Q.
Clomid did not work for me. My physician is offering letrozole or she says I should go directly to the injectables. What do you think?

A.
Both clomiphene citrate (marketed as Clomid), and letrozole (marketed as Femara) are oral medications used to stimulate ovulation. Letrozole is emerging as a viable alternative to Clomid for women undergoing ovulation induction, although no broad scientific studies have yet established the drug’s efficacy as the first course standard treatment. Several preliminary studies have shown letrozole to be useful for anovulatory women, and provides few side effects, especially for women whose uterine lining may be thinned out by Clomid. As to its exact mechanism, letrozole falls in the category of drugs known as nonsteroidal aromatase inhibitors, meaning it is highly specific in suppressing estrogen synthesis. Aromatase is an important enzyme prompting the creation of estrogen. If the body makes less estrogen, FSH level increases and ovulation is stimulated. Letrozole was originally developed for breast cancer treatment, as certain types of breast cancer cells slow their growth in response to decreasing estrogen levels. Letrozole has shown to be particularly helpful for a subset of anovulatory women whose endometrial lining may be thinned out while taking Clomid. As an anti-estrogen, Clomid can limit the development of the endometrial lining, making it difficult for an embryo to implant. For reasons that aren’t quite yet clear, letrozole appears less likely to affect the uterine lining. Furthermore, letrozole has a short life span in the body whereas Clomid can last for 4-6 weeks following an oral dose. Overall, we’re pleased with what we’ve seen so far with the medication and we look forward to seeing the outcome of studies that are underway to further assess its efficacy as standard treatment.

– Philip Chenette, MD

In the last ten years or so in the U.S., we have seen an explosion in the number of over-the-counter dietary supplements for all manner of ailments as well as for the promotion of general health. Some are vitamins with well-known beneficial properties. Some are herbal supplements with a history of traditional Chinese medicine yet with little in the way of Western scientific studies to substantiate their use. Many other supplements contain elements and substances with very little known benefit.

Now there are several preparations being marketed to promote fertility. In this article, I chose to review three of the major products being actively marketed for the purposes of improving sperm.

The oldest supplement is ProXeed™. ProXeed™ is a citrus-flavored powder and can be dissolved in juice or other cold beverages. It is recommended by the manufacturer to be taken twice a day. The active ingredients in Proxeed™ are L-carnitine, L-acetyl carnitine and fructose. The cost is approximately $335.00 per 3-month supply.

Fertile One® is a pill that contains L-carnitine, anti-oxidant vitamins (ferulic acid, vitamins C and E, garlic, co-enzyme Q10 and selenium), ginseng root, zinc and B-complex vitamins (B-6, B-12, B-9 and folic acid). Cost is approximately $273.00 per 3-month supply.

FertilityBlend® for Men is a supplement containing L-carnitine, ferulic acid, vitamins E, B6, B12, and the elements selenium and zinc. The cost is only about $80.00 per 3-month supply.

Several studies have shown that the amino acid L-carnitine may promote sperm development. In a recent clinical trial¹, 102 men with low sperm motility were treated with L-carnitine and acetyl L-carnitine. There was a significant correlation between higher levels of carnitine in the seminal (sperm) fluid and better sperm concentration, total sperm count, sperm total motility, rapid forward progression, live sperm count, membrane function, nuclear DNA integrity, capacity for cervical mucus penetration, linearity of spermatic movement, and amplitude of lateral sperm head movement after 3 and 6 months of L-carnitine/acetyl L-carnitine treatment. Another high quality study, a randomized, placebo-controlled trial of L-carnitine and acetyl L-carnitine showed that after 6 months of treatment increases were seen in all sperm parameters and the most significant improvement in sperm motility was present in patients who had lower initial absolute values of motile sperm (<4 million forward or <5 million total motile spermatozoa per ejaculate)². There are no published randomized controlled trials looking at pregnancy rates on L-carnitine.

Several studies on the B Vitamins have been published showing anti-oxidant effects and virtually all find some benefit to the addition of this group to a daily vitamin regimen.

Ferulic acid is found in various medicinal herbs, has recently been shown to scavenge oxygen free radicals and increase the intracellular cAMP and cGMP (energy molecules). The only published article on ferulic acid involved adding this substance to previously ejaculated sperm specimens where it was shown to improve sperm motility³. A medline search did not reveal any studies on sperm after ingestion of ferulic acid.

It is interesting that Fertile One® contains garlic; at least one study has reported an inhibitory effect on garlic on sperm motility and survival in human and mouse sperm⁴ and crude extracts of garlic bulbs have been shown to immobilize ram sperm and are being investigated as a potential male contraceptive⁵.

Selenium is a trace mineral that is incorporated into several anti-oxidant proteins. It has been shown to improve human sperm parameters⁶ and fertility improved slightly when selenium-deficient mice were treated with it ⁷. What is not clear is whether most men with a normal diet would be selenium-deficient.

Folic acid supplementation may also be beneficial, especially for men who smoke Cigarettes⁸. Treatment of men with folic acid and 5 mg zinc improved sperm counts by 60% and also improved morphology (shape)⁹. Vitamin E has also been shown to improve sperm parameters and sperm-egg binding¹⁰. Co-enzyme Q10 has been shown in one small uncontrolled study to improve sperm motility in males¹¹ but studies of men with a varicocele (dilated scrotal veins) suggest that high levels of seminal fluid Co-enzyme Q10 are found with men with the lowest sperm motility, suggesting that Co-enzyme Q10 would not be beneficial for men with a varicocele¹².

Considering all these studies, there does seem to be a beneficial role for dietary supplementation for men with low sperm counts and low motility. The supplement marketed as FertilityBlend® for Men has almost all of the most well studied ingredients and is considerably less expensive than the others. Avoidance of garlic extracts and further supplementation with folic acid may also be beneficial.

– Carolyn Givens, MD

References:
1. Correlation between seminal carnitine and functional spermatozoal characteristics in men with semen dysfunction of various origins. De Rosa M, Boggia B, Amalfi B, Zarrilli S, Vita A, Colao A, Lombardi G. Drugs R D. 2005;6(1):1-9.

2. A placebo-controlled double-blind randomized trial of the use of combined l-carnitine and l-acetyl-carnitine treatment in men with asthenozoospermia. Lenzi A, Sgro P, Salacone P, Paoli D, Gilio B, Lombardo F, Santulli M, Agarwal A, Gandini L. Fertil Steril. 2004 Jun;81(6):1578-84.

3. Effects of ferulic acid on fertile and asthenozoospermic infertile human sperm motility, viability, lipid peroxidation, and cyclic nucleotides. Zheng RL, Zhang H. Free Radic Biol Med. 1997;22(4):581-6.

4. Spermicidal effect in vitro by the active principle of garlic. Qian YX, Shen PJ, Xu RY, Liu GM, Yang HQ, Lu YS, Sun P, Zhang RW, Qi LM, Lu QH. Contraception. 1986 Sep;34(3):295-302.

5. Sperm immobilization activity of Allium sativum L. and other plant extracts. Chakrabarti K, Pal S, Bhattacharyya AK. Asian J Androl. 2003 Sep;5(3):230.

6. Male fertility is linked to the selenoprotein phospholipid hydroperoxide glutathione peroxidase. Foresta C, Flohe L, Garolla A, Roveri A, Ursini F, Maiorino M. Biol Reprod. 2002 Sep;67(3):967-71.

7. Sperm oxidative stress and the effect of an oral vitamin E and selenium supplement on semen quality in infertile men. Keskes-Ammar L, Feki-Chakroun N, Rebai T, Sahnoun Z, Ghozzi H, Hammami S, Zghal K, Fki H, Damak J, Bahloul A. Arch Androl. 2003 Mar-Apr;49(2):83-94.

8. Low seminal plasma folate concentrations are associated with low sperm density and count in male smokers and nonsmokers. Wallock LM, Tamura T, Mayr CA, Johnston KE, Ames BN, Jacob RA. Fertil Steril. 2001 Feb;75(2):252-9.

9. Effects of folic acid and zinc sulfate on male factor subfertility: a double-blind, randomized, placebo-controlled trial. Wong WY, Merkus HM, Thomas CM, Menkveld R, Zielhuis GA, Steegers-Theunissen RP. Fertil Steril. 2002 Mar;77(3):491-8.

10. A double-blind randomized placebo cross-over controlled trial using the antioxidant vitamin E to treat reactive oxygen species associated male infertility. Kessopoulou E, Powers HJ, Sharma KK, Pearson MJ, Russell JM, Cooke ID, Barratt CL. Fertil Steril. 1995 Oct;64(4):825-31.

11. Coenzyme Q(10) supplementation in infertile men with idiopathic asthenozoospermia: an open, uncontrolled pilot study. Balercia G, Mosca F, Mantero F, Boscaro M, Mancini A, Ricciardo-Lamonica G, Littarru G. Fertil Steril. 2004 Jan;81(1):93-8.

12. Coenzyme Q10: another biochemical alteration linked to infertility in varicocele patients? Mancini A, Milardi D, Conte G, Bianchi A, Balercia G, De Marinis L, Littarru GP. Metabolism. 2003 Apr;52(4):402-

From time to time, PFC conducts clinical research aimed at improving IVF outcomes. Our newest clinical study involves the use of a new contraceptive device for ovum donors. Currently, we prescribe birth control pills to our ovum donors in the month preceding their IVF stimulation. We do this for several reasons.

First, we want to make sure the donor cannot get pregnant in the month prior to IVF at the time she needs to start Lupron. Also, hormonal contraceptives will usually prevent ovulation so that when the donor starts Lupron, there is less of a chance of inducing a cyst from the ovulation follicle. We also use birth control pills to get the donor’s and the recipient’s cycles in sync. Donors must remember to take one pill every day for anywhere from 14 to 35 days (usually 21 days).

A new contraceptive device manufactured by Organon is called NuvaRing. It is already FDA approved for contraception but to our knowledge, has not yet been used in ovum donors prior to IVF. This is a soft silastic ring containing estrogen and progesterone analogs. The patient places the ring in the vagina and removes it after 21 days. The potential advantage is that the donors will not have to remember to take a pill every day and therefore, help avoid any errors in a cycle.

We will be assessing by questionnaire whether or not the donor found the ring to be easy to use and whether or not they would consider using this method for future contraception. Because this is a randomized clinical trial, 15 donors will be randomly assigned to use the ring and 15 will be on our usual birth control pills. Organon will provide the pills or rings free of charge for donors in the study. For more information on NuvaRing and an interactive example of the ring’s flexibility go to www.nuvaring.com

In last month’s Fertility Flash, we introduced readers to the controversy of implicating the immune system in response to repeated IVF failure. In Immunology PART 2 we further describe the types of testing and treatment scenarios that, for the most part, are considered non-evidence-based medical practice.

The majority of reproductive endocrinologists in the U.S. and Europe do not recommend an extensive battery of immunological tests nor is there “immune system” specific treatment after repeated and/or unexplained IVF failures. To clarify, IVF failure is defined as IVF that does not result in a pregnancy.

Because it is frustrating to patients to experience repeated conception failures with no apparent explanation, it is only natural for them to continue seeking answers.

Unfortunately, patients find information on the Internet, which prompts them to seek various tests and treatments, despite the lack of scientific basis. In some cases, these treatment options have been shown to be of no benefit, but patients still seek these in the hope that they might be successful.

It is important to understand that physicians have a limited number of valid tests to perform in these situations. As we continue to understand the biology of embryo development and implantation, we may be able to identify other “valid tests” in the future.

Most of the tests that are included in a typical “immunology” work-up are listed in Table 1. It is important to note that of the battery of tests that purportedly determine immune deficiencies related to infertility, several are standardized for recurrent pregnancy loss (RPL). RPL is defined as three or more consecutive pregnancy losses before 20 weeks gestation. We have noted the tests that are valuable in assessing RPL.

Below are descriptions of the questionable tests and additional treatment options that are administered by a handful of practitioners at great expense to patients. These tests are controversial not only because of their poor predictive value, but also because these laboratory assays are not standardized; the threshold between normal and abnormal/positive and negative differs from one laboratory to another.

The following research studies and medical association positions have negated further consideration of such treatments by the majority of reproductive endocrinologists worldwide.

Antiphospholipid Antibodies (APAs)
Because antiphospholipid antibodies (APAs) have been tied to recurrent pregnancy loss (RPL), particularly anticardiolipin antibodies (ACAs) and the lupus anticoagulant (LAC), medical researchers have investigated the role these antibodies may play in unexplained infertility.

This area has been the focus of several well-conducted studies. Infertile women do show an increased prevalence of phospholipid antibodies. Whether these autoantibodies cause infertility or IVF failure, or are present due to other issues related to infertility, has been the critical question studied.

The controversy surrounding this topic has prompted professional organizations to convene committees to examine the research. The American Society for Reproductive Medicine (ASRM), the world’s largest professional body of reproductive endocrinology and infertility specialists, issued a statement in October 1999 reaffirming that the presence of APA does not affect IVF success.

Anti-sperm antibodies
Reproductive scientists continue to debate whether or not antibodies bound to sperm cause infertility. Fortunately, effective treatments for male factor infertility include intrauterine insemination, IVF, and ultimately intracytoplasmic sperm injection.

Anti-thyroid antibodies
Currently no compelling research data supports the use of routine antithyroid antibody testing in women undergoing assisted reproduction. Data reveals that the prevalence of thyroid antibodies is similar in fertile women and women with unexplained infertility.

Other autoantibodies
There is a lack of compelling evidence that testing for anti-nuclear and anti-smooth muscle antibodies in routine clinical practice is relevant to the diagnosis or treatment of unexplained infertility.

Leukocyte testing (immunophenotyping) for NK Cells
Immunophenotyping for the diagnosis of unexplained infertility or failed IVF lacks strong scientific support. Treatments to correct any presumed leukocyte dysfunction have not demonstrated efficacy in the treatment of infertility, nor for RPL. Very simply, the clinical use of leukocyte testing in fertility practice is not supported by current data.

Treatments
Treatment approaches following such “immunology tests” are similarly of unconfirmed benefit and some may cause harm.

Lymphocyte immune therapy (LIT)
This is a broad-based yet very controversial treatment purporting to improve a woman’s maternal immune tolerance towards her fetus, which necessarily carries dissimilar paternal proteins on the surface of fetal cells. Not only is this therapy expensive, it also has potential serious adverse effects including transfusion reaction, anaphylactic shock and transmission of infection. The US Food and Drug Administration has issued restrictions against transfusion of women with their partner’s white blood cells or cellular products.

Intravenous immune globulin (IVIG)
Intravenous immune globulin treatment has been the subject of several studies. Those by Coulam and DePlacido suggested that women receiving IVIG had improved implantation rates, yet they were too small to be conclusive. A later randomized, controlled study demonstrated that IVIG added no benefit in unexplained recurrent IVF failure.

Steroids
This treatment based on steroids’ immunosuppressive effects has been linked to significant maternal and fetal morbidity. Two randomized, controlled studies revealed that the routine use of steroids was of no benefit to women undergoing IVF treatment. Two additional randomized, controlled studies concluded that steroid therapy in women with RPL did not improve the live birth rate when compared with aspirin or aspirin plus heparin

Aspirin
Treating infertile women with aspirin continues to be debated due to conflicting studies. One randomized, controlled trial found that aspirin did not improve implantation and pregnancy rates in selected women undergoing IVF + ICSI. Yet another randomized, controlled study reported that aspirin significantly improved implantation and pregnancy rates in women undergoing IVF.

Low-dose aspirin is frequently prescribed in IVF cycles to enhance blood flow to the uterus. This is not seen as an immunological issue. The use of low-dose aspirin during pregnancy in cases of RPL has also been shown to improve pregnancy outcome for women with hereditary or acquired blood clotting problems.

Heparin
The therapeutic benefits of heparin are one of the most vociferously debated topics in ART. Some physicians believe that heparin facilitates implantation. Two prospective studies, one randomized and another non-randomized, both showed that combination treatment with aspirin and heparin significantly improved the live birth rate in women with antiphospholipid antibody (APL) syndrome. Antiphospholipid antibody syndrome is a specific entity where the patient has a clinical history with miscarriages (usually second trimester), abnormal clotting events (DVT), various pregnancy complications and various systemic disorders (lupus). A prospective cohort study concluded that aspirin and heparin therapy was of no benefit in APA-positive women undergoing IVF.

Summary
Women suffering from the anguish of unexplained IVF failure may be compelled to take action, even turning to treatment that is not widely accepted in the medical community. These women continue to be presented with testing and treatment cycles by non-specialists as well as a handful of practicing reproductive endocrinologists who appear to be on a mission to defy sound science.

The majority of reproductive endocrinologists worldwide believe the evidence confirms immunology treatments are not valid for unexplained and/or repeated IVF failures. Currently the FDA has issued statements indicating that IVIG and LIT treatment are invalid in the treatment of infertility, unless administered in the context of a randomized study, supervised by clinical researchers. We at PFC concur and do not recommend this form of testing or treatment, even if a woman’s options are narrowing.

Note:
This article presents a basic summation of controversial testing and treatment options related to the topic of reproductive failure and immunology. An extensive packet of information, which includes copies of scientific studies and position papers compiled by our team of physicians at Pacific Fertility Center is available upon request. Call 888-834-3095.

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

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

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

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

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

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

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

When a woman is not able to conceive after one or more attempts at IVF with no apparent reason, she may feel heightened anguish. She may then broaden her research efforts with a determined resolve, even exploring unconventional treatments. She may end up considering immunological testing and treatment.

It is easy for patients to scapegoat the body’s immune system when apparently healthy looking embryos fail to implant, or a pregnancy is thwarted for unknown reasons. Autoimmune factors related to recurrent pregnancy loss (RPL) have been fairly well studied, resulting in treatment methods that are relatively standard.

On the other hand, implicating the immune system for repeated IVF failures represents an area of medicine that can be subject to abuse. Practitioners of reproductive endocrinology in the U.S. as well as Great Britain consider this one of the more controversial topics in their field.

There is no shortage of data analyzing the role of immunology in reproductive success or failure. A number of comprehensive studies in the mid- to late1990s were undertaken to identify a potential cause and effect relationship between abnormal immune test results associated with reproductive failure. Yet the tests reached the same conclusions; the most rigorous studies failed to provide a correlation.

Today many years after most reproductive endocrinologists might have thought the topic was put to rest, women with greater research capabilities on the internet who actively seek answers for their fertility problems continue to come across offers of clinical immunological investigations and treatments that lack true scientific basis. As pointed out by the Royal College of Obstetricians and Gynecologists, “Praying to Artemis of Ephesus, a goddess associated with fertility, might be as useful as undergoing some of the fertility tests offered on the Internet”.

The market for potential abuse is considerable, given that nearly 15% of American couples suffer from infertility, 10% of whom suffer from unexplained infertility. Additionally 2% of childbearing women may experience recurrent pregnancy loss or RPL, (generally defined as three or more consecutive pregnancy losses before 20 weeks gestation) and as many as 60% of such RPL will demonstrate no cause. Despite the costs, the lack of scientific evidence and the majority of skeptical practicing reproductive endocrinologists, people nevertheless seek treatment for purported immune imbalances.

Many such patients might be genuinely mixed up, finding it difficult to distinguish potential immunological causes of RPL from failed implantation following IVF procedures. Indeed, there is some evidence that RPL can occur as a result of an imbalance of some immune factors. But RPL is very different than a failed pregnancy at the implantation stage. If patients are given the impression that studies will support unproven treatments, it is understandable that frustrated patients may agree to experimental treatments.

What is clear, however, among the majority of practicing reproductive endocrinologists is the myriad of studies conducted in the 1990s demonstrated a sound scientific approach to the question, and no causal relationship was found. The American Society for Reproductive Medicine (ASRM) also summarized the literature and published an opinion paper concluded scientific evidence is not sufficient to suggest immune therapies are valuable for IVF. The Royal College concurs: “It is clear that the advice given on many sites is strongly influenced by the personal prejudices of doctors practicing non-evidence based medicine. Much of the data they provide has never been exposed to the rigorous scrutiny of peer review. The couples are emotionally vulnerable, and there is currently no scientific evidence to justify the use of these tests and treatments.” Nevertheless, a highly visible, albeit controversial industry exists, comprised of just a handful of practicing physicians and associated laboratories offering panels of immunological tests and subsequent treatment.

Patients are rarely informed that there is no standardized testing methodology among laboratories, so the interpretation of test results (normal, borderline, or abnormal) is frequently inconsistent. If and when therapies are administered, many are designed to modify the immune system (i.e. glucocorticoid treatment, intravenous immunoglobulin, and peripheral leukocyte immunization) or to compensate for the suspected effects of the immune defect (i.e. heparin or aspirin to reduce thrombophilia from thrombogenic autoantibodies).

Given the lack of strong scientific proof of meaningful associations between abnormal immune testing and adverse reproductive outcome, combined with the poor quality of the standards of such tests, PFC physicians maintain a packet of information for our patients who inquire about potential immunological causes to their infertility.

In the next issue of Fertility Flash, we will provide a follow-up article that will include more detailed descriptions of the tests that have been conducted as well as an introductory description of what is considered viable immunological tests and treatments for RPL, versus those that are considered more controversial for repeated IVF failure.

Each year physicians and staff of Pacific Fertility Center attend the annual conference of the American Society for Reproductive Medicine (ASRM), a non-profit member-based organization established for the advancement of reproductive medicine. This gathering draws thousands of professionals from around the world to share advances in the field. Over 1600 abstracts were submitted for inclusion in the 2004 program. Our physicians Drs. Schriock and Chenette, and Lab Director Joe Conaghan have summarized a few topics here, based on the research’s relevance to clinical practice.

Same Success for Single Embryo Transfer
Some countries have mandated single embryo transfers (SET) in order to reduce the high rate of multiple-births from IVF treatment. Sweden’s rule was set into place January 1, 2003. A retrospective study has examined 1664 fresh IVF/ICSI/ET cycles before, during and after the transition to the new policy. Patients were of similar maternal age (mean 33.3-33.4), similar demographic characteristics and embryo quality scores.

The study revealed no difference in overall clinical pregnancy rate (33.3%, 32.8%, 33.8%) among those women studied. (Note that their mean age is less than the average age of PFC’s patients. Age is a key factor in the success or failure of IVF.) But the rate of twinning drastically reduced as a result of the new law prohibiting more than one embryo transfer (8.8% vs. 22.6% prior, and 16.3% during transition to the new policy). Sweden’s new policy appears to be resulting in a significant reduction of multiple births in young patients, while not impacting the overall clinical pregnancy rate.

Obesity Reduces Pregnancy Outcome
An extensive study has revealed that patients with a high body mass index (BMI), the method of measuring normal weight range, face a significant obstacle to getting pregnant. Specifically, researchers at the Beth Israel Deaconess Medical Center in Boston identified a 60% reduction in pregnancy rates in those with high BMI, or very obese, compared to those with a moderate to low BMI.

Researchers analyzed the records of 6,827 fresh non-donor cycles in which patients’ BMI had been recorded. The group was divided into five different weight categories, the maximum being a BMI 35 -39 kg/m2- considered obese. Researchers found no significant difference among participants with respect to the number of mature follicles observed, oocytes retrieved, mature oocytes produced, cycle number per patient and number of embryos transferred. However, they noticed significantly lower implantation rates and clinical pregnancy rates in those with a BMI >35 kg/m2 compared to all other BMI groups.

Progesterone Supplementation Not Needed
A group of researchers at the Carolinas Medical Center in Charlotte examined two groups of IVF patients to determine significant difference in pregnancy rates between those who continued progesterone supplements into the 12th week of pregnancy vs. those who had not. 237 patients categorized as the “long group” received 25mg intramuscular dose of progesterone the day of retrieval followed by a daily dose of 50mg IM until the pregnancy test and then daily through the first trimester. Another group of 121 patients, the “short group” continued same dose progesterone but only until the pregnancy test.

The study revealed similar conception rates for both groups. There was no significant difference in delivery rates when comparing all patients with a positive pregnancy test. However, both groups showed a similar degree of pregnancy loss, but at different times. Researchers concluded that long progesterone supplementation may support early pregnancy development through viability at 7 weeks but does not improve overall survival through the first trimester, showing more of a trend of delaying, not preventing miscarriage. For this reason, progesterone support of early pregnancy does not appear to be justified.

FDA Changes Ahead
Starting in May 2004, the Food and Drug Administration will be taking an active role in overseeing all aspects of health and safety of IVF clinical laboratory procedures, which are currently regulated by states. The changes are expected to increase the number of, and frequency of tests that patients will be required to undergo. Fertility Flash will publish a more extensive summary of this topic and how it will impact rates/procedures at PFC in one of our Spring 2005 issues. If you have any questions in the meantime, feel free to email us.

Drs. Chenette and Schriock attended the 2004 ASRM convention along with Lab Director Joe Conaghan and other PFC staff members. PFC’s medical team is continually evaluating the latest research. Our patients’ welfare is PFC’s first priority. With this in mind, be assured we do not include new technologies and treatments unless they are backed with solid, evidenced-based research.

Each year physicians and staff of Pacific Fertility Center attend the annual conference of the American Society for Reproductive Medicine (ASRM), a non-profit member-based organization established for the advancement of reproductive medicine. This gathering draws thousands of professionals from around the world to share advances in the field. Over 1600 abstracts were submitted for inclusion in the 2004 program. Our physicians Drs. Schriock and Chenette, and Lab Director Joe Conaghan have summarized a few topics here, based on the research’s relevance to clinical practice.Same Success for Single Embryo Transfer
Some countries have mandated single embryo transfers (SET) in order to reduce the high rate of multiple-births from IVF treatment. Sweden’s rule was set into place January 1, 2003. A retrospective study has examined 1664 fresh IVF/ICSI/ET cycles before, during and after the transition to the new policy. Patients were of similar maternal age (mean 33.3-33.4), similar demographic characteristics and embryo quality scores.

The study revealed no difference in overall clinical pregnancy rate (33.3%, 32.8%, 33.8%) among those women studied. (Note that their mean age is less than the average age of PFC’s patients. Age is a key factor in the success or failure of IVF.) But the rate of twinning drastically reduced as a result of the new law prohibiting more than one embryo transfer (8.8% vs. 22.6% prior, and 16.3% during transition to the new policy). Sweden’s new policy appears to be resulting in a significant reduction of multiple births in young patients, while not impacting the overall clinical pregnancy rate.

Obesity Reduces Pregnancy Outcome
An extensive study has revealed that patients with a high body mass index (BMI), the method of measuring normal weight range, face a significant obstacle to getting pregnant. Specifically, researchers at the Beth Israel Deaconess Medical Center in Boston identified a 60% reduction in pregnancy rates in those with high BMI, or very obese, compared to those with a moderate to low BMI.

Researchers analyzed the records of 6,827 fresh non-donor cycles in which patients’ BMI had been recorded. The group was divided into five different weight categories, the maximum being a BMI 35 -39 kg/m2- considered obese. Researchers found no significant difference among participants with respect to the number of mature follicles observed, oocytes retrieved, mature oocytes produced, cycle number per patient and number of embryos transferred. However, they noticed significantly lower implantation rates and clinical pregnancy rates in those with a BMI >35 kg/m2 compared to all other BMI groups.

Progesterone Supplementation Not Needed
A group of researchers at the Carolinas Medical Center in Charlotte examined two groups of IVF patients to determine significant difference in pregnancy rates between those who continued progesterone supplements into the 12th week of pregnancy vs. those who had not. 237 patients categorized as the “long group” received 25mg intramuscular dose of progesterone the day of retrieval followed by a daily dose of 50mg IM until the pregnancy test and then daily through the first trimester. Another group of 121 patients, the “short group” continued same dose progesterone but only until the pregnancy test.

The study revealed similar conception rates for both groups. There was no significant difference in delivery rates when comparing all patients with a positive pregnancy test. However, both groups showed a similar degree of pregnancy loss, but at different times. Researchers concluded that long progesterone supplementation may support early pregnancy development through viability at 7 weeks but does not improve overall survival through the first trimester, showing more of a trend of delaying, not preventing miscarriage. For this reason, progesterone support of early pregnancy does not appear to be justified.

FDA Changes Ahead
Starting in May 2004, the Food and Drug Administration will be taking an active role in overseeing all aspects of health and safety of IVF clinical laboratory procedures, which are currently regulated by states. The changes are expected to increase the number of, and frequency of tests that patients will be required to undergo. Fertility Flash will publish a more extensive summary of this topic and how it will impact rates/procedures at PFC in one of our Spring 2005 issues. If you have any questions in the meantime, feel free to email us.

Drs. Chenette and Schriock attended the 2004 ASRM convention along with Lab Director Joe Conaghan and other PFC staff members. PFC’s medical team is continually evaluating the latest research. Our patients’ welfare is PFC’s first priority. With this in mind, be assured we do not include new technologies and treatments unless they are backed with solid, evidenced-based research.


Each year physicians and staff of Pacific Fertility Center attend the annual conference of the American Society for Reproductive Medicine (ASRM), a non-profit member-based organization established for the advancement of reproductive medicine. This gathering draws thousands of professionals from around the world to share advances in the field. Over 1600 abstracts were submitted for inclusion in the 2004 program. Our physicians Drs. Schriock and Chenette, and Lab Director Joe Conaghan have summarized a few topics here, based on the research’s relevance to clinical practice.Same Success for Single Embryo Transfer
Some countries have mandated single embryo transfers (SET) in order to reduce the high rate of multiple-births from IVF treatment. Sweden’s rule was set into place January 1, 2003. A retrospective study has examined 1664 fresh IVF/ICSI/ET cycles before, during and after the transition to the new policy. Patients were of similar maternal age (mean 33.3-33.4), similar demographic characteristics and embryo quality scores.

The study revealed no difference in overall clinical pregnancy rate (33.3%, 32.8%, 33.8%) among those women studied. (Note that their mean age is less than the average age of PFC’s patients. Age is a key factor in the success or failure of IVF.) But the rate of twinning drastically reduced as a result of the new law prohibiting more than one embryo transfer (8.8% vs. 22.6% prior, and 16.3% during transition to the new policy). Sweden’s new policy appears to be resulting in a significant reduction of multiple births in young patients, while not impacting the overall clinical pregnancy rate.

Obesity Reduces Pregnancy Outcome
An extensive study has revealed that patients with a high body mass index (BMI), the method of measuring normal weight range, face a significant obstacle to getting pregnant. Specifically, researchers at the Beth Israel Deaconess Medical Center in Boston identified a 60% reduction in pregnancy rates in those with high BMI, or very obese, compared to those with a moderate to low BMI.

Researchers analyzed the records of 6,827 fresh non-donor cycles in which patients’ BMI had been recorded. The group was divided into five different weight categories, the maximum being a BMI 35 -39 kg/m2- considered obese. Researchers found no significant difference among participants with respect to the number of mature follicles observed, oocytes retrieved, mature oocytes produced, cycle number per patient and number of embryos transferred. However, they noticed significantly lower implantation rates and clinical pregnancy rates in those with a BMI >35 kg/m2 compared to all other BMI groups.

Progesterone Supplementation Not Needed
A group of researchers at the Carolinas Medical Center in Charlotte examined two groups of IVF patients to determine significant difference in pregnancy rates between those who continued progesterone supplements into the 12th week of pregnancy vs. those who had not. 237 patients categorized as the “long group” received 25mg intramuscular dose of progesterone the day of retrieval followed by a daily dose of 50mg IM until the pregnancy test and then daily through the first trimester. Another group of 121 patients, the “short group” continued same dose progesterone but only until the pregnancy test.

The study revealed similar conception rates for both groups. There was no significant difference in delivery rates when comparing all patients with a positive pregnancy test. However, both groups showed a similar degree of pregnancy loss, but at different times. Researchers concluded that long progesterone supplementation may support early pregnancy development through viability at 7 weeks but does not improve overall survival through the first trimester, showing more of a trend of delaying, not preventing miscarriage. For this reason, progesterone support of early pregnancy does not appear to be justified.

FDA Changes Ahead
Starting in May 2004, the Food and Drug Administration will be taking an active role in overseeing all aspects of health and safety of IVF clinical laboratory procedures, which are currently regulated by states. The changes are expected to increase the number of, and frequency of tests that patients will be required to undergo. Fertility Flash will publish a more extensive summary of this topic and how it will impact rates/procedures at PFC in one of our Spring 2005 issues. If you have any questions in the meantime, feel free to email us.

Drs. Chenette and Schriock attended the 2004 ASRM convention along with Lab Director Joe Conaghan and other PFC staff members. PFC’s medical team is continually evaluating the latest research. Our patients’ welfare is PFC’s first priority. With this in mind, be assured we do not include new technologies and treatments unless they are backed with solid, evidenced-based research.

My story has a very happy ending. And I’ll start with the ending first. My husband and I have a beautiful girl who will turn two in September and are pregnant with our second child who is due late this year. We feel that this would not have been possible without the expertise of a fertility specialist and, specifically, Dr. Givens.

Four years ago my husband and I decided that we were finally ready to have children. We had been together for over ten years. When we decided to start to try to get pregnant and I stopped taking the pill, we anticipated it might take a few months for my period to start and my cycle to become regular. After many months, I had not had my period and was still not pregnant. Still, we optimistically had sex, thinking that I might get pregnant even without having my period. We had heard and read that it was possible. More months went by. I spoke to my gynecologist who said that it might take a while. Still more months went by.

After almost a year, I went back to my gynecologist to try to uncover what was going on. She advised that I could start taking Clomid to assist with the pregnancy. My understanding was that I would not be able to take Clomid indefinitely until I got pregnant, and I wanted to understand the underlying problem and diagnose it before I started taking drugs. Luckily for us, I had a family member who was able to advise us to seek help from a fertility specialist and even found out the names of the top specialists in San Francisco. I then found out that before I could see one, I would need to jump through a series of hoops. The first one was to try to get my doctor to identify the right tests I would need to take to get the referral to the specialists. After many phone calls to my doctor’s office and insurance company, I was finally able to identify and take the right tests. This took a couple of more months, after which I was diagnosed with polycystic ovarian syndrome.

The diagnosis was frightening to me at first. As it turned out, I had a mild case, and it did not interfere with my ability to get pregnant. Rather, Dr. Givens identified a very simple but elegant way to help me. She prescribed Clomid and monitored my ovulation. I was not able to detect ovulation with a home test, but Dr. Givens could see the egg maturing with ultrasounds. At the critical point, when I was about to ovulate, Dr. Givens prescribed a shot of HCG and said that my husband and I could have intercourse in the next 48 hours. It worked. This same approach worked with both pregnancies on the first cycle. We are fortunate to have found an excellent doctor and cannot underestimate the power of the expertise of Dr. Givens.

– LK (name withheld upon author’s request)

Once women with polycystic ovarian syndrome are successfully induced to ovulate with medications such as Clomid, it is likely that pregnancy will follow, if all else is normal. Sometimes Clomid alone will not work and ultrasound monitoring and appropriate timing of hCG injections will complete the ovulatory process. My patient, LK, is young and she only needed a little extra help to ovulate. She was very fortunate to conceive on the first try with both of her pregnancies. It is more typical that it may take 3-6 cycles of ovulation induction to achieve a pregnancy. Nonetheless, we are delighted that LK was able to have her family with a relatively low-tech approach.

– Carolyn Givens, MD

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

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

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

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

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

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

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

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

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

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

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

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

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

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