PCOS – Where to Turn After Clomid Fails

by Hyacinth Nicole Browne, MD
Associate Medical Director
SIRM-New York/SIRM-Westchester

Should women with PCOS who have failed Clomid do ovulation induction cycles with injectable medications or go straight to in vitro fertilization?

PCOS, also known as polycystic ovarian syndrome, is one of the most common female endocrine disorders.  It affects approximately 5-10% of reproductive age women, and it’s defined as hyperandrogenism and chronic anovulation (absent or infrequent menses).   The infertility associated with PCOS results from a lack of ovulation each month, and to poor egg quality from overexposure of ovarian follicles to male hormones produced by the ovary.  Women with PCOS have ovaries that contain multiple small antral follicles that are thought to be in “follicular arrest,”  but these follicles all have the potential to respond to ovarian stimulation. 

The goal of infertility treatment for women with PCOS is to induce ovulation.  This can be accomplished either through weight loss, oral medications such as Clomid, daily injections of gonadotropins containing FSH (i.e. Gonal-F, Follistim, etc…), or through in vitro fertilization (IVF).   Generally, in vitro fertilization is offered as a last resort for women with PCOS,  because of the higher cost associated with it (unless there’s some other underlying cause for infertility i.e. male factor).  First-line treatment for PCOS generally consists of giving an oral medication called Clomid to induce ovulation.  Up to 80% of women with PCOS will ovulate in response to Clomid, and 50% of women will conceive within the first six ovulatory Clomid cycles.  Increasing the duration of treatment with Clomid adds little to increase pregnancy rates.  When Clomid has failed, ovulation induction with injectable medications, such as FSH, is frequently used as an intermediate step before doing IVF.    

In brief, injectable cycles with medications, such as FSH,  require daily injections for 7 to 20 days and these medications are started early in the menstrual cycle.  Injectable cycles, like IVF,  require close monitoring with ultrasounds and blood tests.  A low dose protocol is generally used, in women with PCOS, to prevent a multi-folliclular response, and the success of treatment ranges from 15-20%  per cycle.  Moreover, the risk of a multiple pregnancy is higher with an injectable cycle than with other forms of infertility treatment (15 to 25% risk of twins, and 5% for triplets or more).  

Even with a low dose protocol in an injectable cycle, it may be hard to get only 1 or 2 follicles to develop in anovulatory women with PCOS.  As a result, this can put one at higher risk for a multiple pregnancy, ovarian hyperstimulation, and even cycle cancellation.  Unfortunately, even with close monitoring or conversion to IVF, the ideal balance between increased pregnancy rates and the risks of multiple pregnancy and ovarian hyperstimulation is unknown.  Given these risks and the high rate of success with IVF, some infertility specialists offer IVF to PCOS patients who have failed Clomid rather than injectable cycles. 

Like an injectable cycle, IVF too requires daily injections and close monitoring and it takes about 4 to 6 weeks to complete.  It is the most effective treatment for infertility associated with PCOS.  Success rates range from 20 to 65% per cycle depending on the age of the woman, and a multi-follicular response is not as worrisome in IVF because an egg retrieval is performed to aspirate excess follicles.  This can sometimes reduce the risk for ovarian hyperstimulation.  Furthermore, in IVF, the risk of a multiple pregnancy depends on the number of embryos that are transferred, which is patient and physician controlled.  However, the number of embryos that implant in an injectable cycle is  harder to predict because all of the mature follicles created during that cycle have the potential to be fertilized.  The only way to prevent this risk is to cancel the cycle.

So, why do infertility specialist offer PCOS patients injectable treatment cycles if IVF is more effective and potentially safer?   I believe this is because it’s less expensive and a simpler alternative to doing IVF.    Some infertile couples also hope for twins,  and they may not fully understand that they also run a risk of having triplets or more from an injectable treatment cycle (i.e. John & Kate Plus 8).   If  IVF was not cost-prohibitive, undoubtedly, injectable cycles would go by the way-side and would not be an acceptable option to most. Understanding this, we at SIRM offer our patients a very low-cost version if IVF (“micro-IVF”) that enables them to reap the enhanced efficacy of IVF without the high costs. We can do this because women with PCOS don’t need extended or complicated protocols, nor do they need much medication to achieve a nice response in terms of egg number.

In general, when a PCOS patient who has failed Clomid comes to our Manhattan or Westchester fertility clinic, I  recommend IVF as their next step.  It’s not always an easy conversation to have with patients, because some couples are just not ready for the emotional and financial commitment associated with doing an IVF cycle.  However, I find it to be easier and less frustrating for all, when the possibility of having to do an IVF cycle is introduced earlier on after there has been a thorough discussion about the risks associated with treating this disorder.  In the end, offering IVF to patients who have failed Clomid seems to be a better alternative to canceling an injectable cycle and forfeiting a patient’s time and means.

Gender Selection – Which Method is Best?

Walid Saleh, MD
Medical Director, Sher Institute Dallas IVF

Many of us know someone who desperately wants to have a girl — or a boy. Perhaps a couple has several children of one gender already and would like to have another child, but would only consider doing so if the 50/50 odds could be shifted in favor of the other gender. Or, perhaps a couple is seeking infertility treatment, already has one child, and would prefer that the next child is the other gender.  As a Dallas fertility doctor, I see quite a number of couples that fall into this category.

Couples have sought to influence the gender of their children for thousands of years.  Many speculative methods of gender selection have been tested, such as timing of intercourse, conception positions, or placing live sperm on an albumin gradient (Erickson method). Unfortunately, none of these methods has been shown to be scientifically valid.

There are currently several valid methods of gender selection available.  The first method, known as MicroSort®, is an FDA approved, patented, preconception sex selection process that involves sorting the sperm into those that bear a “male” vs. “female” chromosome.  As a background, when a sperm with a Y chromosome fertilizes an egg (all eggs bear an X chromosome), it makes a “boy” (XY) embryo. When an X-chromosome-bearing sperm fertilizes an egg, it makes a “girl” (XX) embryo. MicroSort uses a machine called a flow cytometer to sort sperm such that the sorted sperm population is enriched in either X (female) or Y (male) bearing sperm, depending on the desired gender.  Microsort is generally used in conjunction with intrauterine insemination (IUI). It is possible to use sorted sperm for IVF, but not very logical as I’ll explain later. 

There are a number of hurdles to clear when considering using Microsort.  First, couples that wish to use this proprietary technology must meet the following requirements:

• They must be married
• The woman must be between the ages of 18 and 39
• They must be undergoing gender selection because of the presence of a gender-linked disease, or for “family rebalancing” (meaning that they must already have a child of the opposite gender for which they are selecting). 
• They must fly to Virginia or California on a moment’s notice (based on an ovulation predictor kit) and undergo the IUI onsite at one of two facilities in the country where it can be performed.

Success rates in achieving the desired gender are approximately 88% when seeking a female, and 74% percent for a male.  Since MicroSort is still considered as being in its clinical trial phase, actual verifiable pregnancy rates are not available.

Conceiving with Microsort is no easy task either. Considering the cost of the procedure itself (approximately $3,000 per sorted sample, plus the costs of IUI), the accuracy of the sorting method, the natural IUI conception rate of 20% per month, and the travel costs involved, Microsort can easily become the least cost-effective method.

So, is there a better method?  By far, the most effective and accurate method of gender selection is In Vitro Fertilization (IVF) using preimplantation genetic diagnosis (PGD).  Using this method, gender selection is almost 100% accurate and pregnancy rates are quite high.  Even higher pregnancy rates are now possible using a more recent technology called CGH.  Traditional PGD using a method known as FISH tests for gender, Down’s syndrome and a few more anomalies, while CGH tests for all 23 chromosomes. With traditional PGD, two embryos have to be transferred to reach a 60% live birth rate per embryo transfer, whereas using CGH, similar pregnancy rates can be achieved using a single healthy embryo. This is particularly attractive to couples that want to avoid the risk of twins.

As I mentioned earlier, MicroSorted sperm can be used with IVF, though I have not found this additional sorting useful. And at a cost of more than $3,000 on top of IVF cycle costs, travel, freezing, etc., it surpasses the cost of PGD/CGH, which is substantially more accurate and has the additional benefit of screening for chromosomal abnormalities.  In addition, patients utilizing MicroSorted sperm must travel to the Virginia or California office for their IVF procedure if using fresh sperm.  If using frozen sperm, they must use an authorized MicroSort affiliated clinic for their IVF procedure.

The bottom line, in my opinion, is that IVF utilizing PGD/CGH is the superior method for gender selection in terms of accuracy, success rates and cost.  At SIRM Dallas, IVF via PGD for family rebalancing is available to all couples, regardless of marital status or age.

Male Infertility – Basic Diagnosis

by Peter Ahlering, MD
Medical Director, SIRM St. Louis

It wasn’t that long ago that men weren’t thought to have a “biologic clock.” It also wasn’t that long ago that the only assessment of male fertility thought to be important was the sperm count. It was believed that if there was a good number of sperm then everything on the male side was fine. This certainly isn’t the case anymore.

It’s well known that age affects male factor fertility as do many other things including environmental exposures such as smoking, exposure to toxic chemicals, and obesity.  In addition, some jobs are known to increase the risk of sperm and testicular dysfunction in men, for example, farmers, chemical handlers, those exposed to low-level radiation over time, etc. Further, even the area of the country in which one lives might affect fertility in men, e.g., rural inhabitants/workers or those living in densely populated urban areas.

Since many of these factors don’t affect the traditional parameters of sperm count or motility, which are typically assessed on a semen analysis, this analysis is now inadequate as a good measure of male fertility potential. These environmental exposures, age, occupation, etc., affect sperm largely on a qualitative level. These factors can alter DNA constitution as well as chromatin integrity. We can now measure these with several different tests from a single semen sample. Therefore, the male factor assessment now looks at quantitative aspects (count and motility) as well as qualitative aspects, which are, relatively speaking, more influential as independent predictors of fertility potential. 

The measures that are most commonly examined and clinically valuable in helping patients determine treatment options as well as success of those options include DNA fragmentation, high DNA stainability and high-resolution morphologic assessment of the sperm. All of these tests in addition to count and motility can be done on a single semen sample and currently are the optimal assessment for determining male fertility potential.

However, these tests aren’t available at just any laboratory or hospital, but are easy to obtain through physicians’ offices and reproductive specialist centers that take interest in male testing (including our St. Louis fertility clinic). Even if the sperm count is within the normal range on basic analysis, significant abnormalities can be discovered by these other tests, obviously influencing fertility. I believe that men seeking fertility treatment with their partners, or men who are in high-risk situations through occupation or environmental exposure should be screened with these simple tests.

I encourage you to bring these things up with your physician or seek further information by contacting us. The majority of treatment decisions are based upon diagnostic information from a medical standpoint. Obtaining the proper information regarding male and female fertility factors that play a role is of utmost importance.

Understanding the fundamentals of what makes fertility possible is key. These include: the uterus, ovaries and sperm. These are the foundations of what makes a baby and successful pregnancy. While the female side is quite important, remember that just because sperm count is ‘good’, there may be other issues on the male side.

The diagnostic evaluation is geared toward understanding these influences. Unfortunately, often a suboptimal evaluation is relied upon, making the subsequent treatment less effective or worse,  inappropriate. Once these issues are understood, the patient/couple can make intelligent, informed decisions about what treatment options are available, the projected treatment option’s success, and what treatment option best suits them. Once the treatment option is chosen, the last question is, “when do we proceed with treatment?”  In fertility testing, we’re simply trying to answer a series of questions, including:

• What are the problems that are affecting fertility adversely? Meaning, what medical problems exist for this couple?
• What are the treatment options available?
• What are the chances, given the current set of circumstances and problems, of any treatment resulting in ongoing pregnancy?
• How do we best pursue the treatment and manage it to optimize a positive outcome?
• What are the costs of these treatment options?
• When can we initiate treatment?

Hopefully, understanding this basic information and the “ground rules” is helpful. By understanding the concepts of female AND male fertility, we go a long way in understanding how to address infertility issues on a case-by-case basis.

Bad Air and Bad IVF Outcomes?

By Drew Tortoriello, MD 

It is a sad reality that we currently know of no environmental modifications that can actually improve upon our genetically determined baseline fertility, while there are very many things that one be exposed to, either voluntarily or unknowingly, which can significantly impair fertility.  Case in point: the air we breathe.  A study recently published in the journal Human Reproduction has implicated air pollution, and in particular the contaminant nitrogen dioxide, as a risk factor for IVF failure.  (Nitrogen dioxide is a waste product from fossil fuel combustion and is therefore a large pollutant of urban, industrialized areas.) In this study, a team of fertility experts analyzed the relationship between ambient air pollutant concentrations and the IVF success rates obtained by more than 7,000 American women from the period 2000 to 2007.  Researcher Dr. Duanping Liao, a professor of epidemiology at Penn State College of Medicine, suggested that this negative association may have arisen from air pollution’s promotion of general inflammation and blood clotting.  

Cigarette smoking is a more personal form of air pollution, and is known to hasten the menopause by close to 2 years.  It also diminishes the fertile period preceding the menopause.  Cigarette smoke contains over 400 known toxins and can directly hasten oocyte death.  The pollutants within cigarette smoke may also hurt fertility by hastening the age-related oocyte fragility that leads to chromosomal abnormalities. One particularly intriguing protein called sirtuin, which has  been documented to promote longevity and minimize the damage associated with inflammation, has been noted to be lower in smokers vs. non-smokers and in chromosomally abnormal vs. normal eggs.

As a physician working in Manhattan, I cannot also help but wonder about the possible fertility issues that may arise down road in those young adults exposed to the fouled air that stemmed from the aftermath of the World Trade Center attacks on September 11.   The dust was identified to contain several compounds known to hurt fertility including polycyclic aromatic hydrocarbons (PAHs); polychlorinated biphenyls, dibenzodioxins, and dibenzofurans; phthalate esters; and brominated diphenyl ethers.  Although fertility issues are currently overshadowed by the numerous other health issues that have arisen from exposure to this dust cloud, it is my sincere hope that the investigation of this aspect of health will not be forgotten.

There may be a glimmer of hope on the horizon with regard to helping delay or minimize the detrimental effects of environmental contaminants in the form of nutritional supplements, and in future blog entries, I will discuss several of these supplements and their known merits.

What is the role of low-stimulation or no-stimulation IVF in infertile couples?

By Drew Tortoriello, MD — Medical Director, SIRM-New York

 Many of my patients, including both IVF veterans and those contemplating IVF for the first time, have asked me this question. A Reproductive Endocrinologist’s answer to this question depends upon which of 2 general philosophies he or she adheres to:

Philosophy one: “The less ovarian stimulation one is subjected to, the better the egg quality will be. In addition, you can avoid the higher costs associated with more medicine and also avoid injections.”  Doctors adhering to this philosophy tend to use no medication, clomiphene citrate pills, or, at most, 75 IU of gonadotropin medication.

Philosophy two: “Most of the eggs a woman can produce in any given month are chromosomally abnormal; therefore the more eggs we can work with, the more likely you will be to obtain a healthy egg to make a healthy baby.”

There are valid points underlying each of these philosophies, but I tend to base my treatment plans on philosophy number two simply because the bulk of the current literature clearly suggests that the best responders have the best pregnancy rates.

Although IVF helps a woman’s chance to conceive in many ways including overcoming most sperm issues through the use of intracytoplasmic sperm injection and the bypassing of dysfunctional tubes, most women derive their real benefit from an enhancement of their odds of producing at least one chromosomally normal (euploid) egg per month. For example, if on average, a 40 year old woman’s odds of producing a euploid egg are about 1 in 10, we theoretically should be able to increase her chances of getting to that normal egg this month by obtaining several more eggs to work with through IVF.   

At the beginning of each menstrual cycle, an ovary will have varying numbers of eggs that are receptive or mature enough to respond to the influence of the gonadotropin hormones (FSH and LH) being secreted by the brain.  This number depends upon many factors, but is mainly predicated by your age.  The brain controls the reproductive hormonal cascade to such a precise degree that only one of these eggs will ultimately be allowed to complete the maturation process which culminates in ovulation. All of the other eggs that are slightly less receptive than the dominant “winner” will die – a process called atresia.  If we administer gonadotropin medications however, we can “rescue” the entire monthly egg cohort and use it for our patients’ benefit.  Therefore, gonadotropin stimulation does not steal eggs from one’s future potential, it merely salvages those that would have been lost to atresia that month.

For all these reasons, I prefer a regular stimulation approach in my patients, and in women with diminished ovarian reserve, I often move early to an aggressive high stimulation approach that frequently incorporates estrogen priming.  It is very important however, to be judicious in the dosage of medications one uses, as too much medication has the potential to lead to great patient discomfort as well as undo the good one is striving for in terms of the obtaining of healthy eggs. 

I reserve the low-stim/no stim approach for women at the extremes of reproductive potential, i.e. younger women with superb ovarian reserve and those with little to no ovarian reserve left.  In the former situation, a low stimulation protocol should still provide a large number of eggs to work with and also minimize the risk of ovarian hyperstimulation syndrome; in the latter case, it doesn’t make sense to do high stimulation protocols, given that the response will probably be identical to that achieved with low-stimulation (one or two eggs at best).

As we speak, studies are ongoing that compare low-stim IVF to regular stim IVF in a prospective fashion. I eagerly await the results to better guide my patient treatments, but I am fairly certain that what we already suspect will be corroborated, namely that with a bit more medication we will make more pregnancies.

- Drew Tortoriello, MD

Welcome to the SIRM Blog!

We are excited to announce the launch of the SIRM blog! This will be a forum where our physicians and embryologists will be posting relevant content and articles on various fertility related topics. You can subscribe to our feed below to get updates everytime we post new content. Stay tuned for the next post!