Q.
I sought our physician’s opinion about how my fibroids might impact our desire to get pregnant. Eight doctor opinions later, we are no closer to a decision. About half of the experts advise surgical removal; and the other half tell us to try to get pregnant despite them. Why is the medical community divided on this?

A.
Fibroid(s) of the uterus, also known as leiomyomas or just myomas, are benign growths that may be located on the exterior of or within the muscle layer of the uterus, or may be growing within the lining of the uterus. For the vast majority of women, fibroids do not cause significant health problems.

A few women who desire pregnancy may need to have their fibroids removed (myomectomy) prior to conceiving if the fibroids are very large (greater than 6 cm) and/or if they impinge upon and distort the uterine cavity.

Various surgical approaches to removal are further described on PFC’s web site, along with a more in depth summary of the factors that our physicians consider when counseling a patient to undergo a myomectomy.

You probably received different opinions because the impact of fibroids as related to pregnancy chances depends on the size and location of the fibroids. Other issues to consider are that fibroids are dependent on estrogen to grow, and high levels of estrogen produced during pregnancy can lead to rapid growth of the fibroid(s). If the fibroid is on the outer surface of the uterus, this may present little problem. If the fibroid is located within the uterus muscle wall or nearer the uterine cavity where the fetus is growing, a patient may be at higher risk for various pregnancy complications (miscarriage, preterm labor…).

In rare cases, the fibroid may grow so rapidly during pregnancy that it outgrows its blood supply and starts degenerating, which can be painful and sometimes lead to pregnancy complications. Also uncommon but of significance is the fact that some fibroids may block the lower portion of the uterus, prohibiting the baby’s head to descend into the birth canal, making cesarean delivery necessary. However, it is important to keep in mind that the majority of patients with fibroids experience no problems during pregnancy.

What is the impact of fibroids on pregnancy chances? It is unclear that there is any negative impact, if the fibroids are small and not growing within or distorting the uterine cavity.

Q.
I’m confused. I heard that metformin is an alternative to clomid for women who have trouble ovulating, but isn’t metformin a drug to treat diabetes?

A.
Metformin (brand name: Glucophage) is indeed an FDA-approved drug for type 2 diabetes. It is also a promising new treatment in the portfolio of ovulation induction medications for women with polycystic ovary syndrome (PCOS).

Many women with PCOS suffer from insulin resistance (high blood insulin levels), a problem that is thought to possibly impede ovulation and elevate male hormone levels.

By way of background, PCOS is experienced by as many as 10 percent of women of reproductive age. An inability to ovulate normally and problems associated with an overproduction of male type hormone are typical findings in women diagnosed with PCOS. The “polycystic” aspect can be seen in the ovaries via ultrasound, which reveals a large multitude of tiny follicular cysts instead of a smaller group of well-defined emerging follicles preparing for ovulation.

Many women with PCOS respond well to clomiphene citrate (brand name: Clomid), which stimulates increased blood levels of FSH (follicle stimulating hormone) and LH (luteinizing hormone) to induce the growth of a follicle and eventual ovulation. Approximately 70% of patients treated with clomiphene citrate will ovulate and 40% will conceive, the majority within three to six ovulatory cycles.

A small fraction of patients who see no improvement from clomiphene treatment alone are good candidates for metformin, or a combination of clomiphene and metformin. Offering metformin provides such women with an alternative oral medication before being directed to the injectable stimulation medications. As an insulin-sensitizing medication, metformin decreases insulin levels, which is thought to help restore the normal ovarian hormone profile (reduces male hormone), thus allowing for spontaneous growth of a follicle and ovulation to occur. Alternatively, metformin enables the patient to become more sensitive to clomiphene. It is important to note that of those patients who do not ovulate on clomiphene alone, most benefit by the combination of metformin with clomiphene.

Metformin and other insulin-sensitizing medications may offer other benefits for women with PCOS, who are reported to be three times more prone to early pregnancy loss compared to ovulatory women. In several reports involving as yet small populations of PCOS patients, the use of these drugs appears to significantly reduce the rate of early miscarriage. One must approach this news with caution, however, until prospective controlled trials on this topic are conducted.

Q.
We have frozen embryos at PFC that we would like to donate to research. Now that California has passed the Stem Cell Research Initiative, how would this affect the donation process?

A.
The status of your frozen embryos at PFC will not change as a result of this new initiative. Currently, all patients with frozen embryos in storage at PFC are contacted by us on an annual basis to reconfirm their wishes for their embryos for the upcoming year.

All patients are given 5 choices:
1. Return to PFC for a frozen embryo transfer
2. Continue storage (an annual storage fee payment is remitted)
3. Thaw and discard all remaining embryos
4. Donate embryos to another party (known or anonymous donation)
5. Donate embryos for medical research

If option #5 is chosen, we will transport the embryos in a liquid nitrogen carrier tank to one of several scientists (primarily at UCSF) for use in their research. Our patient’s privacy is maintained because we only give UCSF an identifying number with each set of embryos.

Currently, we are working with several researchers who are attempting to develop embryonic stem cells under non-federally funded research grants. The new state initiative may provide these scientists and others with more funding to continue and expand their studies. With the added state funding, their research could contribute to the body of knowledge about how undifferentiated human cells become specific tissues, hopefully leading to the development of specific tissues to treat diseases and conditions such as Parkinson’s, Alzheimer’s, diabetes and spinal cord injury.

Q.
I’m strongly considering an IVF cycle. Is there any way to know how productive my ovaries are likely to be besides blood tests? I’m 38 years old.

A.
There is no reliable screening test that peeks into your ovaries to determine your “ovarian reserve”, that is, how many eggs you might have available for fertilization. However, one good measuring method that we use is to count your antral follicles, which are tiny resting sacs containing immature eggs that are waiting to develop.

Active ovaries continuously form these follicles – they bubble up or percolate from microscopic immature eggs to the antral follicles that are visible on ultrasound. As ovaries age, fewer of these antral follicles are visible. The antral follicle count is a powerful method of predicting the numbers of eggs; it is not quite so good at predicting embryo quality.

The test is usually done early in the menstrual cycle. Ideally, we like to see 6-8 follicles per ovary, although women have been known to get pregnant even with low antral follicle counts.

Q:
Is Clomid always the drug of first resort for treating infertility?

A:
Clomiphene citrate, aka “Clomid,” is in a class of drugs known as anti-estrogens, meaning it binds to estrogen receptors in the hypothalamus region of the brain responsible for reproduction. As such, clomiphene fools the brain into thinking that there is little or no circulating estrogen in the bloodstream, and so the brain signals the pituitary gland to secrete more follicle stimulating hormone (FSH).

Why Clomid is So Common
Many women are prescribed clomiphene empirically, that is, without a specific cause, in hopes of enhancing fertility. For most women, this strategy is fine because clomiphene is a safe and inexpensive medication. However, no real benefit may be gained unless the clomiphene induces the ovulation of more than one follicle (or egg).

Furthermore, as clomiphene is an anti-estrogen, for some women, it may bind to estrogen receptors in the uterine lining and cause it to be too thin, prohibiting pregnancy. To avert this, we perform at least one ultrasound in each clomiphene treatment cycle to check for normal endometrial thickness and hopefully, two or three follicles. We also have our patients monitor for their own LH surge with an over-the-counter ovulation predictor kit. Intercourse or intrauterine insemination is planned accordingly.

Best Candidates
Clomiphene is targeted to patients who do not ovulate regularly, especially if they have a condition known as polycystic ovarian syndrome or PCOS. These women have normally functioning ovaries but do not go through proper signaling of the brain to the pituitary and do not make adequate FSH and LH to induce ovulation. In these women, a small dose of clomiphene can trigger just enough FSH to accomplish ovulation of a single egg.

While most women with PCOS will respond to clomiphene and ovulate, some will require the addition of an insulin sensitizing medication to enhance response. If a woman does not respond to clomiphene, she may have very low FSH and estrogen levels, a condition known as hypothalamic anovulation. These patients usually require injectable FSH to induce ovulation.

Normal Ovulators
Women who ovulate normally are also candidates for clomiphene to improve the hormonal response of their ovulatory cycles. If she is found to have a low luteal phase progesterone level, she may benefit from clomiphene making higher levels of progesterone to support embryo implantation. Unfortunately, many women are diagnosed with low progesterone because they are advised to check the level on “day 21″ of the cycle. But because they don’t have an exact 28 day cycle, the monitoring isn’t exactly in the middle of the luteal, or post-ovulation phase of the cycle. A better way to do this is to have a patient use an ovulation predictor kit and have the progesterone level drawn 7 days after the LH surge. If this level is 10 ng/ml or greater, the level is normal and there is no “luteal phase defect.”

Who Should Avoid Clomid
In general, we recommend that women 35 and older skip the Clomid step and consider more aggressive treatment, such as injectable FSH with intrauterine insemination or even in vitro fertilization. Women who experience a thinning of the uterine lining should not be given clomiphene.

Potential Side Effects
Many women will experience no side effects while others experience side effects similar to those seen in early menopause: hot flashes and irritability. These are rarely bothersome enough to discontinue treatment. Women who experience a rare side effect of significant visual changes (flashing lights) are advised to discontinue treatment immediately. Regarding risk of multiple pregnancy, Clomid doesn’t have a large impact; the risk of twins is about 5% and triplets or more is 1% or less, depending on the patient’s age.

Q. How can I be sure that PFC will not accidentally confuse my eggs and my husband’s sperm and our embryos with someone else’s?

A. PFC recognizes that even with the best intentions, human error can occur. We’ve therefore designed our strict SurTransfer^SM laboratory security system of color-coding and clearly labeling all specimens and verbally identifying all patients. We have also devoted considerable time and effort into assembling one of the most highly trained teams in the country. Each of our Embryologists is Board Certified and Licensed, even though the State of California does not currently require licensure for Embryologists.
When a patient is scheduled for a procedure, a written procedure requisition is sent by the Physician to the laboratory staff, giving them at least 24hour notice and clear instructions on what is to be done. Each patient is assigned a specific color for their test tubes and Petri dishes; no two patients having procedures on the same day will be assigned the same color. Each of the patient’s specimens is carefully labeled with clear and unique identifying information that includes the patient’s name and date of birth.

During their stay in the lab, eggs, sperm and embryos are kept in incubators. We avoid assigning two cases to a single incubator on the same day. Each incubator has an exterior door and an interior door. Both doors are clearly labeled with name and color code. This labeling protocol allows the embryologist to verify the name twice before ever handling the specimen.

We have two embryologists performing all critical procedures to ensure accuracy; generally one handles the material while the other observes and verifies. We are not required to assign two people to procedures, but redundancy eliminates the possibility of an error.

Both embryologists sign off after checking the paperwork, labeling the specimen and performing the procedure.
Accepting sperm samples: When a man delivers his sample, we require it to be labeled with his unique information, including name, birth date and signature. We ask to see identification. The embryologist receiving the sample will sign that s/he received it and note the time and date of receipt. If s/he passes the sample to another member of staff, that individual will sign for it, thus continuing a chain of responsible custody.

Egg retrieval: A patient undergoing egg retrieval is asked in the retrieval room to identify herself before receiving sedating drugs. The embryologist will not rely on the physician, nor state the patient’s name and ask for a “yes or no” answer, but will instead ask her to state her full name. This avoids any possible miscommunication. As the procedure gets underway, two embryologists will take responsibility for accepting the collected eggs.

Inseminating eggs: This is arguably the most important part of the IVF procedure. While it is a relatively simple procedure to perform, we are sensitive to its significance. Without any exceptions, two embryologists perform the insemination. Even if there is only one egg to inseminate, or even if there is only one insemination on a given day, two people do it.

Embryo transfer: Similar to the retrieval procedure, one embryologist will ask the patient her name and a second embryologist will witness and verify that the correct embryos are loaded into the transfer catheter. As a final check, the embryologist will hand the catheter to the physician and state the patient’s full name and the number of embryos.

Freezing and thawing of sperm or embryos:

Frozen specimens are extensively labeled and catalogued. Thawing can only be directed by a physician, and as a rule an embryologist never handles or thaws a specimen without a witness. Once a specimen is thawed, there’s no going back.

Q. Considering how much trouble we’re going through to get pregnant, I don’t mind if we have twins, or even triplets. What do you think?

A. Many parents undergoing infertility treatment are open to, or even welcome the idea of having more than one baby without fully understanding the risks that a multiple gestation pregnancy poses to the mother and infants. You are wise to research this thoroughly before entering into your cycle.
Let’s first look at the facts:
– Over 50% of twin pregnancies result in preterm births;
– Over 90% of triplet pregnancies result in preterm births;
– Virtually all pregnancies of quadruplets (and greater) result in premature labor;
– Compared to a singleton pregnancy, a twin is seven times more likely, and a triplet is
over 20 times more likely to die in the first month of life.

Even with medical advances to handle early birth trauma, premies are more likely to suffer from respiratory distress syndrome, intra-cranial hemorrhage, cerebral palsy, blindness and neonatal morbidity. These stark statistics and more have been compiled by the American Society for Reproductive Medicine (www.asrm.org), and distributed in a patient’s fact sheet.

Because these facts are undisputed, infertility specialists with the help of our professional associations began a campaign to actively educate couples about the risks of multiple gestations, and to make responsible decisions. Fortunately, this work is now showing results. Research published in the April 14th 2004 New England Journal of Medicine revealed a drop since 1997 in the number of high-order multiple pregnancies. In 1997, women under 35 faced nearly a 14 percent chance of having triplets or more! Today that figure has dropped to 8.1 percent, which is still higher than the natural incidence of multiple gestation.

Couples who share the goal of conceiving a single, healthy child generally end up as happy, and with far fewer complications, as those couples that have more. If the embryos are of good quality, our doctors will transfer no more than two embryos in a first IVF cycle for women under 35. Bear in mind that identical twins are possible, since an embryo can split in two. If a couple is opposed to selective reduction, a single embryo transfer is sometimes the best choice, especially if a young donor’s eggs are used.

With our guidance and your understanding, we trust you will make the right decision for your health and the health of your baby.

Q:
My husband and I have two sons, age 3 and 6, and we would really like to have a girl. Is there anything we can do to make sure our next child is a girl?

A:
From a purely medical point of view, the answer to your question is yes. There are ways to significantly shift the odds of having a child of one gender or another. Gender is conferred on an embryo by whether an X-bearing sperm (for a girl) or a Y-bearing sperm (for a boy) enters the egg. Unfortunately, despite highly publicized claims, there are no proven effective “at home” methods of sperm separation. Nor does timing of intercourse relative to ovulation affect the 50:50 gender ratio. By natural methods, it’s a flip of the coin.

The only commercially available method for sperm separation that appears to be effective is the sperm sorting process available through Microsort.net. This method is still under FDA investigation for safety and efficacy but does appear to do a reasonable job in separating sperm, especially if the desired gender is female.

The company reports a 90% success rate with separating X-bearing sperm and a 73% success rate in separating Y-bearing sperm. With only a couple of hundred babies born thus far, there does not appear to be any increase in birth defects. Because it is still an experimental process, couples wanting to try this will have to travel to either Fairfax, Virginia (Microsort headquarters) or an affiliated clinic in Southern California for fresh sperm insemination as freezing and thawing of sperm reduces these numbers even further.

Unfortunately, after processing, Microsort severely decreases the number of sperm available for insemination. Because sperm counts are so low after sorting, it is usually necessary to do in vitro fertilization with sperm injection (IVF-ICSI) to significantly improve the chances that the sperm will fertilize the egg in the IVF laboratory. PFC is a participating site in the FDA investigation for Microsort and we have used sperm specimens that have been previously Micro-sorted for IVF-ICSI.

Beyond Microsort, the only way to improve the odds of recovering one gender over another to close to 100% is to undergo preimplantation genetic diagnosis (PGD). PGD uses a DNA-binding technique to determine if there are a correct number of chromosomes in the embryo at the time of IVF. To do this, embryos on Day 3 of culture (5-10 cells) undergo a biopsy to remove a single cell. The rest of the embryo remains in culture in the IVF laboratory. The cells from the embryos are analyzed for the correct number of chromosomes. Currently, PFC with its cytogenetic partner, St. Barnabas Medical Center, tests for 9 chromosome pairs, 13, 15, 16, 17, 18, 21, 22, X and Y. This screening is called “aneuploidy screening” and we allow our patients to know and select the gender of their normal embryos for transfer if they so wish.

Although IVF with PGD is the most effective method for gender selection, it is certainly the most expensive and there is no absolute guarantee that the transfer of the screened embryos will result in pregnancy. A PFC physician can best discuss the odds based on the woman’s age and the couple’s history of childbirth.

Many couples undergoing PGD are doing so to screen for specific genetic defects or are specifically undergoing gender selection because of their risks of having a genetic disease that only affects males (X-linked diseases).

On the other hand, PGD for elective gender selection, either for “family balancing” as in your case, or even for having a first child of a particular gender poses difficult ethical issues. Just because we can do this, should we? What will the couple do with normal embryos of the undesired gender? At PFC, we do not encourage PGD for elective gender selection but if a couple is undergoing IVF and wishes to undergo aneuploidy screening for the 9 chromosomes, we do allow them to select to transfer embryos by gender. We encourage them to consider donating excess embryos of the undesired gender for adoption by other couples.

Women or couples interested in this procedure should discuss it with their Reproductive Endocrinologist. At PFC, we also refer our PGD patients for a special genetic counseling session in preparation for this process.

Q:
Can I collect my sperm at home and store it in my freezer? I have heard there is a kit that allows me to do this?

A:
There are collection and storage kits that allow you to initially collect and freeze your sperm specimen at home, but are not intended for storage in your kitchen freezer. The necessary temperature for maintaining sperm viability is far colder than a home freezer maintains. Specialized kits sold by only a few andrology clinics are designed to let you manage the collection process in the comfort of your own home. They can be purchased and shipped to you for about $350. (Please go to www.nwcryobank.com). These kits maintain the necessary frigid temperature for up to about a week, providing plenty of time to store several specimens for return to the andrology clinic. The kits include the necessary sterile implements for collection.

Naturally, home sperm collection is preferable over visiting a clinic, but freezing sperm is rather involved, and requires a great deal of attention to detail. Be sure to carefully follow the clinic’s instructions.

If you decide this process is for you, here’s what to expect:
The kits usually contain several vials for collecting multiple specimens over several days, thus ensuring back-ups. The specimen must be collected through masturbation using no lubricants, to avoid contamination. Once collected, the sample needs to sit at room temperature for 30 minutes while enzymes in the seminal fluid allow the initially thick sample to become more liquid.

Then the sample needs to be mixed with cryoprotectant, or antifreeze, which should be prepackaged inside the vials included in the sperm collection kit. The antifreeze must be separated from the sperm before insemination.

Do not attempt to freeze and thaw the sperm on your own for home insemination. Only an andrology lab can perform the critical step of extracting the sperm from the antifreeze upon thawing.

Also, even if you know that the sperm is of good quality, it is important to know how well it tolerates freezing and thawing. Your infertility clinic or a sperm bank can provide you with valuable information on the quality of the sperm and its capacity to withstand freezing. Results can be extremely variable. Northwest Andrology reports that on average, healthy normal sperm in one out of ten men simply do not hold up to cryopreservation. Poor sperm survival rates can greatly impact the outcome of IUI, which requires more sperm than other procedures like IVF and IVF with ICSI.

Unfortunately, there is no “in between” process that allows for short term home freezing in one’s freezer for out-of-town moments, or other reasons. And timing fresh sperm for home insemination also requires a certain degree of precision. If the sperm provider cannot be there at the exact time he is needed, the sperm will die in the seminal fluid fairly quickly. If fresh sperm are to be used, it is necessary to do the insemination within an hour or two of collecting the sample.

Q:
Can vaginal Viagra increase my odds of having a successful IVF cycle?

A:
Some fertility physicians turn to vaginal Viagra as a tool to improve uterine function. However, there is a great deal of skepticism about the use of Viagra for fertility patients.

One of the key parameters we monitor during a fertility treatment cycle is the development of the endometrial lining: both thickness and pattern. Our aim is to achieve a lining with a minimum thickness of >=7mm, and a trilaminar (or triple) pattern of the endometrial layers, by the day of HCG administration. For some patients, we cannot obtain this type of a lining, despite various hormonal manipulations.

For these patients, and even many without endometrial lining issues, we will typically recommend that she take a baby aspirin per day (81 mg) starting with gonadotropin stimulation. The rational for the use of baby aspirin is that on a micro-vascular level, vasodilation and decreased blood platelet aggregation occurs and therefore improves blood flow to the uterine lining, providing a lining with functional improvement. Blood platelets are the blood cells, which promote blood clotting. Two well designed studies confirm the benefit of baby aspirin use in improving pregnancy rates for patients with endometrial linings <8mm. It is important to note that the lining does not necessarily thicken with the use of baby aspirin – this is a qualitative improvement. It is also important to take only a baby aspirin, NOT a full dose aspirin.

Some fertility practitioners have suggested that Viagra vaginal suppositories for women, which are also a vasodilator, may provide improvements in pregnancy rates in the same way baby aspirin does. It needs to be noted however, that Viagra as a vasodilator works via a different mechanism compared to aspirin. While these claims have been made, well designed studies have yet to prove this. In the interim, Viagra should be used with caution.