These tests can be done by your primary care physician or gynecologist prior to consulting your Reproductive Endocrinologist:

• Day 3 FSH (follicle stimulating hormone) and Estradiol (Day 2-3 is acceptable)
• TSH (thyroid stimulating hormone)
• Prolactin
• Progesterone: 7 days prior to menses, this test is occasionally helpful
• Semen analysis

These tests may be useful based on each patient’s particular needs:

• Hysterosalpingogram (HSG) or documentation of tubal status
• Hysteroscopy
• Laparoscopy: The surgeon should be able to treat during this procedure, not just diagnosis.

The following treatments may be done, if indicated, for a limited number of cycles:

• IUI (intrauterine insemination)
• Clomiphene citrate (Clomid, Serophene)

At Pacific Fertility Center, we bring a complete team of specialists together to focus on your fertility situation. With extensive backgrounds as REI specialists, embryologists, nurses, marriage and family therapists and financial counselors, we develop a single, integrated solution to your medical, psychological and financial needs.

Please use our Ask the Experts resource if you have further questions.

– Philip Chenette, MD

These tests are best done through your Reproductive Endocrinologist (fertility specialist):

• Strict sperm morphology
  Strict morphology is a very specific method of evaluating the shape of sperm. Most laboratories do not use strict criteria thus potentially missing a sperm problem. Our laboratory is staffed with embryologists trained to analyze sperm with these strict criteria.
• Evaluation of ovarian reserve
  Evaluation of ovarian reserve includes family history, ultrasound to detect the antral follicle count (AFC), a cycle day 2-3 FSH and estradiol level (both must be done at the same time), Anti-mullerian Hormone AMH, and clinical and family history.  An REI can bring all of these assessments together into one consistent picture of a woman’s ovarian reserve.
• Ultrasound
  A pelvic ultrasound is a very useful test when it is done at the appropriate time in the menstrual cycle. A few days prior to ovulation an ultrasound can evaluate ovulation, follicle growth, endometrial thickness and pattern, polyps, and fibroids. During menses is the best time to evaluate the ovary for cysts and endometriosis.
• Genetic testing
  Genetic testing is important in women with premature menopause and multiple miscarriages and men with very low sperm counts.  Patients with a family history of a genetic disease can use genetic testing to determine if they are carriers of the disease.  Universal genetic testing (Counsyl, www.counsyl.com) can be used to assess risk for certain genetic illnesses that run in families. If detected, Preimplantation Genetic Diagnosis (PGD) can help prevent genetic illness in your child.
• Insulin
  Women who have irregular periods and have been told they have Polycystic Ovary Syndrome (PCOS) should be evaluated by an REI.  Testing can lead to more effective treatment.

Treatments by a fertility specialist

The advanced training of an REI is helpful to provide the most successful treatments for infertility.

Some of these treatments include:

• In vitro fertilization with embryo transfer (IVF, or IVF/ET),
• Fertility preservation
• Egg freezing
• Intracytoplasmic sperm injection (ICSI)
• Preimplantation genetic diagnosis (PGD)
• Ovulation induction
• Intrauterine insemination

A specialist is able to evaluate simpler treatments and finely tune them to make them more effective. For example, a specialist can monitor ovulation induction with clomiphene (Clomid) with ultrasound and blood tests. The vaginal ultrasound can be used to assess follicle development and endometrial pattern and thickness. Intrauterine inseminations can be done to bypass hostile mucus caused by clomiphene. The specialist can also help decide when to stop a particular treatment and/or proceed with more.

Alternative medications like letrozole (Femara) are just as effective as clomiphene but have fewer side effects.  Since letrozole is not approved by the FDA for marketing for fertility use, its use is generally restricted to specialty clinics, that is, REIs.

Gonadotropins, the injectable drugs, for example Follistim, Gonal-F, Bravelle, and Menopur, are potent stimulants to the ovary.  They are designed to produce multiple follicles, in order to improve pregnancy rates.  Due to the risk of multiple pregnancy and overstimulation of the ovaries, the medications should be used only by experts in the field.  Most of these treatments are performed by REIs in the United States.

At Pacific Fertility Center, we bring a complete team of specialists together to focus on your fertility situation. With extensive backgrounds as REI specialists, embryologists, nurses, marriage and family therapists and financial counselors, we develop a single, integrated solution to your medical, psychological and financial needs.

Please use our Ask the Experts resource if you have further questions.

– Philip Chenette, MD

Ovarian reserve is an expression of the number and quality of eggs available for conception. As a parameter for predicting pregnancy, ovarian reserve testing is often part of a fertility evaluation. Such testing requires specific measurement, and clinical judgment to interpret the results.

Egg numbers are at a maximum before birth, at around 20 weeks gestation. After birth, there is a progressive decline in the number of eggs from roughly one million at birth to 300,000 at puberty. Through the reproductive years the remaining eggs are lost, with the rate accelerating around the mid-30s, resulting in few eggs left at menopause, around age 50-52. The number of eggs available for reproduction at a certain age is the ovarian reserve, which is the target of the diagnostic tests described here.

Age is the most accurate predictor of egg health, but within age groups, there is considerable variation in the number of eggs remaining for reproduction. Age alone as a predictor of ovarian reserve is not sufficient, since, for individuals, fertility may be better or worse than the average for that age. Extreme examples of this variability include the teenager in menopause and the 59 year-old that delivered a natural pregnancy in 1997. This variability in pregnancy rates within an age group is present in all reproductive age groups.

To predict an individual woman’s fertility rate, in addition to her age, both clinical and laboratory methods are available to evaluate ovarian reserve. The best tests are direct measures of the ovary, such as the Antral Follicle Count (AFC) and Anti-mullerian Hormone (AMH) level; indirect measures, such as clinical history and levels of pituitary hormones, are common tools for prediction of ovarian reserve.

The simplest method of predicting fertility rates is clinical history, of both the individual and her closely related family. The number of months spent attempting to conceive predicts fertility. A couple that has been trying for some time will naturally have a lower fertility rate than a woman that has not had unprotected intercourse. Response to ovarian stimulation can also be used as a marker, as it is fairly consistent between cycles. Family history, i.e., the fertility of the woman’s mother or sisters reflected in age at menopause and age at conception are useful predictors. Such factors from clinical history can help define the risk of a problem with ovarian reserve.

Ultrasound is a useful tool for predicting ovarian reserve, as in measuring the Antral Follicle Count (AFC). Antral follicles are the smaller follicles, visible on ultrasound, between 2 and 10 mm, that are lost as a woman ages. In younger women, the AFC is 10-20, declining by 5% per year through age 37, and then accelerating to a loss of 10% per year thereafter. Women show a fairly consistent AFC loss rate of one follicle every two years.

AFC predicts the response to ovarian stimulation at least as well as blood tests, but its ability to predict pregnancy outcomes is limited, particularly when low. A woman with a higher AFC will show a better response to fertility drug treatments. A high AFC seems to predict pregnancy rates, but data remains limited, as there are no prospective studies published. A low AFC seems to be a less accurate predictor of ovarian reserve, particularly in older age groups. AFC may help predict outcomes, but should not be used to exclude patients from treatment.

Anti-mullerian hormone (AMH) is a blood test that directly measures ovarian reserve. Produced directly by early stage ovarian follicles, high levels (over 1.0) are favorable, while low levels (less than 1.0) indicate decreased ovarian reserve. AMH may be the best measure of the menopausal transition and ovarian age. It may also be useful in predicting ovarian hyperstimulation syndrome, the effects of chemotherapy, and in determining the treatment of PCOS.

AMH seems a superior predictor of ovarian response compared to other markers, including age, and day 3 FSH and estradiol. It offers similar predictive value compared to AFC. AMH can be drawn at any time in the menstrual cycle, and is not affected by hormonal therapy, including oral contraceptives.

AMH still requires further study. The range of normal variation is still being determined, and the true predictive value of the test requires a great deal more analysis. The specific range of reliability and predictive value by age is yet to be established.

Cycle day three FSH and estradiol, and, to a lesser extent, the clomiphene challenge test, remain viable tests for estimating ovarian reserve. These tests are established as predictors of response to ovarian stimulation. Prediction of pregnancy rates is more difficult. Recent studies concentrating on the predictive value of these tests have shown that they cannot be used to determine which patients cannot conceive, but are useful for screening and counseling.

All in all, these tests are only rough predictors of ovarian reserve. They are moderately good predictors of ovarian response to stimulation, and relatively poor predictors of pregnancy outcome. In a particular patient, the tests can be used to counsel about potential response to ovulation induction, but it remains difficult to predict pregnancy outcome based on the test results.

The ultimate test of ovarian reserve is response to treatment and whether a pregnancy results from that treatment. Stay tuned as we evaluate further research to establish the validity of ovarian reserve testing methods.

For patient(s) who need to use an egg donor to create or expand their family, medical scrutiny is performed on the chosen egg donor before she can proceed with the IVF cycle.

The medical screening of egg donors is an important process. Here at the PFC Egg Donor Agency, we proceed with an extensive screening process PRIOR to allowing the egg donor to become eligible for choosing by the intended parent(s). This extensive screening is performed to help determine and identify any medical factors which may disqualify the donor, or to identify information which may require additional testing prior to determining donor eligibility. At PFC, our philosophy is that we want to identify any issues prior to intended parents choosing the donor, so that the risk of identifying medical issues with the donor after the start of the IVF cycle is minimized, and the risk of canceling the cycle is much reduced.

Medical screening for the donor includes an extensive review of her personal and family medical history, physical exam and pelvic ultrasound, psychological evaluation (in-person visit with our MFT Peggy Orlin),

standardized personality assessment (PAI), and blood testing including ethnic appropriate genetic testing.

The PFC Egg Donor Agency complies with current recommendations by the American College of Obstetrics and Gynecology (ACOG), and the American College of Medical Genetics (ACMG). The donor identifies her ethnic background, and based on this information, appropriate testing is performed (see article by Lauri Black, Genetic Counselor, outlining current recommendations). This testing is done and results reviewed prior to approving the egg donor as eligible to be in the donor database. If the donor is a carrier for a genetic mutation, this may disqualify her from being an egg donor; some genetic mutations may not be disqualifying, but the sperm source may need to be screened for that mutation, prior to deciding to choose that egg donor. These tested mutations are for recessive disorders, so an embryo would only be at risk of having the disorder if BOTH the egg and sperm source were carriers for the identified mutation (see above noted article).

It is important to understand that new genetic mutations are identified almost every day; so recommendations for ethnic-based testing do potentially change year by year. While many genetic mutations have been identified on the human genome, many of these are very rare, and only mutations that are more frequently seen within one’s ethnic group are those that are recommended to be tested for. It is not appropriate, nor feasible, to check for all known possible mutations. The PFC Egg Donor Agency is kept apprised of current recommendation by our affiliated genetic counselors, so that our list of genetic screening tests may change over time. Rest assured that we keep informed of these changes, and comply with up-to-date recommendations.

While all this testing may seem cumbersome, it is to help assure that once you choose your egg donor, we can proceed with the IVF cycle with minimal risk of a cancellation, and start you on your way to achieve your dream of a healthy family.

Question: I’m 38 years old and have been trying to get pregnant for about a year. All of my lab tests and my husband’s semen analysis have been normal. What do you think is the problem?

Answer: For women in their late 30s, it is naturally going to take longer to get pregnant. They are experiencing what I like to call “age-related sub-fertility.” Some may be lucky and become pregnant right away. However, for the majority of women, as we age fewer of the eggs we ovulate are chromosomally normal; and therefore fewer ovulations result in the release of a normal egg. It just may take more ovulations before that normal egg is released, fertilized, implants, and succeeds in becoming a baby. It is estimated that about 1 in 5 eggs are normal at age 35, about 1 in 10 at age 40, and only 1 in 25 at age 45. So, at age 38, if about 1 in 8 eggs are normal, you may have only 1 or 2 chances a year for successful conception. If your intercourse was not well-timed that cycle or there was some other subtle inefficiency, the chance for conception may be lost. The catch-22 with age-related sub-fertility is that it takes longer to get pregnant and meanwhile, you are getting older and your egg quality is also declining. For this reason, many women seek treatment with fertility medications or IVF as they get older. These treatments can increase the number of eggs produced and exposed to sperm in a single month, thus improving the odds that normal eggs will be found. The good news is that for most women still in their 30s, fertility treatments for age-related sub-fertility are often successful.

– Carolyn Givens, M.D.

Question: A friend of mine recently conceived a couple of months after two failed IVF cycles. Did she really need IVF in the first place or did the IVF change things to make it more likely she would get pregnant on her own later?

Answer: For some couples, IVF is necessary because the woman’s tubes are blocked or because the sperm count is drastically low. For these patients, IVF is probably the only way they are going to conceive. For the rest of our patients, those with endometriosis, mild male factor, decreased ovarian reserve, age-related, or unexplained infertility, there is some chance of conception, however low it is. For these patients, IVF is a way to boost (often dramatically) the chances of conceiving sooner than later.

For example, for a couple that has unexplained infertility of one to two years’ duration, the statistical chances that they are going to conceive on their own are probably in the range of 3% per month. Depending on the woman’s age, IVF could increase that to 20-50% per month of treatment. But even if she doesn’t happen to get pregnant with IVF, and the couple continues to try on their own, their chance of conception returns to that 3% per month, so they may conceive, even after a failed IVF attempt. There is no reason that the IVF itself should make that couple more likely to conceive later.

Question: I’m a heavy coffee drinker, consuming five cups per day. I’m concerned that my addiction to caffeine will hurt my chances of getting pregnant. How much caffeine is acceptable?

Answer: Moderate caffeine intake for women trying to conceive is acceptable. As a general guideline, women trying to conceive should limit intake to 3 cups of coffee (or 300 mg of caffeine) per day (Organization of Teratology Information Services (OTIS) 2001). Results from large published studies have not demonstrated that moderate caffeine intake adversely affects fertility (International Food Information Council (IFIC) August 2002). Furthermore, caffeine consumption has not shown to have an impact on fertility or birth defects for the male partner or sperm donor (OTIS 2001).

For women who are pregnant, there have been several studies analyzing the affect of caffeine and pregnancy with the conclusions of those individual studies being mixed (IFIC August 2002). Keep in mind that if you are pregnant or breastfeeding, the caffeine you consume may transfer to the infant. As such, guidelines for caffeine intake of pregnant or breastfeeding women are a little more rigid. The recommendation by OTIS and Motherisk is that consuming less than 1.5 cups of coffee (or 150 mg of caffeine) per day is not likely to increase the chances of miscarriage or a low birth weight baby. The American Academy of Pediatrics states that: “no harm is likely to occur in a nursing child whose mother drinks one cup of coffee a day.”

For more information on the affect of caffeine on fertility, visit the National Toxicology Program-Department of Health and Human Services website. The website provides a more detailed look at some of the clinical studies referenced above. Additionally it provides a chart showing the levels of caffeine in certain food and drinks. This information is available at: http://cerhr.niehs.nih.gov/common/caffeine.html.  

In the June 2008 issue of the Fertility Flash, Dr. Isabelle Ryan answered a question on how to choose an egg donor from a medical perspective. This month I’ll focus on the psychological aspects of choosing an agency egg donor. As the Marriage and Family Therapist at Pacific Fertility Center, this is a question I address regularly. All PFC patients considering ovum donation will have a complimentary meeting with me

Choosing an egg donor may seem like a daunting and foreign process. You are undertaking an unfamiliar task that you probably never planned on. But now that you are here, it may help to remember that the gene pool is huge. No matter whose gametes create your offspring; your children will be a magical and unique blend of nature and nurture. DNA is not destiny. Your love, your values, your womb, all have an impact on the person your child will become.

I find the following to be helpful reminders as you move forward with choosing a donor:

• The experience of attachment to a child, the feeling of being in love with him or her, happens regardless of whether one or both parents share the child’s DNA.
• Mothers and fathers are the ones that raise and love a child. Donors are the ones that donated or helped.
• Most donors donate for a complex blend of altruistic and monetary reasons.
• Each of our PFC agency donors has a psychological interview with me. In addition they take a psychological test (PAI); this test assists me in assessing not only their personality, but also their honesty and reliability.
• The more stringent your criteria for choosing a donor, the longer it will take to find her.

So, how in the world do you choose a donor?

I think there is a relatively simple answer to this seemingly complex question.

Choose the donor that jumps off the page at you. Choose the donor whom you like best, resonate with, feel a connection to, are impressed by.

That donor may or may not look exactly like you, but she will be someone you might have chosen as a friend or you could imagine as your daughter.

I believe the goal in choosing an egg donor is to be able to look at your child and either say or think to yourself, “we couldn’t use my DNA, but we chose someone we thought was lovely, interesting, attractive, smart, motivated (add the adjectives of your choice) to be our child’s donor. “

Practically speaking, if you have a partner, it may work best to look at donor profiles separately from him or her. After each of you note your favorites, you should then come together and choose from the selections that you both indicated. This process helps assure you both were able to choose without pressure from your partner.

Finally, please remember there is no “perfect donor,” but that does not mean you won’t be blessed with the “perfect child.”

Question: I am an educator for a human sexuality class. A student asked me an interesting question that I was unsure how to answer. Given that we know sperm can survive about 72 hours in a woman’s body, how is it possible to keep sperm viable by freezing them?

Answer: Sperm can survive for a long time under the right circumstances. In a woman’s body we think that 72 hours is approximately correct, but the data supporting this estimate is not conclusive. In the lab, sperm can live 5 days or more provided they are removed from the seminal fluid and placed in a more nurturing environment. Seminal fluid contains many enzymes that first clot and then liquefy. This change in the fluid allows the ejaculated sperm to stay in the vagina initially, but then swim out as the seminal fluid becomes more liquid. These enzymes quickly destroy any sperm that can’t swim out of the semen within a few hours.

It takes approximately 72 days for sperm to mature in the body. During the last 14 days of this process, the sperm are very much alive and swimming. They are alive a long time prior to leaving a man’s body.

During freezing, sperm are cooled to a very low sub zero temperature (minus 196 degrees Centigrade). At that temperature, all biological activity is effectively stopped. The sperm cells are not metabolizing or depleting their energy reserves. They are truly in suspended animation. Bacteria or other microbes cannot attack or degrade the sperm in any way because they are also unable to function at such a low temperature. Everything is on hold.

Biologists believe that correctly frozen cells in long term storage can literally last forever, as long as the temperature is properly maintained. It is believed that constant exposure to normal levels of background radiation is the only thing that could cause loss of viability and this effect is difficult to measure. Studies done in the 1970’s, exposing frozen mouse embryos to the equivalent of 2,000 years of background radiation, showed no measurable mutagenic effects in offspring.

Cryobiology is a relatively new science, and human fertility treatments are newer still. Consequently, in humans there are no long term results with frozen sperm or embryos. There are a handful of reports showing babies born from embryos that had been frozen for 12-15 years. A couple in New York had a child in 2005 from sperm that had been stored for 28 years. Sperm frozen for domestic animal species have a longer record because samples frozen in the 1950’s are still viable.

The process used for freezing is very precise and works best when cells exist individually (such as sperm) or in very small groups (such as an embryo). Larger masses of cells, tissues or even whole bodies cannot be frozen and subsequently thawed alive. It is not currently possible to freeze and thaw a whole ovary or kidney.

To successfully freeze cells we must remove cell water (water expansion during freezing would burst the cell) and replace the water inside the cell with antifreeze. This is done by incubating the cells in a solution of antifreeze. The water and antifreeze swap places through the process of simple osmosis. In a complex tissue like an ovary, there is no way to get all the water out of all of the cells so easily, thus a whole ovary cannot be frozen. If the ovary is chopped up into tiny pieces however, more water can be extracted. Some success has been reported with freezing ovarian pieces in this way.

The following student experiment demonstrates the challenges of freezing. Place a whole peach into your freezer for 24 hours and then thaw it out and see what a mess you have. If however you slice the peach up and mix the slices with sugar for 15 minutes (the sugar will draw out water from the cells), you can freeze the peach quite successfully. If the technology is used correctly, you can keep your peach (or your sperm) for leaner times.

Joe Conaghan, PhD, HCLD

Question: I am 35 years old and single, but am still hoping to find my life partner. I am getting a little concerned as my gynecologist has asked me about my plans for having children. She mentioned that I might want to consider freezing my eggs for future pregnancies. Is this something I should do?

Answer: Vitrification is a very new process for preserving unfertilized eggs. As noted in this month’s lead article, PFC has successfully been vitrifying oocytes from proven egg donors. Our first birth from this process occurred in October. Three additional pregnancies from this trial are ongoing. PFC undertook this vitrification trial in order to develop expertise with the technology of oocyte vitrification. For this reason, our study population was confined to donor eggs from healthy donors in their mid-twenties who had successfully completed conventional egg donation.

Why do we want to freeze eggs? For the many single young women diagnosed with cancer and facing fertility-threatening chemotherapy, egg vitrification will provide a fertility preservation option. This group of women has a compelling reason to consider undertaking the procedures and costs involved with in vitro fertilization. The potential threat to their ability to have their own biological children in the future may justify the unknowns that are involved with preserving their eggs in this manner. These unknowns include whether their eggs will survive the vitrification process and whether egg vitrification will ultimately prove to be as safe as conventional in vitro fertilization and embryo cryopreservation. The answers to these questions may not be answered until the patient’s eggs are warmed, fertilized and implanted, which may be years later.

We recognize that a much broader spectrum of the population will look upon oocyte vitrification as a way for women to preserve their fertility. Single women, such as you, who have not yet met their life partner, may be particularly interested in this option. In addition, it may also become an option for women in their 30’s who wish or need to delay their childbearing.

Many questions remain unanswered. Will eggs from women in their 30’s do as well as eggs from proven egg donors in their 20’s? Logic suggests older eggs will not do as well, but will the differences be significant? How many eggs would a woman need to preserve in order to have a reasonable chance for one or two children in the future? How many IVF cycles will that take? Is it safe to rely on these preserved eggs? Would having preserved eggs change a woman’s approach to reproductive planning in her life?

These are not trivial issues. They are important, life-changing concerns. For these reasons, we are not encouraging single women to prematurely jump on the egg vitrification bandwagon. Stay tuned. This area is changing rapidly.

Dr. Carolyn Givens