Fertility Consultation with a Reproductive Endocrinologist

A reproductive endocrinologist is a specialist trained in helping women / couple get pregnant. Careful preparation for fertility consultation and adequate time devoted to the encounter itself can help identifying infertility factors and pointing to the most cost-efficient fertility treatment.

Who should consider fertility consultation?

1. Women or couple not able to conceive after two years (female age <35 years), one year (female age >35 years) or 6 months (female age >40 years) especially after repeated unsuccessful attempts at timed intercourse or simple treatment (e.g clomid)

2. Women with known fertility factor (no ovulation, endometriosis or tubal disease / pelvic scarring, fibroids..)

3. Men with known fertility factor (decrease count, motility or morphology of sperm, difficulty with ejaculation or erection)

4. Women or men who are at risk for reduced fertility due to disease or disease treatment (e.g. cancer, cancer treatment, chemotherapy, lupus, prior surgery, irregular menses or absence of menstruation)

5. Recurrent pregnancy loss in the first or second trimester of pregnancy

6. Women or men known to be carriers of genetic disease, conceived in a baby affected with a genetic disease or with family history of genetic problems (e.g. chromosomal abnormality, sickle cell disease, BRCA carrier..)

7. Other indications: same sex couple, individuals desiring pregnancy through donor sperm or donor oocytes, women desiring fertility extension through social egg freezing

Preparation before fertility consultation

Collect prior medical documents 1. Sperm analysis 2. Hysterosalpingogram (HSG) report and films if available 3. Lab tests 4. Genetic consultations if any 4. Medical reports from your physician about any significant disease 5. Operative reports of any abdominal or pelvic surgery. Allot 1.5 hours for the consultation and write down any questions that come to your mind.

During Consultation

Structured consultation with  a reproductive endocrinologist consumes approximately 60 to 90 minutes. Components of encounter include

1. History: to review information related to ovarian, tubal and male factors of infertility as well as medical, surgical and personal histories. Detailed family and genetic history is essential to identify and possibly test for risk factors of genetic disease in the newborn.

2. Examination including general, abdominal and pelvic examination

3. pelvic ultrasound aiming at detecting abnormalities in the uterus, ovaries and the pelvis. Ultrasound is an excellent tool to estimate ovarian reserve–antral follicle count.

4. Explaining the required tests needed to investigate ovarian reserve, male and tubal factors as well as prenatal tests required of any woman attempting to conceive.

5. Outlining a provisional plan for investigation and treatment of infertility.

All the required tests can be finalized within 2 to 3 weeks, enabling the person or couple to make informed decision about the next step in fertility treatment

 After Consultation

Before making any treatment decisions concentrate on completing the required investigation including sperm analysis, test for tubal patency (HSG) and tests for ovarian reserve. Prenatal tests before attempting to conceive including reproductive hormone assay, infectious disease profile and genetic screening tests should also be obtained.

A second visit or phone call with your reproductive endocrinologists outlining the results of fertility tests is highly advisable. Based on theses tests, treatment plans are finalized.

Five points to consider before starting treatment

1. Time commitment: Fertility treatment may require multiple visits over several months. Its important that visits are tailored around your schedule with minimal time off work.

2. Cost is also an important consideration as well as resources available to help you.

3. Potential undesired outcome especially multiple pregnancy. For example women desiring only a singleton pregnancy should lean towards IVF with single embryo transfer rather ovulation induction with gonadotropin injections.

4. Risk of pregnancy in older women and women with medical disorders

5. Is surgery required before fertility enhancing treatment e.g. removal of polyps or fibroids

If you decide to pursue treatment you need to be advised of the schedule of treatment cycle, type and self administration of medication.

After achieving pregnancy

You should undergo all recquied pregnancy screening including screening for abnormal chromosomes in the fetus, amniocentesis of chorionic villous sampling-CVS even if preimplantation genetic diagnosis-PGD was done on embryos as well as consult with high risk obstetrician if needed.

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Fertility and Fertility Preservation-Beware of What You Read

Fertility treatment especially assisted reproductive technology-IVF enabled many women to achieve pregnancy even those with the most difficult cases of infertility. Advances include ICSI-injection of a single sperm into an egg ,  PGD-biopsy of embryos and polar bodies for genetic diagnosis, of specific genetic diseases, prolonged culture of embryos to blastocyst stage-day 5 to 7 and TESE-surgical sperm retrieval.

Meanwhile, a new host of fertility treatments emerged in the past 10 or so years that were not thoroughly studied including egg freezing, ovarian tissue freezing and transplantation, IVM-in vitro maturation of oocytes, PGS-preimplantation genetic screening for chromosomal abnormalities in the emryo or oocyte and generation of ‘artificial’ eggs or sperm. These procedures carry great promise to advance reproductive options for men and women and can be tailored to their medical or social circumstances.

Potential issues with new reproductive technologies include efficacy, short and long term risks to the mother and children. The American Society for Reproductive Medicine-ASRM states that “procedures for the diagnosis or treatment of infertility will be considered experimental or investigational until the published medical evidence regarding their risks, benefits and overall safety and efficacy is sufficient to regard them as established medical practice”

Information disseminated about fertility procedures online and in lay press are sometimes inaccurate or convey unrealistic expectations. Recently, a same sex couple curbside me to recommend a physician to harvest one partner bone marrow to produce artificial gametes that can then be used with the other partner gametes. When I explained to them that this experimental and was never accomplished in humans, they were very  dismayed and disappointed, confirming that they read about the procedure  online.

Looking at published studies discussing new reproductive technologies one can infer

Egg freezing

Still considered investigational by the American Society for Reproductive Medicine. Not suitable for all patients based on their ovarian reserve. No large studies comparing the efficiency of egg freezing in comparison to the established technology of embryo freezing. No long term follow up data for children conceived using thawed oocytes.

Ovarian stimulation in estrogen sensitive cancers

Using conventional protocols for ovarian stimulation in breast cancer and other estrogen sensitive cancers was not studied in terms of its effects on cancer recurrence. Using special protocols to reduce estrogen exposure during stimulation was not studied long enough. In short and intermediate terms, however, it does not appear to increase recurrence.

Ovarian Tissue Freezing

This is the most investigational technique for fertility preservation. Ovarian tissue is harvested and frozen for later transplantation. Only sporadic case reports were published. It is considered in women with very high risk for ovarian failure e.g. after chemotherapy. There is also the risk for transmission of malignant cells within the graft at the time of transplantation. The outcomes of children conceived after transplantation is unknown.

In vitro maturation

Immature eggs are not suitable for fertilization with sperm. Immature eggs can be harvested, matured in the lab then fertilized or frozen. ‘Cultivating’ very immature eggs from primordial follicles in the lab is experimental and was not done in humans yet. Immature eggs obtained after short period of ovarian stimulation can produce a viable children.  This procedure is more applicable to women with very good ovarian reserve. The long term safety of the procedure is not known yet.

Pre-implantation genetic screening for aneuploidy

Many eggs in every woman are not chromosomally normal-having an extra or missing chromosome-egg quality. Fertilization of these eggs result in chromosomally abnormal embryos. The majority of abnormal embryos do not implant or are miscarried. Testing of embryos to select the normal ones was suggested as a method to increase the pregnancy rate. This is yet to be proven in a peer-reviewed scientific publication. The exact embryo stage to test and the method of testing are still debated.

Artificial gametes

The concept that eggs and sperm can be generated from human embryonic stem cells was shown in mice. The function of the resulting gametes is unknown. This was never accomplished in humans. If functional gametes can be produced from other cells, likely applying this technology in medicine will require another decade or more.

Beware of what you read

Many new reproductive technologies are available to address one or more medical or social issues related to reproduction. Some of these technologies are experimental, not efficient or their outcomes not studied long enough to ensure its safety. They may be applied in limited or monitored settings e.g research or for those that at risk for loosing their fertility and have no other options. Detailed discussion with woman / couple is essential to ensure that the they have realistic expectations concerning their outcomes and that uncertainty about their safety is clearly explained.

Read more at http://nycivf.org

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Fertility Preservation via In Vitro Maturation

In vitro maturation of human oocytes can be used for fertility preservation. In vitro maturation-IVM indicates that eggs are retrieved without stimulation or after a short period-about 3 days-of treatment with fertility medication. Oocytes are then either 1. Frozen as immature eggs, 2. Matured in the lab for 24 to 30 hours and then frozen as mature eggs or 3. matured in the lab and fertilized using direct injection of sperm-ICSI and the resulting embryos as frozen. Freezing mature eggs generally yields better outcomes that freezing immature eggs. Vitrification appears to result in better survival than slow freezing of oocytes.

Advantages of in vitro maturation

IVM can be accomplished without prolonged exposure to fertility Mature oocytemedication-3 days versus 14 to 21 days for classic IVF cycles.  Estrogen does not increase to the same levels as seen with IVF, which may be advantageous for some estrogen sensitive cancers as breast cancer. Newer approach to ovarian stimulation using aromatase inhibitors in women diagnosed with breast cancer, enables ovarian stimulation to proceed without marked increase in estrogen levels. Because less fertility medication are used, the cost and the risk for ovarian hyperstimulation syndrome are less than conventional IVF

Disadvantages of in vitro maturation

As a reproductive endocrinologist attempt to retrieve eggs from small immature follicles, he or she is successful in doing so 50% of the time-approximately five eggs are retrieved from 10 follicles. Furthermore, 70 to 80% of those complete maturation in the lab making the process much less efficient than IVF. Very few labs in the world reported consistent success with IVM and only in select patients-those with high ovarian reserve. Research is ongoing to improve our ability to complete maturation of eggs in the lab. The success of this method is however, limited by woman’s ovarian reserve and our ability to retrieve these immature eggs. IVM is more suitable for women with PCOS or large number of small follicles in the ovary.

Safety of in vitro maturation

A relatively small number of babies were borne worldwide using IVM. There are no long term data on the health of children conceived using IVM. Moreover, data on outcomes are very scarce on babies borne after both IVM and egg freezing. One study showed that babies born after IVM are larger than those conceived with IVF and more frequently required cesarean delivery. Long term neurological outcomes are still unknown.

In vitro Maturation of immature oocytes after a conventional IVF cycle can be performed, aiming at increase the egg yield. After stimulation with fertility medication for 10-14 days, eggs are retrieved. Mature eggs are fertilized with sperm and immature eggs are left in culture to mature-instead of discarding them. Immature eggs are left over oocytes and in the experience of many labs seldom produce a good quality embryo or pregnancy.

In select patients with good ovarian reserve, in vitro maturation can be considered after counseling patients that this so far a less efficient approach than IVF and that the long term outcomes of children conceived via IVM is still unknown. Read more at http://nycivf.org

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You are a breast cancer survivor, what next? Roadmap to pregnancy after treatment

Young women treated for breast cancer at risk for decreased fertility  due to exposure to chemotherapy and delaying pregnancy for several years after treatment. Twenty percent of women diagnosed with breast cancer are in their reproductive years. By the year 2010, 2.9 million breast cancer survivors are predicted in the US, approximately 2% of the female population. California, Florida and New York will rank first among states in the number of survivors.

Women considering pregnancy after completing breast cancer treatment  require extensive counseling of risks and benefits as well as discussion  of available options to achieve pregnancy, tailored to their medical and social circumstances. Psychological counseling is also helpful  in coping with stresses of treatment.  I usually start with consultation session to get to know the individual woman as well as information about her breast cancer. During this session I initiate testing for ovarian reserve through blood work and ultrasound. I also present her with printed material to read about ovarian stimulation and pregnancy after breast cancer. With her permission, I also contact her oncologist to discuss assess his or her opinion in relation to pregnancy after breast cancer treatment. I request that the woman or couple visit me few days later to discuss  test results and options for fertility treatment.

Testing & Counseling. 1. Ovarian reserve. This indicates the number and quality of the eggs remaining in the ovary. Its related to the woman’s age, type and dose of chemotherapy received. There is marked variation among women in their ovarian reserve due to genetic factors and type and intensity of chemotherapy. Estimating ovarian reserve may predict response to treatment and chance for success of fertility treatment. Ovarian reserve can be estimated using ultrasound to visualize the tiny follicles in the ovary. Blood tests for markers such as FSH, LH, Estradiol and AMH can  also help in determining ovarian function. Patency of the fallopian tubes is also tested using a hysterosalpingogram. Partner semen analysis is also ordered. 2. Safety of ovarian stimulation. To enhance fertility, stimulation of egg production in the ovary is commonly employed.  Common ovarian stimulation methods result in increase of estradiol. To avoid this increase in estrogen sensitive cancer, we have  shared in developing a protocol that employ a drug that prevent the ovary from making estrogen. When tested this method did not appear to increase breast cancer recurrence. We however do not know the effects of ovarian stimulation on the long term, 5 years or more. 3. Safety of  pregnancy. Studies published so far indicate that pregnancy does not increase the risk of recurrence in women treated for breast cancer. Moreover, some studies even detected reduced risk of recurrence and death due to breast cancer in women who became pregnant. 4. Transmission of BRCA mutation to the baby. Five to ten percent of young women diagnosed with breast cancer carry mutations in BRCA1 or 2 genes. These mutations can be transmitted to their children. It is possible to avoid this transmission by testing their embryos before placing them into the uterus. Pre-implantation genetic diagnosis – PGD was successfully performed in women carrying these mutations.

Options. If pregnancy is judged to be safe, several options for reproduction exist 1. Timed intercourse. Women with regular menstrual cycles and good ovarian reserve, can attempt pregnancy spontaneously for 6 months to a year. Ovulation can be monitored using home predictor kits that test urine for LH hormone. When a surge is indicated by the test, intercourse for the next three days is usually advised.  2. Ovarian stimulation-IUI. Stimulation of the ovary aiming at recruiting two or three eggs can be accomplished using letrozole or letrozole and gonadotropins. This is usually followed by intrauterine insemination when the eggs are judged to be need maturity. This is usually attempted for three cycles. 3. Embryos or oocytes frozen prior to breast cancer treatment frozen / thaw embryo transfer. Women who preserved their fertility prior to cancer treatment can thaw those and transfer one or two embryos into the ovary. This commonly carry a reasonable pregnancy rate for embryos, about 30% per cycle. In case of frozen eggs, they need to be fertilized using ICSI-direct injection of a single partner or donor sperm into the egg. Thawed eggs usually carry lower pregnancy rates than embryos. 4. IVF. In vitro fertilizationcarry the  highest pregnancy rates of all fertility treatment. Its success, however, depends on age and ovarian reserve. a. Natural cycle IVF. Women interested in avoiding excessive estrogen exposure and cost can consider natural cycle or minimal stimulation IVF b. Ovarian stimulation IVF. In this option the ovary is stimulated to produce multiple follicles, eggs are aspirated , fertilized and  the resulting embryos are transferred into the uterus. 5. Third party reproduction-egg donation and gestational carriers. Donor oocytes are considered in women with very low ovarian reserve or who develop ovarian failure after treatment. The use a gestational carrier is considered for women who cannot carry a pregnancy due to breast cancer or other condition. Woman’s biological embryos are transferred to the uterus of another woman.

Women treated for breast cancer show variability in terms of ovarian reserve after chemotherapy. They require testing for ovarian function and counseling about the most feasible and safe method to get pregnant after treatment.  Read more at http://nycivf.org

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Mobile application and breast cancer

I recently read about this iPhone application at Breast oncology nurses fan page. This is a simple and free mobile application that allows women and men to track their chemotherapy, medication type, schedule and dose- iChemodiary. The information can be shared with physicians and nurses and can be downloaded to a computer.

Another free phone application is tailored to breast cancer symptoms and understanding the diagnostic steps-pathology and other tests and how to interpret these reports-Breast cancer diagnostic guide.You can also input your diagnosis and read an explanation of terms and other articles pertinent to it. A breast cancer risk calculator is also available for iPhone. It is dependent on Gail model, which assess breast cancer risk based on age at first menstrual period, age at first pregnancy, number of breast biopsies and number of first degree relatives diagnosed with breast cancer.

There are other software applications worth mentioning also. One is BRCAPRO, which calculates the risk for breast cancer in women with multiple family members diagnosed with breast cancer. Another application is Adjuvant!online. This web application allows for calculation of the risk for recurrence in women based on age, stage of breast cancer, grade, number of lymph nodes, estrogen receptor status and intended chemotherapy and hormonal treatment. Both are somewhat more complicated for use without the help of specialists.

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Fertility preservation in uterine cancer and endometrial hyperplasia

The endometrium is the inner lining of the uterus. Changes in the endometrium can take place with prolonged exposure to estrogen, unopposed by progesterone. This can take place in women who do not ovulate regularly. Changes usually start as excessive proliferation-cell division- and then may progress to cancer. Endometrial hyperplasia and cancer are problems encountered in older women. During reproductive years, they are encountered in women diagnosed with polycystic ovary syndrome-PCOS. It is recommended that women with PCOS should prevent these changes either using progesterone treatment if they are not trying to get pregnant or induction of ovulation if they are trying to conceive.

The definitive treatment for endometrial hyperplasia and cancer involves a hysterectomy-surgical removal of the uterus. Although fertility in women depends on the number and quality of eggs in the ovaries, removal of the uterus markedly complicates a woman’s reproductive capacity. There are multiple options available for women diagnosed with hyperplasia or cancer.

Avoiding hysterectomy after diagnosis with endometrial hyperplasia. Progesterone or synthetic substitute can reverse endometrial hyperplasia to normal endometrium. The medicine can be taken orally or usinf an intrauterine device loaded with progestin. It is important that the physician check the lining of the uterus periodically to assure regression to normal status. This treatment is effective in regressing hyperplasia in about 80% of women.

Preservation of fertility in women diagnosed with endometrial cancer. When uterine cancer is diagnosed the usual treatment is surgery. The aim of surgery is to evaluate the extent of the disease. This is achieved by removing the uterus and sometimes the ovaries and submitting them for pathological examination. One of two options can be used to protect future fertility;

1. Progesterone or synthetic progestin to induce regression of cancer. The caveat to this method is that the extent of the disease is not evaluated. In 20% of women, the disease maybe more widespread e.g. to the cervix or the ovary, than originally thought.

2. Ovarian stimulation, egg retrieval and embryo freezing followed by definitive surgical treatment. Pregnancy is then achieved by transferring the embryos to a gestational carrier-surrogate. Although a more complex treatment, it allows for adequate evaluation of the extent of the disease and definitive surgery. I use a modified regimen, similar to that used for breast cancer, to stimulate the ovaries to prevent the rise in estrogen during stimulation. Estrogen rise can increase cancer cell proliferation. The eggs can be retrieved just before surgery through the vagina or during surgery directly from the ovary. When the woman or couple want to use the embryos, the lining of the uterus of the gestational carrier is prepared then the embryos are thawed and transferred to her uterus.

So even if the uterus is involved with a disease process, its possible to tailor implement a fertility preservation plan to enable a woman to conceive a biological child.

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Cancer in children and future reproduction

In 2010, approximately 10,500 boys and girls in the US and 160,000 worldwide are expected to be diagnosed with cancer before the age of 15. In addition hundreds of thousands of adolescents are treated for cancer yearly between the ages of 15 to 19.

Getting beyond cancer treatment involves a focus on wellness and ways to improve quality of life. Discover ways to maintain a healthy lifestyle, signs to look for, potential risks and ways to celebrate the life of a child with cancer.

The specific type of cancer varies with age and geographical distribution.  In the US the most common (American Cancer Society)  are                  Leukemias (31%)
Brain and nervous system (21.3%)
Neuroblastoma (7.1%)
Wilm’s tumor (5.2%)
Non-Hodgkin Lymphoma (4.3%)
Rhabdomyosarcoma (3.3%)
Retinoblastoma (2.6%)
Osteosarcoma (2.5%)
Ewing sarcoma (1.6%)
Others e.g ovarian germ cell tumors, Hodgkin lymphoma, liver cancer

With improvement in survival (80% in the US), Current priorities for childhood cancer management aim at improvement of quality of life of the growing number of childhood cancer survivors. Specific to reproduction, preservation of fertility aims at enabling children and adolescents to make reproductive choices that cannot be delayed till they reach maturity.

Effect of treatment of childhood cancer on fertility. It is very important for children and their families are informed about the effects of cancer treatment before shortly after diagnosis and certainly before they start treatment.

Children treated for childhood cancer are at risk for delay or failure of puberty. They are less likely to be biological parents in adulthood. Two large studies (The Childhood Survival Study in the US and The Norwegian Radium Hospital study) indicated that children treated for cancer are 50% less likely to become parents when compared to those not exposed to cancer treatment. Modern cancer treatment include surgery, multi-drug chemotherapy, radiation, biological agents and sometimes hematopoietic stem cell transplantation (bone marrow transplantation). Some cancers especially in boys can impair fertility independent of treatment e.g Hodgkin lymphoma and testicular cancer.

Chemotherapy especially alkylating agents cause accelerated loss of germ cells (oocytes or sperm producing cells).

Radiation of the ovary or testes can lead to partial or complete loss of germ cells depending on the total dose and fraction used. Also radiation of the head can affect hormone production from the master gland in the brain and impair ovulation or sperm production.

Bone marrow transplantation requires pre-treatment with high dose chemotherapy and total body radiation and is associated with loss of fertility in the vast majority of boys and girls.

Surgery to remove the ovary or testes is sometimes required  for cancer treatment e.g. germ cell tumors of the ovary or testes.

Methods of fertility preservation in girls. Modification of treatment plan is sometimes possible to prevent damage to reproductive tissue. For example, girls diagnosed with germ cell tumors of the ovary, its possible to preserve one ovary and the uterus. Freezing of ovarian tissue or eggs are available options for preservation of fertility in girls. After puberty, ovarian stimulation is possible, followed by egg retrieval and freezing. This require about 2 to 3 weeks to accomplish. This method require ovarian stimulation.  Estrogen produced during stimulation may lead to advancement of secondary sex characters e.g. breast development. Ovarian tissue freezing is possible for girls before and after puberty. It can be performed in one day and does not delay cancer treatment. It is considered when cancer treatment is expected to be associated with very high risk for ovarian failure. One ovary is harvested using minimally access surgery. Visible follicles in the ovary are aspirated using a needle and any eggs obtained are frozen. The ovary is the cut into thin slices and frozen. The ovary can be transplanted later for the purpose of initiation of puberty and reproduction. Unfortunately, transplantation is not suitable for certain cancers that carry high risk for contaminating the graft e.g. leukemias.

Methods of fertility preservation in boys. The standard for fertility preservation in men is sperm freezing. In boys, ethical and physical consideration issues may interfere with sperm collection from young boys. In studies done two decades ago, most boys start to emit sperms at ages 9 to 11 years, even in the absence of pubic hair. Practically this can be assisted by a vibratory stimulation device. Sometimes, for social or religious reasons its difficult to ask young boys to produce sperm samples. The other available option is a simple surgical procedure to retrieve sperm from the testes, testicular sperm aspiration or extraction (TESE). Tissue from the testes is then frozen for later use at maturity, using ICSI (direct injection of sperm into an egg). There are options for young boys e.g. testicular stem cell freezing, but they are experimental and not ready for general use.

Genetic issues and preservation of fertility in children. Some children develop cancer because they carry a faulty gene e.g. retinoblastoma. Children can be tested for this gene. If the abnormal gene is detected, embryos or eggs produced by these children can also be tested – preimplantation genetic diagnosis (PGD) and only healthy ones are used. This will prevent the gene from being transferred to their future children.

Ethical considerations. Fertility preservation in children is a complicated issue for parents and children alike. Ethicist advised that fertility preservation procedures should be offered to children when there is high risk for loss of fertility. If the proposed method entails delay in cancer treatment, this delay should not affect treatment outcome. Informed consent should be obtained from parents and ASSENT should be obtained from the child. Minors who are sufficiently mature to achieve a developmentally appropriate awareness of their condition and the risks and benefits of the available treatment alternatives should give their approval to the use of such treatment. Every measure should be taken to assure that the child will control the fate of sperm, eggs or reproductive tissue when they reach maturity. Nobody will have custody over reproductive cells or tissue except the person who produced them.

Recent psychological research from UK indicated that (Crawshaw & Sloper 2010)

For some young men and women treated for childhood cancer, fertility concerns dominates cancer legacy. Professional and social networks provided few opportunities to ask questions, receive information, process feelings or develop handling strategies. Beliefs about the extent of fertility damage did not necessarily relate to information received. For some, fertility matters affected identity, well-being and life planning as well as reproductive function. This was not restricted to particular ages, life stages, gender or time since treatment ended and was heightened by associated stigma and silence. Opportunities for dialogue should be offered regularly across health and social work disciplines given fertility’s psychological and social as well as medical significance.

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Estrogen receptor negative breast cancer and future fertility

Breast cancer is diagnosed in 240,000 reproductive age women each year worldwide and approximately 25,000 in the US. Breast cancer is usually classified into estrogen receptor positive or estrogen receptor negative depending whether the cells express the protein that renders the cell responsive to estrogen.  In 2010, The American society for Clinical Oncology and College of American Pathologist using a technique called IHC classified breast cancer according to the amount of estrogen receptor protein into estrogen receptor negative when <1% of cells express the protein, weekly positive (1-10% of cells) and estrogen receptor positive (>10% of cells). Approximately 45% of premenopausal breast cancers are estrogen receptor negative.

All women in this video are breast cancer survivors

Triple negative breast cancer (TNBC) indicates that the cells are negative for three markers – estrogen receptor, progesterone receptor and  do not over-express a third protein called HER2. Estrogen receptor negative and triple negative breast cancer is especially important because its commonly diagnosed in younger women while they are still in their reproductive years (24% of breast cancers diagnosed in women before menopause). Its more common in African American than Caucasian women and tend to be more aggressive and less responsive to treatment than estrogen receptor positive breast cancer. Also a large proportion of breast cancers diagnosed in women carrying BRCA1 mutations or shortly after delivery are estrogen receptor negative. It has also been recently linked to diabetes, insulin resistance and abdominal obesity. Since hormone treatment is not usually advocated, the mainstray of treatment is surgery and radiation followed by chemotherapy. In addition multiple additional agents are used or under trial as added treatment for TNBC.

Fertility preservation in women diagnosed with triple negative breast cancer is challenging. In my experience approximately 10% of women  diagnosed with cancer seeking counseling for future fertility are estrogen receptor negative.

Options for preservation of future fertility include, ovarian stimulation followed by embryo or egg freezing, In vitro maturation of oocytes or ovarian tissue freezing.

1. Ovarian stimulation and embryo freezing. This is the standard method . It is suitable for women with a stable partner and when treatment does not need to start immediately. Usually there is a 3-4 week gap between surgery and chemotherapy that can be used for preserving fertility. Minimizing estrogen exposure appears to be an important safety issue. A protocol that utilize a medicine that prevents the ovary from making estrogen during stimulation appears to be safe on intermediate term followup, thus far. In my opinion, even in estrogen receptor negative cancers, low estrogen stimulation may be safer. This is because estrogen can stimulate cancer cell growth through indirect ways e.g. increase formation of blood vessels in the tumor. Hundreds of thousands of babies were borne using this method worldwide.

2. Ovarian stimulation and egg freezing. This method should be considered in women with no partner. It requires ovarian stimulation and that treatment does not need to start immediately. This was discussed in details here. About a 1000 babies were borne using this method worldwide.

3. In vitro maturation of oocytes. The aim here is to retrieve immature oocytes after no ovarian stimulation or stimulation for 2-3 days. Eggs are matured in the lab for about 24 hours then fertilized and embryos are frozen or eggs are frozen unfertilized. Eggs are retrieved from 50% of follicles aspirated. Of those about 60-70% are successfully matured in the lab. Because of its low efficiency, its suitable for select women with high ovarian reserve where many small follicles (15 to 20) seen on initial evaluation and its not suitable for general use. It has the advantage of very short or no delay in cancer treatment. Few hundred babies were borne using this method worldwide.

4. Ovarian tissue freezing. This is the most experimental method of preservation of fertility. Its can be accomplished within few hours. The ovary is removed using minimal access surgery or at the time of other surgeries e.g. during cesarean delivery. Cancer treatment can start next day. It does not require stimulation of the ovary and does not require a partner. It usually reserved for women younger than 40 and when chemotherapy carries high risk for ovarian failure or if the ovaries have to be removed for another reason e.g. BRCA mutation. After the ovary is removed its cut into very thin strips and frozen. Part of the ovary is examined for contamination with malignant cells. The ovary can be transplanted back after treatment. about 10 babies were borne using this technique worldwide.

My approach is to

  • Make myself available for consultation as soon as possible and at a time suitable to the couple / woman’s schedule. Certainly women have to see many providers and its very difficult for her fit yet another consultation.
  • Careful review of all records related to biopsy and lab results, surgery, oncology notes and intended treatment plan.
  • With the patient permission I contact her oncologist to discuss his treatment plan, its timeline and the likelihood of cure.
  • During consultation I would discuss the state of science in relation to fertility preservation – what is known and what is uncertain about methods for preservation of fertility pertinent to her.
  • One important aspect of consultation is evaluation of ovarian reserve. This include ultrasound and ovarian reserve tests (blood work). These would indicate the potential for egg production and prospect of success for preservation of fertility irrespective of the method used
  • Careful evaluation of spread into the abdominal cavity especially the ovaries, since TNBC tend to spread to the abdomen early.
  • I provide the couple / woman with printed material to read and explain to her that this is the time for fact finding. I advice her not to make a decision for the coming few days and encourage her to seek advice from her oncologist, a second opinion from a colleague and support from other family members.
  • I would contact her few days later to inquire about any questions she may have and discuss lab results.
  • If she needs psychological support to cope with stresses of treatment and decision making with or without a partner, I usually refer them to a reproductive psychologist.
  • Whatever the final decision maybe, I discuss other elements of survivorship plan, including testing for ovarian reserve after chemotherapy, maintenance of bone, genital and sexual health.
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BRCA mutations, breast cancer and fertility

Mutation in the breast cancer susceptibility genes (BRCA1 and 2) increases the lifetime risk for early breast and ovarian cancers. Women are commonly approached by physicians to be tested (a blood test) if they fit certain criteria that are associated with increased risk for finding these mutations. Actually there are now two software packages that allow individuals to calculate their probability of carrying a mutation and subsequently make decisions about testing. Attitudes towards testing and risk reducing procedures vary widely even among women in the same family (see for example this case study from The New York Times)

Young women carrying these mutations face several issues: Reproductive health issues

1. When should I get pregnant ? The exact impact of pregnancy and child-bearing on breast cancer risk in BRCA mutation carriers is not totally clear and may be different for BRCA 1 mutation carriers than for BRCA 2 mutation carriers in an age relater manner.

2. Are my chances for getting pregnant reduced due to these mutations ? Likely no. In spite of anecdotal suggestions that ovarian reserve (number of eggs in the ovaries) maybe diminished, this is not proven. In fact when women carrying BRCA mutations were compared to relatives who do not carrying these mutations, there were no differences in the number of deliveries and the need for fertility treatment.

3. Can I use oral contraceptive pills ? The use of OCPs reduces the risk of ovarian cancer in mutation carriers. Risk of breast cancer may be increased in BRCA1 carriers using the pill for long period of time.

Psychological issues related to risk-reducing procedures

Risk reducing bilateral salping-oophorectomy and bilateral mastectomy are commonly offered to reduce the risk of cancer in the future. Surgical removal of both ovaries and / or both breasts reduces but does not eliminate the risk (residual risk 10%). Some women report impaired body image and reduced sexual satisfaction after the procedure(s).

Future Fertility in women carrying mutations in BRCA1 and BRCA2 genes

1. Young women carrying BRCA mutations and not diagnosed with cancer are encouraged to attempt pregnancy as early as possible. If an unrelated fertility problem arises, they are encouraged to seek consultation from a reproductive endocrinologist.

2. Young women carrying BRCA mutations and diagnosed with breast can preserve their fertility through ovarian simulation and embryo or egg freezing.

3. Young women carrying BRCA mutations and elected to undergo risk-reducing removal of both ovaries should consider the following options (a or a and b) a. Ovarian stimulation followed by embryo or egg freezing and b. Ovarian tissue freezing (experimental). Since both ovaries will be removed it is reasonable to attempt to freeze ovarian tissue for future use. Future use means transplantation of ovarian tissue outside the abdomen (under the skin) followed by stimulation and egg retrieval. The tissue is then removed after pregnancy is achieved. Alternatively, if the technology permits in the future, the tissue can be cultured in the lab and eggs retrieved directly from the tissue (not successful in humans so far).

3. Young women interested in getting pregnant should be counseled to the risk of transmission of mutation to future children.

Both men and women carrying the mutation are at a significantly increased risk of cancer. It is very possible to prevent this transmission if the eggs or embryos are tested before replacement into the uterus in women undergoing in vitro fertilization – IVF Eggs are tested by polar body biopsy (this is a small cell attached to the egg and carry chromosomes representative to those of the egg). Embryos are tested by testing one cell of a 6 to 8 cell embryo. Testing has many medical and ethical dimensions and is better handled by providers specializing in these area.

Women carrying BRCA mutation can still conceive their own children and prevent the transmission of BRCA to them. With adequate support and guidance, this can be achieved even if you decided to remove both ovaries.

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