Preservation of Fertility
Living Beyond Cancer
NYCIVF Personal & Innovative Fertility Care
Preservation of Fertility ÂŠ 2010 Amr Azim, NYCIVF. Preservation of fertility after the diagnosis of cancer and other allied conditions is a complex task requiring careful evaluation of risks and benefits. The information contained in this document is not intended or implied to be a substitute for professional medical advice, diagnosis or treatment. All content, including text, graphics, images and information, contained in this document is for general information purposes only. Please consult with your physician about the risks and success of fertility preservation issues before pursuing or declining any option for preservation of fertility. This work is available for download for educational purposes only by actual patients and their families. No part of this work should be copied for profit purposes, distribution or production in different format without writen permission from the author. 10 9 8 7 6 5 4 3 2 1
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Table of Contents 1
Preservation of Fertility in Women
Who needs preservation of fertility. . . . . . . . . . . . . . . . . . . . . . 1 Effects of cancer treatment on future fertility. . . . . . . . . . . . . . . . . 2 Ovarian function after exposure to chemotherapy & radiotherapy. . . . . . . . 3 Methods used for preservation of fertility. . . . . . . . . . . . . . . . . . . 3 Genetic Perspective. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Coordination of treatment and preservation of fertility . . . . . . . . . . . . . 8 Real Cases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Pregnancy after breast cancer. . . . . . . . . . . . . . . . . . . . . . . . 9 2
Preservation of Fertility in Men
Who needs to consider preservation of fertility . . . . . . . . . . . . . . . . . 11 Methods used for preservation of fertility . . . . . . . . . . . . . . . . . . 12
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Preservation of Fertility in Women
Fertility is a key aspect for quality of life for cancer patients of childbearing age. Preservation of fertility is defined as the application of medical, surgical and laboratory procedures to preserve the potential of genetic parenthood in adults and children at risk of sterility before the end of natural reproductive lifespan (Gosden 2009). Decrease or loss of fertility can take place due to exposure to medication (chemotherapy), radiation or surgery (e.g. Removal of the ovaries). The American Cancer Society estimates that cancer affects one in each 3 women living in the United States. Modern cancer treatment commonly involve exposure to chemotherapy and sometimes pelvic radiation.
a. In 2009 about 700,000 women will be diagnosed with cancer, about 10% of them under the age of 45. Breast cancer is the most common cancer affecting women.
Cancer and its treatment though is not the only situation that affect fertility. Fertility can also be diminished by bone marrow transplantation and treatment of kidney disease usually due to lupus. If you are a women or a man living in the United States and recently diagnosed with cancer or another condition that threatens your future ability to mother or father children, this bulletin is writen with you in mind. The odds are you will beat your disease and survive for many years to come. Considering fertility-sparing before starting disease treatment may greatly enhance your ability to conceive a biological child after cure.
Who needs to consider preservation of Fertility?
Proportion of cancer by site in women. (From American Cancer Society, 2009)
Each year bout 15,000 women will be diagnosed with breast cancer before 45year Women can also be diagnosed with leukemias, lymphomas, cancer of the colon, uterus, ovary, skin or thyroid gland. Treatment of all these cancers is associated with long term effects during the survivorship period including decline in fertility. The effects of cancer treatment go beyond the harm caused by the method of treatment itself to the time spent in treatment and time needed for follow up. This delay
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means women will probably attempt pregnancy several years later than they intended. b. Women undergoing bone marrow transplantation for treatment of cancer, anemias (e.g. Sickle cell disease) and other diseases. The use of chemotherapy and radiation prior to transplantation is usually associated with fertility loss in the vast majority of patients. c. Some women develop breast or ovarian cancers due to abnormality in breast cancer gene (BRCA1 & 2). Reducing the risk of future cancer may require removal of both ovaries with loss of fertility. d. Women diagnosed with connective tissue disease (Systemic lupus, rheumatoid arthritis...) or autoimmune disease may have severe disease affecting their organs (e.g. Kidney). Chemotherapy is sometimes used to suppress their immunity which may lead to fertility decline. Moreover, the antibodies generated by the disease process may directly affect ovarian function. e. Individuals exposed to accelerated loss of eggs due to genetic disease (e.g. Mosaic Turner syndrome) can also benefit from preservation of fertility f. Fertility extension. Women delaying pregnancy for career or social reasons (no male partner at this time) can consider freezing their eggs or embryos (using donor sperm). This option was not studied in large population studies.
Cancer treatment (chemotherapy, radiation and bone marrow transplantation) will not only diminish fertility by accelerating loss of oocytes but also by delaying attempts to become pregnant for years
Effects of Cancer Treatment on Ovarian Function In general the younger the woman, the more oocytes she harbors in the ovary and the higher the likelihood that some oocytes will remain in the ovary after treatment. A. Chemotherapy and the Ovary. The use of chemotherapy can lead to fast loss of oocytes (eggs). Oocytes carry the genetic material that women pass to their children after fertilization by a sperm. The effect of these agents is variable depending on the drug, dose, frequency of administration, and age of the woman at the time of treatment. Cyclophosphamide is the most harmful agent for future fertility. These medication appear to cause loss of eggs through damage of its DNA and inducing spontaneous demise of the egg. There is no proven method that can prevent this loss. B. Pelvic Radiation and the Ovary. Exposure of the ovary to radiation can damage the eggs and the remaining tissue of the ovary. The amount of radiation that leads to complete loss of ovarian function is dependent on the age. A dose of 1500cGy will sterilize the majority of women at age 30. Smaller doses will sterilize older women. C. Time factor. Cancer treatment usually requires several months. For some cancers (e.g. Breast cancer) medical treatment (tamoxifen) is required for 2 to 5 years after surgery and chemotherapy. For others oncologists recommend a period of observation for 1 to 2 years. This will a womanâ€™s plan to start a family to a later age when fewer oocytes remain in the ovary. Actually the effect of cancer treatment on the ovary appears to be similar. Continuous loss of eggs from
the ovary takes place in all women. Cancer treatment accelerates this loss so that the number of eggs in the ovary would correspond to older age. D. Pelvic Radiation and the Uterus. Exposure of the uterus to radiation increases the risk of miscarriage, preterm labor and abnormal pregnancy outcome.
Evaluation of Ovarian Function after Cancer Treatment Although many think that resumption of menstruation after cancer treatment indicates that the woman retains the ability to conceive, this is not true. Some women have regular menses with near exhaustion of the eggs in the ovaries. Thus, menstruation is not a reliable indicator of the ability to conceive. The function of the ovary before after cancer treatment can be evaluated using hormone tests and ultrasound. ♦♦
Cycle day 2 or 3 FSH (normal is less than 12mIU/mL)
Antimullerian hormone (AMH). This is a new and promising marker and appear to be more accurate than the other markers.
Vaginal ultrasound to evaluate the number of small follicles visible in the ovary.
Although these markers are more accurate than menstrual history, normal markers after treatment does not mean that ovarian function is completely preserved after exposure to treatment.
Women exposed to chemotherapy exhibit a much lesser response to medications that stimulate egg production in the ovary than women presenting before exposure to chemotherapy, hence the importance of considering preservation of fertility early after cancer diagnosis.
Methods used for Fertility Preservation Methods used to preserve fertility in women are generally divided into three categories:
Modification of cancer treatment plan to reduce damage to the ovaries and uterus: 1. Preserving one ovary in women affected with early ovarian cancer. 2. Preservation of the body of the uterus with removal of the cervix in early cervical cancer. 3. Use of progesterone treatment instead of removal of the uterus in endometrial cancer.
Protection of the ovaries from the damage caused by cancer treatment: 1. Ovarian transposition is a surgical procedure to
move the ovaries upwards, away from radiation field before pelvic radiation. Results are variable as some scattered radiation still reaches the ovaries. 2. Protection of the ovaries from the effect of chemotherapy. GnRH agonists are a group of medications that suppress the master gland in the brain, preventing the release of the hormones that stimulate development of follicles in the ovaries. Although suggested, there is no proof that they actually protect the ovaries and improve the chance of pregnancy after the use of chemotherapy.
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Low Temperature Storage of Embryos, Oocytes or Ovarian Tissue: a. Embryo Freezing. This is considered the standard method for preservation of fertility. Its suitable for women with a male partner or accepting the use of donor sperm and when cancer treatment does not need to be started immediately. This method entails stimulation of the ovary with medications and frequent monitoring of response using ultrasound and blood work. This stimulation usually requires 12 to 14 days. The eggs are then removed from the ovary by an outpatient procedure under sedation. Egg retrieval requires passing a needle through the vagina into the ovary. Eggs are then fertilized in the lab and the resulting embryos are frozen 2 to 6 days later and stored for later use. Cancer treatment can start immediately after egg retrieval. After cure, women can request to use their embryos, that are placed back into the uterus after simple preparation of the lining of the uterus. The transfer of two embryos into the uterus yields a pregnancy rate of about 30%.
special attention. The use of fertility medication is usually associated with considerable rise in estrogen levels. One potential risk of estrogen rise, though not proven, is increase in activity of cancer cells. This is addressed during stimulation by adding a medicine (letrozole) that blocks the enzyme that makes estrogen in the ovaries, so that stimulation with gonadotropins can progress without increase in estrogen. When the follicles (the bag that contain the eggs) reach adequate size, final maturation is triggered using another hormone, hCG. This is followed by egg harvest. The safety of this method for stimulation of the ovary was studied. We compared women presenting for ovarian stimulation after the diagnosis of breast cancer with women diagnosed with breast cancer and declined ovarian stimulation. The follow up period was approximately 2 years. There was no increase in breast cancer recurrence between both groups (Azim et al , Journal of Clinical Oncology 2008). Although further follow up is required, results so far are reassuring that this method is probably safe.
Women diagnosed with an estrogen sensitive tumors (e.g. Breast cancer, uterine cancer) require
hCG GnRH antagonist FSH/hMG Letrozole
Protocol for stimulation of the ovaries in women diagnosed with breast or endometrial cancer.
egg at thawing. The egg is placed in a solution that prevents damage caused by ice crystals (cryoprotectant) and then stored in liquid nitrogen at -170.
Embryo freezing is the standard method for preservation of fertility in women with male partner (or using a donor sperm) and when cancer treatment does not need to be started immediately. For women not diagnosed with estrogen sensitive cancer (e.g. Lymphoma) or those at risk for decline of fertility due to non-cancer conditions, standard methods for ovarian stimulation are used. The ultimate success of this option is dependant on the number and quality of embryos produced which is related to womanâ€™s age and ovarian function at the time of stimulation. Cancer diagnosis in itself does not appear to affect success provided stimulation is started before cancer treatment.
Three oocytes frozen in a small film of fluid.
After cure some women transfer the embryos to their own uterus or to a gestational carrier. b. Oocyte Cryopreservation (egg freezing). It is considered for women with no male partner and declining the use of donor sperm. It requires stimulation of the ovaries and egg harvest as described earlier. The human egg is unique. Its the largest cell in the body with high water contents. The membrane surrounding the cell is not very permeable. Moreover, its the only cell in the body where chromosomes are spread on flimsy structure called the spindle, rather than being enclosed inside the nucleus of the cell. The egg requires special expertise to freeze. Two techniques are used; slow freezing or vitrification (rapid freezing). The newer vitrification method has the advantage of avoiding the formation of ice crystals inside the egg and yields better survival of the
The success rate for egg freezing based in all published reports in the world are given below. In general 2/3 of eggs frozen using slow freezing method survive compared to about 90% of oocytes frozen by vitrification method. After thaw, the eggs need to be fertilized using intracytoplasmic sperm injection (ICSI). About 70 to 90% fertilization rate is expected. Embryos are cultured to day 3 stage or blastocysts before transfer. Each thawed egg yield about 2-3% pregnancy rate after slow freezing and about 8 to 10% when vitrification was used. Transfer
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The only caveat to vitrification is that this method has not been around long enough to ascertain its safety.
Cleavage stage (day 3) embryo.
c. Ovarian Tissue Freezing. This is an experimental method for preservation of fertility. In this method one ovary is removed, processed and frozen. After cure, the ovary is transplanted back in the pelvis (orthotopic) or under the skin (heterotopic). Processing of the ovary means that the outer 2-3mm (this is the part that contains the eggs-the cortex) is shelled out and cut into thin strips. So far the ovary cannot be frozen as a whole organ because its too thick for cryoprotectants (the substance that protects the tissue from damage caused by freezing) to diffuse into it before freezing. Removal of the ovary is performed using laparoscopy (minimal access surgery) or at the time of surgery for other indication. The inner part of the ovary (does not contain eggs) is sent for tissue examination to make sure it does not contain any malignant cells. Since ovarian harvest can be accomplished in 1 to 2 hours, this method is used when there is no time to complete ovarian stimulation (2 to 3 weeks) or when stimulation of the ovary is not possible as in girls before puberty. Because of the experimental nature of the procedure, its offered to women with very high risk for ovarian failure after treatment. The main risk for transplantation is transferring cancer cells in the graft leading to recurrence of cancer. Although possible, no such case was reported thus far. Worldwide, several hundred women froze their ovaries. So far much smaller number came back for transplantation. There were eight babies born after transplantation. (Belgium 1, Israel 1, Spain 1, Denmark 5) All the ovaries resulting in live births were transplanted in the pelvis.
Blastocyst stage (day 5-6) embryo.
Vitrification is a very promising method for egg freezing. It yields outcome comparable to embryo freezing.
of two to three embryos can yield a pregnancy rate similar to that obtained after embryo thawing.
Oocyte cryopreservation; World Experience Slow freezing
(EG 2.7M+DMSO 2.1M+sucrose 0.5M)
Oocytes injected with a sperm
Clinical Pregnancy per oocyte thawed
16.8% Amr Azim, MD, FACOG
d. In Vitro Maturation of Oocytes. In this method a very short ovarian stimulation for 3 to 5 days is performed followed by retrieval of immature eggs. Eggs are then matured in the lab, fertilized and the resulting embryos are frozen for later use. The efficiency of this method is lower than retrieving fully mature oocytes. About 50% of follicles punctured yield an egg. Approximately 70% of the eggs reach maturity in the lab and about 70% of those fertilize with ICSI. This method is suitable for women demonstrating high response to stimulation to fertility medication.
Genetic susceptibility to cancer is now recognized for a number of malignancies. The most famous is breast cancer susceptibility genes BRCA1 &2. Women diagnosed with cancer that associated with mutation of one of the known genes are at risk for passing this gene to her future children. If a woman is a carrier of one of these known genes, the effort to preserve her fertility can be combined with testing of oocytes or embryos to prevent the transmission of the gene to her children. Pre-implantation genetic diagnosis (PGD) is a techniques where one or few cells from an embryo can be analyzed for specific genetic information. The majority of cancer susceptibility genes can be detected in the embryo, so that affected embryos can be excluded from transfer back to the uterus. Not all women though accept screening or embryo testing.
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Some Genetic syndromes with increased susceptibility to cancer
Questions to ask
*Type of cancer *Stage *Treatment plan 1. Surgery 2. Chemotherapy 3. Bone marrow transplant 4. Radiotherapy 5. Hormonal treatment *Is Preservation of fertility suitable for me?
Ask for a referral letter Obtain medical records; Surgery records Pathology records Other tests; ER, PR, her2/neu, BRCA General medical tests
*How is cancer and cancer treatment expected to impact future my fertility? *What are the suitable options for preservation of fertility? Embryo freezing Oocyte freezing Ovarian tissue freezing Others Combination *Is it safe? *What to do with the frozen embryos, eggs or tissue after cure *What is the success rate for my options
Blood work; FSH, estradiol, AMH Ultrasound Semen analysis Other general tests required for IVF and cell and tissue freezing Referral for genetic counseling Coordinate fertility preservation plan with the oncologist
Psychologist How to deal with stresses of treatment
Make an appointment
E.g. fertilehope.org livestrong.org youngsurvival. org lbbc.org
Women interested in preservation of fertility should be counseled about the availability of genetic screening pertaining to their cancer and if carriers about PGD to avoid transmission to future children.
Coordination of Cancer Treatment and Preservation of Fertility Multiple studies in the US surveying patients or oncologists found that discussion and referral for preservation of fertility takes place in less than 50% of patients. Referral was more likely when patients inquire about fertility issues. This underlines the importance of educating women about fertility issues and the diagnosis of cancer and other allied diseases. Empowering women to ask questions appears to one of the most important initial steps to receive appropriate information about and possibly pursue preservation of fertility. Collecting information and coordination of care between providers concerned with cancer treatment and those that deal with preservation of fertility can be a demanding task, especially at difficult and busy times. The table below aims at organizing your thoughts and collecting information about the feasibility of preservation of fertility after diagnosis, before making a decision to pursue these options or to bypass them and proceed directly to disease treatment.
Help with referral Help with medications
Things to do
Real Cases Breast Cancer 1. A 28 year old Caucasian system analyst presented with her partner shortly after the diagnosis of duct carcinoma of the breast. The tumor was stage II after lumpectomy and axillary lymph node sampling and was estrogen receptor positive. Her treatment plan per her oncologist was 4 cycles of cyclophosphamide, adriamycin and taxol followed five years of tamoxifen. She was counseled to the effect of chemotherapy on ovarian function. The risk for ovarian failure is about 30%. Time factor also should be considered (she will be 35 by the time she could attempt pregnancy). The possibility of underlying genetic factor was also discussed and breast cancer gene testing was offered (she turns out to be BRCA1 and 2 negative). As she had a steady partner, she was offered ovarian stimulation using letrozole and gonadotropins followed by oocyte retrieval and embryo cryopreservation. The risks and benefits of this approach was discussed in details. She accepted this option and so did her oncologist. After retrieval, 6 blastocysts were frozen within 18 days. She completed cancer treatment and her period stopped after chemotherapy and did resume yet. 2. A 37 year old mathematician presented shortly after the diagnosis of stage I, estrogen receptor positive breast cancer. She does not have a partner. The size of the tumor was small that her oncologist did not recommend chemotherapy. She, however, recommended 5 years of tamoxifen. This delay in attempting pregnancy (she would be 42 at the end of treatment) and because she declined the use of donor sperm, she was offered egg freezing. With the approval of her oncologist, she underwent two cycles of egg freezing and 10 eggs were cryopreserved after each cycle by vitrification. She is in good health so far.
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Colon Cancer A 34 year old presented with her husband after a recent diagnosis of colon cancer. Her planned treatment was chemotherapy, pelvic radiation followed by surgery. She wanted to preserve the ability to have biological children. She was counseled that 1. Chemotherapy used for colon cancer has mild or no long term effects on future ovarian function 2. Pelvic radiation at the planned dose, however will very likely result is complete cessation of ovarian function 3. Pelvic irradiation will likely damage the tissue of the uterus so that pregnancy would not be safe. She was offered a combined approach to preserve her fertility 1. Ovarian stimulation and egg retrieval and embryo freezing 2. Laparoscopic surgery to move one ovary upwards away from radiation field 3. Harvest of the other ovary during the same surgery and freezing it for later transplantation. She accepted only ovary stimulation and embryo freezing. This was performed after consulting with her oncologist and 20 blastocysts were frozen. After radiation, her menses stopped. She came back with her to use the embryos. One embryo was transferred to the uterus of her sister resulting in pregnancy and delivery of healthy baby.
Pregnancy after Breast Cancer
Is it safe to get pregnant after treatment for breast cancer? It is the general consensus that pregnancy after treatment and a follow up period of 6 months to two years is not associated with increase in the odds for breast cancer recurrence. Most oncologists advise their patients to wait for a variable period after treatment before attempting pregnancy. Recent evidence from multiple studies including a large Danish study indicated that there is no evidence
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that pregnancy after breast cancer diagnosis increases the risk of poorer outcome. Remember that the use of a gestational carrier is always an option for women that do not want to or cannot get pregnant in their own uterus.
The vast majority of young cancer survivors view themselves as potential parents. Inquiring about survivorship issues including fertility increases the odds that you will referred for counseling and subsequently become informed about your options.
Further Reading 1. Azim et al. Safety of Fertility Preservation by Ovarian Stimulation With Letrozole and Gonadotropins in Patients With Breast Cancer: A Prospective Controlled Study. Journal of Clinical Oncology 2008, 28(18):2630-5. 2. Gook & Edgar. Human oocyte cryopreservation. Human Reproduction 2007,13(6):591-605. 3. Lee et al. American Society of Clinical Oncology Recommendations on Fertility Preservation in Cancer Patients. Journal of Clinical Oncology 2006. 4. http://ulmanfund.org/Portals/0/files/Education/NoWay.pdf
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Preservation of Fertility in Men
Like women, men are also diagnosed with diseases that directly or by virtue of their treatments impair future fertility. Recognition of these diseases enables timely counseling and effort to preserve male germ cells. This is specially important since the intervention to preserve future fertility in men is easier and less invasive compared to women. 50–70% of men diagnosed with cancer wanted children in the future. Only 24% of young cancer patients banked sperm, including 37% of childless men. The most common reason for failing to bank sperm was a lack of information.
Who needs to consider preservation of Fertility? a. The American Cancer Society estimates that 760,000 men will be diagnosed with cancer in 2009. Cancer itself (before treatment) is known to be associated with less sperm production in men. This is specially the case in Hodgkin’s lymphoma, testicular cancer, leukemias and colon cancer. Cancer treatment (chemotherapy and radiation) also significantly impair sperm production. The effect of chemotherapy depends on age, drug used, dose and duration. Cyclophosphamide appears to be the most harmful agent. Radiation also impairs sperm production especially at doses of 1200cGy or more.
Sperm count sometimes recover to a variable extent years after cancer treatment. This depends on the type of cancer and treatment used. For example 90% of men diagnosed with Hodgkin’s lymphoma, treated with MOPP chemotherapy regimen, do not have any sperm in the ejaculate after one year. b. Bone marrow transplantation for cancer of nonmalignant diseases usually require prior irradiation and chemotherapy. This is associated with high risk (85%) of complete failure of sperm production. c. Connective tissue / autoimmune diseases as lupus and rheumatoid arthritis requiring treatment with chemotherapy. d. Genetic abnormalities associated with rapid loss of male germ cells e.g. Kleinefelter syndrome, Y chromosome microdeletion (AZFc).
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Methods used for Fertility Preservation Methods used to preserve fertility in men are generally divided into two categories:
Protection of the testes from damage caused by cancer treatment: 1. Shielding the testes from radiation field. 2. Protection of the testes from the effect of chemotherapy. GnRH agonists are a group of medications that suppress the master gland in the brain, preventing the release of the hormones that stimulate sperm production in the testes. Although suggested, there is no proof that they actually increase the odds for pregnancy after the use of chemotherapy.
There is no effective protective medication available for use in humans.
Low Temperature Storage of Sperm and Testicular Tissue: a. Sperm Cryopreservation.
This is the standard method for preservation of fertility in men. A sperm sample is obtained by masturbation and frozen for later use. If feasible multiple samples are obtained. In the future sperm sample are used for intrauterine insemination or IVF / intracytoplasmic sperm injection (ICSI). Banking sperm was found to offer not only a chance to father children in the future but also encouragement and improved morale during disease treatment especially if it was initiated by the patient own initiative. Lack of information and counseling is the most important reason why men diagnosed with cancer do not bank thier sperm. Although freezing may reduce the quality of sperm especially if it was not optimal before freezing,
modern reproductive medicine can handle the majority of compromised specimens yielding excellent pregnancy rates, similar to those of fresh sperm. b. Testicular Sperm Extraction (TESE). This surgical procedure retrieves sperm from inside the testes if no sperm was found in the ejaculate. If this procedure is used before cancer treatment, sperm are retrieved in over 50% of cases. Sperm or testicular biopsies are frozen for later use. ICSI is used for fertilization. In case of testicular cancer, sperm retrieval can be performed at the same time of surgery for cancer. c. Testicular Tissue or Germ Cell Freezing. This is an experimental technique. Immature germ cells or testicular pieces are frozen for later transplantation. No pregnancy was achieved using this method so far. In conclusion, fertility-sparing strategy is readily available to the majority of men at risk for diminished fertility through sperm cryopreservation. Men interested in fathering children in the future should be counseled about this option.
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NYCIVF Personal & Innovative Fertility Care