It is always frustrating, both for patient and physician, when we perform a full fertility evaluation and conclude that that patient’s diagnosis is “unexplained infertility.” But unexplained infertility does not mean “no” infertility. It means that we recognize there is some abnormality or inefficiency in the process of getting pregnant, but that we do not have a good test to assess what is the actual problem.

There are many critical steps in the process of getting pregnant which we can not directly assess; such as how efficiently the eggs are captured by the fallopian tubes, how efficiently the tubes push the eggs along to the uterus, how well the sperm are fertilizing the eggs, how well the fertilized eggs are developing to embryos, and how efficiently the embryos find their way to the uterus. All these steps are critical—yet we have no direct test. If one were to proceed to an IVF cycle, we can then make some assessment of these steps, but not prior.

So, if the evaluation shows normal egg quality (FSH, Estradiol, ultrasound), dye study (HSG) shows open tubes, sperm test shows normal count and motility, and there is no evidence of endometriosis—this typically defines unexplained infertility.

One of the first studies addressing the efficacy of treatment for unexplained infertility was published in 1998 (1), and indicated that patients who underwent no treatment had a 1-4% pregnancy rate per month; insemination alone, 3.8% pregnancy rate/cycle; clomid alone, 5.6% pregnancy rate/cycle; Clomid plus insemination, 8.3% pregnancy rate/cycle; gonadotropins alone, 7.7% pregnancy rate/cycle; and gonadotropins plus insemination 17.1% pregnancy rate/cycle. This study was retrospective, and did include patients with mild endometriosis, so while providing good insight, more studies were needed to better define treatment efficiency for these patients. However, it was important to see that insemination alone did not provide an improvement, and best improvement was noted with combination therapy.

Next, Guzick and colleagues published a large randomized study addressing superovulation with gonadotropins and insemination, for patients with unexplained infertility (though again mild endometriosis was included) (2). The control group was patients who had intracervical inseminations (to assure sperm exposure). Pregnancy rates for this group were 10% per cycle. Those who underwent intrauterine insemination had an 18% pregnancy rate. Those who underwent gonadotropin stimulation plus intracervical insemination have a 19% pregnancy rate, verses 33% for those with gonadotropin plus intrauterine insemination. Therefore, couples who undergo superovulation and intrauterine insemination have a 3 times higher chance of achieving a pregnancy, than the control group.

The question of which type of ovulation induction agent to use, oral verses injectable, has been addressed in a meta-analysis published in 2002 (3). This review of 5 randomized controlled trials shows that pregnancy rates were higher in injectable cycles (gonadotropins), though live-birth rates were not different between oral and injectable cycles. Their conclusion was that oral agents may therefore be more suitable for ovulation induction, since the multiple rates were lower, and cost of the cycle less.

Last year, a prospective trial looking at using oral Clomid verses Letrozole with inseminations in patients with unexplained infertility was published (4). This study showed that the total number of follicles was greater for the Clomid users (3.1 vs 1.6), but the pregnancy rates were the same for each group (Letrozole 19%/cycle verses Clomid 18.3%/cycle). Therefore, both agents are equally effective, and the multiple rate may be less with Letrozole.

Last year, another randomized control trial evaluated expectant management (no treatment), verses Clomid alone or intrauterine insemination alone in patients with unexplained infertility ( though included mild endometriosis patients) (5). This study again confirmed that Clomid alone (14% live-birth rate) or insemination alone (23% live-birth rate) was not statistically different than expectant management (17% live-birth rate). They evaluated patient satisfaction with the treatment process, and patients who were randomized to the “expectant management” arm were much less satisfied than those who were doing Clomid or insemination therapy, despite no improvement for those patients’ live-birth rates.

So, some take home points are as follows:

• Unexplained infertility does not mean “no” infertility
• Empirical clomiphene and/or unstimulated intrauterine inseminations are unlikely to offer an improvement over expectant management (no treatment)
• Best options are to consider Clomid or gonadotropins with intrauterine inseminations (depending on patient age, etc..)
• If this fails, then IVF is best option
• Depending on age and other evaluation, IVF may be best first option

Footnotes:

1. Guzick DS, et al. Efficacy of treatment for unexplained infertility. Fert Ster 1998; 70:2, 207-213.
2. Guzick DS, et al. Efficacy of superovulation and intrauterine insemination in the treatment of infertility. N Engl J Med 1999;340;177-83.
3. Athaullah N, et al. Oral vs injectable ovulation induction agents for unexplained subfertility. Cochrane Database Syst Rev 2002;3:CD00352
4. Badawy A, et al. Clomiphene citrate or aromatase inhibitors for superovulation in women with unexplained infertility undergoing intrauterine insemination: a prospective randomized trial. Fert Ster Aug 2008
5. Bhattacharya S, et al. Clomiphene Citrate or unstimulated intrauterine insemination compared with expectant management fro unexplained infertility: pragmatic randomized controlled trial. BMJ 2008;337:a716

In January, Dr. Carolyn Givens and I attended a meeting in Hawaii organized by the American Board of Bioanalysts (ABB). This organization board certifies and licenses embryologists, andrologists, and a number of other laboratory specialists in the United States. Our meeting was under the direction of the College of Reproductive Biology, a special interest group within the ABB and for which I am the immediate past Chair.

The meeting was small and intimate, a situation always welcomed among reproductive biology professionals. The location allowed for good interaction with embryologists from Japan who have always been a great source of ideas and innovation within our specialty.

In fact, the highlight of the meeting was a series of videos shown by Dr. Yasuyuki Mio from the Mio Fertility Clinic in Yonago, Japan. He was able to take time-lapse cinematography of human embryos in culture, and as a result reported some novel observations on how oocytes fertilize and how embryos develop. The actual moment of sperm entry into the oocyte was recorded and it was possible to see that human oocytes form a fertilization cone (a membrane that helps bring the sperm into the oocyte), shortly after sperm entry. The events that follow (2nd polar body extrusion, which is the egg extruding a set of chromosomes, and pronuclear formation, alignment of the nuclei from the egg and sperm) occurred as expected, but for the first time the male and the female nuclei could be distinguished from each other.

After fertilization, the embryos were seen to change dramatically as they developed. In particular, they appeared more disorganized and untidy immediately after a cell division event and more symmetrical and organized several hours later. This discovery has implications for those embryos that sometimes may appear poorly. It suggests that they may look better later in the day when they are clear of the cell division process. Another important observation regarding blastocysts, is that those that develop 2 inner cell masses (ICM: the precursor cells of the fetus) do so in a predictable way. At PFC, we avoid using embryos with two ICMs whenever possible, as they are likely to lead to the formation of identical twins. A normal embryo should have only a single ICM. Currently, it is possible that one of the ICMs may be small enough to avoid detection. The observation was made that the fine cellular bridges within the embryo cavity appear to correlate to the presence of an extra ICM.

Another notable presentation was that of Dr. Tetsunori Mukaida, of Hiroshima HART Clinic, on sperm morphology. He demonstrated that observing sperm under ultra-high magnification can show structural defects that are not always visible when using standard microscopes. While magnifying sperm thousands of times has its difficulties, Dr. Mukaida reported that sperm with subtle physical defects have a much lower chance of making an embryo that can become a baby. Sperm that are close to perfect in size, shape and structure are difficult to find in any sperm sample and it can take hours just to find a few ideal sperm. However, the extra effort may be worthwhile, especially in patients that have had a previous IVF cycle where the embryos did not develop well or implant after transfer. PFC is currently looking into this technology and we will report more details in a future issue of Fertility Flash.

Attending meetings like this and keeping up with the latest developments in our field is an important part of the culture at PFC. We share the load of traveling to educational events and are always excited to bring home ideas and thoughts to share with our colleagues. PFC is committed to implementing the latest technology and innovations to maximize pregnancy rates for our patients. We will continue to stay updated with all of the research and development in our specialty.

Both Dr. Givens and Dr. Conaghan contributed to this article.

	Joe Conaghan, Ph.D., HCLD is PFC’s laboratory director. Dr. Conaghan is internationally recognized for his work on improving embryo culture conditions. His interests include developing programs for the treatment of severe male factor infertility; diagnosis of genetic disease in embryos; and improved embryo culture. See more posts
	Carolyn Givens, M.D. was the first in San Francisco to successfully initiate a pregnancy using intracytoplasmic sperm injection (ICSI). She currently co-directs the Bay Area Pre-Implantation Genetic Diagnosis Program (PGD) and is director of PFC’s PGD program. See more posts

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

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

– Carolyn Givens, M.D.

An Example X-Ray of a normal HSG	An example X-Ray of an abnormal HSG

Infertility due to blocked fallopian tubes was a common cause of infertility in the 1970’s and 1980’s. Some textbooks from that era quote an incidence as high as 25% of all infertility causes. At Pacific Fertility Center in 2005, only 10% of our in vitro fertilization patients were noted to have a tubal factor contributing to their infertility. Fallopian tube damage is most commonly due to prior infection with a sexually transmitted disease such as gonorrhea or Chlamydia. Most chlamydial pelvic infections are relatively asymptomatic and may go unrecognized; therefore many patients with tubal obstruction are unaware they have a tubal problem. Better safe-sex practices and improved screening of young women are possible factors for the lower incidence of tubal disease we are seeing, at least in our Bay Area infertility population.

Even though there is less tubal factor infertility these days, if there is a tubal obstruction, the course of fertility treatment becomes quite definitive: in vitro fertilization. No other treatments, including surgery, are likely to result in a healthy intra-uterine pregnancy. Therefore, we are still advocating some type of screening test for tubal factor in the evaluation of infertile couples.

There are two common ways to determine whether there is tubal obstruction. One is surgery, where dye is passed through the cervix, uterus and tubes, and there is direct visualization of the flow of the dye out the ends of the tubes into the pelvis. The other is the HSG, or hysterosalpingogram. The HSG is an X-ray procedure that involves placing into the cervix a small flexible catheter with a balloon around the tip to hold the catheter in place and close off the cervical opening. Radiographic contrast dye is then instilled into the uterine cavity, using a syringe attached to the tube. Under X-ray visualization, the dye is tracked into the uterine cavity and into the tubes. Pictures are taken during this process to document the shape of the uterine cavity and whether or not the dye enters and flows through both tubes into the pelvis.

HSG procedures are usually performed by radiologists; however, if there is difficulty placing the catheter securely into the cervix, the radiologist may ask the patient’s gynecologist to assist. This test is valuable in determining tubal blockages, but it has some disadvantages. It is very important to get the balloon properly inflated in the cervix to keep enough pressure on the fluid (no back flow into the vagina) so it will enter the fallopian tubes. Unfortunately, this pressure on the walls of the uterus can cause the uterus to contract, causing the patient to experience significant cramping. For this reason, it is recommended the patient take 2 or 3 ibuprofen prior to the procedure.

In some cases, the pressure is enough to cause the smooth muscle walls of the fallopian tubes themselves to spasm, blocking any dye from entering the tube. Sometimes the dye flows so easily through one tube that there is not enough pressure generated to get the dye to fill the other tube. These are some of the drawbacks of the procedure. This is why, even when we get a report of one-sided tubal obstruction, we are often skeptical that this is really due to some abnormality of the tube.

Although there are some false positives associated with this test, if the dye fills both tubes and does not flow out the ends of the tubes, this is highly suggestive of true tubal obstruction. In this instance, IVF is indicated.

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

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

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

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

1. A healthy woman in her late 30’s or even in her 40’s, will have the fertility of a younger woman.
   Although it is always better to be healthy, especially when it comes to carrying a pregnancy, the likelihood of conception is tied to the age of a woman’s eggs and is not closely related to her general health.
2. You should have sex every other day during the fertile window.
   For most men, sperm recovery is very rapid. Sometimes when an IVF cycle is done and there are many eggs to fertilize, we ask for a second semen sample. We are often amazed when the second sample, collected just 2 hours after the first sample, has even better numbers. So, rather than attempting to “save up good sperm” by having less frequent intercourse during the most fertile time period, we recommend more frequent intercourse. A home ovulation predictor kit is useful to time sex to ovulation. When using the ovulation predictor kit, we recommend sex on the first day of the LH surge and the next day too.
3. Fertility medications are associated with a higher risk of cancer.
   In the early 1990’s, some concerns were raised that taking fertility medications might be associated with a higher lifetime risk of ovarian cancer. Since then, several studies have been published that did not find this to be true. Because of this thorough and extensive research we feel comfortable using these medications not only on patients, but our egg donors as well.
4. Fertility medications (especially injectable fertility medications) cause women to be emotional wrecks.
   Although Clomid (clomiphene citrate) has well-known side effects related to its anti-estrogen effects, the injectable fertility medications do not tend to cause the same negative mood alterations. These drugs increase estrogen levels, a hormone which tends to have positive affects on mood.
5. Using fertility drugs and getting multiple eggs might use up my future eggs and cause me to go into menopause earlier than expected.
   Humans usually only ovulate one mature egg each month. This egg is contained in the dominant follicle and grows in one ovary or the other. For each dominant follicle that develops in any particular cycle, there are several other follicles/potential eggs available that are also trying to become that dominant follicle. The number of these other “antral” follicles varies from woman to woman and to lesser degree, from cycle to cycle. In general, the number of antral follicles declines with female age. Once the dominant follicle has been selected and the egg ovulated, the menstrual period or a pregnancy begin, and the other antral follicles, undergo programmed cell death, called atresia. The use of fertility medications rescues this group of antral follicles from atresia. For this reason creating multiple mature follicles and obtaining multiple eggs in any one cycle does not use up future eggs. We are simply rescuing eggs that would have otherwise died that month.
6. Having a miscarriage is a good sign that a woman is fertile.
   Approximately 70% of miscarriages are due to abnormal chromosomes (DNA) in the embryo. As a woman ages, more and more of her eggs become abnormal In fact, at age 40, only 1 in 10 eggs on average has normal chromosomes; so a woman at that age may only ovulate one normal egg per year. While a miscarriage may indicate that fertilization and implantation can occur, it doesn’t necessarily mean that overall egg quality is good. Egg quality is the best indicator of the ability to produce a viable pregnancy.
7. Stress is a major cause of infertility.
   There is enough circumstantial evidence to indict stress as a collaborator when it comes to fertility; however, there is very little evidence to convict stress as a major perpetrator. Usually there is some other underlying cause to the problem, even if it is just age-related sub-fertility (decline in fertility due to female age and therefore higher numbers of abnormal eggs). Stress, however, can compound the problem and possibly negatively impact egg quality and uterine lining quality. Look for a new addition to our website, the Domar Fertility Stress Questionnaire, to assess your stress levels.
8. In Vitro Fertilization can help women in their late 40’s and even 50’s to conceive with their own eggs.
   Despite the number of celebrities having babies in their mid-forties and beyond, these babies may not necessarily have been the result of an in vitro fertilization process using their own eggs. While we respect a woman’s right to privacy and their decision not to divulge this little detail, the perception left with the public is that fertility treatments can extend one’s reproductive life. Unfortunately, this simply is not true. There is a very, very low probability of improving one’s success of conceiving after age 43 by using assisted reproduction, unless the woman considers using donor eggs.
9. In Vitro Fertilization success rates are low.
   Across the United States, including patients of all ages, the delivered success rates for in vitro fertilization have risen from about 20% in the mid-1990s to about 35% in the mid-2000s. During this same period, fewer embryos were being transferred to the uterus per cycle and the triplet and higher-multiple pregnancy rates dropped dramatically. Though it may take more than one attempt to conceive, the majority of patients are successful.
10. Very few people ever experience infertility.
    Many fertility patients feel they are the only ones in their circle of friends and acquaintances suffering from infertility. At times, it seems as though everyone else is having a baby. Actually, one in six couples is having trouble with conception, they just may not talk about it. Since they are not pushing a stroller, there is no outward visible sign of their fertility status. When couples decide to share the story of their fertility quest, they often find there are many of their peers experiencing similar difficulties. They discover friends who can not only relate but also provide valuable support.

Interested in self-diagnosis of fertility? The ability to screen for fertility in private, on one’s own schedule, with an at home diagnostic kit is an appealing option. A company from the UK, Genosis, has developed such a kit, called Fertell.

Fertell is a testing kit that offers a basic assessment of male and female fertility.

Fertell for the male is a specimen collection and testing kit that measures the concentration of motile sperm. A sperm specimen is collected into a cup and allowed to liquefy and then warmed to body temperature. Motile sperm pass through a filter and are colored red by exposure to a gold-coated antibody. Appearance of two red lines in a testing chamber indicates a sperm count over 10 million total motile.

Fertell for the female is a conventional urine test strip very similar to an ovulation prediction kit. The female places the absorbent tip in her urine stream for 5 seconds. FSH in the urine reacts with antibodies on the test strip and shows as a red line in the result window. The intensity of this line reflects the FSH concentration (the darker the line, the more FSH present in urine). High FSH levels are indicated by two dark red lines.

Traditional semen analysis measures sperm volume, count, and motility. Multiplied together, these numbers yield the total motile sperm count, that is, the number of moving sperm in the ejaculate. Total motile sperm count is a reasonable predictor of fertility for men. Fertell establishes that the sperm count is over a specific value of 10 million total motile, a reasonable threshold for male fertility.

The male test kit is not able to determine subtle gradations of male fertility. It cannot detect the effects of treatment or change in lifestyle that may cause improvement in sperm count, nor can it detect alterations in sperm morphology (shape). More sophisticated testing is available at a sperm lab.

The female test kit is used as a screening test, and cannot detect subtle gradations in FSH levels, or the relationship of FSH to other important hormones such as estradiol. Such issues have dramatic effect on the patient’s prognosis.

Neither of these tests can replace an expert’s opinion. An expert’s ability to interpret test results with a broad knowledge base and experience remains the best way to diagnose and treat infertility problems.

Of primary importance is that, while both test kits have been correlated with existing assays, neither has been evaluated for its ability to predict pregnancy. Such research takes time, and hopefully will be forthcoming. For now, Fertell is an interesting option for those seeking a private screening assessment of their fertility.

Every year, several Pacific Fertility Center professionals participate in ASRM’s national meeting. They evaluate the research and share their findings with PFC and Fertility Flash.

Among those attending the conference from PFC were Dr. Philip Chenette and Dr. Isabelle Ryan and Peggy Orlin, MFT. Their reviews cover the following topics: Update #1: Ovarian Stimulation Techniques, Update #2: PGD and Aneuploidy Screening Techniques, Update #3: Egg Freezing, Update #4: Acupuncture, and Update #5: Men and ART.

ASRM Update #3: Egg Freezing

Oocyte cryopreservation is the storage of the female gamete, the egg, prior to fertilization. Preservation of fertility for single women that must undergo cancer therapy or surgery, or that must delay or choose to delay childbearing, and donated oocyte banking are all applications of oocyte cryopreservation. The need for this technology is clear, but reports of success with oocyte cryopreservation have been limited.

Highly successful oocyte cryopreservation is now attainable. New studies are showing pregnancy rates with oocyte cryopreservation that are equal to traditional IVF techniques.

The key to this technology is oocyte vitrification – an ultrarapid cryopreservation technique. Researchers from Atlanta described their experience with vitrification. Out of 11 patients with transfers, nine conceived, with an implantation rate of 65%.

Pregnancies after oocyte cryopreservation have developed normally. An Italian study of 105 children born after oocyte cryopreservation showed no problems. A Chicago study of the genetics of oocytes, embryos, and children born after oocyte cryopreservation was reassuring. No increase rates of aneuploidy or malformations were reported, and normal development was found in post-natal follow-up.

These results are similar to those we have previously reported from our own research at Pacific Fertility Center (see December 2007 Fertility Flash). Oocytes are now cryopreserved with high success rates. Oocyte cryopreservation technology has matured, and we look forward to providing these techniques for our patients.

Philip Chenette, MD

Every year, several Pacific Fertility Center professionals participate in ASRM’s national meeting. They evaluate the research and share their findings with PFC and Fertility Flash.

Among those attending the conference from PFC were Dr. Philip Chenette and Dr. Isabelle Ryan and Peggy Orlin, MFT. Their reviews cover the following topics: Update #1: Ovarian Stimulation Techniques, Update #2: PGD and Aneuploidy Screening Techniques, Update #3: Egg Freezing, Update #4: Acupuncture, and Update #5: Men and ART.

Update #1: Ovarian Stimulation Techniques: Changes in ovarian stimulation techniques evolve as a better understanding of the medications and their effects on eggs and ovaries develops.

Letrozole (Femara) is increasingly being used as a mild stimulation for ovarian follicle growth and as an additional medication with gonadotropins (e.g. Follistim). In a study on the use of letrozole in preparation for IVF in breast cancer patients, a group from New York showed that breast cancer recurrence or the incidence of invasive carcinoma in the opposite breast does not appear to be increased after stimulation using letrozole and FSH for fertility preservation.

For patients with PCOS, researchers from France compared stimulation with a GnRH agonist, similar to Lupron, with oral contraceptives plus agonist. In these preliminary results, dual suppression does not provide any obvious effect in harmonizing the group of developing follicles nor in improving the quality of oocytes and embryos. This study is still ongoing in order to test these results in a larger population.

In patients that produce an excessive number of follicles in response to stimulation, ovarian hyperstimulation syndrome (OHSS) is possible. To prevent this, the fertility drugs are sometimes stopped mid-stimulation; the follicles are “coasted” – they grow without stimulation, with a lower risk of OHSS. An alternative to “coasting” is the use of Ganirelix, a GnRH antagonist, in a “salvage protocol.” Probability of live birth with the Ganirelix salvage protocol was similar to controls. High-grade embryos were more common with this regimen, in contrast to “coasting”. The miscarriage rate was slightly higher, but not statistically significant. These results suggest that the Ganirelix salvage regimen is a superior alternative to “coasting” in women at risk for OHSS.

A group in Montpelier, France is interested in gene expression in the follicle after use of fertility drugs. Using gene chips they measured gene expression in patients exposed to urinary FSH products and recombinant FSH. Significant differences were found meaning that different genes are being expressed in follicles of women receiving pure FSH (Gonal-f or Follistim) as compared to genes being expressed in follicles of women receiving urinary FSH (Repronex or Menopur)– the meaning of these changes will have to await further study.

On the other hand, a long debate about the effectiveness of urinary and recombinant FSH products is a bit closer to resolution. A meta-analysis from a group in Egypt examined pregnancy outcomes and risks in a group of previously published studies. No significant differences were found. Their conclusion was that urinary gonadotropin (hMG) is as effective as recombinant gonadotropin with regards to clinical outcomes and patient safety.

Philip Chenette, MD

Introduction

Sara (a hypothetical patient) found a breast lump. 36 years of age, she was a single active professional, otherwise healthy, careful about her diet, and carefully evaluating her options after a diagnosis of breast cancer. Along with the discussion on surgery, chemotherapy, and radiation therapy came the question “Were you planning to have children?”

A diagnosis of cancer presents many decisions that must be made quickly. Confirming the diagnosis and planning therapy will be the primary concerns, but the implications of therapy on long-term quality of life must be assessed. One of the primary issues facing women with a diagnosis of cancer is future fertility.

Candidates

Cancer treatment can interfere with future fertility. Toxicity varies by treatment. Cyclophosphamide, an alkylating agent used in many chemotherapy regimens, is highly toxic to sperm and eggs; methotrexate and 5-flouro-uracil (5FU) are not. Medications used for longer time intervals create a higher risk of fertility problems than shorter time intervals; effects on women in older age groups are more severe than younger. Radiation therapy, in high doses, can have effects on eggs and sperm. Surgery and anesthesia are not known to have direct effects.

It is difficult to give specific fertility risks for chemotherapeutic regimens, since studies are not yet definitive. Among the more toxic treatments are stem cell transplantation for leukemia in which total body irradiation and cyclophosphamide are used, beam radiation to a field that includes the ovaries, and extended chemotherapy of up to 6 cycles using cyclophosphamide in combination with other agents. After conventional chemotherapy for breast cancer for women under 40, the chance of infertility is roughly 50%, in older women the risk is over 80%.

Treatment options

What are the options for fertility in patients diagnosed with cancer? The best choices are available to those that have not yet initiated treatment and involve cryopreservation. During treatment, the risk of problems rises, and after treatment, there may not be adequate recovery of fertility to achieve pregnancy.

Cryopreservation allows cells to be stored with great stability for long periods of time. The record time from sperm cryopreservation to pregnancy is 28 years; there probably is no real limit to the time that cells can be stored. To store cells requires technology that reduces the formation of ice crystals, which disrupt cells, and prevents the rapid rise in salt concentration that occurs as water freezes. Cryopreservatives and management of temperature changes (slow freeze or vitrification) are used to reduce the risk of these problems.

Male

The option for fertility preservation in men is straightforward, cryopreservation of sperm. Sperm is obtained by masturbation and frozen in multiple vials in liquid nitrogen. 2-3 sperm samples can be obtained per week, with 2-4 vials stored per ejaculate; two weeks worth of donations could yield 8-24 vials of sperm. Costs vary widely, but would range from $1500-$3000 for processing and 3 years of storage.

Testicular sperm extraction is an option for individuals with azoospermia. Testicular tissue cryopreservation remains a theory that has not yet produced a human pregnancy. It has been proposed as an option for preservation of fertility in children, but has yet to be proven in clinical practice.

Female

Women have the option of cryopreservation of oocytes or embryos. For women without a partner, oocyte cryopreservation holds promise as a means to preserve fertility potential without committing to a specific sperm source or partner. For women with a partner or sperm donor, embryo cryopreservation is a proven technology.

To create cryopreserved oocytes, Follicle Stimulating Hormone (FSH) is administered over a ten day time period to stimulate ovarian follicles. The oocytes are retrieved under sedation with a needle guided by ultrasound and then stored in liquid nitrogen.

Newer techniques of oocyte vitrification secure good pregnancy rates for those with good oocyte quality. Traditional oocyte cryopreservation is performed using a slow freeze technique, but more rapid vitrification procedures optimize results. The trick with cryopreservation is to lower the temperature while avoiding ice crystals that disrupt cell membranes and proteins. Vitrification, an ultrarapid freezing process utilizing a minimal fluid volume, reduces the risk of these problems and optimizes cell quality.

For those women with a partner, or that are willing to commit to a specific sperm donor, embryo cryopreservation is an excellent option. After stimulation and retrieval, oocytes are inseminated and cultured in an incubator for 1-5 days, followed by cryopreservation. The embryos can be thawed and transferred at a later date, after clearance from the oncologist. Embryo cryopreservation is the best established of the fertility preservation techniques, with years of experience in its applications. Good pregnancy rates can be anticipated.

Ovarian tissue cryopreservation, the cryopreservation of whole pieces of the ovary, as opposed to cells, remains experimental. Complex tissues are more difficult to cryopreserve than cells, though rare success has been reported.

Cancer recurrence

Is there risk to the use of fertility drugs in patients with cancer? It does not appear in studies to date that breast or ovarian cancer risk is affected by use of fertility drugs. Studies indicating an increased risk are balanced by other studies indicating a reduction in risk. Studies to date have been limited, and treatment decisions still must be individualized.

Does pregnancy increase the risk of cancer recurrence? In theory, certain types of cancer could be aggravated by the hormones of pregnancy, but studies have not confirmed an overall risk. Certain types of cancer are less common in women that have delivered a pregnancy. Treatment decisions must be individualized, as future studies gather more information.

Pregnancy

Certain cancer treatments create organ toxicity that must be evaluated in considering patients for pregnancy. Heart output is limited in patients that have received doxorubicin. Uterine irradiation is associated with miscarriage and pre-term labor.

Children

Children born after fertility preservation procedures do not carry any increased risk for birth defects. There are hereditary syndromes that can be associated with cancer that could be transmitted to children, but there does not appear to be any other increased risk for cancer or genetic disease in children of cancer survivors.

Patients contemplating conception must consider life span expectations as part of their decision on whether to conceive. Such considerations are not, however, a reason to withhold treatment, and are ultimately the individual and family should decide.

Philip E. Chenette, MD

Resources:

www.fertilehope.org Fertile Hope

www.livestrong.org Lance Armstrong Foundation

www.cryobank.com California Cryobank

www.PacificFertilityCenter.com Pacific Fertility Center