Fertility Preservation in Reproductive Aged Women

Oncofertility is a term that bridges the fields of cancer therapy and reproductive endocrinology and infertility. Our true utility in the field of oncology is to provide newly diagnosed cancer patients the ability to undergo ovarian stimulation, as well as preserve their fertility for the future — prior to starting potentially harmful cancer treatment.

Breast Cancer and Oncofertility

Breast cancer is the most common diagnosis among women referred to oncofertility program for two reasons:

  1. Breast cancer is the most common cancer in reproductive-age women.
  2. The gold standard treatment has been surgery followed by chemotherapy, which provides oncofertility specialists a window of opportunity (approximately 6 weeks) between surgery and adjuvant chemo or radiotherapy.

This critical window affords time for preparation of the patient, including the scheduling of ovarian stimulation and, in some instances, even in managing to complete two fertility preservation cycles.

Conversely, neoadjuvant therapy reverses the order of treatment — chemotherapy is usually initiated first in order to reduce the size of the mass prior to proceeding with surgical intervention. Breast cancer treatment is one example of a growing shift from surgery first to neoadjuvant chemotherapy. Furthermore, the National Comprehensive Cancer Network has outlined clinical scenarios in which neoadjuvant is the preferred approach.

Chemotherapy and Ovarian Dysfunction

The ovarian dysfunction, following chemotherapy in patients with malignant tumors, is affected by the patient's age, ovulatory function at the time of treatment, the type of medications used, and the length of treatment. Alkylating agents, such as cyclophosphamide and ifosfamide, have an especially high risk for ovarian failure. These agents are oftentimes used in most breast cancer protocols due to their efficacy, unfortunately.

On the other hand, other agents, such as antimetabolites (often used in combination with alkylating agents), pose a relatively low risk. The average rate of chemotherapy-related absence of menses is approximately 40% in women aged less than 40 years (depending in egg reserve) and 76% to 95% in women aged 40 or more years after cyclophosphamide, methotrexate, and 5-fluorouracil treatment for at least 3 months. In contrast, four cycles of anthracycline, cyclophosphamide, and paclitaxel lead to amenorrhea (absence of menses) in 13.5% of women younger than 40 years — but 69.9% of women aged 40 to 49 years.

There is no difference in amenorrhea, according to trastuzumab use in patients with human epidermal growth factor receptor 2-positive breast cancer. It is also important to note that these studies address early menopause/amenorrhea after chemotherapy. Unfortunately, even if patients resume their cycles, a large subset of patients may be rendered infertile after completing chemotherapy due to compromised egg quality.

Ideally, fertility preservative ovarian stimulation cycles are completed before exposure of the ovary to these toxic agents.

Concerns with Fertility Preservation

Estrogen Exposure to Patients with Estrogen Responsive Tumors

A concern of patients to undergo fertility preservation resides in the need for ovarian stimulation and the resultant temporary elevation in estrogen (estradiol) levels. Specifically, estrogen-dependent tumors, theoretically, could grow and progress as serum estradiol levels rise with ovarian stimulation — since more follicles/eggs are developing.

However, reassuringly, a strong body of evidence suggests that stimulation protocols that add letrozole, an aromatase inhibitor, have been successfully implemented and keep serum estradiol close to physiologic levels during the cycle. This adjunct medication is also typically used after completion of therapy to keep estrogen levels low in the years following successful treatment of some estrogen-responsive cancers.

As a result, 5-year survival rates after fertility preservation are similar to patients who begin oncology treatment right away without undergoing fertility preservation.

Delay in Chemotherapy Initiation

Another concern for patients is the delay of treatment while awaiting ovarian stimulation; does this negatively impact their future outcomes? One strategy to combat this concern is “random start” ovarian stimulation.

Although in the past, we would have initiated the simulation early in the follicular phase (at the beginning of the cycle), newer protocols enable us to start patients at any point of the cycle. This approach allows physicians to start fertility drugs as early as the same day as the initial consultation at the oncofertility center, thereby eliminating the need to wait for the start of a new menstrual cycle.

Studies reveal that using a random start stimulation protocol in fertility preservation patients who undergo neoadjuvant therapy does not delay treatment. Thankfully, even if the treatment plan is immediate chemotherapy, fertility preservation remains a possibility for patients — since ovarian stimulation cycles are completed within 2 weeks. Studies have also shown no differences in long-term outcomes for patients who have opted to a delayed start of treatment in order to wait to complete their fertility preservation cycles first.

Genetics

Genetic testing panels for inherited cancer can identify genetic mutations that significantly increase cancer risk. The most commonly diagnosed mutations in patients with breast cancer are found in BRCA1 and BRCA2, which are present in 10% of patients less than 40 years of age.

Patients often worry about passing along these deleterious genes to their offspring. However, we now can test embryos before transferring them into the uterus for any genetic conditions. By using preimplantation genetic testing, a biopsy of cells from the blastocyst (day 5 embryo) can be done to analyze DNA for the cancer gene mutation; this allows future transfer of an unaffected embryo, and prevention of inheritance of the mutation by the offspring.

Vitrification

A newer technique of freezing embryos or oocytes (eggs), known as vitrification, has drastically improved future pregnancy outcomes of both embryo and oocyte cryopreservation. Traditionally, freezing eggs or oocytes has been fraught with challenges due to the sensitivity of organelles within the oocytes. Oocyte vitrification has been a game-changer that preserves these structures and results in higher post-freezing survival and fertilization rates.

In fact, frozen eggs at the right fertility preservation program have pregnancy rates equivocal to those of fresh oocytes. The American Society for Reproductive Medicine has deemed oocyte cryopreservation to no longer be experimental, and it is now routinely used in fertility centers for nonmedical reasons. Reassuringly, cryopreservation of embryos has had long-term follow-up--with viable pregnancies, documented in the literature, up to 18 years after freezing!

Newer advances, such as vitrification, have dramatically changed our ability to serve women who are single or with an uncommitted partner; since excellent success rates with egg freezing have obviated the need to create embryos for fertility preservation through the use of donor sperm.

Treatment Options

Ovarian Stimulation

After a diagnosis of breast cancer, there are still options to preserve your fertility. The most effective and standard approach would be to undergo ovarian stimulation. This process takes approximately 2 weeks and is most commonly done after breast surgery and before chemotherapy. As previously mentioned, studies have shown that this delay does not affect long-term breast cancer outcomes.

The process involves the following:

  1. 2 weeks of taking daily injections of follicle stimulating hormone and luteinizing hormone. During this time, you will come for ultrasound and lab visits every few days, for a total of 4-5 visits.
  2. When your ovarian follicles have grown to the appropriate size, you will take a trigger shot.
  3. Then 2 days later, we will perform an egg retrieval under anesthesia, where the eggs are removed vaginally with a needle. The eggs can be frozen at this time or used to create embryos with your partner's sperm.

Our lab is very experienced with the freezing of eggs and embryos. Much of our experience with freezing donor eggs for our donor egg bank, has given us long standing expertise in freezing eggs. We are one of the few select clinics in the country with our own frozen egg bank.

Our excellent and proven success rates with frozen eggs are a prerequisite to maintaining a successful donor egg bank. As such, patients can feel reassured that, unlike other clinics, we have proven success with egg freezing.

Alternative Avenues

If chemotherapy must be started immediately (rare cases of aggressive breast cancer), an injection of depo-lupron is also an option. This injection places you in a medical menopause, theoretically, providing some protection from chemotherapy. Unfortunately, while this modality may improve rates of return to menses, it has not been proven effective in preserving fertility or increasing live birth rates after chemotherapy. As such, this modality is considered experimental by the American Society of Reproductive Medicine.

Ovarian tissue banking is another experimental option. This option is ideal for adolescents who have not yet started menses and is better suited for pediatric cancers. It does provide the advantage of not having to wait 2 weeks for ovarian stimulation, but does require surgical intervention for removal of ovarian tissue.

Fertility Preservation in Atlanta

Whatever your cancer journey is, we at ACRM are here to help you preserve your fertility during a tumultuous time and make the experience as easy and streamlined as possible. With our physicians’ expertise, our state of the art IVF CCRM laboratory, and our diligent and caring staff, we look forward to walking with you every step of the way.

Additional References:

Bines J, Oleske DM, Cobleigh MA. Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol. 1996;14:1718–1729

Burstein HJ, Winer EP. Primary care for survivors of breast cancer. N Engl J Med. 2000;343:1086–1094

Abusief ME, Missmer SA, Ginsburg ES, Weeks JC, Partridge AH. The effects of paclitaxel, dose density, and trastuzumab on treatment-related amenorrhea in premenopausal women with breast cancer. Cancer. 2010;116:791–798

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