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Melanoma-What Every Woman Need to Know about Fertility and Pregnancy

Women diagnosed with melanoma may require counseling for fertility preservation, fertility treatment and safety of pregnancy after treatment. Melanoma is one of the most common cancers in young adults in the United States. In the US and worldwide, there is  dramatic increase in the incidence  of skin melanomas. Approximately 30,000 women are expected to be diagnosed with melanoma in 2010, one third will be in their reproductive years. Its the most common cancer in young adults 25 to 29 year old. Its more common in white women compared to African Americans and Hispanics.  Approximately  10% of melanomas run in families or are genetically inherited. Treatment of melanoma requires surgery. In advanced melanoma, chemotherapy is added. Dacarbazine-DTIC is an alkylating agent used for treating melanomas. Immune therapy is also used for advanced melanomas- interferon α or IL-2.

In early stages, surgery is the only required treatment. In advanced stages if chemotherapy is used, ovarian reserve may be diminished and this may reduce woman’s ability to get pregnant. The use of immune therapy is not known to affect future fertility. The effects of newer targeted therapies and vaccines on fertility are also unknown.

Melanoma and fertility treatment. The estrogen receptors were found on melanoma cells. Some researchers detected no significant increase in the risk of melanoma after treatment with fertility drugs, except possibly slight increase in risk in women who delivered children before. The relationship between estrogen exposure and melanoma is controversial. Women seeking fertility preservation before exposure to chemotherapy or melanoma survivors desiring pregnancy after completing treatment should consult with a fertility preservation specialist about the risks and benefits of fertility treatment and the safety of pregnancy. The ovarian stimulation regimen can also be modified to minimize estrogen exposure. It may also be possible for women with inherited predisposition to melanoma to avoid transmission to future children through testing of embryos-PGD.

Melanoma and pregnancy. Ten studies including 5600 women found that pregnancy does not reduce survival in women diagnosed with melanoma. Women treated for melanoma who subsequently became pregnant were not adversely affected compared to women who did not get pregnant after treatment. For thin tumors-<1.5mm most experts do not recommend deferring pregnancy. For thicker tumors, physicians may recommend deferring pregnancy for two years as most recurrences take place during that interval. Read more at http://nycivf.org

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What Does Borderline Ovarian Tumor Mean to Your Fertility?

What Does Borderline Ovarian Tumor Mean to Your Fertility?

Fertility in women diagnosed with borderline ovarian tumors can be reduced or lost due to surgical treatment. Counseling regarding fertility preservation shortly after diagnosis can increase the chance of pregnancy following treatment.

Borderline-low malignant potential ovarian tumorLow malignant potentials

The cells in borderline tumors, proliferate more than benign ovarian cysts but less than frank malignant ovarian tumors. Multiple layers of these cells are seen on pathology slides, but they do not invade surrounding tissues as in malignant tumors. They are diagnosed in approximately4000 of women each year in the US and are more commonly encountered in reproductive age women. These tumors are usually cystic, sometimes with surrounding implants. Low malignant potential tumors are treated surgically (removal of cyst, removal of the ovary or sometimes removal of both ovaries and the uterus). They generally do not require chemotherapy for treatment. The majority of these tumors are associated with very high survival (10 year survival >90% in stage I and II ), although some may recur or turn malignant.

There is no difference in survival if borderline tumors were treated with removal of the cyst, removal of the ovary or removal of the uterus and both ovaries. Recurrence may be lower after hysterectomy (5%) compared to salpingoophorectomy (15%) and cyst excision (30%). The high rate for recurrence after conservative surgery indicates the need for strict and long term follow up (pelvic exams, ultrasound and tumor markers). Some recurrences take place years after initial surgery and are sometimes malignant.

Fertility risks in women diagnosed with borderline tumors

Fertility risks in women diagnosed with low malignant potential ovarian tumors include loss of ovarian tissue and pelvic scarring that can block the fallopian tubes especially if open approach is used for treatment compared to laparoscopy (minimal acess surgery). Some loss of ovarian tissue does occur even during cyst removal from the ovary. Ovarian reserve can be tested after surgery using transvaginal ultrasound evaluation for ovarian volume and number of antral follicles. Ovarian function can also be assessed using day 2 FSH and estradiol levels and antimullerian hormone (AMH).

Fertility preservation strategies in women diagnosed with borderline ovarian tumors

1. Conservative surgery

Ovarian cystectomy can be considered in reproductive age women, especially in early disease with favorable pathology and absence of implants. Recurrence is relatively high but can be managed with repeat excision if not malignant. If pregnancy is desired following surgery, fertility factors; ovulation, fallopian tubes and sperm factors should be investigated and treated accordingly

2. Embryo and oocyte cryopreservation

Women at risk for diminished fertility due to surgery, especially if requiring removal of the ovaries or repeat excision of cyst, can consider ovarian stimulation, egg retrieval and egg freezing or  IVF and embryo freezing. There is no evidence that ovarian stimulation and exposure to high estrogen increases the risk for recurrence. It is not clear if border line cells are sensitive to estrogen increase during ovarian stimulation. Two options are available to reduce estrogen exposure: to perform IVF in a natural cycle (low egg yield) or to modify the stimulation protocol, through adding an aromatase inhibitor, similar to that used for breast cancer. Alternatively, short stimulation followed by retrieval of immature eggs followed by in vitro maturation can be performed.

Women diagnosed with borderline ovarian tumors are at risk for diminished fertility because of surgical treatment(s). This is especially true if repeat surgical excision is required. Collaboration between a gynecologic oncologist and a reproductive endocrinologist enable adequate surgical treatment, strict follow up and preservation of future fertility in reproductive age women.

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What if You Have Dual Infertility Factor

What if You Have Dual Infertility Factor

What if You Have Dual Infertility Factor

Many Times You Do

Infertility factors are generally classified into tubal factor (blocked fallopian tubes), male factor (abnormal sperm concentration, movement or shape) and ovarian factor (no ovulation). In the majority of situations though multiple factors exist. If you partner has low sperm count, you also may have a blocked tube. Women who do not ovulate can also have endometriosis. Some men think that their female partners are infertile due to a female factor while they also have subtle sperm abnormality that prevents fertilization. Women sometimes think their male partners sperm is abnormal while they also have low egg reserve and low egg quality. Couples potentially have a dual infertility factor, most of the time. Most notably, low egg number and quality should be considered in any couple seeking fertility evaluation and treatment. Even young women with good egg reserve have abnormal eggs.

Irrespective of infertility factors, consideration of other general factors e.g genetic screening results can have a significant impact on choice of fertility treatment modality. If both partners are carriers for cystic fibrosis, they may require embryo testing (PGD) in the setting of IVF as opposed tosimilar couples without this genetic risk factor.

Do not Accept Treatment Before a Complete Workup. Do not Accept Empiric Treatments

For that reason, no assumptions about fertility factors and treatment should be made before a completed workup for sperm, ovulation, ovarian reserve, Fallopian tubes and general factors (genetic and preconception screening). This careful and deliberate testing is unfortunately not always followed. In many cases, couples are treated with empiric treatments. Here are two very common empiric treatments commonly prescribed

a. Clomid used for everyone. Clomiphene is suitable as initial treatment for women who do not ovulate due to polycystic ovary syndrome (PCOS), have open tubes and normal sperm analysis. In modern reproductive medicine, clomid should not be used without testing of male and tubal factor. Clomid also should not be used in older women that ovulate regularly. The majority of these women are older and do not get pregnant because of lower egg quality. They require superovulation (more than one eggs) to compensate for lower egg quality.

b. Progesterone supplementation. Low progesterone can cause early miscarriage (not infertility) in a small percentage of women. Women that yield low progesterone after ovulation do so because of abnormal development of follicles. They are better served by induction of ovulation to produce better follicles, rather than progesterone supplementation. During fertility treatment, progesterone levels are monitored and maybe supplemented if low. Progesterone treatment in itself is not a treatment for any form of infertility.

c. Laparoscopic surgery for endometriosis. The magnitude of benefit for surgical treatment of infertility associated with endometriosis is limited and maybe harmful. Laparoscopic surgery for severe endometriosis is risky e.g bowel injury. Resection of endometrioma can reduce ovarian reserve. IVF is a better than laparoscopic surgery in treating infertility due to moderate and severe endometriosis . The increase in pregnancy rate after excision of mild endometriosis is limited (probably 30 surgeries are needed to produce one newborn).

d. Varicocele repair for male factor infertility. Although sperm parameters may improve after varicocele repair, there is no conclusive evidence that it will translate into higher odds of pregnancy in female partners. There is a limited indication for varicocele repair aiming at improving fertility in males.

Many of these empiric treatments and prescribed with no or limited scientific basis and represent bias and expertise of the prescriber.

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How to Select an Egg Donor

How to Select an Egg Donor

How to Select an Egg Donor

Egg donation entails the fertilization of eggs of a young woman and transfer of the resulting embryo or embryos into the intended mother uterus. In the majority of cases, women are interested in egg donation when their ovarian reserve is diminished in quantity and quality, commonly after multiple unsuccessful IVF cycles. The eggs of young women are usually high in quality making the chance for pregnancy and delivery very high. Women can select an egg donor from one of two pools

Egg Donors

Egg Donors

Eggs from a Live Donor

An young woman is selected for donation, her ovaries are stimulated then eggs are retrieved. Two types of egg donors exist:

   i. Known Egg donor

The egg donor is known to the intended mother. The donor could be a related e.g. sister or not a relative but agreed to open identity egg donation.

   ii. Anonymous Egg donor

The egg donor is not known to the recipient. The majority of eggs donated are contributed by anonymous donors. If you select a closed identity donor you will still be able to know a great deal about her as age, ethnicity, religion, education, medical and family history, prior donations, physical features, childhood or even adult photo. Anonymous egg donors are usually recruited by a third party: IVF clinic or an egg donation agency.           Shared Donor cycle: Sometimes the eggs from one donor are shared between two recipients to reduce cost. Sharing however may yield lower chance for pregnancy per couple.

Donor Egg Bank

An egg bank will recruit the donors, stimulate their ovaries and freeze them. Recipient select from an already frozen inventory. The advantage is that they do not need to wait for a donor to be found, tested and her eggs harvested. In addition it is cheaper because only some of the eggs resulting from stimulation are obtained and no expenses incurred for donor travel and accommodation. On the other hand, it may yield lower chance for pregnancy (eggs are frozen and fewer of them are available). Donor selection is also restricted to available inventory of eggs that were already donated at an earlier time.

Results of Donor Egg Cycles Based on Donor Selection

Based on hundreds of thousands of donor egg cycles some general expectations of pregnancy and live birth rates can be made:

a. Anonymous cycles usually yields a higher pregnancy rates than known donors. Anonymous donors are selected on pure medical grounds first. They tend to have better ovarian reserve and are commonly younger than known donors. Many times known donors are based on other grounds e.g sister donor or a friend that will donate without compensation

b. Donor egg cycles distributed to one recipient are more successful than those shared between two recipients due to more eggs and embryos being available for selection and transfer.

c. Fresh eggs from live donors produce more babies than frozen donor eggs. A study of 11,148 egg donation cycles performed in 380 U.S. clinics in 2013, including 2,227 that used frozen eggs indicated that

for each IVF cycle the live birth rates were 50% with fresh eggs, and 43% with frozen eggs and

for each embryo transfer, 56% of embryos created with fresh eggs resulted in a live birth, compared to 47% of embryos created with frozen eggs.

The Process of Selecting an Egg Donor

The process of selecting an egg donor is complex that involves you, your partner, your reproductive endocrinologist and sometimes other parties. The guiding principals for selecting a donor are

a. Selecting a donor with good ovarian reserve    b. Protecting the mother from the transmission of infectious diseases   c. Protecting the babies from the transmission of genetic diseases   d. Protection of the egg donor from potential complications of IVF   e. Partners preferences.

Ovarian reserve: an egg donor should have an excellent ovarian reserve. This predicts excellent response to treatment with fertility medications and the collection of large number of mature goo quality eggs. Egg reserve is assessed through history taking, vaginal ultrasound estimation of antral follicle count, day 3 FSH and estradiol assay and AMH levels. Donors should be younger than 32 years and preferably younger than 30.

Infectious disease screening: donor are screened using first a thorough history and examination. Donor practicing in high risk behavior and those that lived in certain geographical areas are excluded. Lab tests are obtained for hepatitis B, hepatitis C, HIV I/II, Syphilis, gonorrhea and chlamydia. Other tests for infectious diseases could include testing for human T lymphocyte virus I/II, West Nile virus and South American trypanosomiasis. Tests are run at initial encounter then repeated in specialized labs within 30 days of retrieval to minimize the possibility of acquiring any of these infections at a later time.

Genetic screening: Extensive genetic and family history is first obtained from the donor. This is followed by screening for at minimal cystic fibrosis and any genetic disease related to donor ethnicity e.g hemoglobin abnormalities in African, Asian and Meditranean donors-Ashkenazi pannel in Jewish donors. Spinal muscular atrophy and fragile X syndromes are commonly also screened. More recently a universal genetic test that include 100 most common genetic diseases is routinely used. If an abnormality is found, a genetic counselor is consulted.

Donor related precautions: Egg donors should have the ability and intelligence to understand the process. This is evaluated by a trained psychologist. egg donors are counseled that the process does not impair their ability to conceive children of her own. Stimulation is tailored to avoid excessive stimulation and ovarian hyperstimulation syndrome. Donor are followed up after the procedure to monitor for any complications form retrieval and that the ovaries regained their normal size after stimulation.

Partners preference: Partners are offered a session with a psychologist to express their feelings about the process and to discuss some of the early and long term aspects of the process inducing legal issues an disclosure to children when they reach maturity. Partners may prefer certain race or ethnicity e.g Asian, Jewish…Some agencies specialize in recruiting donors of specific demographics. Physical features are also strongly considered and discussed with couples. Academic achievements are also desired by many couples.

Other considerations: Male partner sperm analysis and labs are obtained. The mother is assessed for any medical disorder and the ability to carry a pregnancy safely. The uterine cavity is evaluated using hysteroscopy or saline sonography. The endometrium is evaluated for its response to hormones. The cervix is mapped to avoid difficult embryo transfer.

The process of egg donation is commonly satisfying to recipients, donors and physicians and is flexible to allow for safe selection of an egg donor and still consider your preferences and aspirations.

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Testosterone Therapy-Male Infertility

Testosterone Therapy-Male Infertility

Testosterone Therapy-Male Infertility

Many men are prescribed testosterone for a variety of reasons. Low testosterone levels (Low T) with no symptoms, general symptoms of low energy and feeling  tiered and sexual symptoms, among others. Approximately 2.5 million men are prescribed testosterone each year in The US, mostly with no proper testing. Testosterone is only approved by FDA for low testosterone associated with specific diseases affecting testicular function.  The FDA recently issued a safety communication cautioning the use of testosterone replacement for low testosterone levels and requiring labeling change to inform men of a possible increase in side effects.

From the fertility standpoint, there is no role for testosterone treatment, that could be detrimental. There is also no proven role for other medical treatment as clomid, letrozole, nolvadex, hCG and others in enhancing fertility in the vast majority of men

Effects of testosterone on male fertility

When men are prescribed testosterone, sperm production slows down significantly and may completely stop. Many of them, no sperm can be found in the ejaculate (azospermia). Testosterone therapy can markedly lower the ability of men to father children. Testosterone inhibits a key master gland hormone (FSH) that is required to stimulate spermatogenesis (making sperm). The specific effects of testosterone on sperm count are unpredictable. In some men sperm count drops to zero even after a short use of testosterone.

Interestingly, when testosterone is stopped some men but definitely not all of them recover sperm production, commonly in one to six months. The extent of the recovery of sperm count is also unpredictable. The recovery of sperm count maybe limited requiring fertility treatment for conception to take place. A short course of testosterone can lead to a low sperm count for a very long time.

What can be done about low sperm count related to testosterone treatment

In addition to evaluation of female factors especially ovarian reserve, always a priority, men on testosterone and showing low sperm count should be advised to

1. Stop testosterone administration immediately

2. Repeat sperm analysis in 2 months. Sperm analysis should be performed in a facility that can perform diligent search for even very few sperm and  can freeze sperm. If sperm is found in the ejaculate it should be cryopreserved immediately. If no sperm is found then sperm analysis should be repeated in another 2 months. The wait for recovery cannot be indefinite because of further deterioration of ovarian reserve in female partner with time.

3. Depending on the extent of recovery sperm can be utilized to promote conception. If sperm count recover close to 10 million moving sperm, natural conception can take place. Also sperm can be used for IUI, if needed. If the number of motile sperm is significantly lower, IVF is required, sometimes with intracytoplasmic sperm injection (ICSI).

4. If still no sperm were found after repeat analysis, TESE (testicular sperm extraction) can be attempted. A male reproductive urologist can perform diligent search for areas of spermatogenesis in the testes through repeat minute biopsy and searching under the microscope.

From the preventive aspect, avoid testosterone treatment if you intend to father children in the future. Know that there are very few solid indications for testosterone. If testosterone treatment is inevitable, consider pretreatment sperm freezing. Use gel preparation preferential to injection as they are not stored for a long time in the body.

Testosterone treatment is a preventable cause for infertility in males and could be detrimental to future fertility.

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Why are You Afraid of Infertility Treatment (and generally should not)

Why are You Afraid of Infertility Treatment (and generally should not)

Why are You Afraid of Infertility Treatment (and generally should not)

When have been trying to conceive for a while, women and men often are reluctant to seek help from a fertility specialist. What if they told me you cannot conceive? what if they find a major problem with my fertility? what if I need extensive treatment? All are viable questions. One deviation at that point is to consult with a specialist in your immediate circle but in another discipline: gynecologist or internist. This deprives you from valuable resources and tend to underestimate any issues you may have. This is a very common reaction in general use of supplements instead of medicine, go to a holistic specialist instead of a physician..

Why are you afraid of Fertility Consultation

When you consult with a reproductive endocrinologist you may anxious about a discovery of one or more fertility issues, that may require treatment. Fertility problems are very private, maybe more than any other medical problems. They are certainly more private,  though less risky, than heart disease or intestinal problems. You are also worried about the treatment of such factors and the required time and financial resources. One evidence of evidence of such fear is reluctance to seek consultation for years sometimes.

Why are you afraid of fertility treatment

Once you start a consultation with a fertility specialist and treatment is recommended, couples are worried about the treatment process: complications and results.

Possible Complications of Fertility Treatment

All the complications of fertility can be classified into proven complications and unproven complications

Proven Complications

i. Multiple Pregnancy

Multiple pregnancy

Multiple pregnancy

Twins and higher order multiple pregnancy is an established complication of fertility treatment. It is directly related to the type of treatment (IUI or IVF), age and the number of embryos (IVF) transferred or follicles observed (IUI). The general incidence of twins is 1% after natural conception, 30% after IUI or two or more embryo transfer and 1% after single embryo transfer. The general incidence of triplets or higher is less than 0.1% after natural conception and 3% following fertility treatment.

ii. Ovarian Hyperstimulation Syndrome

Also an established complication of ovarian stimulation. It is more common in younger patients with large number of antral follicles seen in the ovary and high AMH levels. Women with PCOS are particularly at risk. The incidence of sever forms is 0.5 to 1%. In its severe forms it may lead to accumulation of fluid in the abdomen, blood clotting and may require hospital admission.

iii. Complications from egg retrieval

Egg retrieval is associated with very low level of comlications <1/1000, including bleeding, infection and anesthetic complication.

iv. Pregnancy Complications

Like any pregnancy there is a risk for miscarriage (15%) and ectopic pregnancy (3%) (e.g pregnancy in the fallopian tubes).

Unproven Complications

Cancer

There is no conclusive evidence that ovarian stimulation or any fertility treatment, in itself,  increases the risk of cancer (any type). It is true that women who delay conceiving are at an increased risk for some types of cancer e.g breast cancer, ovarian cancer…There is however no proof that there is an increased risk of cancer due to treatment. For example, the risk for breast cancer in women living in the US is 1 in 8. This risk is slightly increased for women who deliver their first child after age 30. If a woman decided to undergo fertility treatment, her risk for breast cancer is not increased say to 1 in 6 because of that above her baseline risk

Congenital abnormalities

There is also no conclusive evidence that congenital abnormalities in babies conceived after fertility treatment is significantly increased after fertility treatment, for the vast majority of couples. In any population in the world, the incidence of birth defects after natural conception is 3-4% (not zero). This is the baseline risk. If a couple undergo fertility treatment, there no proof that that incidence is increased, say to 5%, compared to couples that declined fertility treatment. Many women seeking fertility treatment are older and are at increased risk for chromosomal abnormalities. Also infertility itself appear to be a risk for factor for slight increase in birth defects. But there is no evidence that medical procedures themselves increases the risk for congenital abnormalities. There are some special situations e.g severe male factor that even associated with further increase in risk of abnormalites, so a couple specific risk should be discussed with your reproductive endocrinologist. Note also that becoming pregnant at a younger age (with or without  fertility treatment) reduces your risk for chromosomal abnormalities.

Results

You are certainly worried about the result of fertility treatment. That may make some women fearful of proceeding with treatment. Do confront this heads on. Ask your reproductive endocrinologist to give you a customized chance for pregnancy and delivery. Generally, fertility treatment is ultimately very successful. Over 60% of women seeking treatment ultimately deliver a baby or more after fertility intervention. There are many factors that indicate high chance for success, prior to starting treatment: age, ovarian reserve markers, the order of the cycle (first and second cycles are more successful)..

Long Term Effects

Outcomes of babies and young adults conceived after ovarian stimulation and IVF are definitely a long term concern. The first baby conceived at delivered following IVF was in 1978. Since then, approximately 1% of the world population are born after IVF. The scientific community have long term follow up data on babies born after fresh and frozen embryo transfer. There is even data on the third generation of babies (children of women who were conceived after IVF).

Egg freezing recently gained ground into as a procedure that broadens reproductive options for women. There are no long term data, nor a large number of babies (millions) conceived after egg thawing.

Why you should not be afraid of fertility consultation and fertility treatment

Fertility Consultation

The majority of women undergoing a fertility consultation turns out to have no specific fertility factors and simply regular intercourse is advised. A fertility consultation is crucial in identifying risk factors (e.g genetic, multiple pregnancy) and to estimate odds for a healthy baby without or with treatment. Here is an example. A Caucasian couple are seeking fertility treatment. No fertility factors found, female partner is young. The only abnormality found is that they are both carrier for cystic fibrosis gene mutation (risk of transmission to baby is 25%). Same example apply to an African American couple in the case of sickle cell anemia. Would you want to know this? Another example, you are young but on fertility testing it was found that both of your fallopian tubes are blocked  and you may need help conceiving. Is this an important information for you to know? Knowledge is very important, even if you decide not act upon.

Fertility Treatment Complications

Multiple pregnancy: is definitely the most dreaded complication of fertility treatment. There are many steps in evaluation and treatment that can minimize the risk of multiple pregnancy to a rate close to natural conception. Avoiding ovarian stimulation and IUI in favour of IVF with single embryo transfer appears to be the most important treatment decision that can minimize multiple pregnancy. IUI appears more conservative but actually that is not true. IVF with a single embryo transfer is more conservative due to lower risk for multiple pregnancy. Acceptability of fetal reduction is also another issue that should be discussed before starting treatment. The indiscriminate use of clomid appears to contribute the largest magnitude of risk for multiple pregnancy due to its widespread use without monitoring.

Ovarian Hyperstimulation Syndrome: is largely preventable complication through judicious use of fertility medication and avoiding the use of hCG as a trigger shot in favor of using lupron. An astute reproductive endocrinologist is able to keep this complication to a bear minimum.

Fertility Treatment Results

From one aspect the success rate of fertility treatment (per treatment cycle) is a factor of female medical factors and quality of fertility treatment she receives, if needed. On the other hand, the majority of courageous women who persevere, do get pregnant with fertility treatment. Those who are very unlikely to conceive are identified early on during evaluation and are should counseled accordingly. Women who do get pregnant do not write about it in lay media. Because the chance for conception is personal, you should seek to know your own chance for conceiving fertility treatment success, paying no attention to what your peers say or what you read. They cannot in any way reflect your own odds for success.

Long term effects of fertility treatment

Data on long term outcomes of young adult conceived with fertility treatment are reassuring of normal development and no significant abnormalities. In relation to egg freezing, there are reports of about a 1000 babies followed for short interval. They appear to show no increase in abnormalities. There are no long term follow up studies of babies conceived from thawed eggs.

The anxiousness about fertility treatment is natural, considering its intimate relationship to our life. Input from lay media and peer anecdotal stories is skewed and not readily applicable to anyone else. Irrespective of the decisions you make, knowing the facts about fertility treatment, personalized to your own personal medical reality is probably empowering and can prevent harm even if you decide not to pursue fertility treatment.

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Endometriosis: Fertility Options are Clear

Endometriosis: Fertility Options are Clear

Endometriosis: Fertility Options are Clear

Endometriosis means tissue of the lining of the uterus is present outside the its normal boundaries. It can involve the pelvic lining, the ovaries (endometrioma), the fallopian tubes, the intestine and the muscle of the uterus (adenomyosis). As menstruation takes place in the uterus, these deposits menstruate into itself, become distended and causes pain (pain with menstruation, chronic pelvic pain, pain with intercourse, urination or defecation). Moreover, because of its chemical effects or associated pelvic scarring endometriosis may cause infertility.

Accurate diagnosis of endometriosis requires laparoscopy and biopsy of the areas suspicious because of its appearance. If you are suspect you have endometriosis (usually because of pelvic pain) and want to get pregnant or having difficulty becoming pregnant you face a small dilemma. You are usually given different recommendations from different headquarters, depending on their expertise and biases. Examples of such recommendations:

‘Lets do laparoscopy to diagnose endometriosis, remove any endometriosis we find as well as remove any scarring’

‘Lets give you medications for endometriosis’

The questions is which recommendation is “good for your specific case”.

Few basic principals about endometriosis treatment

These are not disputed principals, just facts related to the treatment of endometriosis in general.

1. Accurate diagnosis of endometriosis requires a laparoscopy and pathological examination of tissue biopsies obtained.

2. Medical treatment of endometriosis does not allow you to get pregnant while you are using it: oral contraceptive pills, synthetic progesteron, danazol and GnRH agonists (lupron) prevent ovulation. While you are taking these medications you will mostly not ovulate so you will not get pregnant.

3. Endometriomas (endometriotic cysts of the ovary) do not respond to medical treatment. Moreover their removal mostly require removal of a part of the ovary, because they are firmly attached. Thus their removal can lower the number of eggs remaining in the ovaries (ovarian reserve).

Treatment of infertility associated with endometriosis

Though each specific situation may require a different course of action as recommended by your physician, there are general guiding principals for treatment of infertility when endometriosis is suspected.

1. Infertility investigation: do not make any treatment decisions without a full fertility workup. Do not proceed unless you know your partner sperm analysis, obtained the results of ovarian reserve tests, tested if your fallopian tubes are open or not via an HSG as well as general preconception lab tests. Why? if you undergo surgical treatment for endometriosis and later discovered that your partner has very low sperm count requiring IVF and ICSI, then surgery had no potential to help you get pregnant.

2. What is your priority treating infertility or treating pain? This is important because medical treatment, although effective in treating pain cannot help you with infertility because it mostly prevents ovulation. Please note that the best treatment for pain associated with infertility is pregnancy. The large amounts of progesterone produced during pregnancy suppresses endometriosis, sometimes for years after delivery.

3. Resection of endometrioma; If a cyst consistent with endometriosis is seen on ultrasound be very careful with a recommendation to resect that cyst. Resection requires surgery. it reduces ovarian reserve because of removal of ovarian tissue. Unless the cyst is suspicious of malignancy or complication they are better left alone with observation while proceeding directly to fertility treatment e.g IVF. There is no evidence that removal of the cyst improves IVF success. On the contrary, removal of the cyst is associated with low response in that ovary.

4. Laparoscopis surgery for mild and minimal endometriosis: There are two studies that showed an improvement in pregnancy rate after laparoscopy for mild endometriosis. To put this in perspective, yes laparoscopy for infertility and mild endometriosis and infertility is an option but the magnitude of benefit in this case is limited at best. You first have to undergo surgery (with its possible complications). If endometriosis is found and ablated you would get a small bump in pregnancy rate in the year following surgery. The surgery may also help you with pain. On the contrary, endometriosis may not be found and you still have to try after surgery. Considering all the risks and benefits, the odds for pregnancy is not dramatically improved.

5. An alternative approach to mild and minimal endometriosis: The general thinking about infertility associated with minimal and mild endometriosis is that it is unexplained infertility. In these cases there is no mechanical distortion of pelvic organs and fallopian tubes are open. If sperm analysis is within normal enhancing fertility could be achieved through stimulation of the ovary to produce multiple eggs followed by IUI or IVF. This approach avoids surgery with its potential complication. IVF carries approximately three times the odds of pregnancy and can control the risk for multiple pregnancy, compared to IUI.

6. Moderate to severe endometriosis: These cause distortion or blocking of the fallopian tubes. Surgery is an option but its much more complicated than mild cases and has the risk of injury to the intestine, ureter, fallopian tubes, oavries..Scarring also may recur after surgery. An alternative approach is to proceed to IVF. It avoids major surgery and can address tubal, male and ovulatory factors. IVF success is not reduced in women with endometriosis.

7. Adenomysis (endometriosis of the uterus): MRI is sometimes needed for accurate diagnosis of adenomyosis. Adenomyosis is a surgical disease and its cure require removal of the whole uterus. This is because it cannot be shelled out of the uterus like a fibroid. Better ignored and proceed with fertility treatment.

Do not make any decisions related to infertility before a complete workup; sperm analysis, ovarian reserve tests and fallopian tube patency test. Avoid surgery in the ovary as it may reduce ovarian reserve. There is no established evidence that the chance for successful fertility treatment is reduced in women with endometriosis. Laparoscopic surgery is an option but is associated with surgical complications.

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Even with Diminished Ovarian Reserve You Can Achieve Pregnancy

Even with Diminished Ovarian Reserve You Can Achieve Pregnancy

Even with Diminished Ovarian Reserve You Can Achieve Pregnancy

Diminished Ovarian Reserve: What Does it Means

The number of eggs and their quality are reduced at a given age. Women with diminished ovarian reserve have less eggs and more chromosomally abnormal eggs than women in the same age group. It reflects low response to fertility medications and more difficulty achieving a pregnancy. Women with diminished ovarian reserve may reach menopause one or more years earlier. As few eggs remain, still some of the eggs are chromosomally normal and pregnancy is very possible in women with diminished reserve.

Diminished Ovarian Reserve: How it is Diagnosed

History: Some historical factors may indicate low reserve including cigarette smoking, prior surgery of the ovary (removal of a cyst or an ovary), prior exposure to chemotherapy (particularly cyclophosphamide) or pelvic irradiation, early menopause in other family members (mother, sister), recurrent early first trimester pregnancy loss (indicating low egg quality) and others.

Day 3 FSH: It is an aindirect marker for ovarian reserve. It is produced by the master gland in the brain. levels> 12mIU/mL indicates low reserve. It is less accurate than AMH or ultrasound.

AMH: is a protein produced by the cells surrounding the egg in small size follicles. It is more accurate than day 3 FSH. Levels <1.5ng/mL indicates lowe reserve

Low antral follicle count (Ovarian Reserve)

Low antral follicle count (Ovarian Reserve)

Good antral follicle count (Ovarian Reserve)

Good antral follicle count (Ovarian Reserve)

Vaginal Ultrasound: in expert hands (a reproductive endocrinologist), it is an accurate measure for ovarian reserve. The number of small follicles <10mm especially on day 2-5 of menstrual cycle is an accurate indicator for ovarian reserve and response to fertility medication. The presence of an advanced follicle >13mm on day 2 or 3 is also an indicator for low reserve as it indicates that the ovary is under increased stimulation from FSH produced the master gland.

More details on ovarian reserve tests can be found here.

Diminished Ovarian Reserve: What Should you Do

If all other fertility factors (male factor, tubal factor..) are normal you should attempt to conceive irrespective of ovarian reserve. Ovarian reserve tests are not absolutely accurate. They do predict response to ovarian stimulation but are not very good in predicting pregnancy. Two general options exist: i. regular intercourse or ii. ovarian stimulation to produce more than one egg followed by IUI or IVF.

Diminished Ovarian Reserve: What Should your Reproductive Endocrinologist Do

Your reproductive endocrinologist should ascertain ovarian reserve with multiple modalities: ultrasound and blood work. The infertility workup should be completed first: sperm analysis, hysterosalpingogram test for patency of fallopian tubes as well as preconception labs. Your infertility specialist should be able to advice you on the treatment protocol that is more likely to achieve a pregnancy. Fertility specialist should not deny treatment to women based on diminished ovarian reserve. Every woman with diminished reserve should be offered treatment at least once.

If the treatment plan involves ovarian stimulation, a special stimulation protocol or adjuvant treatment should be considered hopping at increasing the ovarian response (number eggs produced during the cycle). Some of the modifications commonly used are increasing the dose of gonadotropins, use of antagonist or flare antagonist, addition of clomid or letrozole, pretreatment with testosterone and use of growth hormone.

Diminished Ovarian Reserve: What would you expect from fertility treatment

Well it depends on few factors: Age and Relative Response to Fertility Medications

If a younger women e.g <37 years produce two or three good quality embryos at the end of stimulation, they have a reasonable potential to achieve a pregnancy after IVF. The chance of getting pregnant in women older than 40 with few embryos is much lower. When one compare effects of low ovarian reserve and age on reproduction it is clears that age has more negative effect on reproduction than age. Age is associated with low egg quality while ovarian reserve mainly speak for the number of eggs in the ovary. Younger women with low egg production fairs much better than older women with good reserve.

Response to ovarian stimulation is not created equal. Women that produce four or more large follicles >15mm are at much better chance for pregnancy after IVF. On the other hand those that have lesser response <3 follicles are a much lower chance for success and should consider converting their cycle to IUI or just cancel the cycle if they have male or tubal factors. They then can try again after considering a modification of the stimulation protocol. In women that produce > 3 -4 eggs IVF is substantially more successful (about three times) than IUI.

Because the response to fertility medication is difficult to judge just based on ovarian reserve markers, most women should be encouraged to try ovarian stimulation once at least and most women should not be denied treatment based on the notion of low ovarian reserve.

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Androgens: Improving Response to Ovarian Stimulation prior to IVF

Androgens: Improving Response to Ovarian Stimulation prior to IVF

Androgens: Improving Response to Ovarian Stimulation prior to IVF

Ovarian stimulation is the most significant improvement in IVF. Response to stimulation together with age are the most important determinants of successful outcome. Women with prior low response to stimulation and women with expected low response (diminished ovarian reserve) are at higher risk for cycle cancellation and  produce a smaller number of mature eggs and embryos. Many approaches were suggested to improve response in low responders including

Increasing the dose of gonadotropins (injection medications)

Use of antagonist protocol

Use of flare lupron protocol

Use of oral medications  e.g clomid or letrozole

Synchronization of follicles prior to stimulation using estrogens

Minimal stimulation IVF

Adjutant use of growth hormone

Use of androgens.

Androgen may Improve Ovarian response to stimulation

Testosterone is known to increase the sensitivity of the ovary to FSH (the hormone that stimulate recruitment and development of follicles in the ovary). Testosterone increases the number of FSH receptors in the follicle and thus its response to stimulation. Women that naturally have high androgens e.g polycystic ovary syndrome (PCOS) show an strong response to FSH. Androgen stimulation increase growth of early follicles and expand the number of follicles available for stimulation. Agonists (lupron) and antagonists (ganirelex) used in ovarian stimulation suppresses testosterone levels in some women.

Androgen Preparations

Two major preparations are available to deliver androgens prior to starting stimulation

Testosterone gel 10 to 12.5 mg applied to skin per day for 21 days or

DHEA oral tablets 75 mg for variable period 4 weeks to 4 months

Transdermal Testosterone

There were three randomized clinical trials (generally the best type of studies in biological sciences) investigating the use of transdermal testosterone prior to IVF. Of the 221 patients included in these studies. Women receiving testosterone required less fertility medications, had significantly more eggs retrieved and  less cycles were cancelled due to low response. There were no side effects in all studies. There was a two fold increase in pregnancy and live birth rates in women that used transdermal testosterone. There is evidence that transdermal testosterone prior to stimulation improves IVF outcomes.

Oral DHEA

The mechanism of action of DHEA is not well understood. There were many studies on DHEA but only one was randomized clinical trial. When all the studies with control group were considered, they demonstrated a significantly lower number of oocytes retrieved in DHEA treated women when compared to the controls. There was no significant difference in the clinical pregnancy rate between women pre-treated with DHEA compared to those without DHEA pre-treatment.  It is possible that DHEA can improve embryo quality, but this dud not translate into higher pregnancy rate. It is suggested that DHEA should be used for 2-4 months prior to IVF which delays treatment start.

The conclusions related to the use of androgens prior to IVF require more confirmation in larger studies. However, if andregens are used, transdermal testosterone is the preferred androgen pre-treatment prior to ovarian stimulation and IVF.

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Practical Approach to Male Infertility

Practical Approach to Male Infertility

Practical Approach to Male Infertility

Male factor infertility is present in approximately 40% of couples having difficulty to conceive. In most cases, however, it is seldom one factor. A basic element that is encountered in every case is the number and quality of eggs. Other factors in also include sexual factor and other female factors (e.g blocked fallopian tubes). Hence, evaluation of female factors is integral to evaluation and successful treatment of male factor.

Evaluation of female factors includes testing for ovarian reserve and testing of the fallopian tubes for patency. In addition to evaluation of medical, obstetric and genetic risks of getting pregnant.

Evaluation of Male Factor

Reproductive ability in males is initially evaluated through i. Detailed history of male partner and ii. sperm analysis. History can indicate many factors that may reduce the ability to conceive: social habits, erectile dysfunction, childhood infections (mumps), medical disorders, genetic diseases (chromosomal abnormalities, specific genetic diseases as cystic fibrosis), occupational exposure..etc. Unfortunately  in the majority of cases history may not predict abnormalities in male factor

Sperm Analysis

Accurate interpretation of sperm analysis (volume, concentration,  movement and shape) is the most important step in evaluation. It is important to take in consideration each factor separately and then in combination. Normal parameters are volume >2mL, concentration 15million/mL, motility 40% and normal shape 4% using strict morphological criteria (Kruger).

Repeat sperm analysis is commonly recommended when abnormalities are detected. There is no strong evidence to repeating the sperm analysis. If the sperm analysis is to be repeated this should be done at least 2 months later as it would take that long for new sperm to be ‘manufactured’.

Generally 10 million moving sperm sperm per ejaculate (volume x concentration x % motility) is required for successful reproduction with intercourse and IUI. Approximately 2 million motile sperm are adequate for IVF. Lower parameters especially if low morphology <2% require IVF with intracytoplasmic sperm morphology (ICSI).

Other Tests

Genetic screening for chromosome analysis and Y chromosome micro-deletion is required in low sperm concentration (<10 million /mL) and azospermia is required. Abnormalities are found in 5-10% of men and can be transmitted to children. Genetic screening for cystic fibrosis and its congenital absence of the vas deferens is also required if azosprmia (obstructive) is present.

Other sperm tests as pH, fructose and sometimes hormone analysis are sometimes helpful.

Tests for sperm DNA fragmentation is still being evaluated but are not part of routine fertility workup.

Treatment of Male factor Infertility

Improvement in sperm analysis is not the main aim of treatment. The main aim is conception and delivery of a healthy child. Sperm analysis improvement is a surrogate outcome not a final goal. In most cases, the improvement in sperm parameters (count, movement and shape) does not translate into a higher chance for conception. In addition, in the majority of cases there is no specific cause identified for male factor abnormalities. The two practical strategies left are to wait (within what is allowed by female ovarian reserve) for sperm analysis to improve and conception to occur or to use the small / abnormal sperm available for assisted reproduction (ICSI) which is a very efficient strategy.

Four Important Considerations before Treating Male Infertility

a. Female age and ovarian reserve: any treatment for male factor should be guided with the number of eggs in the ovary and their quality (age related). In women with women with low egg reserve and 35 or older consideration to ovarian stimulation (to increase mature egg production) followed by IUI or ICSI should be exercised.

b. Sperm Freezing: In men with moderate to severe male factor one should consider freezing one or more sperm samples. The future sperm parameters cannot be predicted and can deteriorate even to a complete absence of sperm in ejaculates. Sperm freezing is cheep, non invasive and can save men from the need for surgical retrieval of sperm. Men undergoing vasectomy can also consider sperm freezing, prior to procedure,  in case they decide to father children in the future

c. Genetic screening: there are two main values to screening males with moderate to severe sperm abnormalities to chromosomes, Y micro-deletion and cystic fibrosis. To avoid transmission to children and to counsel the couple about the chance of successful surgical sperm retrieval (TESE). In some cases the chance for finding sperm is extremely low that TESE is not indicated.

b. Urological consultation: After female and initial male evaluation is complete, evaluation by a male urologist is very useful. A urologist well versed in male infertility can counsel the couple about the chance for success of surgical sperm retrieval and following correct of obstruction.

Four Treatment Options to Consider

Surgical sperm retrieval: in obstructive and non-obstructive azospermia sperm can be retrieved directly from the testes by a male urologist. Micro-TESE involves dissecting one or both testes and obtaining multiple tiny biopsies from many areas. In real time each biopsy is examined under a microscope. The process is repeated till sperm are obtained. The best chance

Surgical treatment for obstructive azospermia: in men that underwent vasectomy before vasectomy reversal can, if successful, restore fertility. Other areas of obstruction can also be restored by urological surgery.

IUI: in few cases of mild male infertility (producing close to 10 million motile sperm) or mild shape abnormalities, ovarian stimulation and IUI is an aoption for 3 cycles. IUI using donor sperm is also an option.

IVF-ICSI: assisted reproductive technology is very robust and can address the majority of male infertility: low sperm count, low motility, abnormal sperm shape, prior fertilization failure. Its is very efficient that it can achieve a conception with very few available fresh or frozen sperm. It can be synchronized with surgical sperm retrieval so that fresh sperm are used for ICSI. Once sperm are available, the success of IVF is dependent on female age and ovarian reserve.

Interventions to Avoid or Consider Cautiously

Surgical treatment of varicocele: Varicocele is a common finding in infertile males and can be associated with low concentration and motility and higher abnormal shape of sperm. Varicocele surgery does improve sperm parameters. The problem with varicocele surgery is that it is not proven to increase the odds of delivering a child by female partner. Varicocele surgery should be cautiously considered due to lack of solid evidence of its benefits.

Medical treatment: The use of medications (e.g clomid, nolvadex, anastrozole) should be avoided as there is no evidence that they will improve the chance of pregnancy and improvement in sperm parameters. The use of injection medications should only be employed in men with a specific indications related to deficiency of such hormones

Supplements: so far there is NO supplement or ‘vitamin’ proven to increase the chance for successful reproduction in male with sperm abnormalities.

A practical approach to male infertility requires initial evaluation of sperm analysis, ovarian reserve and genetic risk factors followed by a treatment plan oriented with the ultimate goal: conceiving healthy child not intermediate issues as cause of male infertility and improving sperm analysis.

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