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

Polycystic ovary syndrome (PCOS) is the most common endocrinologic disorder in women of reproductive age. Approximately 5-10% of reproductive age women have PCOS. The various symptoms of PCOS can be irregular or absent menstrual cycles, infrequent or absent ovulation, excess facial and body hair, obesity, and infertility. The key components defining this disorder are chronic anovulation (inability to ovulate an egg), clinical hyperandrogenism (elevated male type hormones) and more recently discovered, insulin resistance.

Insulin resistance, the precursor state to diabetes, is present in 35-40% of women with PCOS, even if they are not overweight. Insulin resistance is diagnosed by blood testing, either as fasting glucose to insulin ratio, or as a complete glucose tolerance test. Long term follow up of women with PCOS reveals that up to 40% develop impaired glucose processing or diabetes by age 40. The prevalence of diabetes in women with PCOS is seven times higher than for the non-PCOS population. Excessive insulin production is thought to promote excess male hormone production, though the actual mechanism explaining this observation is still unclear. Insulin resistance may increase the long-term risks of heart disease and hypertension.

Interventions that reduce circulating insulin levels in women with PCOS may restore normal reproductive endocrine function. Non-pharmacologic methods, such as weight loss and exercise, have clearly led to reduced insulin and male hormone levels, resulting in resumption of ovulatory function. However, these regimens are at risk for poor compliance and, over time, the benefit of weight loss is rarely maintained.

Insulin-sensitizing (anti-diabetic) medications can be used to decrease insulin levels, which may help restore the normal ovarian hormone profile (i.e. reduce male hormone), thus allowing for spontaneous ovulation to occur in about 75% of patients. The most commonly used medication is metformin (Glucophage®). Side effects of metformin include gastrointestinal symptoms, which are dose-related and tend to resolve after several weeks. While there are no well-controlled studies of safety during pregnancy, metformin has been administered to a small number of women with diabetes throughout their pregnancies, and no fetal abnormalities have been described⁽¹⁾.

Clinical studies have shown that metformin (500 mg three times per day or 850 mg twice daily with meals) administration to women with PCOS increased the frequency of spontaneous ovulation, menstrual cyclicity, and ovulatory response to clomiphene citrate (CC) (Clomid^®). Benefit has been demonstrated with metformin treatment in PCOS patients both with and without insulin resistance⁽²⁾. Metformin alone may be less effective in obese PCOS women.

Women with PCOS are considered to be at increased risk of miscarriage, as high as 30 – 50 %. When women were treated with 1000-2000 mg daily of metformin throughout pregnancy, rates of early pregnancy loss were 11.6% in the metformin group compared with 36.3% in the control group (p < 0.0001). Administration of metformin throughout pregnancy to women with PCOS may decrease miscarriage rates⁽³⁾.

Controversy exists when comparing metformin to clomiphene citrate (CC) for treating infertility. A well-designed study showed metformin is better for ovulation induction than CC alone and equivalent for pregnancy achievement. The authors suggest that metformin can be used first for ovulation induction in patients with PCOS regardless of their weight and insulin levels because of its efficacy and known safety profile⁽⁴⁾. Alternatively, another study found benefit with metformin if obese (BMI >30 kg/m⁽²⁾ subjects and women older than 34 years were excluded⁽⁵⁾. Another paper pooled the results of 6 studies to examine whether metformin is efficacious when given to patients resistant to CC. They found the addition of metformin in the CC-resistant patient is highly effective in achieving ovulation induction⁽⁶⁾. Most studies showing benefit were small with fewer than 100 patients.

Conversely, two large multicenter trials, one conducted in the US (PPCOS)⁽⁷⁾ and one in the Netherlands⁽⁸⁾, have shown no benefit from metformin either as a single agent or as adjuvant therapy in combination with clomiphene for the treatment of infertility in women with PCOS. They found metformin increased the occurrence of ovulation but did not increase the chance of becoming pregnant. The PPCOS study is large and well designed, with 626 participants. It differs from other studies by using the extended release form of metformin. One very notable result was the absence of any statistically significant effect of this extended release form of metformin on insulin levels or insulin resistance. There were none of the expected metabolic effects of metformin. Extended-release metformin has not previously been studied in women with PCOS. Thus, it has not been ascertained that its efficacy is comparable to regular metformin in PCOS⁽⁹⁾.

Additionally, metformin and clomiphene citrate (CC) differ in their therapeutic time frames (the period of time from initiating therapy to achieving maximum effectiveness). CC produces higher rates of ovulation and pregnancy in the early months of treatment than that of metformin and might be preferable to women who wish to become pregnant quickly ⁽⁵⁾. However, a patient with more time to become pregnant may benefit from metformin’s metabolic effects. During the 3 to 6 months that it takes for metformin to become maximally effective, the patient can prepare for pregnancy by losing weight through diet and exercise. Reducing a patient’s weight might considerably optimize her pregnancy⁽⁹⁾.

Metformin induces normal ovulation, and the risk of multiple gestation is no more than that in the general population. Conversely, CC can precipitate the release of multiple eggs in a given menstrual cycle and carries a risk of multiple gestation: in the PPCOS study, multiple gestation was 6% in the clomiphene group and 0% with metformin.

Metformin may significantly increase the incidence of multiple pregnancy when used in combination with gonadotropins⁽¹⁰⁾.

Short-term co-treatment with metformin for patients with PCOS undergoing IVF/ICSI cycles does not improve the response to stimulation but significantly improves the pregnancy outcome and reduces the risk of ovarian hyperstimulation⁽¹¹⁾.

Conclusions:

• PCOS patients should be screened for diabetes before becoming pregnant. Hemoglobin A1c levels should be normal.
• Metformin alone can induce ovulation and may improve the effectiveness of CC. Extended release metformin may not be as effective.
• Metformin may decease miscarriage rates.
• Weight loss may improve the effectiveness of metformin.
• Time to achieve pregnancy may be longer with metformin than CC.
• Metformin may be less effective in older women.
• Metformin does not increase multiple pregnancy rates when used alone.
• Metformin may increase multiple pregnancy rates and decrease ovarian hyperstimulation when used with gonadotropins.
• Long-term benefits of metformin in preventing hypertension and heart disease need further study.

Eldon Schriock, MD

References:

1. The Practice Committee of the American Society for Reproductive Medicine Committee Opinion. Use of insulin sensitizing agents in the treatment of polycystic ovary syndrome. Fertility and Sterility
2. Nawrocka J, Starczewski A. Effects of metformin treatment in women with polycystic ovary syndrome depends on insulin resistance. Gynecol Endocrinol. 2007 Apr;23(4):231-7.
3. Khattab S, Mohsen IA, Foutouh IA, Ramadan A, Moaz M, Al-Inany H. Metformin reduces abortion in pregnant women with polycystic ovary syndrome. Gynecol Endocrinol. 2006 Dec;22(12):680-4.
4. Neveu N, Granger L, St-Michel P, Lavoie HB. Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction and achievement of pregnancy in 154 women with polycystic ovary syndrome. Fertil Steril. 2007 Jan;87(1):113-20.
5. Palomba S, Orio F Jr, Falbo A, et al. Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90:4068-4074.
6. Siebert TI, Kruger TF, Steyn DW, Nosarka S. Is the addition of metformin efficacious in the treatment of clomiphene citrate-resistant patients with polycystic ovary syndrome? A structured literature review. Fertil Steril. 2006 Nov;86(5):1432-7.
7. Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356:551-566.
8. Moll E BP, Korevaar JC, Lambalk CB, van der Veen F. Ovulation induction in women with polycystic ovary syndrome: A randomized double blind clinical trial comparing clomiphene citrate plus metformin with clomiphene citrate plus placebo. BMJ. 2006;332:1485.
9. Baillargeon JP, Legro RS. Should metformin be used as front-line therapy for fertility in women with PCOS. Sexuality, Reproduction, and Menopause 2007; 5(2):17-19.
10. Shibahara H, Kikuchi K, Hirano Y, Suzuki T, Takamizawa S, Suzuki M. Increase of multiple pregnancies caused by ovulation induction with gonadotropin in combination with metformin in infertile women with polycystic ovary syndrome. Fertil Steril. 2007 Jun;87(6):1487-90.
11. Tang T, Glanville J, Orsi N, Barth JH, Balen AH. The use of metformin for women with PCOS undergoing IVF treatment. Hum Reprod. 2006 Jun; 21(6): 1416-25.

My husband and I have a long history together. We met in high school, and after 10 years of marriage, we were ready to have a family. My sister had experienced trouble getting pregnant, so as a result I worried that I might have the same problem.

My worries were partially confirmed when my husband and I unsuccessfully tried to conceive. In our case, we discovered we had the unlucky combination of both male and female factor infertility. At that point we were under the care of our gynecologist. On our doctors’ recommendation, we went through IUI near the end of 2003. It was a nightmare for a lot of reasons. I reacted poorly to Clomid and did not conceive.

While I was still trying to conceive, my sister was happily on her way to having a family. She had gone to the next level of care: an expert reproductive endocrinologist at Pacific Fertility Center. We were of course delighted to hear the news of her pregnancy, but at the same time frustrated because we were still not pregnant. We had always thought that once we were ready to have a family, we would be able to get pregnant easily and naturally.

After our disastrous IUI cycle, we tried again naturally, but to no avail. Frustrated and tired, we took a break. After a while, I spoke with my sister Alison, who referred us to Dr. Herbert at Pacific Fertility Center. He was wonderful and had great bedside manner. He was positive and upbeat despite our combined infertility diagnosis. We went straight to IVF with Gonal F and Repronex. Unfortunately, my body didn’t respond well.

I really appreciated Dr. Herbert during this discouraging time. He was frank with us and indicated that my follicles were not looking good. Without good follicles, the ability to retrieve a reasonable number of quality eggs was in question, so we did not continue our IVF cycle. Dr. Herbert was very flexible; he listened, explained our options and didn’t dictate what we should do. He suggested IUI as a way to salvage the IVF cycle and much to our surprise, we became pregnant! When I got the good news that my husband and I were going to be parents for the first time, I was “over-the-top” happy calling everybody I knew. In addition, on our first ultrasound, we saw two beating hearts. We not only were pregnant, but also were pregnant with twins!

The irony is that after my sister Alison had twins, I too envisioned having twins. During our initial OB ultrasound, Dr. Herbert indicated that he saw two heartbeats. We had a scare at one point as we thought I had experienced a miscarriage. However, I had just had some bleeding and passed a blood clot. I appreciated Dr. Herbert during this time, as he remained calm at all times. Much to our delight, I gave birth to a healthy, beautiful set of twins (Justin and Eva) who are now over a year old.

I thoroughly enjoyed my experience at PFC. They were great from a logistical standpoint, and were great about getting all of the paperwork out of the way quickly. I appreciate the nurses—Anne was awesome and whenever we called she was very kind and understanding. I loved going to appointments as it was such as positive experience. Additionally, I appreciate PFC for their professionalism. Dr. Herbert was so experienced and knew what he was doing the whole time; I trusted him a lot. I truly love our children. It is wonderful for my sister and me to be able share experiences as we learn about the joys of parenthood firsthand. It is sweet irony indeed.

Leslie

Leslie’s journey to a successful pregnancy was a bit unconventional but contains several important messages for you, our patients. The stimulation of her ovaries during her first IVF attempt did not progress as we had hoped. There were fewer follicles and some were large and others small (follicle disparity). Had this been her final attempt on very high doses of medication, we might have proceeded on to egg retrieval. However, we felt the stimulation was suboptimal and we expected to improve this process in another cycle by changing the medication regimen. As Leslie and her husband were diagnosed with unexplained infertility, we also felt she might conceive by ovulating the few larger follicles which were present and using intrauterine insemination. Fortunately we were correct, and Leslie now has two wonderful children. These conversions from a planned IVF cycle to IUI cycle can produce pregnancies as often as 10% of the time as long as there are no other fertility factors like tubal damage or severe sperm problems and the age of the woman is not advanced (less than 38 years). Leslie’s story is a good example of persistence in spite of initial disappointment, of using all the options available in the most effective manner, and of “keeping the faith”. We hope Leslie’s story can be an inspiration to others who may face similar disappointments on their journey to parenthood.

Carl Herbert, MD

Progesterone is the hormone that prepares the uterus and endometrial lining to support an early pregnancy (Progesterone = “Pro-gestation hormone”). Produced in the ovary between ovulation and the following menstrual period, and by the placenta in the early embryo, progesterone stimulates cells in the endometrial lining to become receptive to the early embryo and, after implantation, to support growth of the embryo. Without progesterone, implantation could not occur; if progesterone were to be removed in early pregnancy, miscarriage would be certain to follow.

Hormones are produced in the ovary by the developing follicle, or egg sac. In the first two weeks of the menstrual cycle, as the egg sac matures, stimulated by Follicle Simulating Hormone (FSH) and Luteinizing Hormone (LH) from the pituitary, the follicle increases its production of estrogen to a peak just before ovulation. At the mid-cycle surge of LH, the follicle abruptly shuts down its estrogen production pathway, converting over to producing large amounts of progesterone. The follicle becomes the corpus luteum, a richly vascularized progesterone production factory.

As the pregnancy is established, the placenta produces chorionic gonadotropin, hCG, a hormone that stimulates the corpus luteum to produce additional progesterone. hCG is very similar to LH, binds to the same receptors, and stimulates the ovary much like LH. Rising hCG stimulates rising progesterone, which strengthens the pregnancy and allows it to produce more hCG, again increasing progesterone; this feedback loop is essential to enabling a strong pregnancy.

Progesterone is essential to the development of the early embryo. Progesterone from the corpus luteum circulates through the bloodstream to the uterus, where the endometrium that has been prepared by estrogen starts to change to support the early pregnancy. This change in the endometrial lining, luteinization, is essential for the embryo. The role of the corpus luteum was demonstrated years ago in experiments where the ovary containing the corpus luteum was removed; miscarriage immediately followed. More recently, progesterone antagonists, such as RU-486, which block the progesterone receptor, have been used in animal studies to induce miscarriage when given in early pregnancy.

Progesterone also has effects on the immune system, stimulating protective proteins, such as HLA-G, in the early pregnancy (Yie, Xiao et al. 2006). Without HLA-G the maternal immune system would reject the embryo, therefore, production of HLA-G antigens are critical to protecting the early pregnancy. Progesterone plays an important role in stimulating HLA-G and preventing rejection of the embryo.

Progesterone also acts as a chemoattractant for sperm (Albano, Smitz et al. 1999; Teves, Barbano et al. 2006). Progesterone in tiny amounts will draw sperm, and may attract sperm to the egg after ovulation. Uterine contractions, which play a role in sperm movement, are also controlled by progesterone.

Because it aids in creating a receptive environment for the embryo, insufficient progesterone can be a source of infertility and miscarriage. Low progesterone levels will result in luteal phase defect, a condition in which there is insufficient hormonal support for the early pregnancy. Failure of implantation of an otherwise healthy embryo, or loss of an early pregnancy, may occur with luteal phase defect. Some women do not produce any progesterone at all, for example, after menopause, or when a menopausal state is temporarily induced using medications to prevent ovulation. Without progesterone, pregnancy cannot occur.

The progesterone receptor mediates the action of the hormone and is critically important to pregnancy; some cases of infertility may be related to abnormalities in the progesterone receptor (Spandorfer, Normand et al. 2006). A simple alteration in the genetic code for the progesterone receptor is common in patients with infertility, and appears to be associated with poorer pregnancy outcomes.

The method of In Vitro Fertilization (IVF) is associated with luteal phase defects and low progesterone levels (Albano, Smitz et al. 1999). With IVF treatment, many of the cells that produce progesterone are removed from the ovary in the course of oocyte retrieval. In addition, the use of GnRH agonists and antagonists (leuprolide, ganirelix, cetrorelix) prevent the release of LH and FSH from the pituitary, removing the primary stimulus for progesterone production from the ovary. Progesterone levels may not be adequate to support the pregnancy, resulting in a luteal phase defect, implantation failure, and early miscarriage.

For treatment, progesterone usage falls into two broad groups, progesterone supplementation, where progesterone is produced in the ovary and supplemented with medication, and progesterone replacement, where there is no natural progesterone production. Progesterone replacement would be used in an oocyte donation recipient. Since ovulation occurs in the donor, and there is no natural progesterone in the recipient, all progesterone must be administered. Progesterone replacement is also common for cryopreserved embryo transfers, though natural cycles can also be used in many women with regular menstrual cycles. Medical supplementation might be used in a variety of conditions associated with luteal phase defect or to reduce the risk of early miscarriage associated with low progesterone levels.

Progesterone is supplemented medically to reduce the risk of pregnancy problems arising from low progesterone levels. Progesterone may be given orally, by vaginal supplement, by injection, or its production enhanced by injection of hCG, which stimulates the corpus luteum to produce additional progesterone(Pouly, Bassil et al. 1996).

Oral progesterone is relatively weak in its effect. Absorbed through the upper intestine, progesterone taken orally is metabolized in the liver. This is known as “first pass effect”, because the hormone passes through the liver first before traveling to its site of action. These metabolites are not effective in inducing luteinization and can induce effects on the central nervous system such as sedation. Very little active progesterone is available after oral use (Friedler, Raziel et al. 1999).

Vaginal progesterone, in the form of creams, gels, and suppositories, is highly effective in supplementing or replacing natural progesterone, and has been the most popular form of progesterone supplementation. Progesterone is absorbed through the vaginal wall and moves through local circulation directly to the endometrium. Levels are sufficient to induce the normal changes in endometrial lining to support the early pregnancy (Pritts and Atwood 2002). The primary clinical concern with vaginal progesterone is the variability in absorption. While most women absorb progesterone vaginally without difficulty, some may not; as an indirect mode of administration, one cannot be certain of the amount that is absorbed.

Progesterone by intramuscular injection is well absorbed, and in some ways closest to natural ovarian secretion (Lightman, Kol et al. 1999). High serum levels of progesterone are achieved with effective preparation of the endometrium. Traditional intramuscular injections, in an oil base, require a relatively large needle; local reactions to the oil base at the site of injection are common. Newer preparations of intramuscular progesterone, such as progesterone ethyl oleate, are considerably easier to inject, but still require daily administration. Injectable progesterone remains the primary progesterone for those patients that produce no natural progesterone, such as for a donated oocyte recipient, or for a frozen embryo transfer in a medicated cycle.

hCG, by acting directly on the ovary, is a good stimulant to progesterone production (Herman, Raziel et al. 1996). Its use requires that an active corpus luteum be present, so it can only be used in a natural or stimulated ovulation cycle. It produces good progesterone levels and reduces the risk of luteal phase defect (Mochtar, Hogerzeil et al. 1996). hCG requires periodic injections and may increase the risk of ovarian hyperstimulation syndrome in patients that have been on fertility drugs. As the hormone that is measured in a pregnancy test, hCG causes a false positive pregnancy test, potentially confusing the diagnosis of early pregnancy. hCG is used occasionally to supplement progesterone production in women with an active corpus luteum.

Vaginal and injectable progesterone appear to be similar in actions on the endometrial lining (Khan, Richter et al. 2007); while the amount of progesterone absorbed can be dramatically different, the clinical effects are similar. Progesterone receptors appear to be saturated at fairly low levels of progesterone in the blood, and additional progesterone does not seem to increase pregnancy rates or reduce miscarriage rates. The specific route or agent for progesterone supplementation is probably not as important as assuring that at least some progesterone is present. Equivalent pregnancy rates have been shown using vaginal gels, progesterone vaginal capsules, and progesterone in a dissolving effervescent vaginal tablet (Schoolcraft, Miller et al. 2007). Vaginal and injected progesterone, in general, show higher bioavailability than oral progesterone.

In patients with no ovarian function, recipients of egg donors, or those patients utilizing cryopreserved embryos in medicated (estrogen/progesterone replaced) cycles, all progesterone must be supplied medically. These patients require a reliable source of progesterone, and injectable progesterone has been established as the best standard (Prapas, Prapas et al. 1998). Vaginal progesterone has also been used successfully, though less commonly. In these patients, progesterone replacement must be continued for an extended period. Because there is no corpus luteum in the ovary, the rising hCG from the placenta cannot stimulate progesterone production, as it would in a conventional pregnancy.

In those patients with an active corpus luteum, such as after in vitro fertilization, external progesterone is required for only a limited time period. In the first two weeks after ovulation, the pregnancy is critically dependent on ovarian progesterone. After a positive pregnancy test, progesterone administration can be stopped entirely (Proctor, Hurst et al. 2006), relying on the embryo to stimulate the corpus luteum through the placental hCG effect on the ovary.

Leuprolide, a GnRH agonist, seems to supplement progesterone and its actions. A single injection of a GnRH agonist releases LH from the pituitary, stimulating progesterone production in the ovary, and may act directly on the endometrium and the embryo, enhancing implantation (Pirard, Donnez et al. 2006). With more study, this may prove to be a useful adjunct to use of progesterone.

Philip Chenette, MD

References

Albano, C., J. Smitz, et al. (1999). “Luteal phase and clinical outcome after human menopausal gonadotrophin/gonadotrophin releasing hormone antagonist treatment for ovarian stimulation in in-vitro fertilization/intracytoplasmic sperm injection cycles.” Hum. Reprod. 14(6): 1426-1430.

Friedler, S., A. Raziel, et al. (1999). “Luteal support with micronized progesterone following in-vitro fertilization using a down-regulation protocol with gonadotrophin-releasing hormone agonist: a comparative study between vaginal and oral administration.” Hum. Reprod. 14(8): 1944-1948. Herman, A., A. Raziel, et al. (1996). “The benefits of mid-luteal addition of human chorionic gonadotrophin in in-vitro fertilization using a down-regulation protocol and luteal support with progesterone.” Hum. Reprod. 11(7): 1552-1557.

Khan, Richter, et al. (2007). “Case-Matched Comparison of Intramuscular Versus Vaginal Progesterone for Luteal Phase Support After In Vitro Fertilization and Embryo Transfer.” Fertility and Sterility 87(4): S13-S13.

Lightman, A., S. Kol, et al. (1999). “A prospective randomized study comparing intramuscular with intravaginal natural progesterone in programmed thaw cycles.” Hum. Reprod. 14(10): 2596-2599.

Mochtar, M. H., H. V. Hogerzeil, et al. (1996). “Endocrinology: Progesterone alone versus progesterone combined with HCG as luteal support in GnRHa/HMG induced IVF cycles: a randomized clinical trial.” Hum. Reprod. 11(8): 1602-1605.

Pirard, C., J. Donnez, et al. (2006). “GnRH agonist as luteal phase support in assisted reproduction technique cycles: results of a pilot study.” Hum. Reprod. 21(7): 1894-1900.

Pouly, J. L., S. Bassil, et al. (1996). “Endocrinology: Luteal support after in-vitro fertilization: Crinone 8%, a sustained release vaginal progesterone gel, versus Utrogestan, an oral micronized progesterone.” Hum. Reprod. 11(10): 2085-2089.

Prapas, Y., N. Prapas, et al. (1998). “The window for embryo transfer in oocyte donation cycles depends on the duration of progesterone therapy.” Hum. Reprod. 13(3): 720-723.

Pritts, E. A. and A. K. Atwood (2002). “Luteal phase support in infertility treatment: a meta-analysis of the randomized trials.” Hum. Reprod. 17(9): 2287-2299.

Proctor, Hurst, et al. (2006). “Effect of progesterone supplementation in early pregnancy on the pregnancy outcome after in vitro fertilization.” Fertility and Sterility 85(5): 1550-1552.

Schoolcraft, Miller, et al. (2007). “Efficacy of a Novel Form of Vaginal Progesterone on Continuing Pregnancy Rates in Women Undergoing IVF with Elevated BMI and Advanced Age.” Fertility and Sterility 87(4): S24-S24.

Spandorfer, Normand, et al. (2006). “O-7 A G->A POLYMORPHISM AT POSITION +331 IN THE PROGESTERONE RECEPTOR GENE IS STRONGLY ASSOCIATED WITH IVF OUTCOME.” Fertility and Sterility 86(3): S3-S4.

Teves, Barbano, et al. (2006). “Progesterone at the picomolar range is a chemoattractant for mammalian spermatozoa.” Fertility and Sterility 86(3): 745-749.

Yie, S.-m., R. Xiao, et al. (2006). “Progesterone regulates HLA-G gene expression through a novel progesterone response element.” Hum. Reprod. 21(10): 2538-2544.

Question: I had two elective abortions more than 10 years ago and I am worried that somehow that has something to do with the infertility I am now experiencing. Could the abortions be the reason I am now having trouble conceiving?

Answer: Most elective pregnancy terminations are done in the middle of the first trimester and are relatively simple, uncomplicated procedures. There is no reason to automatically assume that abortions have anything to do with subsequent infertility. Unless there is an infection, excessive bleeding requiring a second procedure or some other complication, the uterus and fallopian tubes should not suffer any long-term damage. On the other hand, any uterine procedures associated with prolonged bleeding or infection can lead to minor or major scarring of the uterine cavity or the fallopian tubes.

A mid-cycle ultrasound, just before ovulation, should be able to verify that your uterine lining is adequately thick and free of scar tissue. Also, a hysterosalpingogram (HSG) can detect uterine scarring or any obstruction of the fallopian tubes. Even if there is any scarring, which is unlikely, a simple procedure called operative hysteroscopy can often remove the scar tissue effectively. Only the most severe cases would require the use of a gestational carrier (surrogate).

Many, many women have had prior elective abortions and go on to have uncomplicated pregnancies. Women suffering from infertility often also suffer feelings of guilt about prior terminations. Some even think they are being punished for having elected to terminate a pregnancy. This thinking is irrational and is best replaced with positive thinking and a healthy attitude towards the future. This allows them to be active partners in the process of overcoming infertility.

Carolyn Givens, MD

Will my fibroids prevent me from getting pregnant?
A recent PFC study can help answer that question.

Every complete infertility evaluation includes a thorough evaluation of the uterus, where embryo implantation is expected to occur. At Pacific Fertility Center we typically start with a vaginal ultrasound to evaluate for the presence of fibroids (benign growths of the muscle layer), polyps (benign growths of the lining of the uterus), measure the lining thickness of the uterus and observe the uterine lining pattern. If uterine abnormalities are noted, a saline hysterogram (saline ultrasound) or hysteroscopy (visualizing the uterine cavity with a thin telescope) may be recommended.

Fibroids (uterine leiomyomas) are present in 20-40% of reproductive age women. The location of the fibroid(s), relative to the lining of the uterus, is important in determining if it will impact chances of pregnancy. Fibroids which distort the uterine lining and cavity are known to decrease pregnancy rates for patients undergoing fertility treatment. Only about 5% of fibroids directly distort the uterine cavity. The influence of fibroids which do not distort the uterine cavity has remained controversial.

To best determine if non-distorting fibroids also may have an impact on fertility treatment, requires the analysis of a large number of fertility cycles following patients who have non-distorting fibroids, and patients who have no fibroids. Most studies have small numbers of observed cycles, making statistical analysis difficult. One strategy for circumventing this problem, and gathering enough treatment cycles to draw meaningful statistics, is to have large IVF centers collaborate and “pool” data. This type of study is called a multi-center study.

Pacific Fertility Center (PFC) and the University of California San Francisco (UCSF) IVF centers collaborated in just such a study; gathering data on past treatment cycles of egg donor recipients with non-cavity distorting fibroids and without fibroids. Analysis of pregnancy (PR) and implantation (IR) rates were assessed. A total of 369 cycles were analyzed, of which 94 were for patients with fibroids. All recipients underwent their first oocyte donor cycle, and a fresh embryo transfer. Any uterine abnormalities other than non-distorting fibroids were excluded from the study analysis. The primary outcome measure was a clinical pregnancy. Implantation rate was a secondary outcome of the study. We also analyzed to see if the fibroid location: subserosal (growing towards the outside of the uterus) versus intramural (confined to the muscle layer) or if the fibroid diameter impacts PR and IR, as well as miscarriage and ectopic rates.

The following results were revealed.

The clinical pregnancy rate (PR) was not different between the two groups (no fibroids vs fibroids) (54% vs 47%). The implantation rate (IR) was also similar between the groups (38% vs 36%). Miscarriage rates were similar (9% vs 15%). Ectopic pregnancy (which is typically a rare outcome) showed results of 1% vs 4%, which also was not statistically significant. Location and diameter of fibroids did not show a significant impact on PR.

When screening ultrasounds identify fibroids, “treatment” of these lesions is tempting to both providers and patients, especially in cases of unexplained infertility. Our data suggest that there is inadequate evidence to conclude that fibroids which do not distort the uterine cavity have a significant effect on clinical pregnancy rates (PR) in patients undergoing IVF. Thus, there is inadequate evidence to support myomectomy for patients with non-distorting fibroids. Myomectomy may unnecessarily place the patient at risk of delayed treatment, as well as possible surgical morbidity. It is also unknown whether surgery itself may have a negative impact on pregnancy outcome- though our data did not show a lower PR in patients who had past myomectomies.

Future collaborative studies will investigate whether the distance of the closest fibroid to the uterine lining may impact PR and IR. Fibroid volume will also be investigated. These studies are currently in the design phase.

Isabelle Ryan, MD

“The effects of fibroids without cavity involvement on ART outcomes independent of ovarian age”, PC Klasky, DE Lane, IP Ryan, VY Fujimoto, Hum Reprod Advance Access, published September 22, 2006.

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

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.

PFC patients often inquire about the use of acupuncture as a part of their infertility treatment, and, as such, PFC brings you insight from Bethany Richardson M.S., L.Ac and Leslie Oldershaw, L. Ac., two Bay Area acupuncturists who integrate fertility treatment into their practices. As background, Bethany Richardson was originally a massage therapist who took a Chinese diagnosis course while working on her Shiatsu certification. That course sparked her interest in pursuing a degree in acupuncture and led her to discover her love for science and the integration of eastern and western medicine. Leslie Oldershaw entered the field of acupuncture after spending her college years dedicated to pre-med courses. She became aware of Chinese medicine as a system of treatment while in college, and it fit perfectly with her passion for eastern philosophy and culture. She had always been interested in women’s health and found that fertility treatment in Chinese medicine truly encompasses all aspects of a woman’s health. Recently, PFC interviewed Leslie and Bethany about their approach to infertility, integrative medicine, and the strengths and weaknesses of acupuncture as a fertility treatment.

PFC: When a patient first comes to you and cites infertility as the reason for their visit, what sort of initial work-up do you do?

Leslie Oldershaw: I do a very comprehensive intake that involves an interview that takes a full medical history. Depending on their history, they may have had labwork done, or I may be ordering tests. From a fertility standpoint I like to see the basic hormone panels, including a cycle day 3 FSH, TSH, Estradiol, and also a mid-luteal progesterone test. If they have done a Clomid Challenge test, I love to see those results. If they have had a HSG or an ultrasound, I like to see that as well. From a general wellness perspective, I need to see a CBC and lipid panel and a comprehensive metabolic panel. When it comes to age, if a patient is younger we can be less aggressive. If a patient is older, we will be more aggressive. If they are 30, I will do this basic work-up, but I will be more inclined to just look at how they do over the next 6 months. If someone who is 40 comes to me, I will recommend that they consult a reproductive endocrinologist. They may want to have more of an accelerated timeline in terms of their treatment options. One of the challenges that I have is that I get patients who don’t want to do the western tests. They don’t want a workup, or the partner doesn’t want to do a semen analysis. I spend a lot of time educating patients to make an informed decision rather than shooting in the dark. I will be more persuasive with my arguments as the patient gets older!

Bethany Richardson: Normally, by the time a patient sees me they have already been to a fertility expert. I ask them to bring in their most current blood work. If they have had an antral follicle count, I want to know what that is. The basal temperature chart gives me a wealth of information. I look at it more in terms of a Chinese diagnosis, not necessarily are they ovulating or when they are ovulating, which is important, but are they running too hot or too cold. It gives me a lot of subtle information from a Traditional Chinese Medicine (TCM) standpoint. If I am looking at a woman who is younger, maybe 31 or 32 years old, then I look at her history of antibiotic use and if they have a history of digestive problems. I look at her menstrual cycle, her PMS, and if she is able to detoxify her hormones correctly. If I am looking at an older woman, I look and see if she is too hot or too cold. Does she have an excess of hormones? I see people mainly when they are desperate. They come to me after two cycles of IVF and want to do everything they possibly can for the next cycle. And unfortunately, I would be more effective if I saw them earlier on, but I do what I can when patients come to me.

PFC: If a patient comes to you and she already knows she must do IVF or IUI to get pregnant, what type of protocols do you offer in conjunction with her fertility treatment?

Leslie Oldershaw: When I work with a patient leading up to the treatment cycle, there are a couple of different protocols we can utilize. The more comprehensive protocol requires 2-4 months and allows you to incorporate nutrition, acupuncture and herbal modalities. We can do a tremendous amount to build a patient up, particularly if they are coming out of a miscarriage. We also work with patients on a shorter timeline, where they might be coming in to work with us a few weeks before an IVF cycle, and then we are primarily relying mostly on acupuncture to promote good blood flow and circulation. We will talk to the patient about nutritional support, including a pre-natal vitamin and omega-3 essential fatty acids. There is not enough research at this point to use fertility medications in conjunction with herbs. If things don’t go as expected the doctor needs to be able to troubleshoot what went wrong. My feeling is that acupuncture is of benefit to everyone. The people for whom acupuncture does not work are the patients who are very needle phobic. And I have to say, my IVF patients are champs. They look at my very small needles and they scoff!

Bethany Richardson: The type of treatment depends where on the continuum they are. I look at whether or not they have done IVF before, and what the results were. Were they a poor responder? How old are they? Sometimes they come to me and they tell me their IVF cycle is in three weeks. I can’t do anything with herbs in three weeks, but I can do some acupuncture. If it is six weeks or eight weeks, then we will have a real protocol. From my perspective the hormones you inject are a very warm tonic, which can burn out your cooling system. Depending on how they react to the injectables, I might try to work with them to take some time off from IVF and load them up with cooling tonics. What I see then is that cervical mucus increases, sleeping patterns regulate and stress levels go down. It’s hard for me to prove that it works, but I honestly believe that it does. Stress management, diet, acupuncture and IVF combined can add up to a much greater level of success.

PFC: What are the strengths and weaknesses of using acupuncture to treat infertility?

Bethany Richardson: It regulates the hormones, helps detoxify the body so you don’t have systemic inflammation, reduces PMS and pain. I think its only downfall is that it takes time. And a lot of the time—women aren’t willing to wait. And that’s where I come in again and say, it’s not a sprint, it’s a marathon. Acupuncture isn’t a golden pill. If you continue to eat poorly and not give your body good nutrients and antioxidants, then I can’t do as much.

PFC: Is there anything you want to add about treating infertility with acupuncture?

Leslie Oldershaw: I have always been keen on integrative approaches. There is a tremendous amount that western medicine can do to help people achieve a pregnancy. But what makes a critical difference for me is the integrative approach. What I am doing with my patients is different than what a Reproductive Endocrinologist does, but together we can work synergistically to create the best outcome.

Bethany Richardson: I am very excited about the future. I am hoping that eventually there will be research money that is earmarked for this arena. Often times acupuncture is seen as competitive with western medicine, and I don’t think it has to be. If we join forces we can be more effective together.

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