While many factors leading to female factor infertility are out of a patient’s control (genetics, for example), there are several measures patients can take that will help optimize their chances of conception.

At the forefront is receiving routine gynecological care. During the preconception phase, it is important that the patient have an up-to-date Pap smear and mammogram. Furthermore, the patient should undergo testing for infectious diseases (Hepatitis C, Hepatitis B, syphilis) and immunization status for varicella and rubella and hormones which can affect ovulation (prolactin and TSH). Any fibroids or polyps the patient has should be evaluated to make sure they wouldn’t adversely affect the chances of conception. Also, the patient should be taking essential prenatal vitamins as prescribed by her OB/GYN.

Certain behavioral factors should also be assessed and, in some instances, eliminated prior to trying to conceive. Smoking and drinking should be eliminated and exercise should be moderated. Incorporating a regular exercise program along with a balanced diet is recommended. The diet should include lean proteins, a colorful variety of fresh fruits and vegetables, combined with a limited intake of processed and fatty foods.

Women who are extremely thin or very heavy should seek the help of a nutritional counselor to attain a healthy weight without fad or crash diets. Embarking on a new, strenuous exercise regimen or crash diet just before attempting to become pregnant is not recommended. Medications being taken for preexisting medical conditions should also be evaluated to ensure they won’t compromise a pregnancy.

If the patient requires a fertility specialist, it is recommended the following tests be performed prior to seeing a specialist. This will streamline the diagnosis process and expedite them on their path to proper treatment. This includes testing of the ovarian hormones, follicle stimulating hormone (FSH), Estradiol; a semen analysis (for the male partner) and an HSG (dye study) to assess tubal patency. See more about fertility testing…

Age is a critical factor in the outcome of infertility treatment and it is important for patients to be more proactive the older the patient gets. At Pacific Fertility Center (PFC), our guideline for patients is to seek help from a fertility specialist after: 1 year of trying for women less than 35 years of age; 6 months of adequately timed intercourse or inseminations for women ages 35-39; 3-6 months of trying for women over 39. See more about age and fertility…

Again, time is of the essence when it comes to getting treatment from a reproductive expert, and, keeping that in mind, there are several tests that we do not encourage patients to take prior to seeing an infertility specialist based on their limited usefulness.

They include:

• Post coital test
• Sperm penetration assays
• Endometrial biopsy
• Serum antisperm antibodies
• Cervical cultures
• Laparoscopy
• Autoimmune factors

Ultimately, conceiving through assisted reproductive technology (ART) is a team effort involving the patient, OB/GYN, and fertility specialist, with the process beginning several months before the patient steps foot in an IVF clinic.

Click here for more information on pregnancy preparation.

– Eldon Schriock, MD

Male factor infertility is quite common, contributing to 40% of infertility diagnoses. Treatment is designed around the particular type of problem and can be remarkably effective. For those with male factor infertility, the initial course of action is to review personal health habits. Stress, poor diet, and alcohol use have all been correlated with male factor infertility. Alcohol use, in particular, has been shown to have a dose-related effect on sperm; the more one drinks, the poorer the reproductive outcome. High temperature exposure from hot tubs or hot baths (immersion in hot water), or heavy exercise, particularly bicycle riding, have been correlated with male factor infertility as well. Resting a laptop computer on one’s lap has also been implicated in raising testicular temperature.

Diagnosis of male factor infertility starts with a semen analysis. The semen analysis should be performed on an ejaculated sample collected on at least two occasions 2-7 days following abstention from sexual activity. Measurement of the sperm count, motility, and volume can reveal production problems as insufficient or poor quality sperm are released from the testes. Table 1 lists the standards for assessing a semen analysis (Source: The World Health Organization, 1992).

Additional tests to evaluate sperm quality include the detailed or Krueger morphology. This entails viewing individual sperm cells under a high-powered microscope. This is a strict test that reveals abnormalities in the shape and size of the sperm heads, mid-pieces, and tails. A normal morphology is present when over 14% of sperm are normal.

Survival of the sperm on extended testing is also a useful diagnostic test. The sperm survival test, or SST, is a method for testing the lifespan of the sperm. At 24 hours, sperm survival should be over 40% (i.e. 40% of the sperm sample should survive); conversely, lower survival rates correspond to lower pregnancy rates.

Additional testing for male factor infertility includes a physical exam, blood tests for FSH, prolactin, and testosterone, and an ultrasonography of the collecting tubes of the male reproductive system. In some cases, an assessment of DNA fragmentation can give an index of sperm quality as well.

One condition we encounter at our clinic is azoospermia, which is the absence of sperm in the ejaculate. This can occur from birth defects, injury or infection, or rare endocrine abnormalities. In azoospermia, a high FSH level indicates testicular failure. Insufficient levels of testicular hormones lead to an increase in the release of pituitary gland FSH to compensate. High levels of testicular hormones are often accompanied by testicular atrophy (small testicles). Testicular biopsy may confirm the clinical findings.

Men with testicular failure (and very low sperm counts) should be tested for Y-chromosome microdeletions and abnormal karyotypes, or chromosomal count. Microdeletions may be transmitted to offspring, resulting in fertility problems for boys born after treatment.

The most common abnormal karyotype is Klinefelter Syndrome, where the male has three or more sex chromosomes, instead of the normal two. Such chromosomal defects can have effects on children born after treatment, and men should receive genetic counseling and risk assessment prior to treatment. Men with testicular failure may still have partial sperm production. Detailed assessment with microscopic surgery may detect a sufficient amount of sperm to use with in vitro fertilization (IVF).

Obstruction is another type of male factor infertility, as potentially normal sperm cannot move from the testes to the ejaculate. Men with a normal FSH may have an obstruction in the vas deferens or any of the other collecting tubes that gather sperm from the testes. Men with congenital absence of the vas deferens (CBAVD) may be carriers of cystic fibrosis, and should be tested. Surgical obstruction, or vasectomy, is readily repaired. Microsurgical techniques, and an experienced surgeon, will increase success rates. The procedure may be attempted for many years after an initial vasectomy. More unusual obstructions can result after infection of the epididymis. Ejaculatory duct obstruction can be treated with a cystoscopic procedure. Obstructions can sometimes be repaired, but often a simple needle aspiration procedure (percutaneous epididymal sperm aspiration, PESA) will yield enough sperm to achieve fertilization with IVF.

The key treatment when working with low sperm numbers, whether in the ejaculate or obtained by needle aspiration or biopsy, is to perform in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI). ICSI is when a highly trained embryologist uses micromanipulators to inject an individual sperm into an egg, optimizing for fertilization.

ICSI has become a common procedure, resulting in many pregnancies worldwide for men that otherwise could not have children. Sperm with a variety of abnormalities, ranging from low counts, to extremely low motilities, can be suitable for use. The DNA of the sperm is tightly compacted in ways that protect it from injury, even when the other components of the sperm do not function well. Injecting the sperm into the egg can bypass the barriers separating sperm and egg.

Another condition we encounter which can lead to abnormal sperm parameters is the presence of a varicocele. A varicocele is an enlarged vein along the upper part of the scrotum. The blood carried in these veins may elevate the scrotal temperature, and possibly carry toxic materials into the testicle, affecting sperm production. Only varicoceles that are palpable are thought to contribute to infertility. Ultrasound is sometimes used to confirm an uncertain diagnosis, but there is doubt whether subclinical varicoceles are associated with infertility. Varicoceles can be repaired, or various fertility treatments attempted, including sperm wash and insemination, and in vitro fertilization. The decision of treatment depends on both male and female factors, such as age, tubal disease, and ovulation disorders.

In closing, it is important to remember that infertility is not just a “female” issue and that men should engage in lifestyle habits that will not compromise their fertility. Furthermore, advancements in assisted reproductive technology (ART) have given men with infertility diagnoses newfound hope in their quest to build a healthy family.

– Philip Chenette, MD

One of the mysteries that confound reproductive biologists is the issue of why human embryos implant into the uterus at relatively low rates as compared to other animal species. This is evident when looking at implantation rates at the time of In Vitro Fertilization treatment. The chance that any one embryo will implant in the uterus varies with female age such that at age 40, only about 5-10% of transferred embryos will successfully take hold and create a viable pregnancy. Even when looking at donor egg-derived embryos from 21-28 year-old donors, the rates of implantation are about 30-45% per embryo. One mechanism to explain the failure of some embryos in implanting – perhaps the primary mechanism – is chromosomal abnormality. If an embryo does not carry a perfect set of 23 pairs of chromosomes, the embryo will likely stop developing, often before implantation can occur.

Implantation of embryos is a complex process. Initially, the embryo has to attach its placental cells to the surface cells of the uterine lining (the endometrium). This is a process that is mediated by a complex of proteins expressed both on the surface of the embryo and on the surface of the endometrium. Expression of the uterine proteins is under the influence of the ovarian hormone progesterone. There are estimated to be over 300 genes that are either turned off or turned on in the endometrium during the “implantation window,” the 3-4 days during which the endometrium is receptive to an embryo attaching. Most of the products of these genes and their role in implantation remain to be identified. In a small percentage of cases, failure to properly secrete one or more of these proteins may be a cause for implantation failure of normal embryos.

One protein produced by the endometrium during the implantation window that has some evidence for a scientific basis for a role in implantation is the cell-to-cell adhesion molecule known as beta-3 integrin. Integrins are a class of cell surface proteins that appear to act in all types of cell-to-cell recognition and adhesion processes. The beta-3 class of these proteins has been shown to be produced in response to progesterone in the endometrium and are purported to be one of the key proteins for adhesion of embryos to the endometrium. Failure to express this protein appropriately has been theorized to be a cause of unexplained implantation failure. Why some women do not produce beta-3 integrins is usually unknown. However, some proposed causes include presence of blocked fallopian tubes filled with inflammatory fluids (hydrosalpinx), endometriosis, and poor progesterone production.

In order to diagnose whether or not a patient is producing beta-3 integrins, an endometrial biopsy must be performed 8-10 days after ovulation, as determined by LH surge testing. The biopsied endometrial sample is then sent to a laboratory that performs immuno-histochemical analysis on the tissue. The tissue is fixed to a slide and treated with antibodies to beta-3 integrins. These antibodies then are further treated with a second color marker antibody, so that endometrium-secreting beta-3 integrins will light up under the microscope. The tissue is scored by manual analysis by a medical technologist specifically trained to analyze beta-3 integrin expression.

In June of this year, I had the opportunity to visit Adeza Biomedical, a Cupertino-based laboratory that offers beta-3 integrin testing. I was impressed with the facility and the scientific integrity of the staff. I was also impressed with the labor-intensiveness of the analysis process. They receive specimens every day from infertility clinics across the country and are usually processing 6-12 specimens daily. They also send a portion of the biopsied tissue to a local pathologist to determine if the configuration (histology) of the endometrial tissue indicates it has been obtained within the implantation window or whether it is “out-of-phase.” As it turns out, a high percentage of tissue samples (40-45%) at Adeza are reported as negative for beta-3 integrins. A smaller percentage of these negative specimens are “out-of-phase”. So most of the specimens failing to show beta-3 integrins production are “in-phase”. It is unclear why this lab finds such a high rate of their test samples showing negative results for beta-3 integrins when the true incidence of lack of beta-3 integrins in most patients should be low. It may be that either the lab is setting the scoring level for a positive result too high or it may be that the patient samples really reflect a selected population of women who truly have low expression of beta-3 integrins. Unfortunately, there is no clear answer to this.

Previously, we had been less inclined to perform endometrial biopsies. Even if we found out there was a lack of beta-3 integrins, we wouldn’t know what to do to induce their expression. However, we are beginning to find that we can often induce the expression by treating beta-3 integrin-negative patients with the aromatase enzyme inhibitor, letrozole (see A Closer Look at Letrozole; May 2006). Many women, especially if the histology on the original biopsy is “in-phase,” will have a positive biopsy result after treatment with letrozole.

Biopsies are typically performed 8-10 days after an LH surge in a natural cycle. Repeat biopsies on letrozole (taken days 3-7 of the cycle) are also performed at this time. We usually will use some local anesthetic in the cervix prior to passing a small plastic tube through the cervix to scrape out some endometrial tissue. Mild cramping may occur. The cost of the biopsy is $125.00 and the cost of the tissue analysis by Adeza is $400.00. It takes about 4-5 working days for the results to be received.

If you would like more information about this test, visit www.adeza.com and select the E-tegrity logo. You can download a patient brochure from this website. If you would like to know if this testing is appropriate for you, please ask your PFC physician.

– Carolyn Givens, M.D.

Question: Can I collect my sperm sample at home?

Answer: Yes, sperm samples can be produced at home and brought into our office provided that you follow some simple guidelines. Most importantly, the instructions for producing a sample must be followed as if you were producing a sample in one of the two dedicated rooms in our office. You should shower in the morning and wash the genital area with soap and then rinse with plenty of water. Most of the samples we receive are produced by masturbation and you should be careful to wash your hands immediately before and after the collection. If you need lubrication and/or a condom to produce the sample, these must be supplied by PFC. Most condoms and commercially available lubricants are toxic to sperm in some way, but we can supply you with materials that we have tested and that we know do not kill sperm. You can take them home if that’s where you’ll produce your sample. Similarly, we must provide the container into which you will collect; again to ensure that it is sperm friendly.

The most important part of producing the sample at home is getting it to our office within 60-90 minutes of collection. Your semen sample contains sperm but also many enzymes that are important in the natural process of reproduction. One part of your reproductive tract, the seminal vesicles, produces enzymes that coagulate the semen immediately upon emission. This allows the viscous sample to remain within the vagina, a process that might be an evolutionary vestige of the copulation plugs that are seen in other mammals and that prevent the female from mating with a second male. Within 5-20 minutes however, other enzymes in the semen (this time from the prostate gland) liquefy the clotted semen, liberating the trapped sperm so that they can enter the cervix. Sperm in the first fraction of the semen are bathed in prostatic secretions and have better motility and survival than sperm in latter fractions which are bathed in vesicular fluid, since the seminal vesicles emissions are last in the ejaculatory sequence. This is why we always ask if any part of the ejaculate was lost during collection. If the first few drops of semen don’t get into the collection cup, we may have lost the best sperm and we may underestimate the quality of your sample.

All of these enzymes in the semen make it a hostile environment. Sperm trapped or left in semen will die relatively quickly, but sperm washed out of this enzyme bath can survive easily for 4 or 5 days in the laboratory. Semen can also cause uterine contractions, which is why we have to process sperm samples and remove it before performing your intra uterine insemination. Getting your semen sample to the laboratory within 60-90 minutes of collection allows us to assess your sperm before the enzymes can do any damage.

It is important that you have an abstinence period of at least 48 hours but not more than 7 days before giving us a sample. Samples produced after 2 days abstinence will usually have the highest numbers of motile sperm with the greatest forward velocity, when compared to samples produced after shorter or longer abstinence. Waiting too long between ejaculates is the biggest mistake we see, possibly because some men think that they can save all their sperm for the day of their big test. However, older sperm begin to die if ejaculations are infrequent and we see the percentage of live sperm decrease with increasing abstinence. Also, please remember that abstinence means no ejaculation, not just no intercourse!

Once your sample has been collected, it is important to avoid exposing it to extremes of heat or cold before bringing it to us in the laboratory. Don’t put it in the refrigerator while you take a shower. Don’t leave it on your dashboard in the sun while you pick up your dry cleaning. And don’t leave it in the glove compartment, forget about it for a week, and then deliver it to the lab. The sample will be fine at room temperature, and you don’t have to break the speed limit in trying to get it to us.

You will need to have made an appointment with us so that we know you will be bringing in a sample, and when you arrive in our office, a member of our staff will check your specimen in. We need to be sure that it is labeled properly and we will get some details from you regarding your abstinence period and how and when you produced the sample. And we will check your identification (usually your driver’s license). This last step is important in establishing the identity of the sample and is part of a “chain of custody” procedure that we use with all samples passing through our facility. We will examine and if appropriate, process the sample within 30 minutes of receiving it, or immediately if the sample is already 1 hour old. Hopefully we won’t be calling you to say that we need to repeat the test!

– Joe Conaghan, PhD, HCLD

Question: My wife and I have been trying to have a child for a while now. I have been told that she is “allergic” to my sperm. What are our best treatment options at his time?

Answer: Many people say that they are allergic to their partner’s sperm, and that can mean different things, depending on the testing done. True incompatibility with sperm is very uncommon. Some female patients may have had a blood test to see if they have “anti-sperm antibodies” circulating in their blood stream. A positive test result actually does not correlate well to a true problem of incompatibility and infertility, and therefore this blood test is no longer recommended as part of infertility testing. An uncommon, but more relevant problem would be if the MALE partner were making sperm antibodies against his OWN sperm. Men who are at risk of this are those who have had testicular injury (scrotal trauma) or testicular surgery (torsion, tumors, or other indications). Antibodies are also commonly found in men who have undergone vasectomy reversal, especially if the interval between vasectomy and vasectomy reversal is a long one.

The sperm has 3 parts: the head, midpiece and tail. If the male patient makes sperm antibodies against the sperm midpiece or tail, this is probably of no consequence. If he makes antibodies against the sperm head, then this can prevent the sperm head from fusing with the egg membrane, and progressing with the important steps of fertilization. The remedy for this condition is to proceed to IVF, and have the embryologist inject the sperm directly into the egg membrane and cytoplasm. This injection process is called ICSI (intracytoplasmic sperm injection), and will restore normal fertilization rates for that couple.

It therefore is important to be clear about the appropriate testing to be done, if one suspects a sperm incompatibility. The anti-sperm antibody test is done directly on the SPERM, and done in a laboratory which has the ability to do this specialized testing (usually an IVF or an Andrology laboratory). If you have a history that might place you at risk of making antibodies against your own sperm, please discuss this with your fertility physician.

– Isabelle Ryan, MD

The laboratory team here at Pacific Fertility Center tested the over the counter Male Fertility Test from Baby Start. The test, also marketed by Embryotech as “FertilMARQ”, comes with everything needed to test two separate semen samples. We found the instructions easy to follow and we used semen samples from several men to run our tests on the kits.

The kit is FDA approved and readily available from major drugstores and through the Internet. It claims to tell you if you have a normal sperm count, which according to the World Health Organization (WHO) is having > 20 million sperm per milliliter of semen. The test does not measure any other parameters of the semen sample such as sperm motility (how many are swimming) or sperm morphology (size and shape).

We ran the test multiple times using kits that the manufacturer had supplied and asked us to test. We used a variety of semen samples with different sperm counts.

The kit contains a small test strip with 4 “wells” labeled A through D, and it looks similar to a home pregnancy or ovulation predictor test. Two of the wells (A and C) are controls and are a blue green color. The other 2 wells (B and D) are used for testing the semen samples and these change color depending on how many sperm are in the test sample. If the color is as dark as or darker than the control well, you have sperm. If the color is lighter than the control well, you have little or no sperm.

To perform a test, a fresh semen sample is collected either into the supplied cup or condom. If collected with the condom, this is simply emptied into the cup, which contains some small flakes of a dried enzyme. The enzyme helps to liquefy the sample over a period of at least 15 minutes and then the semen is ready to be tested. One drop of semen is added to a test well, followed by 2 drops of “blue solution” 1 minute later. After another minute, 2 drops of “clear solution” are added to the test well. The color of the test well is then compared to the control to determine if normal sperm numbers are present in the sample.

The kit comes with everything that is needed to perform the tests. All you will need to supply is a clock or timer. The instructions are clear and simple with helpful diagrams for guidance. The rules for when you should test are acceptable: no more than 3 days since your last ejaculation before you run the first test, and 3-7 days abstinence before running the second test. The instructions also contain common questions, with answers that might arise when you are doing the test. We also found a good and helpful frequently asked question page at http://www.webwomb.com/fertilmarq_faq.htm.

In our trials, the test easily distinguished between samples with normal sperm counts and those with little or no sperm. Clear positive results were obtained with sperm counts of 99, 73.5 and 32.6 million sperm/ml. Clear negatives were obtained with samples that we counted as 0, 3 and 4.4 million sperm/ml.

Only when we analyzed samples close to the test threshold did we find any discrepancies (a sample counted at 18 million sperm/ml came up positive).

The kit is no substitute for testing in a clinical laboratory. The main shortcomings are that the test only looks at sperm number and not other parameters in the semen sample that are equally important for fertility diagnosis and treatment. If you have sperm, but they are not swimming, you would pass this test. Also, individuals with sperm counts that are slightly below normal can pass the test perhaps giving certain men a false sense of security. For these reasons, your fertility physician may order a more detailed sperm analysis.

In general, the test is easy to perform, readily available and inexpensive. The test kits that we received were part of a batch being shipped overseas, perhaps to a location where good clinical testing is not as accessible as it is in the US. And men that are too shy or embarrassed to go to their doctor for a semen analysis now have a better alternative.

Two of the wells (A and C) are controls and are a light blue green color. The other 2 wells (B and D) are used for testing the semen. Wells B and D change color depending on how many sperm are in the test sample. If the color is as dark as or darker than the control well, you have sperm.

– Joe Conaghan, PhD

For some women, infertility is caused or exacerbated by having a uterus with congenital abnormalities that cause it to be misshapened. These uterine anomalies can lead to greater difficulty with embryo implantation and/or cause higher rates of miscarriage.

Until recently, a physician’s capacity to properly diagnose this problem has been limited to a hysterosalpingogram (x-ray with dye); a MRI (magnetic resonance image); a laparoscopy (surgery which limits the evaluation to the outer contour of the uterus); or a standard 2D ultrasound. The emerging technology of 3D ultrasound is starting to provide a highly improved, noninvasive, more cost effective option. Fortunately in the Bay Area, women can obtain a 3D ultrasound at the CPMC OB/GYN Ultrasound Suite which is directed by Dr. Lourdes Scheerer and two other physicians, Drs. Claire Serrato and Shelly Zaglin.

An ultrasound uses high-frequency sound waves (between 3.5 to 7.0 megahertz) sent through the body via a transducer or a scanner that is placed either on the lower abdomen or inside the vagina. The ultrasound beams scan specific areas of interest within the abdominal cavity and are reflected back onto the transducer to produce an “echo” image of the internal organs. This process had been shown to be both safe and effective.

There are several reasons why a physician would want a 3D image of the uterus, explains Dr. Scheerer. By using a 2D ultrasound one can assess the shape of the uterine cavity, but cannot assess as clearly the positioning relative to other pelvic organs (ovaries) nor the contour of the uterus itself. This information is important in assessing a possible abnormality of the uterus, and on deciding appropriate intervention.

There are some congenital anomalies of the uterus that can impact an embryo’s ability to implant and develop within the cavity. If a woman has an abnormally formed uterus, this can cause a higher incidence of miscarriage or be an obstacle to carrying a pregnancy to full term. In women experiencing unexplained repetitive miscarriages, it is important to rule out the possibility of uterine anomaly as the cause. Women with uterine anomalies can also experience higher rates of preterm labor, bleeding during pregnancy, diminished fetal growth, and fetal malpresentations (such as breech), which lead to a higher rate of Cesarean delivery.

A typical uterus is shaped like a small pear and the cavity within has a hollow triangular form. The uterus develops inside a female fetus by the fusion of two separate halves (Mullerian ducts) into a single organ. The uterus subsequently becomes hollow, creating a normal cavity. Abnormalities in the shape of the uterine body and/or the uterine cavity are called “fusion” defects because they arise from failure in the aforementioned unification and hollowing process. If there is failure of the uterine body to fuse completely, the uterine shape will be abnormal. Because the ovaries are derived from different fetal tissues, the development of the ovaries is not affected by Mullerian defects.

Failure of fusion and hollowing can present as a spectrum of abnormalities from a simple dimpling of the top of the uterus as seen in this arcuate shaped uterus

Arcuate Shaped Uterus One of the most common abnormalities is a bicornuate uterus.

Bicornuate Uterus As shown here, a bicornuate uterus has two uterine horns. Pregnancy within a bicornuate uterus typically occurs within one of the horns and pregnancy outcome is usually as normal as for a fully developed uterus. Surgery is not required for this kind of an abnormality. The uterine abnormality most commonly associated with miscarriages is a uterine septum

Septated Uterus This is an abnormality of the hollowing process where a residual midline septum is present. Normal uterine lining does not grow over a septum, so if the embryo implants in the septum, it will not have an adequate blood supply for growth. The traditional way to correct a septum was performing an abdominal surgery called a “metroplasty”, where the septum was removed, and the uterine walls sewn together. This surgery was not very successful, and nowadays we can remove a septum by hysteroscopy, which provides a much more successful outcome. For a uterine septum, surgery is the correction. Understanding the type of uterine defect one has is critical, because this will determine if surgical intervention is needed to optimize one’s chances of a successful pregnancy. A 2D ultrasound can suggest that an abnormality is present, but does not necessarily differentiate among subtle abnormalities. The advantage of 3D ultrasound is that it will better define the specific defect present. Based on this improved image, the best recommendation can be made. 3D ultrasound provides a cost-effective imaging modality, which gives good resolution when differentiating Mullerian anomalies. Dr. Scheerer reports that 3D ultrasound can also be helpful in differentiating the location of abnormal pregnancies. For example, the improved imaging can be helpful in distinguishing a tubal ectopic pregnancy, versus a corneal pregnancy. The technology that makes 3D ultrasound so reliable is evolving rapidly, partly due to the sudden popularity among pregnant women who want the better-defined early fetal images for their baby books. While this is currently “in vogue”, it is important to understand that there are no long-term studies looking at the effects of 3D ultrasounds in pregnancies. While we don’t endorse the use of 3D ultrasound strictly for photo opportunities, we think it is a very valuable tool for finding and evaluating certain uterine abnormalities. This information gives us the opportunity to optimally treat each individual person and maximize the chance for a successful pregnancy.

– Carl Herbert, MD

Question:
What is my fertility physician looking for in conducting an antral follicle count?

Answer:
Women are born with all of the eggs (oocytes) that they will ever have. This is a set number, which is determined before birth. This pool of eggs is never replenished. A female fetus will have the greatest number of eggs around 16-20 weeks of pregnancy (6-7 million); at birth this number decreases to about 2 million; and by puberty to about 300,000. This constant and dynamic process of decline continues until menopause and is not interrupted by birth control pills, pregnancy, or ovulation. From this reservoir of eggs, fewer than 500 eggs will ovulate during a woman’s reproductive life.

There is a continuous process occurring in the ovaries, where eggs are constantly being prepared for the maturation process. It takes 3-6 months for eggs to develop and mature. As the eggs are developing, they transition from a primordial, to preantral, to then antral follicle. Antral follicles are visible by vaginal ultrasound. Antral follicles therefore represent the reserve of eggs in our ovaries and those that are candidates for selection and growth by fertility stimulation medications (gonadotropins).

When assessing one’s ovarian reserve (potential for a successful pregnancy), a number of parameters are evaluated. One of these is called the “antral follicle count” (AFC). An antral follicle count is typically done during the 2nd-4th days of menstrual flow, though it can probably be as accurately done during other times of the menstrual cycle. Studies show that the AFC is predictive of the expected ovarian response to gonadotropins. An AFC less than 6 total (between both ovaries), predicts a poor stimulation response. For those undergoing IVF, a similarly low AFC will be associated with a higher cancellation rate. As women approach their 40s, and as day-3 FSH results rise above 10 mIU/ml, this typically correlates with fewer eggs overall in our ovaries, and therefore a low AFC. Indirectly, a low AFC can correlate with diminished ovarian reserve.

In the same way that there can be monthly variability in day-3 FSH test results, there can be monthly variability in the AFC. More variability is observed in the AFC of young infertile women than in older women. However, overall a single AFC is still quite predictive of ovarian response under gonadotropin stimulation, and there is fairly good agreement between repeated AFC over consecutive cycles. In conclusion, doing an AFC is an adjunct to the day 3-FSH test to predict ovarian reserve and ovarian response to fertility medications.

– Isabelle Ryan, MD

Q.
I’ve noticed that there are FSH urine test kits for sale over-the-counter to help women confirm the onset of menopause. Since FSH testing is involved in determining fertility reserve, can I use this over-the-counter FSH test to help realize my fertility potential?

A.
It appears as if a fair number of over-the-counter FSH test kits are indeed sold in drug stores and over the Internet. I am not going to comment on their efficacy for measuring hormonal changes that the pre menopausal body starts to undergo. But I can answer your question. These test kits are not useful tools to help you determine your fertility potential.

By way of background, human follicle stimulating hormone (FSH) produced by the pituitary gland stimulates primordial follicular growth and estrogen production by the emerging follicle that will mature into an egg.

The urine test kits provide a black or white – yes or no answer, not a glimpse of your FSH level in the context of a gray scale range of indicators. For accurate fertility potential diagnosis, we analyze FSH level in much more detail. On day two or day three of your cycle (following menses) we test your FSH level in conjunction with other tests including estradiol (E2) and an antral follicle count.

Most home urine tests, such as for pregnancy tests and ovulation predictor tests, use a threshold level of the hormone in the urine to detect a positive. With FSH test kits, only when the level reaches menopausal levels of FSH, equivalent to around 40-50 mIU/mL or higher in the bloodstream, will the test turn “positive.” For most women interested in testing for ovarian reserve, we would be looking for levels equivalent to 5-20 mIU/mL. So the sensitivity of the testing is set for menopausal and post-menopausal levels, not the levels seen in women with regular menstrual cycles. By the same token, they will not be able to discriminate normal from decreased ovarian reserve.

– Carolyn Givens, MD

To the immune system of a pregnant woman, there is no doubt that a baby is a temporary graft of foreign tissue. A baby and its placenta express proteins on its cell surfaces that come from the father, and therefore are “foreign” and could potentially be rejected by a woman’s immune system.

Like all living species that gestate their young within the mother’s body, humans have evolved mechanisms to protect the baby from rejection by the host mother’s system. The last few years has seen an increased interest in the subject of the role of the immune system in implantation of embryos and maintenance of pregnancy. The clinical relevance of perceived abnormalities in the immune system of women with unexplained infertility, unexplained implantation failure and recurrent miscarriage is a controversial topic. Elaborate theories to explain these failures have been proposed but most have not yet stood up to the test of good science. One of the latest theories to lay blame is that of a class of immune cells (lymphocytes) known as “natural killer” cells. Natural killer (NK) cells are responsible for killing certain types of foreign cells. In the current theory, increased NK cell activity potentially leads to attack of placental cells and therefore rejection of the fetus. But NK cells will only kill lab-cultured placental cells in the presence of another protein, called interleukin-2. Yet interleukin-2 is not present in the uterine lining of the uterus at the time of implantation. NK cells are found in both the bloodstream and in the uterine lining. NK cells are present in the uterus only during the second half of the cycle and can be found concentrated at the site of implantation. In mice that have been genetically altered to no longer make NK cells, successful reproduction will only occur if NK cells are given back to these mice. This suggests that, at least for these mice, NK cells may be necessary for implantation. So are NK cells there to inhibit or promote embryo implantation? The answer is not clear. Further complicating the NK cell story is the fact that there are several kinds of specific NK cells. These types can be classified by the expression of specific receptor proteins on the surface of NK cells. As it turns out, NK cells in the uterus are different from the NK cells that circulate in the bloodstream. Therefore, using blood tests to determine if there are too many circulating NK cells would bear little reflection on what is going on within the population of uterine NK cells. Other blood tests have been devised to assess whether these uterine-specific NK cells are being over-produced, such as tests for Tumor Necrosis Factor a (TNF-a), and Interferon g (IFN-g). These are proteins secreted by a particular class of NK cells found in the uterus. Women identified by these blood tests as having elevated NK activity or increased levels of TNF-a or IFN-g have been told that they will never successfully conceive unless they receive treatment with various immune suppressing agents such as intravenous immunoglobulin infusions (IVIG), glucocorticoid (prednisone) medications or anti-TNFa medications. But these treatments are not free from risk. Anti-TNFa medications have been implicated in several serious diseases such as lymphomas and lupus-like syndromes. Glucocorticoids during pregnancy can be associated with an increased risk of pre-term rupture of the fetal membranes, increased risk of pre-eclampsia (high blood pressure during pregnancy) and gestational diabetes. Immunoglobulin infusion (IVIG) is the use of infusions of a pooled blood production (immune proteins) and can be associated with anaphylactic (shock) response, and a host of side effects. This is why the vast majority of reproductive endocrinologists do not support administration of these drugs to women, even if they have been told they have increased NK cell activity in their blood stream. Unfortunately, our understanding of the role of the immune system in implantation and pregnancy is very rudimentary at this point. Trying to take this limited knowledge and develop tests to predict who may or may not be experiencing abnormalities of the immune system is akin to going out on a long limb of unproven possibilities. Furthermore, determining that women with supposed abnormalities in their NK cell activity be treated with anti-TNFa medications, steroids or immunoglobulin infusions to globally suppress the immune system is akin to going out even further on a flimsy stem. These treatments can be expensive and potentially harmful. The good news in all of this is that there is extensive research under way to try to better understand the very complex nature of embryo implantation and the immune privilege of the fetus within the womb. The bad news is that we are still a long way from understanding whether or not there truly are immune system malfunctions that occur which could potentially block implantation or directly cause repeated miscarriage. To therefore say that we can run a clinical test on a woman or furthermore, develop a rational mode to safely treat a woman for such a syndrome is going way beyond the bounds of good clinical medicine.

– Carolyn Givens, MD