Fertility preservation

Fertility preservation is the effort to help cancer patients retain their fertility, or ability to procreate. Research into how cancer affects reproductive health and preservation options are growing, sparked in part by the increase in the survival rate of cancer patients[1].

Indications

Fertility preservation procedures are indicated when it is predicted that there will be exposure to a cause of infertility, mainly cancer treatment.

Cancer treatment

Chemotherapy and radiation treatments for cancer and other serious illnesses can affect reproductive health. The regimens that threaten ovarian and testicular function are mainly radiation therapy to the pelvic area and some types of chemotherapy. Chemotherapies with high risk include procarbazine and alkylating drugs such as cyclophosphamide, ifosfamide, busulfan, melphalan, chlorambucil and chlormethine.[2] Drugs with medium risk include doxorubicin and platinum analogs such as cisplatin and carboplatin.[2] On the other hand, therapies with low risk of gonadotoxicity include plant derivatives such as vincristine and vinblastine, antibiotics such as bleomycin and dactinomycin and antimetabolites such as methotrexate, mercaptopurine and 5-fluoruracil.[2]

These regimens attack rapidly dividing cells in the body, including healthy cells like sperm and those belonging to the ovarian follicle (egg). Depending on the dose and duration of administration, these therapies can have varying effects on reproductive health. Surgery involving reproductive tissue affects reproductive function and fertility.

For many cancer patients, the decrease or loss of reproductive function is temporary; many men and women, however, do not regain fertility after cancer treatment. Patients undergoing serious radiation, chemotherapy, or surgery sometimes experience symptoms resembling menopause (in women) or andropause (in men), which indicate reproductive damage. In women, decreased estrogen levels as a result of ovarian deficiency lead to weakened bone, changes in temperature control, altered mood, and decreased sexual desire. Men with testicular insufficiency also experience similar symptoms.

A study indicated that fewer oocytes are recovered from cancer patients wanting to perform embryo preservation when compared with an age-matched control group, but the mean number of zygotes generated appears to be similar.[3] The same study found that, of 65 patients referred to the program, 28% declined to undergo embryo, oocyte, or tissue cryopreservation. 9% were found not to be eligible for medical reasons. Of the remaining 41 patients, 85% chose to cryopreserve embryos, 10% chose to cryopreserve oocytes, and 5% chose to undergo ovarian tissue freezing.[3] No serious clinical sequelae resulted from participation.[3]

In women with cancer, a testing for the level of anti-Müllerian hormone (AMH) is useful in predicting the long-term post-chemotherapy loss of ovarian function, in turn predicting the need for fertility preservation strategies.[4]

Aging

Fertility preservation, such as ovarian tissue or oocyte cryopreservation, may also be used to prevent infertility, as well as birth defects, associated with advanced maternal age.

Methods

The main methods of fertility preservation are ovarian protection by GnRH agonists, cryopreservation of ovarian tissue, eggs or sperm, or of embryos after in vitro fertilization.[5] The patient may also choose to use egg or sperm from a donor by third party reproduction rather than having biological children.

Semen cryopreservation
Further information: Semen cryopreservation

Men hoping to preserve their fertility before undergoing treatment for cancer or another fertility-threatening disease can cryopreserve, or freeze, their sperm, which can be obtained through masturbation in post-pubescent boys and men. This is the most established fertility preservation method for males. For pre-pubescent boys, sperm can be obtained through testicular aspiration or electrostimulation and then stored for future use. Researchers are also looking at methods for cryopreserving testicular tissue samples so that they can be re-implanted into the body after treatment.

Cryopreservation of ovarian tissue or oocytes
Further information: Oocyte cryopreservation and Ovarian tissue cryopreservation

Some female patients choose to have mature eggs extracted and fertilized outside of the body with sperm from a partner or donor. The resulting embryo is then frozen until the woman is in remission from disease. When the woman is ready to initiate pregnancy, the embryo is thawed and implanted into the uterus for maturation and birth. While this option is the most common fertility preservation method in women, it is not available to pre-pubescent girls, who do not have mature eggs that can be fertilized. Women who do not have a partner will need to use donor sperm. Additionally, because this procedure requires a two-week period of hormonal stimulation to encourage egg maturation, it is not optimal for female patients who are diagnosed with hormone-sensitive cancers (such as breast cancer, ovarian cancer, etc.) or those who cannot delay cancer treatment. Alternative methods of hormonal stimulation using letrozole or tamoxifen may be used for women with hormone-sensitive cancers.

Strips of cortical ovarian tissue can also be cryopreserved, but it must be re-implanted into the body to allow the encapsulated immature follicles to complete their maturation. Furthermore, ovarian tissue is fragile under hard freezing conditions and putting it back into the body carries the risk of re-introducing cancerous cells. In vitro maturation has been achieved experimentally, but the technique is not yet clinically available.[6] With this technique, cryopreserved ovarian tissue could possibly be used to make oocytes that can directly undergo in vitro fertilization.[6]

Third-party reproduction

Many patients diagnosed with a malignancy or another disease requiring treatment that may impair their fertility consider alternatives to bearing biological children, such as assisted reproductive technology (ART) using in vitro fertilization (IVF) with donor eggs or donor sperm. The resulting embryo can be implanted into the woman's uterus after her endometrium (the lining of the uterus) is stimulated with hormones to prepare for the development of the embryo.

Others

In women requiring local pelvic radiation therapy may benefit from surgical transposition of the ovaries to a site remote from maximal radiation exposure.[7][8]

The use of GnRH agonists for ovarian protection during chemotherapy is suggested to benefit the ability to ovulate, but benefits in terms of e.g. pregnancy rate are lacking.[7]

Adverse effects

Compared with the general population, people with cancer have a higher risk of arterial thrombotic events such as stroke, myocardial infarction and peripheral arterial embolism. This risk has a potential to be further increased in women undergoing controlled ovarian hyperstimulation for fertility preservation, but is usually only associated with cases of ovarian hyperstimulation syndrome (OHSS). On the other hand, venous thromboembolism rarely occurs unless a pregnancy is achieved, and is therefore usually not particularly relevant in the stage of oocyte retrieval.[9] Therefore, the recommended controlled ovarian hyperstimulation protocol for in women with cancer is an antagonist protocol using a GnRH agonist for final maturation induction, in order to decrease the risk of OHSS.[9] When used in conjunction with oocyte or embryo cryopreservation, using GnRH agonist rather than hCG for final maturation induction has no evidence of a difference in live birth rate (in contrast to fresh cycles where usage of GnRH agonist has a lower live birth rate).[10] Anticoagulant prophylaxis is recommended to be administered only to selected subgroups of women such as those with other risk factors of hypercoagulability or those who do develop early OHSS.[9]

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References
  1. King, David; Lane, Shelia; Yeomanson, Daniel (15 May 2020). "Fifteen-minute consultation: Fertility preservation in children with cancer". Archives of Disease in Childhood - Education and Practice: edpract-2019-318619. doi:10.1136/archdischild-2019-318619.
  2. Brydøy M, Fosså SD, Dahl O, Bjøro T (2007). "Gonadal dysfunction and fertility problems in cancer survivors". Acta Oncol. 46 (4): 480–9. doi:10.1080/02841860601166958. PMID 17497315.
  3. Klock, S.; Zhang, J.; Kazer, R. (2010). "Fertility preservation for female cancer patients: early clinical experience". Fertility and Sterility. 94 (1): 149–155. doi:10.1016/j.fertnstert.2009.03.028. PMID 19406395.
  4. Broer, S. L.; Broekmans, F. J. M.; Laven, J. S. E.; Fauser, B. C. J. M. (2014). "Anti-Mullerian hormone: ovarian reserve testing and its potential clinical implications". Human Reproduction Update. 20 (5): 688–701. doi:10.1093/humupd/dmu020. ISSN 1355-4786. PMID 24821925.
  5. Cruz, M.; Prestes, J.; Gimenes, D.; Fanelli, M. (2010). "Fertility preservation in women with breast cancer undergoing adjuvant chemotherapy: a systematic review". Fertility and Sterility. 94 (1): 138–143. doi:10.1016/j.fertnstert.2009.02.055. PMID 19339000.
  7. American Society for Reproductive Medicine: Practice Committee of American Society for Reproductive Medicine (2013). "Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: A committee opinion". Fertility and Sterility. 100 (5): 1214–1223. doi:10.1016/j.fertnstert.2013.08.012. PMID 24011612.
  8. Irtan Sabine, Orbach Daniel, Helfre Sylvie, Sarnacki Sabine (2013). "Ovarian transposition in prepubescent and adolescent girls with cancer". Lancet Oncol. 14 (13): 601–8. doi:10.1016/S1470-2045(13)70288-2. PMID 24275133.CS1 maint: multiple names: authors list (link)
  9. Somigliana, E.; Peccatori, F. A.; Filippi, F.; Martinelli, F.; Raspagliesi, F.; Martinelli, I. (2014). "Risk of thrombosis in women with malignancies undergoing ovarian stimulation for fertility preservation". Human Reproduction Update. 20 (6): 944–951. doi:10.1093/humupd/dmu035. ISSN 1355-4786. PMID 25013217.
  10. Youssef, Mohamed AFM; Van der Veen, Fulco; Al-Inany, Hesham G; Mochtar, Monique H; Griesinger, Georg; Nagi Mohesen, Mohamed; Aboulfoutouh, Ismail; van Wely, Madelon; Youssef, Mohamed AFM (2014). "Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist-assisted reproductive technology". Reviews (10): CD008046. doi:10.1002/14651858.CD008046.pub4. PMID 25358904.

Further reading
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