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Infertility eNews Fall 2013


Ovulation Induction Agents in Women with PCOS Provides Effective Treatment

By Rebecca Flyckt, MD

Ovulation disorders represent 20 percent of female infertility. These patients typically describe unpredictable bleeding patterns and/or cycle intervals greater than 35 days. These reports usually signal underlying oligoovulation, defined as irregular or infrequent ovulation, or, less commonly, anovulation, defined as the absence of ovulation. The majority of patients with ovulation disorders will ultimately be diagnosed as having polycystic ovarian syndrome (PCOS) -- the presence of at least two of the following signs and symptoms:

  • Oligoovulation or anovulation
  • Clinical evidence of elevated androgens
  • Polycystic-appearing ovaries on ultrasound

Fortunately, ovulatory dysfunction is amenable to treatment and remains one of the more correctable causes of infertility. The majority (up to 85 percent) of patients will ovulate in response to oral medications, such as antiestrogens (clomiphene citrate/Clomid) or aromatase inhibitors (letrozole/Femara), and up to 40 percent of these patients will conceive.

Initial treatment

In the initial treatment of ovulatory disorders due to PCOS, clomiphene citrate is an FDA-approved oral medication with few side effects and documented efficacy over many decades of use. Doses larger than 50 milligrams daily for a five-day course are often not needed, and the lowest dose required to achieve ovulation is preferred. Unnecessary increases in the dose carry the risk of thinning the endometrial lining and altering cervical mucous adversely. Common side effects include hot flashes, abdominal discomfort and breast tenderness. The risk of multiple pregnancy (twins or higher) is about 9 percent. In contrast to controlled ovarian hyperstimulation, the risk of ovarian hyperstimulation syndrome with oral agents is minimal. Most prescribers limit clomiphene use to four to six months due to decreased efficacy as well as the concern for ovarian neoplasms with less than 12 months exposure.

An alternative agent

In the past decade, the use of letrozole as an alternative agent for ovulation induction has risen. In contrast to clomiphene, it is not FDA approved for ovulation. Letrozole is, however, free of adverse antiestrogenic effects on the endometrium and cervical mucous and appears to have similar efficacy to clomiphene. Side effects of letrozole are very rare at doses of 2.5 to 5 milligrams daily for five days, but can include hot flashes, nausea and headaches. The concern with aromatase inhibitors relates to an early report of possible fetal toxicity/malformations; this risk has not been substantiated by any subsequent publications on the topic.

In the past, metformin was used liberally in oligoovulatory PCOS patients. In more recent large trials, the use of metformin in patients with PCOS did not appear to increase the live birth rate when administered with clomiphene citrate or as a single agent. Metformin is generally not used in our practice unless there is documented abnormal glucose tolerance test, hemoglobin A1C or fasting glucose.

In summary, oral agents such as clomiphene and letrozole are relatively inexpensive, easy to administer, and effective in treating fertility due to PCOS and ovulatory dysfunction. For refractory cases, fertility specialists can assist with more advanced techniques, such as injected gonadotropins, laparoscopic ovarian drilling and in vitro fertilization to achieve ovulation and pregnancy in these patients.

For more information, contact Dr. Flyckt at 216.839.3100 or flyckr@ccf.org.


Embryoscope Adds Precision to In Vitro Fertilization

By Nina Desai, PhD, HCLD

The health risks for both patient and fetus associated with high-order multiple pregnancy has spearheaded a movement to limit the overall number of embryos transferred during in vitro fertilization (IVF) to just two for young patients.

During IVF, patients undergo a surgical procedure to extract oocytes. The oocytes are subsequently inseminated or directly injected with sperm to create embryos. The average young patient generates eight to 15 embryos per IVF cycle.

Embryo selection for transfer is based on critical assessment of morphologic parameters during embryonic development. Currently, these morphological assessments are limited to once a day at set times, since repeated removal of embryos from the incubator environment for observation may result in undesired temperature and pH shifts in the embryo culture dish.

Embryo development is a dynamic event. Static observations on embryonic growth can therefore be limiting in their ability to discern differences between embryos at a similar cell stage. Numerous data suggest that the timing of specific events such as pronuclear formation, syngamy, early cleavage, compaction and cavitation are indicators of an embryo’s developmental potential. The ability to continuously monitor an embryo’s progression toward these benchmarks may therefore aid in selecting the best embryos for uterine transfer.

The New Tool: EmbryoScope – An Incubator with Eyes

The EmbryoScope (Unisense ® Fertilitech, Rockland, Va.) is a new FDA –cleared incubator with a built-in camera that allows continual observation of embryos using time-lapse imaging. This special incubator and the software to simultaneously analyze and contrast developmental benchmarks for up to 72 embryos at a time (six patients with 12 embryos per dish) is a powerful new tool for the IVF laboratory. This instrument will also contribute to our understanding of early events in preimplantation embryo development and identification of new grading criteria that may be more predictive of implantation potential. The EmbryoScope also provides a safe, controlled environment for human embryo cultivation without disturbance.

Promising Early Results

We initiated a study in April 2012 to measure the effectiveness of the EmbryoScope in the clinical IVF laboratory. The study had three primary objectives: (1) to collect data on embryo development using continuous embryo monitoring, (2) to determine if kinetic data in conjunction with conventional grading criteria could be used to identify high-quality embryos, and (3) to determine if there are specific events or cleavage patterns that are more often associated with embryos leading to pregnancy or in vitro blastocyst formation.

Patients under 39 years of age with 10 or more mature oocytes and/or at least eight embryos were offered the opportunity to participate in this study. A total of 81 patients were enrolled. Embryo selection for transfer was based on conventional criteria.

Culture in the EmbryoScope yielded a wealth of information on normal growth patterns and cleavage anomalies, as well as high pregnancy outcomes. The results showed that the clinical pregnancy rate for patients having a Day 5 transfer was 72 percent (41/57) vs. 65 percent (13/20) for those having a Day 3 transfer.

Morphokinetic data indicated significant differences in timing of specific cellular events in embryos leading to formation of high-quality blastocysts and ultimately pregnancy. The laboratory is now using some of these morphokinetic criteria to aid in embryo selection for transfer with the hope of further increasing pregnancy rates and ultimately reducing the number of embryos being transferred.

For more information, contact Dr. Desai at 216.839.2907 or desain@ccf.org.


Surgical Management of PCOS

By Jeffrey M. Goldberg, MD

Laparoscopic ovarian drilling (LOD) is an alternative to ovulation induction with gonadotropins for polycystic ovarian syndrome (PCOS) patients unresponsive to clomiphene. It is quick and easy to perform, and its advantages include shortening the interval to pregnancy, obviating the need for ovulation inducing medications, and assisting in the diagnosis of anatomic factors.

The mechanism of LOD is unclear, but it is likely mediated by an increase in intraovarian androgen production. Serum luteinizing hormone and testosterone levels are rapidly normalized and these changes are often sustained over long-term follow-up. Studies have shown that ovulation and pregnancy rates are comparable between ovulation induction with gonadotropins and LOD, but LOD avoids the risks of multiple pregnancy and ovarian hyperstimulation syndrome. LOD is also more cost-effective and better tolerated than gonadotropin therapy. Further, studies indicate a patient preference for treatment with LOD over gonadotropin therapy.

Performing LOD

LOD is performed using the standard two or three incision laparoscopic approach. A unipolar electrocautery needle is used to puncture the ovary at a right angle to a depth of approximately 8 mm. The punctures are placed evenly around the ovary taking care to avoid the hilum, thereby averting bleeding and avoiding the risk of compromised ovarian blood supply.

To date, there is no standard number of punctures or dose /duration of energy delivered to the ovary for optimal results with minimal risk. In general, 4 to 10 punctures are made in one or both ovaries. A reasonable power setting is 40W for each puncture for a duration of two to four seconds.

According to numerous studies conducted over the past two decades, women who had greater than five punctures per ovary were more likely to ovulate than women who had three punctures per ovary. However, each procedure should be individualized, employing the minimum number of punctures possible relative to the size of the ovary to reduce the risk of postoperative adhesion formation or diminished ovarian reserve.

Measures of Success: Ovulation and Pregnancy

Approximately 70 to 80 percent of CC-resistant PCOS patients ovulate following LOD. Widely variable rates of pregnancy have been reported following LOD, with most estimates between 50 and 80 percent within one year of the procedure. LOD may also reduce the higher rate of spontaneous abortion inherent in PCOS patients. Normalization of hyperandrogenemia has the additional benefits of improving the clinical signs of acne and hirsutism.

In summary, LOD is a one time minimally invasive procedure that provides high ovulation and pregnancy rates while eliminating the risks and inconvenient daily injections and frequent office visits required for gonadotropin treatment.

For more information, contact Dr. Goldberg at 440.519.6960 or goldbej@ccf.org.


Freezing Eggs — The New Standard in Preserving Women’s Fertility

Freezing unfertilized eggs has been an investigational procedure since 2003. Patients needed to sign a consent form acknowledging the procedure was investigational. Last fall, the American Society for Reproductive Medicine declared egg freezing a first-line fertility treatment, clearing the way for more women and couples to pursue it.

Studies have shown that in vitro fertilization (IVF) with frozen eggs produces similar rates of pregnancy and healthy babies as IVF with fresh eggs.

Much of the credit goes to a recent advance in cryobiology called vitrification. Vitrification is a flash-freezing technique that doesn’t cause damaging ice crystals to build up inside egg cells, which was more likely with slower conventional freezing.

Cleveland Clinic's IVF laboratory was a pioneer in using vitrification to freeze 6- to 8-cell embryos and now uses it for freezing all embryos.

Why Freeze Eggs Instead of Embryos?

“The benefit of freezing eggs is that you don’t have to fertilize them,” says Cynthia Austin, MD, Director of Cleveland Clinic’s IVF Program. “That can be appealing to, say, cancer patients who want to preserve their fertility for after their cancer treatments, or women in their early 30s who don’t have a partner and want to delay childbearing.”

Freezing unfertilized eggs also helps patients avoid the ethical dilemma of what to do with embryos they don’t use.

“It’s also easier to donate frozen eggs instead of trying to align the cycle of the donor with the cycle of the recipient at the time the eggs are made,” says Dr. Austin.

Target Age: 32 to 34

Freezing eggs is no guarantee that a woman will be able to get pregnant, however. Eggs don’t have the same potential that embryos do, notes Dr. Austin. Some may not survive the freeze. Some may not fertilize, because not all eggs do. Some may make hardier embryos than others.

“Out of eight eggs, we may only get three or four embryos,” says Dr. Austin.

And when it comes to freezing eggs, the biological clock is still ticking.

According to Dr. Austin, ages 32 to 34 are the best time to freeze eggs. (Younger women typically have no reason to freeze eggs because they still have time to pursue pregnancy without IVF.)

“As women get older, the quantity and quality of their eggs decrease,” says Dr. Austin. “By age 40, IVF doesn’t work as well. By age 43, there’s very little we can do to increase a woman’s fertility.”

Cleveland Clinic fertility specialists also offer other fertility preserving options — particularly for women preparing for cancer treatment. For more information, contact the IVF program at 216.839.3150, and select option five.


New OB/GYN Joins Our Staff

Dr. Flyckt is a board-certified OB/GYN with subspecialty training in Reproductive Endocrinology and Infertility. She earned her medical degree from Stanford University School of Medicine in Palo Alto, California. She then returned to her native city of Cleveland to complete residency training in Obstetrics and Gynecology at the University Hospitals of Cleveland followed by fellowship training in Reproductive Endocrinology and Infertility at Cleveland Clinic. Dr. Flyckt is Director of the Fertility Preservation and Cancer Program.

Dr. Flyckt's interests include fertility preservation, in vitro fertilization, reproductive endocrinology and infertility, minimally invasive surgery, endometriosis, fibroids, recurrent pregnancy loss and tubal reversal surgery. Her research interests focus on fibroids and fertility outcomes, uterine factors and reproduction and reproductive surgery.

Dr. Flyckt has published multiple scientific articles, abstracts and book chapters. She is a Fellow of the American College of Obstetrics and Gynecology and is a member of the American Society for Reproductive Medicine and The American Association of Gynecologic Laparoscopists.

To contact Dr. Flyckt, please call 216.839.3100 or flyckr@ccf.org.