We are approaching a time that freezing eggs will be a standard option for an IVF program much like Embryo freezing is today.  Despite the fact that hundreds of babies have been born apparently without an increase in defects or abnormalities, the American Society for Reproductive Medicine (ASRM) has proclaimed that Egg freezing is still considered experimental.

This is not just a scientific decision but is a philosophical and political one as well.  In the 1980’s, IVF was being performed likewise on an experimental basis.  Insurance companies denied that it had become standard of care until recently.  In fact, there are insurance providers who in an effort to deny claims continue to call IVF experimental despite the million babies already born without significant increases in abnormalities or defects noted.  However, the ASRM is afraid to push the envelope and take a risk that may make them appear to be promoting a procedure that could theoretically be associated with increased problems with the children created after egg freezing.

But why should we be interested in egg freezing anyway when we have IVF that is successful and known to be relatively safe after 33 years of experience?  The reasons are multiple.  A young woman who develops cancer and will have radiation therapy or chemotherapy that may affect her eggs or have her ovaries removed would with egg freezing have an option to preserve her fertility and still have her cancer treated.  In the past, the loss of a woman’s future ability to bear children was sometimes more emotionally depressing for her than the cancer itself.  The prospect of offering hope to such affected women is spreading throughout the community in part through the efforts of the Lance Armstrong Fund supported group, Fertile Hope.  They are attempting to educate not just affected individuals but oncologists and other physicians who come into contact with patients who may be able to take advantage of new IVF technologies to preserve their fertility while undergoing cancer treatment.

Another great potential use for frozen eggs is in the donor egg program.  Currently, our egg donors go through fresh IVF cycles coordinated in time with the recipients so that the eggs are fertilized fresh when they are retrieved.  This is highly successful in achieving pregnancies in approximately 80% of donations.  However, cycles can be delayed in trying to synchronize patients.   If programs can achieve similar success rates using frozen eggs it will allow recipient patients to choose donor eggs much like they select donor sperm today.

Yet, another benefit of the ability to bank frozen eggs is for women who either because of their career or lack of finding a suitable partner need to put off their childbearing until a time when they would otherwise put their future fertility at significant risk.  This is a more controversial use of this technology but a practical concern for countless women today for whom conceiving before age 35 is unrealistic.

Needless to say, egg freezing will be a great benefit for many when it becomes a safe acceptable IVF standard.  That time for consideration by patients is rapidly approaching and is something that the public needs to be made aware of.

Last week a patient presented to my office with a question that made me feel like I was responding to a Dear Abbey letter requesting help to make some crucial life decisions that were related to her reproductive health.  As I pondered her query that I had heard so many times before I wondered how terribly nerve racking it must feel like for this woman.

Dear Fertility Doc,

“I am 39 years old, single and I enjoy my career.  However, I always dreamed I would have children.  Unfortunately, I have not yet met a man that I would feel comfortable with to marry and with whom to have a baby.  What should I do?”

Signed,

At Reproductive Crossroads

The issues that this woman brings up are universal in my practice.  She basically has to weigh her desire to have children now rather than delay, using her own eggs or potentially with an egg donor or to adopt.   She needs to consider the ramifications of taking time off from her career as well as creating a child with donor sperm.  She expressed concern to me that if she were to meet Mister Right how will he respond to this child?  Are there any tests that I can perform that can help this woman make a decision?

First of all, it is imperative in cases like this to do a full fertility screen so that we understand from a fertility perspective how much time she has left and how urgent this patient needs to make a decision.  To assess her fertility I do a Day 3 serum Estradiol and FSH, an AntiMullerian Hormone and a sonographic antral follicle count.  The FSH is regulated by negative feedback from serum Estradiol and inhibin both of which are produced by the granulosa cells of the ovarian follicles.  With diminishing ovarian activity there are fewer follicles, less estradiol and inhibin so with less feedback, the FSH level is high.  Occasionally, in patients with low ovarian activity, often called reserve, a patient may have an ovarian cyst that produces estradiol.  This will lower the FSH level to otherwise normal activity levels even when there is minimal ovarian activity and inhibin.  One would misinterpret the low normal FSH in the presence of higher estradiol which is why this must be measured concurrent with FSH.

AntiMullerian Hormone is also produced by the granulosa cells and low levels therefore indicate depleted ovaries.  Likewise, few antral follicles seen on ultrasound typically performed during the early follicular phase of the cycle will indicate low ovarian reserve.

Once we know a patient’s relative fertility through this screen we need to decide whether she is prepared to delay her career for pregnancy and motherhood or should she do IVF and freeze her embryos thereby freezing her fertility potential at the current state.

Since she is single without a participating partner we would be using the sperm from an anonymous donor.  The specimens are obtained from sperm banks that are certified by New York State by virtue of their screening and testing for infectious and hereditary diseases.  Patients may review what is available from the sperm banks.  They can review on the internet the donor’s demographic information, physical attributes, educational and occupational histories, etc for the offered specimens.

If a woman does not have any infertility issues I would attempt donor insemination.  However, due to her advanced age, I would progress to more aggressive therapies if we were not successful after a few cycles.

A common concern for women in this circumstance is that they may meet their soul mate in the future and he may not be comfortable with a child produced with someone else’s sperm.  This is an issue that is very individual and I can only offer to support the patients as they decide what is best for them.

As she prolongs the decision her fertility is diminishing, and thereby risks not being able to have a child using her own eggs.  If conceiving with one’s own eggs is crucial then she must weigh the downside of conceiving a child from an anonymous donor and if she does so, the potential problems associated with finding a man in the future who she may want to have a family with.

It is enormously stressful making these decisions at these reproductive crossroads.

I discuss these issues with my patients and help them arrive at the decision that is right for them.

I grew up on baseball in the 1960’s with the likes of Mickey Mantle and Roger Maris.  A few years later Tom Seaver and the Miracle Mets held my fancy.  Over the years I have been intrigued by many baseball spectaculars such as Mark McGwire and his run to break Roger Maris’s homerun record and Barry Bonds’s overcoming Mark McGwire’s record.  Roger Clemens winning his 300^th game and pitching his 3000^th strikeout was unforgettable.  I was enchanted with these baseball heroes when they achieved their record breaking accomplishments.

Then the story about how modern day athletes were using steroids became public and the glory of those heroes from the past 20 years disappeared.  Many of us lost our youthful innocence with the discovery that steroids had intruded into the daily routines of professional baseball.  But as my bubby (my Russian grandma) used to say; c’est la vie.  At least that was the French translation.

This week someone’s little boy who was pitching in the big leagues for the first year had a perfect game, meaning no batter reached first base the entire game with only one out to go.  This is a rarity in baseball having previously occurred only 20 times in major league history.   The final out was weakly hit, a ground ball to the infield, the pitcher covering first base beat the batter, and the throw was caught before the batter reached the bag.  Replays documented the batter was out but unfortunately, the umpire mistakenly shot his arms out signifying a safe sign thus preventing the last out which would have made this a rare perfect game.

So why should I blog about a botched call ruining a perfect game?  This arbitrary wrong turn of events which prevented a perfect game crushed me emotionally the same day my patient who I wanted so much to have her baby, miscarried after 3 years of trying to conceive.  She, like the rookie, Galarraga, deserved to have their day, the perfect game, the perfect baby.  Randomly, both were denied.  How is an individual who has such hopes, dreams and aspirations focused on the denied event to deal with this catastrophic disappointment?

As an observer of both, I was feeling distraught, angry, pushing me to cry out for justice for some supernatural power to make things right again.

Forty five minutes after the game after umpire, Jim Joyce, had the opportunity to review the play he went to the dugout to speak with pitcher, Armando Galarraga.  He apologized to the pitcher for spoiling his slice of fame. … There were few words, just a deep apology, as tears welled in Joyce’s eyes. “He feels really bad, probably worse than me,” said Galaragga, who began the season in the minors in Toledo. “I give a lot of credit to that guy, to say he’s sorry. I gave him a hug. His body English said more than the words. Nobody’s perfect, everybody’s human.”

We, in the field of infertility face disappointments as regularly and the menstrual cycle.  When a pregnancy is conceived, in our minds, the “perfect baby” is essentially created.  Miscarriage, the loss of one’s “perfect baby” seems to be a life crushing blow.  Perhaps, we can gain strength from the story about these two men, Armando Galarraga and Jim Joyce, who were able to reconcile this catastrophic schism in their path to obtaining their “perfect” goal and move forward to the next game.

Thank you, Armando and Jim for helping us to see the way.  After all, if you can get this close once only to miss because of a random mistake, then why can’t we expect that we have a good shot that it will work next time?

In the mean time, again as my Bubby would say, “Play ball”.

Pre-embryo genetic screening (PGS) was developed to help weed out embryos containing inherited metabolic disorders and genetic abnormalities prior to implantation. It was thought that PGS could be used to minimize the risk of miscarriage and perhaps even increase live birth rates in older women IVF undergoing .

We have thus far been disappointed in our results obtained using the FISH technique, the procedure performed for PGS for the past decade and a half. But an alternative new technology that was recently developed makes me very excited about PGS once again: Array Comparative Genomic Hybridization (aCGH).

ACGH is a technique actually applied to detect deficiencies and excesses of genetic material in the chromosomes. DNA from a test sample and a normal reference sample are labeled using colored fluorophores that hybridize to several thousand probes. These probes are created from most of the known genes of the genome and placed on a glass slide.

The differential color of the test compared to the normal sample DNA reflects the amount of DNA in the test specimen. It can pick up monosomies, trisomies or significant deletions on an embryo’s chromosomes.

The first baby born from this procedure was in September 2009 to a 41-year old woman. When aCGH is performed on a Blastocyst biopsy, it is effective in screening out mosaicism (mixed cell lines in the same organism). ACGH is 20 percent more sensitive than the best FISH assays with an error rate of two to four percent. Fifty percent of the embryos tested were normal with pregnancy rates exceeding Blast transfers without aCGH screening.

So, who could benefit from using this new technology?

1. Patients with repeat miscarriages can eliminate up to 90 percent of their miscarriages.

2. Older patients who naturally have a higher percentage of genetically abnormal embryos may now screen for and only transfer their normal embryos.

3. Patients who want to maximize their success with a single embryo transfer.

4. Patients who have experienced repeat implantation failure can be screened for genetically abnormal embryos.

This technology is available for about the same cost as the FISH procedure yet, since it is performed on a Blastocyst, it is safer with less effect on the integrity of the embryo and without significant risk of wrongly identifying abnormal embryos. A concern with FISH is that embryos identified as abnormal can actually result in a normal fetus. This risk is practically eliminated with aCGH and is another reason making it more successful.

I expect PGS will now become a commonly used addition to standard IVF to promote more successful single embryo transfer, improve success in older patients, eliminate miscarriages and treat patients with repeat implantation failure.

We are approaching a new era in IVF. Brace yourselves for a thrilling ride into IVF’s future.

Those of you with secondary infertility need to know that you are not alone in feeling this way. My patients all express this alienation which exacerbates the depressing effects of infertility universally experienced among those affected. You have as much a right to fertility care as anyone else as well as the respect and care.

There are some unique characteristics to patients with secondary infertility that are worth discussion. Those of you who have had a caesarian section, ectopic pregnancy or abdominal surgery are more likely to have a tubal factor causing your infertility. Scar tissue can form that can obstruct, or displace a fallopian tube making it more difficult for the tube to pick up an ovulating egg or the fertilized egg to make it to the uterus.

Borderline sperm counts and endometriosis typically make it more difficult to conceive so that it is not unusual that it took longer than expected to conceive the first time and now you are not experiencing any success at all.

We perform a semen analysis and hysterosalpingogram and consider the potential benefit of laparoscopic investigation. Alternatively, if the semen analysis is not too bad and the HSG is normal, patients may benefit from insemination with hormonal stimulation. Otherwise, in vitro fertilization either with minimal or full stimulation will offer significantly superior success rates.

Facing secondary infertility may be as difficult emotionally as infertility for those without prior pregnancies. However, treatment options are available that are highly successful in delivering you the family of your dreams.

I have received an enormous amount of email from patients over the years asking for information about how they should get started with their infertility workup.  Apparently, they are women, men and couples who have experienced difficulty conceiving and now want some direction about how they should proceed.  Building a family was something they had imagined their entire lives to be a natural progression–from student to career, getting married then having a family–and they’re frustrated that their difficulty conceiving has affected their lives.  For many—some of whom have never experienced a health problem– it prevents them from appreciating or even doing anything else.

See an RE for a Fertility Workup

My response to these emails has been to tell the patients to seek assistance from a reproductive endocrinologist, whose specialty and experience is in helping infertility patients conceive.  A reproductive endocrinologist, who has two to three years of additional specialty fellowship training in infertility after completing an OB/GYN residency.

The RE will conduct a history and physical examination during your initial consultation.  This exam typically includes a pelvic ultrasound of a woman’s ovaries and uterus.  He/she can tell if there are any uterine abnormalities that may affect implantation or pregnancy as well as assess ovarian activity and rule out cases of moderate or severe endometriosis.

Pelvic Inflammatory Disease

If he elicits a history of previous abdominal or pelvic surgery, a physician may suspect that scarring may have developed that typically interferes with fallopian tube transport of the egg to the sperm and the conceptus to the uterus.  An infection that develops after a pregnancy may lead to pelvic adhesions affecting the tubes as well as scarring within the uterine cavity itself which can prevent implantation.  Pelvic inflammatory disease, PID, can lead to tubal disease and may be associated with other sexually transmitted diseases including HPV, Herpes and especially Chlamydia.

Semen Analysis

The semen analysis is the simplest test to perform and will reveal a male factor in 50% of cases.  A post coital test performed midcycle around the time of ovulation when the cervical mucus should be optimal can detect a male factor or cervical factor when few motile sperm are detected within hours of intercourse.

Hysterosalpingogram

A hysterosalpingogram, HSG, is a radiograph x-ray of the uterus and fallopian tubes after radio opaque contrast is injected vaginally through the cervix directly into the uterus.  It can detect uterine abnormalities that can affect implantation and pregnancy as well as tubal patency.  Unfortunately, this exam may be painful and in some patients with PID can result in serious infection.  Some physicians will administer antibiotics prophylactically for this reason.

Hydrosonogram

A hydrosonogram is an ultrasound of the uterine cavity performed after injecting water vaginally through the cervix directly into the uterus.  It can also detect uterine abnormalities and shares some of the risks seen with HSG but to a lesser extent and usually with less associated discomfort.

Hysteroscopy

A hysteroscopy is a surgical procedure in which a telescope is placed vaginally through the cervix directly into the uterus.  The physician can visually inspect the cavity to detect uterine abnormalities.  The risks of pain and infection are also seen with hysteroscopy.

Blood Tests

Blood tests may be run to identify if a patient is ovulating with adequate progesterone stimulation of the uterine lining.  Day 3 E2, FSH and LH levels can give information regarding ovarian activity and ovulatory dysfunction.  AntiMullerian Hormone (AMH) levels correlate with ovarian reserve.   That is the number of eggs remaining in the ovaries.  Hormones that can affect fertility such as thyroid and prolactin are also assessed to ensure that extraneous endocrine problems are not the cause of the infertility.

Laparoscopy

Laparoscopy is a surgical procedure in which a telescope is placed abdominally through the navel thereby allowing a physician to inspect the pelvic organs.  He/she can identify endometriosis, cysts, adhesions, infection, fibroids etc. that may be causing the infertility.  Unfortunately, only about 25% of cases in women who have a laparoscopy performed will conceive because of treatment performed at the time of the laparoscopy.

Workup Results and Treatment

Treatment can be directed at the cause such as surgery to correct adhesions or remove endometriosis, uterine polyps or fibroids.  Treatment can also be independent of the cause but improve fertility nonetheless.   Ovulation induction increases the number of eggs and therefore the likelihood that an egg will fertilize.  Gonadotropin injections stimulate many more eggs to develop in a cycle than clomid fertility pills.  IVF with minimal or full stimulation is the most successful treatment for any cause of infertility.  The decision as to what treatment to undertake will depend on numerous factors including your age, duration of infertility, cause of infertility, cost of treatment and success of treatment as well as your insurance coverage for the treatment and your motivation to conceive and willingness to accept the risks associated with the treatment.   Today, there is a highly successful treatment available for nearly all women.

What Do You Know About Fertility Screening?

Statistics and general truths aside, every woman is unique. Given just how complicated it is to make a baby in the first place, understanding your own body’s reproductive capability and the changes it might undergo from year to year is an invaluable planning tool.

Consider an annual fertility evaluation or screening.
Simply put, the screening involves a few simple blood tests and an ultrasound to assess your ovarian function. These tests have been around for years and are tried and true tools in the assessment of fertility.

We propose using these tests as a screen to prevent future infertility. We recommend that annual screening begin at 30 years of age or earlier if you have irregular menses, hot flashes, difficulty conceiving after 6 months or a family history of early menopause or infertility.

Taken together with your individual and your family’s medical histories, fertility screening helps establish where you are on your personal fertility curve. The first screening establishes your baseline, subsequent annual evaluations will flag changes in key hormone levels and mature follicle and egg production that could signal potential trouble. Mind you, any warning flares are just that and may mean nothing. But they could indicate that follow-up with your doctor, gynecologist or a reproductive specialist is warranted. And if there’s a problem, you’re ahead of the game with the opportunity for early intervention and, where possible, corrective action.

Fertility screening can help identify women whose ovarian function is diminishing so they can get timely treatment. The fact is, some women in their 30’s prematurely age from a reproductive perspective and their fertility may look more like that of a woman in her 40’s.

What Does the Screen Involve?

The screening itself is fairly low-tech.

Part one consists of a blood test to check the levels of FSH (follicle stimulating hormone), estradiol and AMH (antimullerian hormone). The FSH and estradiol must be measured on the second or third day of your period. The granulosa cells of the ovarian follicles produce estradiol and AMH. The fewer the follicles there are in the ovaries the lower the AMH level. It will also mean that less estradiol is produced as well as a protein called inhibin. Both inhibin and estradiol decrease FSH production. The lower the inhibin and estradiol the higher the FSH as is seen in diminished ovarian reserve. The higher the estradiol or inhibin levels are then the lower the FSH. Estradiol may be elevated especially in the presence of an ovarian cyst even with failing ovaries that are only able to produce minimal inhibin. However, the high estradiol reduces the FSH to deceptively normal appearing levels. If not for the cyst generating excess estradiol, the FSH would be high in failing ovaries due to low inhibin production. This is why it is important to get an estradiol level at the same time as the FSH and early in the cycle when it is likely that the estradiol level is low in order to get an accurate reading of FSH.

Part two is a vaginal ultrasound to count the number of antral follicles in both ovaries. Antral follicles are a good indicator of the reserve of eggs remaining in the ovary. In general, fertility specialists like to see at least a total of eight antral follicles for the two ovaries. Between nine and twelve might be considered a borderline antral follicle count.
As you start to screen annually for your fertility, what you and your doctor are looking for is a dramatic shift in values from one year to the next.

What Does the Screen Indicate?

A positive screen showing evidence of potentially diminishing fertility is an alarm that should produce a call to action. When a woman is aware that she may be running out of time to reproduce she can take the family-planning reins and make informed decisions. The goal of fertility screening is to help you and every woman of childbearing years make the choices that can help protect and optimize your fertility.

Although none of these tests is in of and of themselves an absolute predictor of your ability to get pregnant, when one or more come back in the abnormal range, it is highly suggestive of ovarian compromise. It deserves further scrutiny. That’s when it makes sense to have a discussion with your gynecologist or fertility specialist. Bear in mind, the “normal” range is quite broad. But when an “abnormal” flare goes off, you want to check it out.

It’s important to remember that fertility is more than your ovaries. If you have risk factors for blocked fallopian tubes such as a history of previous pelvic infection, or if your partner has potentially abnormal sperm, then other tests are in order. And if, for example you do have blocked tubes, it’s better to have them corrected sooner rather than later when the becoming pregnant is an urgent matter.

Learn More About Your Fertility

Also, make sure you read Part I of our series, What Do You Know About Your Biological Clock?

These encounters I have with patients are more frequent than they should be. Unfortunately, many women delay seeking help in their efforts to conceive until their age has become significant both because they have fewer healthy genetically normal eggs and because their ability to respond to fertility drugs with numerous mature eggs is depressed. Women often do not realize that fertility drops as they age starting in their 20s but at an increasing rate in their 30s and to a point that may often be barely treatable in their 40s.

A common reason women delay seeking help is the trend in society to have children at an older age. In the 1960’s it was much less common that women would go to college and seek a career as is typical of women today. The delayed childbearing increases the exposure of women to more sexual partners and a consequent increased risk of developing pelvic inflammatory disease with resulting fallopian tube adhesions. When patients have endometriosis, delaying pregnancy allows the endometriosis to develop further and cause damage to a woman’s ovaries and fallopian tubes. They are more likely to develop diminished ovarian reserve at a younger age due to the destruction of normal ovarian tissue by the endometriosis. Even more important is that aging results in natural depletion of the number of follicles and eggs with an increase in the percentage of these residual eggs that are unhealthy and/or genetically abnormal.

Diminished ovarian reserve is associated with decreased inhibin levels which decreases the negative feedback on the pituitary gland. FSH produced by the pituitary is elevated in response to the diminished ovarian reserve and inhibin levels unless a woman has a cyst producing high estradiol levels which also lowers FSH. This is why we assess estradiol levels at the same time as FSH. Anti-Mullerian Hormone (AMH) can be tested throughout a woman’s menstrual cycle and levels correlate with ovarian reserve. Early follicular ultrasound can be performed to evaluate a woman’s antral follicle count. The antral follicle count also correlates with ovarian reserve.

By screening women annually with hormone tests and ultrasounds a physician may assess whether a woman is at high risk of developing diminished ovarian reserve in the subsequent year. Alerting a woman to her individual fertility status would allow women to adjust their family planning to fit their individual needs.

Aggressive fertility therapy may be the best option when it appears that one is running out of time. Ovulation induction with intrauterine insemination, MicroIVF and IVF are all considerations that speed up the process and allow a patient to take advantage of her residual fertility.

With fertility screening of day 3 estradiol and FSH, AMH and early follicular ultrasound antral follicle counts, the biological clock may still be ticking but at least one may keep an eye on it and know what time it is and act accordingly.