte meiotic spindle. This results in ovarian ageing and its clinical consequences of infertility, miscarriage and pregnancy with a Down syndrome foetus.


Chemotherapy, pelvic irradiation and ovarian surgery are iatrogenic factors that are known to accelerate the natural decline in ovarian reserve. The devastation to the ovarian reserve and resulting risk of premature menopause depends on the type of treatment and its ovarian toxicity, the age of the woman and her baseline ovarian reserve.

Hence, timely referral to a gynaecologist who specialises in reproductive medicine is crucial when a reproductive-aged woman requires chemotherapy or pelvic irradiation, or has undergone ovarian surgery.

Patient criteria

Women who are suitable candidates for medical fertility preservation have the following characteristics:

  • Age ≤ 40 years
  • Premenopausal
  • Has a realistic chance of surviving for five years
  • Not pregnant
  • Desires to have a child in the future

What Are the Options for Female Fertility Preservation?


Ovarian stimulation followed by the freezing of mature eggs or embryos is the most established method of fertility preservation.


The patient self-administers subcutaneous gonadotropins for about 10-14 days to stimulate multifollicular development in her ovaries, following which she undergoes an egg retrieval procedure under sedation. The patient would be fit to tart chemotherapy as early as two days after egg collection.

If there is no male partner, the eggs are supercooled and stored in tanks containing liquid nitrogen.

If the woman is married, the eggs can be fertilised and the resultant embryo cryopreserved. The process is essentially similar to in-vitro fertilisation (IVF), the main difference being that the embryos are frozen rather than transferred in utero.

Potential risks and complications

The risk of complications is low and includes the following:

  • Ovarian hyperstimulation syndrome
  • Venous thromboembolism
  • Procedural risks associated with egg collection – bleeding, infection, ovarian torsion

Oestrogen-sensitive tumours and breast cancer recurrence

In patients with oestrogen-sensitive tumours such as breast cancer, aromatase inhibitors are given concurrently to alleviate the supraphysiological estradiol levels during ovarian stimulation. Women who were given letrozole during ovarian stimulation had the same risk of breast cancer recurrence as for those who did not undergo ovarian stimulation, wthout compromise in stimulation results.1

Ostetric and perinatal risks

No increased obstetric and perinatal risks were found in pregnancies achieved with frozen eggs or embryos, compared with IVF pregnancies conceived with fresh eggs or embryos. However, the long-term health of babies born as a result of gg freezing is not known.

Although the risk of miscarriage and chromosomal abnormality is related to the age at which the eggs were retrieved and frozen, egg/embryo freezing does not prevent the other obstetric complications (e.g., eclampsia, gestational diabetes, growth restriction, caesarean section) associated with advanced maternal age.

For example, a 45-year-old woman attempting to conceive with eggs that were frozen when she was at age 30 would have the same risk of maternal and perinatal complications as women in her current age group. However, her risk of miscarriage and chromosomal abnormality would be similar to that of a 30-year-old.


The success of female fertility preservation is highly dependent on the woman’s egg quality and ovarian reserve, which are in turn significantly influenced by age.


Live birth rate stratified by age - SingHealth Duke-NUS Transplant Centre
Figure 1 Live birth rate stratified by age after one complete cycle of embryo freezing in 20,687 Chinese women2

Oocyte-to-baby rate stratified by age - SingHealth Duke-NUS Transplant Centre
Figure 2 Oocyte-to-baby rate stratified by age3


A large study2 reported the live birth rate after one cycle of embryo freezing in 20,687 Chinese infertile women of various ages (Figure 1),while another study3 reported the oocyte-to-baby rate for different ages of women (Figure 2).

Besides egg quality, other factors such as smoking, history of polycystic ovarian reserve and previous ovarian surgery are also important.

A common misconception is that fertility preservation is an insurance against future infertility; it is not. The reality is that live birth is not a guarantee, and it is more realistic to consider fertility preservation as offering an extra opportunity to conceive with younger and better-quality gametes.


Ovarian tissue freezing offers a different approach to fertility preservation, other than the freezing of mature eggs or embryos.

A typical cycle of egg freezing allows the retrieval of a small number of eggs (usually less than 30), whereas the freezing of ovarian tissue with whole follicles, each containing a single oocyte surrounded by steroid hormone-producing cells, allows thousands of oocytes to be frozen in one instance.

Premature ovarian failure is a known adverse effect of highly gonadotoxic chemotherapy as well as pelvic radiotherapy. As ovarian tissue freezing also preserves the steroid hormone-producing cells of the follicular unit, it can restore fertility as well as the hormonal function of the ovary.


The ovarian tissue is retrieved by surgery, which can usually be performed laparoscopically. As most of the follicles in the ovarian tissue are in the primordial stage, the ovarian tissue needs to be reimplanted back into the body via a second operation to regain its functionality.

Typical graft sites are the remaining ovary and pelvic sidewall (orthotopic) and anterior abdominal wall (heterotopic). Currently, the only way to use frozen-thawed ovarian tissue is in vivo; in-vitro methods to retrieve mature oocytes from primordial follicles are still being researched on.

Unlike in conventional organ transplants, patients do not need to take any long-term immunosuppressive medications after ovarian tissue transplant surgery. This is because the ovarian tissue that is harvested and reimplanted back into the body is the patient’s own, thus there is no risk of organ rejection.

Timing considerations

The lifespan of the graft is very variable, and depends on the amount of tissue transplanted and the age of the woman when the ovarian tissue was first removed. Graft survival ranging from a few months to up to ten years has been reported.4 Given the limited lifespan of ovarian tissue grafts, transplantation should be postponed until the patient is ready to conceive or experiences symptoms of ovarian hormone deficiency.


Ovarian function was restored in more than 95% of cases, within four to nine months after transplantation. Among women who were trying to conceive after ovarian tissue transplant, a live birth rate of about 30% has been reported, of which half were spontaneous conceptions.5

Ovarian tissue freezing is a relatively new procedure, and its experimental label was removed by the American Society of Reproductive Medicine only as recently as 2019.

Overall, data on the efficacy, safety and reproductive outcomes after ovarian tissue freezing is still limited. It is currently considered an ‘established medical procedure with limited effectiveness’ that should be offered to carefully selected patients.6


Ovarian tissue freezing is currently the only option for prepubertal girls.

It can also be offered to patients undergoing moderate- or high-risk gonadotoxic treatment (e.g., stem cell transplant, pelvic radiotherapy) or where egg/embryo freezing is not feasible. For example, patients who need to start cytotoxic treatment urgently would not have time to undergo the ovarian stimulation required for egg/embryo freezing.

Potential risks and complications

In addition to the surgical complications of freezing and grafting the ovarian tissue, there are concerns regarding the presence of occult metastases in the frozen ovarian tissue and retransplanting the original malignancy. The risk is theoretical with careful patient selection, and depends on the type and stage of cancer.7

​Egg / embryo freezing​Ovarian tissue freezing
​Requires hormonal stimulation – delay in cytotoxic treatment needed​Does not require hormonal stimulation – no delay in cytotoxic treatment
​Does not require surgery; procedure (usually transvaginal) done under sedation to retrieve eggs​Requires surgery (partial or total oophorectomy) performed under general anaesthesia; a second operation is needed to reimplant the ovarian tissue when fertility is desired
​Smaller numbers of oocytes/embryos frozen (usually less than 30)​Allows the freezing of thousands of oocytes at one time
​Mature oocytes or fertilised oocytes (i.e., embryos) are frozen​Immature (primary) oocytes are frozen
​Requires assisted reproductive technology​Allows opportunity to conceive spontaneously
​Does not preserve ovarian hormonal function​Allows restoration of fertility and ovarian hormonal function
​Risks related to ovarian stimulation and egg collection​Surgical risks
​More established method of fertility preservation​Less established method of fertility preservation

Figure 3 Key differences between egg / embryo freezing and ovarian tissue freezing


Although GnRH agonists are commonly used during chemotherapy to reduce the chance of premature ovarian insufficiency, the mechanisms which underlie this effect are uncertain.


In addition, studies have shown conflicting results regarding the risk reduction for premature ovarian insufficiency, with better results seen in breast cancer patients compared to those with haematological malignancies.

Finally, a reduction in premature ovarian insufficiency may not result in higher fertility rates.8 Very few studies on the use of GnRH agonists for reduction of chemotherapy-induced gonadotoxicity included pregnancy rates as an end-point, thus evidence for the fertility-preserving potential of GnRH agonists is scarce.

As such, international guidelines are unanimous in stating that because of the limited evidence, GnRH agonists should not be considered an equivalent or alternative option for fertility preservation and should not be used in place of proven fertility preservation methods.8


Patient background

A 24-year-old lady with early-stage Hodgkin’s lymphoma was referred for fertility preservation. She was single and virgo intacta with a good ovarian reserve. She had regular periods with no known gynaecological issues.

The patient was planned to start urgent chemotherapy with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD).

Assessment and counselling

The patient was offered ovarian tissue freezing as there was insufficient time for the ovarian stimulation needed for egg freezing.

She was reviewed by the anaesthetist prior to surgery and was assessed to be low-risk for general anaesthesia. In addition to the operative risks, the patient was also counselled about the risk of ovarian metastasis and reimplantation of the original malignancy with ovarian tissue grafting, although the risk is small with Hodgkin’s lymphoma.

Fertility preservation and chemotherapy

She underwent laparoscopic unilateral oophorectomy and made an uneventful recovery from the surgery. Chemotherapy was started two days post-surgery. GnRH agonist was started on the day of surgery and continued throughout the duration of chemotherapy to reduce the risk of premature ovarian insufficiency.



As cancer survival rates for children and young adults improve and patients are looking to enhance their quality of life after cancer survival, the demand for fertility preservation services will increase. General practitioners may occasionally see young women who have been cured from cancer in their practice.

It is important to be aware that these patients are likely to have a reduced fertility potential compared to their counterparts in the same age group. Many of these patients may not have had the opportunity to receive fertility counselling before starting cancer treatment. Some of these patients may have been offered fertility preservation at the point of diagnosis, but may have been too overwhelmed to pursue any definitive fertility preservation procedures.

For cancer patients who are keen to start a family, the fertility discussion does not stop with cancer treatment. It is equally important to continue this conversation after treatment has been completed, given the limited reproductive lifespan of many of these women.

As long as premature ovarian insufficiency has not occurred, there is still a role for fertility preservation after cancer treatment, although pregnancy outcomes would be expected to be inferior to that before starting cancer treatment.



  1. Rodgers et al. The safety and efficacy of controlled ovarian hyperstimulation for fertility preservation in women with early breast cancer: a systematic review. Hum Reprod. 2017 May 1;32(5):1033-1045.

  2. Zhu et al. Live birth rates in the first complete IVF cycle among 20 687 women using a freeze-all strategy. Hum Reprod, 2018 May 1;33(5):924-929.

  3. Doyle et al. Successful elective and medically indicated oocyte vitrification and warming for autologous in vitro fertilization, with predicted birth probabilities for fertility preservation according to number of cryopreserved oocytes and age at retrieval. Fertil Steril. 2016 Feb;105(2):459-66.e2.

  4. Jensen et al. Outcomes of transplantations of cryopreserved ovarian tissue to 41 women in Denmark. Hum Reprod. 2015 Dec;30(12):2838-45

  5. Gellert et al. Transplantation of frozen-thawed ovarian tissue: an update on worldwide activity published in peer-reviewed papers and on the Danish cohort. J Assist Reprod Genet. 2018 Apr;35(4):561-570.

  6. fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion. Fertil Steril. 2019 Dec;112(6):1022-1033.

  7. Dolmans MM, Masciangelo R. Risk of transplanting malignant cells in cryopreserved ovarian tissue. Minerva Ginecol. 2018 Aug;70(4):436-443.

  8. Blumenfeld Z. Fertility Preservation Using GnRH Agonists: Rationale, Possible Mechanisms, and Explanation of Controversy. Clin Med Insights Reprod Health. 2019 Aug 21;13:1179558119870163


Dr Serene Lim is a Consultant at Singapore General Hospital. She received her specialist accreditation in obstetrics and gynaecology in 2015. In 2018, she was awarded the Health Manpower Development Plan Scholarship by the Singapore Ministry of Health to pursue a one-year fellowship in reproductive medicine and fertility preservation with Professor Kate  Stern at the Royal Women’s Hospital, Melbourne. Dr Lim sees both general obstetrics and gynaecology patients and has clinical interests in reproductive medicine, infertility, fertility preservation, in-vitro fertilisation, pregnancy and​ labour care.


To find out more about our transplant programmes, GPs can contact the SingHealth Duke-NUS Transplant Centre:
Tel: 6312 2720
Email: sd.transplant.centre@singhealth.com.sg