Back to Basics

Ah, the end of summer. How sad that always made me as a little kid. It meant loading up our station wagon and driving back from Cape Cod after spending the whole summer in West Dennis. It meant no more mini-golf and no more trips to the beach and of course, the beginning of a new school year. Fall was not a favorite of mine as it meant classes and homework and the approach of winter. But times change and now I relish the change in the weather, especially here in DC where August is so hot and humid (pretty much like June and July!). And since I am no longer in school the feeling of dread in the pit of my stomach is not a problem…

So what does this have to do with infertility? Nothing. Well, almost nothing. I just think that with the beginning of a new academic year upon us we should step back and address some basics since we had covered some pretty specific issues in reproductive medicine. So here we go with some of the basic questions from 100 Questions and Answers about Infertility…


2. What is infertility?

Approximately 80% to 85% of couples who are trying to become pregnant will successfully conceive within a year. Thus infertility is commonly defined as the inability to achieve a pregnancy within 12 months of unprotected intercourse. However, certain patients may have recognized factors that would lead to problems conceiving; for them, the 12-month period of waiting would make no sense. Common examples of such women include those who have extremely irregular periods, a history of severe endometriosis, a history of previous tubal pregnancies, or other anatomical factors that would clearly lead to diminished fertility. Such couples are encouraged to seek evaluation for infertility if the woman is older than age 35 and they have been attempting pregnancy for a total of 6 months without success. Another problem related to reproduction is recurrent pregnancy loss. Many women can readily conceive, only to suffer repeated pregnancy losses. These women represent a special subset of those who are unable to successfully reproduce and should be evaluated by a medical professional.

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What's the Plan?

Patients can usually be divided into active and passive subtypes. Active patients read books (like this one), cruise the internet, pepper their RE with questions and engage in extensive discussions of the options available to them. Passive patients look across the desk at us and say “Doctor, you decide what is best.” Although at the end of the day, the active patients can certainly leave you feeling exhausted, I really enjoy these interactions and the challenge of making a treatment plan with them. I worry about the passive patients. Do they really understand what they are doing? Can they justify the treatments that they are pursuing in terms of finances and the emotional/physical/psychological costs of infertility care? If they abdicate all responsibility for the decision making process then I am left on the hot seat.

So when making a plan where do we start? First of all, we consult the “Magic 8 Ball” of fertility care and whatever treatment appears in that little window is what we do…not really. This question is the “Question of the Day” from the book that has yet to generate any interest in Hollywood…although rumor has it that Matt Lauer wants to play me if the movie ever gets made.

18. How will my reproductive endocrinologist determine a plan of therapy?

In general, reproductive endocrinologists recommend a particular course of treatment only after obtaining the results from the full spectrum of fertility tests. These tests usually include a pelvic ultrasound, an assessment of tubal patency (hysterosalpingogram or laparoscopy), a semen analysis, and a variety of blood tests. The therapeutic plan for any couple is unique to them. If testing has demonstrated a clear problem, such as blocked fallopian tubes or a markedly abnormal sperm count, then in vitro fertilization (IVF) may be recommended as the only reasonable alternative.

However, most couples are not sterile but merely subfertile, so they may be offered a range of therapeutic options—from expectant management, to the use of insemination with or without fertility drugs, to IVF with or without intracytoplasmic sperm injection (ICSI). IVF can be performed using the patient’s own eggs, donor eggs, or donor sperm. A couple’s particular therapeutic plan will be developed with their specific needs in mind. For those patients in whom IVF is not an option, whether because of religious, financial, or philosophical reasons, the physician will offer counseling about the alternative treatments available to them. Not all couples are prepared to undergo extensive treatments for their infertility, so their physician will likely tailor the options appropriately when proposing a course of action to a particular couple. Given that infertile couples can sometimes achieve spontaneous pregnancies, the desire of a couple to proceed with therapy needs to be weighed against the likelihood of success for that therapy and the cost involved. These costs may include financial, physical, and emotional considerations.

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Going to Blast! Part 2.

So yesterday we discussed blastocyst transfer in general and today we get down to brass tacks…You know, it amazes me that some of the Residents and Medical Students that I teach do not know some of these quaint little sayings like the one I just used. I have said to them “a watched pot never boils” and received just blank stares. Is this a sign of advancing age on my part or is it because they watched too much TV as kids? I have no idea. All I know is that it still really disturbs me that the 80s music that I listen to in the operating room was released before some of the medical students were born! Yikes.

In any case, back to blast transfer. So how do we choose? That is the “Question of the Day.” So if you are wracked with guilt over reading these questions for free rather than buying the book 100 Questions and Answers about Infertility, then ease your guilty conscience and click over to Amazon.com pronto!



70. My clinic allows me to choose between a day­3 and a day­5 embryo transfer. How do I
decide?

The decision to transfer embryos on day 3 or day 5 is one that requires careful thought. In general, embryos that have formed blastocysts have a better chance of implanting successfully. Unfortunately, not all embryos will progress to the blastocyst stage outside of the body. This inconsistency raises the question as to whether the embryos that fail to form a blastocyst would have initiated pregnancy had they been transferred back into the uterus on day 3. Some studies have, indeed, demonstrated acceptable pregnancy rates with day-3 transfers of embryos that were of marginal quality and that, based on historical data, would have been unlikely to form blastocysts in culture. Clearly, the pregnancy rate in the absence of an embryo transfer will be zero, whereas even embryos of borderline quality, if transferred on day 3, may potentially lead to a pregnancy.

So how can you decide between a day-3 and a day-5 embryo transfer? Many clinics make the decision on day 3. If a patient has a certain number of high-quality embryos on day 3, then the embryos are maintained in culture for 2 additional days to allow for further embryo selection at the time of transfer. If the embryos fail to progress to the blastocyst stage, however, then there is no transfer—which often results in profound patient disappointment. If a limited number of embryos are available on day 3 and no embryo selection is needed, then the benefit of a day-5 embryo transfer may be limited.

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Going to Blast!

“Going to blast” is different than “having a blast.” When your RE talks about going to blast he/she is referring to the stage of embryo development at the time of the embryo transfer. When I began practicing infertility in 1996 most embryo transfers were done on the second day after egg collection (egg collection is day zero). However, most clinics moved rapidly to day 3 ET to allow for better embryo selection. The move to day 5 ET was a bit more difficult as commercially available media was a problem and by media I am not referring to CD or DVD but to the liquid that embryos are cultured in after retrieval of the eggs. Now many clinics have had very good success with day 5 ET and it has become more common. So today’s question is the simple one whereas tomorrow we will deal with the pro/cons of blast transfer. Of course, if you are dying to hear the next question you can always run down to your corner bookstore and purchase “100 Questions and Answers about Infertility.” There are a couple of copies left at the Barnes and Noble at Clarendon (Arlington, VA)…I know because I put them on the shelf (actually, I didn’t but I admit that the thought crossed my mind).

69. What is a blastocyst transfer?

Embryos on the third day after egg collection are referred to as cleavage-stage embryos. At this point, each embryo contains 6 to 10 discreet cells (blastomeres). When assessing these embryos for quality, the embryologist grades them based on the number and appearance of the blastomeres. Embryos that have equal-size blastomeres with no fragmentation are usually given a high grade, whereas embryos that have extensive fragmentation with unequal-size blastomeres are given a low grade. In general, higher-grade embryos have a much better chance of implanting successfully and generating a pregnancy. If the embryos are maintained in culture beyond day 3, they first form a solid ball containing approximately 30 to 50 cells, called a morula. Over the next day or two, this solid ball of cells becomes a hollow sphere with a clearly defined inner cell mass. This hollow ball of cells is called a blastocyst. Many clinics maintain the embryos in culture until the fifth day to allow for improved selection of embryos to transfer. Patients who undergo an embryo transfer on day 5 or 6 after egg collection are referred to as having a blastocyst transfer.

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Why is nothing working?

Clearly the million dollar question that all patients usually ask is "why is it not working?" The "it" can range from natural attempts at conception up to and including IVF. In some cases we really don't understand what the problem is and are faced with approaching fertility treatment with the "more eggs, more sperm...in the right place at the right time" approach. This logic is really the basis of most of our treatments. However, paradoxically we often recommend the most expensive and invasive treatment to those without an identifiable problem..why? Are we just a bunch of greedy, money grubbing slime bags?? Yes....no wait that describes only a few of us (just kidding, I hope). So why the aggressive approach in these cases? Well, here's the problem. If a couple fails to conceive on their own or after an IUI we have learned nothing new.

Did the egg ovulate? Unknown.
Did the tube catch the egg? Unknown.
Did the sperm find the egg? Unkown.
Did the sperm fertilize the egg? Unknown.
Did the egg divide? Unknown.
and so on...

At least with IVF we can provide some answers to the above questions.

So that leads to today's Question of the Day....and for all those who read this blog (besides my Mother) and have copies of the book, how about some 5 star reviews on Amazon.com? You don't usually have to beg for reviews but hey, I need that $0.27 per book to pay for my new laptop. So here is today's question:

68. Why would my doctor suggest IVF if all of my tests are normal?

Upon completion of the diagnostic evaluation, approximately 10% to 15% of couples will be found to have unexplained infertility, meaning that all of their tests are normal. Such couples are probably best called “subfertile,” and most can successfully conceive with IVF. Prior to the introduction of IVF, couples with unexplained infertility had a poor chance of achieving pregnancy with other treatment methods. We do not know precisely why couples with unexplained infertility are infertile. Some evidence suggests that the source of the problem may be tubal dysfunction or sperm egg interaction. Often, an infertility center uses IVF together with ICSI in such couples to ensure that fertilization of the ova occurs. Thanks to these techniques, today couples with unexplained infertility have a very strong likelihood of ultimately achieving a successful pregnancy with IVF.

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How to do an FET

In my last blog post I discussed the general concept of frozen embryos which is certainly a bit of a mind bending concept by itself. But I want to emphasize how important the option of having cryopreserved embryos can be to a patient’s overall chances for success. Many times over the years we have ended up with success by using the last frozen embryo that a patient had to work with after multiple failed cycles. Of course, the natural response would be that if we were really smart, then we should have known which embryo out of the whole bunch would go on to make a baby. I agree, but we are not that smart…yet. So until that time we all just have to ride that emotional roller coaster up and down as we try our best to achieve success.

As we head into one of the final weekends of summer let’s discuss the process of setting up an FET and review how do we get those frozen embryos back inside of our patients at the right time in the reproductive cycle. Here is today’s “Question of the Day” from 100 Questions and Answers about Infertility: the book that so many people are having trouble putting down because we coated the outside with superglue.

76. What is the difference between a natural­cycle frozen embryo transfer (FET) and a medicated FET?

There are two possible options for performing a frozen embryo transfer (FET): natural-cycle FET and medicated FET. Natural-cycle FET is available to women with regular ovulation and monthly menstrual cycles. In patients with predictable menstrual cycles, we can carefully monitor the cycle to determine the precise timing of ovulation. Alternatively, ovulation can be induced with the administration of an HCG injection. Once the precise date of ovulation is set, then the uterine lining should be receptive to embryo transfer 5 days later (for embryos frozen on day 3 in a previous IVF cycle). In this way, the embryos can be replaced at approximately the time when they would normally be arriving in the uterus.

One problem with natural-cycle FET is that the optimal time for implantation may fall at an unpredictable time during the laboratory work schedule. In addition, natural-cycle FET demands frequent patient monitoring around the time of ovulation. If a cycle is suboptimal in terms of the estrogen level and endometrial development, then the embryos should not be thawed and the cycle should be canceled.

A medicated FET allows the couple to avoid some of the pitfalls associated with a natural-cycle FET. In this type of FET, estrogen pills, shots, or patches are used to prepare the endometrium for embryo implantation. Three days prior to embryo transfer, the woman begins taking progesterone to modify the endometrial lining so that it will be receptive when the embryos are placed. Some clinics prescribe GnRH agonists (such as Lupron) to their female patients the month prior to a medicated FET cycle so as to reduce the chances of spontaneous ovulation. The use of Lupron reduces the chances of cycle cancellation owing to unexpected ovulation to near zero.

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To Freeze or Not to Freeze...

The previous post discussed egg freezing which is a much more difficult technique compared with embryo freezing which has a much longer, proven track-record. We will discuss egg freezing some other time. In general, if there are high quality embryos that are not going to be transferred it is always a good idea to consider freezing them for future use. However, the mere fact that these embryos exist has led to other concerns that are not only medical but social, philosophical, ethical, and moral. What obligations do a couple have to their frozen embryos? Several years ago over 4000 frozen embryos were destroyed in England because the couples who had created them had abandoned them and the clinics had no other option given that the status of these embryos was uncertain.

In this country several high-profile law suits have grown out of disputes following divorce of who controlled the embryos. Similarly a clinic in New England was sued by a man whose ex-wife had undergone a frozen embryo transfer following their divorce without informing the clinic of her change in marital status. In this case the clinic ended up paying a pretty hefty settlement as the man argued that his decision to NOT reproduce should have trumped her decision to reproduce with embryos that were from his sperm...yikes.

http://www.ivf.net/ivf/index.php?page=out&id=263
http://www.boston.com/news/science/articles/2005/05/18/technology_legal_gaps_leave_embryos_in_limbo/
http://www.all.org/abac/efd001.htm

So although I am all in favor of freezing these extra embryos one must proceed with caution. If you are still with me then read on as we cover today's Question of the Day from 100 Questions and Answers about Infertility: the book that still needs all (?some) of you to write some reviews on Amazon.com as they keep rejecting the ones that my mother has sent in..


75. What is embryo freezing, and how successful is it?


On the day of embryo transfer, the couple may learn that they have additional embryos of good quality in addition to those embryos that have been selected for embryo transfer. These embryos can be cryopreserved by freezing them in liquid nitrogen. Through a series of carefully orchestrated steps, the embryos are ultimately frozen at a temperature of –196 °C, leaving them in a state of suspended animation in which they can remain for many years. Embryos that have been stored for more than 10 years have successfully generated pregnancies (although most patients tend to use their frozen embryos within 3 to 5 years after they are produced). The pregnancy rates associated with replacing frozen embryos depend on the age of the patient and the quality of the embryos at the time of cryopreservation. Top-quality embryos from young patients may yield pregnancy rates around 50%, whereas poor-quality embryos may not even survive the thawing process. In some clinics, more than 75% of embryos survive the freeze–thaw cycle. Many couples are often concerned about their moral obligations concerning their frozen embryos. In such cases, couples may elect to defer embryo freezing, choose to alter their stimulation or pursue natural cycle IVF so as to avoid this problem of excess embryos. Extra embryos that are not used to initiate a pregnancy could represent a source of embryonic stem cells. This potential use of extra embryos lies at the heart of the recent political debate in the United States regarding government funding of stem cell research. Clearly, patients should carefully consider the implications of excess frozen embryos as they embark on an IVF cycle. However, not all patients will have extra embryos of high enough quality to be considered for embryo cryopreservation.

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Cross Generational Egg Donation and Beyond

A recent case in Canada raises some very interesting ethical questions. A women with a young daughter with Turner Syndrome wished to undergo IVF with cryopreservation of the unfertilized eggs so that her daughter could use them later in her life in order to conceive rather than rely on another egg donor to provide her this opportunity for parenting.

http://www.associatedcontent.com/article/221699/medical_first_mother_to_daughter_egg.html

Never a dull moment in the world of reproductive medicine! In the above situation the girl would give birth to her 1/2 sister and raise her as her daughter. Well, I must admit that is a new one on me although I have been asked whether we could use a patient's daughter from her first marriage as an egg donor for her and her new partner. In this case, the patient's ex-husband would be the genetic grandfather of the child born to her and her new partner. Try that question out on the cocktail party circuit.

So would we do the daughter to mother egg donation? We elected not to...as the issue of consent was problematic given the unmeasurable issue of coercion between parent and child. We used to discuss such cases at UCSF with Dr. Mary Martin who served on the Ethics Committee of the American Society of Reproductive Medicine. Dr. Martin described such cases as having a high "yuck factor." The "yuck factor" was that intangible aspect of a case that simply causes a visceral negative reaction.

So what about screening tests for egg donors (and their recipients)? That is the topic of today's question of the day from 100 Questions and Answers about Infertility, the book that has yet to crack the 500,000 mark on Amazon.com.

84. What screening tests are performed on donors?


Both the ASRM and the FDA have issued clear screening guidelines and regulations for egg and sperm donors; the guidelines are available on these organizations’ respective websites. A typical evaluation involves a comprehensive history of the donor’s health and his or her family. A physical examination and comprehensive laboratory screening tests for communicable diseases are also performed. Many centers add genetic testing of the donors. A psychological assessment of all ova donors is routinely performed. Although the anonymous donor’s anonymity is preserved, the results of his or her laboratory tests, psychological profile, physical characteristics, and historical information are shared with the infertile couple. This information allows couples to carefully choose their donor and provides a certain level of comfort in knowing that proper screening was performed. Some clinics provide adult photos of their donors, but in our practice we have limited photos to those from childhood to preserve the donors’ anonymity

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How to Choose a Fertility Clinic

Not a week goes by when a couple asks during a consultation "Why should we come here instead of clinic X." I know that many fertility books advise patients to ask this question but what response are they looking for....

This question always takes me back to my college, medical school and internship/residency interviews and to tell the truth I usually interviewed badly. My Harvard undergrad interview was particularly memorably bad and I remember my high school guidance counselor shaking his head slowly and asking what happened. I blew it. In retrospect it was the best thing that ever happened to me at that point because I ended up at another school which is pretty well known located in Princeton, NJ. Then after a wonderful 4 years at Princeton I found myself back at Harvard for a medical school interview and I screwed up again. Meanwhile I had great interviews at Duke, Michigan and Rochester. Again fate steered me, this time south to Durham and if that hadn't happened I would not have met my lovely wife the first week of classes (introduced by my classmate, her next door neighbor). Years later I was actually really sought after to do my Fellowship in REI at Harvard but we elected to stay on the Left Coast and I went up the road from Stanford to UCSF.

So....when a patient's husband leans forward over my desk and says "OK, so why should we come here" it seems like old times. Many glib answers rise to the surface:

- because I am such a great guy.
- because I am an Eagle Scout.
- because I am such a sensitive guy and like rainy days and walks on the beach.
- because I can recite the entire script of Monty Python and the Holy Grail.
- because I am God's gift to reproductive medicine.

...and on and on.

But seriously, I never know what to say. How do you inspire confidence and yet not come out as an arrogant SOB? How do you appear to be a nice, compassionate, caring doctor and yet not get labeled as "not aggressive enough." Who knows? Not me, that's for sure.

So with that intro here is today's Question of the Day from the book that the B&N at Clarendon down the street says is coming this fall to their shelves. Just remember that this is advice from the idiot who left his laptop overnight in an unlocked car.....


7. How do I choose a fertility clinic?

Choosing a fertility doctor for your care may be the single most important factor that leads to a successful pregnancy, so choose carefully.

Many patients are referred to us by their OB/GYN, friends, relatives, former patients, news articles, or through the Internet. But the one common denominator we have routinely observed with the sophisticated patient is that she is well prepared before coming for her initial office visit or she quickly becomes informed and knowledgeable before we begin any treatments.

Patients often say to us, “I checked you out before making this appointment.” Of course, we are always flattered by such comments, but we know that this patient will ask all of the important questions and make an intelligent decision regarding her treatment options. She will also probably experience less stress during the evaluation and treatment process, as she has developed a better knowledge base and understanding of what to expect.

All fertility clinics come with a unique flavor of their own. Some clinics are run by a solo practitioner, others by 2 to 6 member groups, while others are “mega” clinics with over 15 doctors. Regardless of the size of the group, be sure you are getting the attention and treatments you desire and deserve. You should never feel like a number with a revolving door of doctors. Of course, patients are not doctors and will not have the knowledge or experience of a reproductive endocrinologist, but a caring doctor will always welcome any and all questions and will take the time to answer them in a way that you can understand. We view patients as our partners, and once we understand what they are willing or not willing to do, we can devise a treatment plan that offers hope without subjecting them to any unnecessary additional stress.

Other things to consider:

Statistics, statistics, statistics: You want a baby, so choose a fertility clinic with good success rates. However, a wise man once said: “There are lies, damn lies and statistics” So how does one determine what to make of these statistics? In truth, there is no easy answer. Clinics that are more selective can inflate their success rates while those that have a different philosophy may suffer the consequences eventhough they have an excellent program. When considering a clinic it is important to know what your specific chances for success will be within that clinic. If there is one yardstick to compare clinics, then that is the pregnancy rate using donor eggs. In this patient population the pregnancy rates should be very high. A low donor egg pregnancy rate may be concerning. Individuals should evaluate the clinic statistics and obtain a good understanding and feel for what their specific chances for pregnancy will be per treatment. Patients may also evaluate the clinic success by reviewing IVF statistics at the Centers for Disease Control and Prevention (www.cdc.gov).

Experience: Experience of the clinic, in our opinion, may be one of the most important factors when deciding which doctor and which clinic to seek for fertility care. One should ask how long the doctors have been performing various treatments and whether cutting-edge procedures are either being offered or are being developed in the practice.

Subspecialty board certification: Most doctors practicing in the field of in vitro fertilization and infertility are subspecialty board certified in reproductive endocrinology and infertility. This certification can be found by going to the Society of Reproductive Endocrinology’s Web site, which lists doctors who are subspecialty certified in reproductive endocrinology and infertility. Additionally, patients may find it beneficial to see that their doctor has a faculty position at one of the local medical universities or actively participates in the teaching of the medical students and residents in their locality.


Availability and accessibility of doctors: It is important that you have access to your doctor in order to have your questions answered and needs addressed. Evaluate whether or not the availability and accessibility of the doctor is an easy process or a difficult one when making decisions as to where to seek care. The friendliness and helpfulness of the staff will also give you a feel for the character of the practice.

Cost: It is always important to get the total cost. Factor in extra expenses such as the fertility drugs, which can cost thousands of dollars; ICSI; assistedembryo hatching; embryo cryopreservation; and preimplantation genetic diagnosis (PGD). These drugs and procedures can quickly increase the overall cost for treatment.

Finally, he is a word of caution. In general, Internet chat rooms may be a dangerous place for seeking advice regarding finding an infertility doctor. Be careful what you hear online, as it always represents just one half of the story. It is far better for you to do your own homework and research than to rely on information provided from others, which may be based on misimpressions or experiences.

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Where has Dr. Gordon been??

I know that the 5 people who read this blog have been wondering that for the past 2 weeks. Gee, he was so good about posting questions from that fantastic book and then...POOF..he disapparated. Well, the answer is that I have been here but too overwhelmed to post to the blog. Sorry but true. When returning from vacation you always get hit hard and this month was no exception. So my patients in cyberspace had to take a back seat to the real flesh and blood patients.

And then last Friday night disaster struck...Upon returning from dropping off the babysitter at midnight I made several fateful decisions....I left my laptop case in my car...I left the car open....you can guess where this is going....YUP, next morning my MacBook Pro was in the hands of persons unknown. No patient info was on the laptop but there were over 6000 photos and my iTunes (all 80s hits by the way) and all my email.

But wait...on Wednesday night I had done a complete backup of my Home folder and so after a visit to the Mac store my laptop was back but in a new body..who says reincarnation doesnt exist... However, it did still take some time to get everything loaded back and I am still not there yet.

So, dear reader, please bear with me. I will say that this whole experience has proven to me the benefit of a good backup plan!

Given my state of exhaustion let's tackle a simple little question from the book that I am trying to get into your local Barnes and Noble store: 100 Questions and Answers about Infertility. Now, I used to be pretty good about working out on the elliptical trainer but then I got plantar fasciitis and my orthotics gave me a Morton's neuroma so I have been a slug this summer.

87. Can I exercise? How much is okay?

Mild to moderate exercise is beneficial to infertility patients and is highly encouraged. Healthy amounts of exercise decrease stress and clearly improve a person’s sense of well-being. Studies show that women who exercise before and during their pregnancy have better obstetrical outcomes and healthier babies than women who are sedentary. For most patients, we recommend exercising 30 minutes per day, 4 or 5 times per week, but lesser amounts of exercise are still beneficial. Even 15 minutes of exercise each day can help reduce stress and improve your physical health. We highly recommend that women begin or continue exercising during their infertility evaluation and treatments, and perhaps more so for those undergoing treatment with IVF. In our experience, these patients are better able to tolerate the stress related to infertility and IVF.

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Beyond Metformin

Well, I am back having spent a very relaxing vacation in Wyoming. If only there were more people in that beautiful state, then I would seriously consider relocating from the Metropolitan DC area. Returning back to DC was like entering a swamp and considering the current state of our elected officials there are more similarities than I really would care to admit...

In any case, as sales of the book on Amazon.com place it only 599,997 book rankings behind Harry Potter, I am taking up where we left off in discussing PCOS. Actually, there are several excellent books dedicated to PCOS and insulin resistance. Just yesterday I printed out info from Amazon.com on the "Insulin Resistance Diet" which many of our patients have found helpful. The book is ranked #300 on Amazon.com...which seems pretty impressive to me...

Moving right along, the problem with Metformin and PCOS is that not all patients will resume ovulation with this drug by itself. In fact, the majority of patients will require additional medications (either Clomid or gonadotropins). I still believe that pretreatment with Metformin makes sense as a higher percentage of women will ovulate with combination therapy compared with clomiphene alone. So here is the next sample question from "100 Questions and Answers about Infertility."



25. I have PCOS and am still not having normal cycles with metformin. What comes next?


Patients who fail to respond to metformin may require ovulation induction with either clomiphene citrate (Clomid) or injectable fertility medications (gonadotropins). Clomid has been an FDA-approved treatment for anovulation since the late 1960s. This anti-estrogen has been used successfully in millions of women with few complications. Clomid binds to estrogen receptors in the brain, causing the pituitary gland to resume normal release of FSH, and thereby inducing follicles to grow and ultimately release an egg. Patients should take the lowest effective dose of Clomid needed to induce ovulation. With increasing doses, the anti-estrogen side effects can reduce fertility by altering the cervical mucus and leading to a thinner endometrial lining. Many physicians initially prescribe a dose of 50 mg of Clomid to be taken on cycle days 5–9. The physician may perform ultrasound monitoring after day 12. Most patients will ovulate around day 17. If no dominant follicle emerges by this day, then an increased dose of 100 mg should be used in the next cycle. A dose of 150 mg is rarely prescribed, because the vast majority of Clomid-responsive patients will ovulate while taking the 50- or 100-mg dose.

Women with PCOS who fail to respond to Clomid can be treated with injectable fertility medications. Gonadotropins (FSH-containing medications) are prepared either using re- combinant DNA technology (Follistim, Gonal-F) or by isolating these hormones from the urine of postmenopausal women (Bravelle, Menopur). By following a very-low-dose protocol (37.5 IU as the starting dose), approximately 90% of patients will achieve a single dominant follicle. If the treatment produces multiple follicles, however, the woman’s risk of multiple pregnancy and ovarian hyperstimulation syndrome (OHSS) may lead to cycle cancellation. Almost all of the high-order multiple pregnancies (e.g., sextuplets) born today result from PCOS patients who took gonadotropins and demonstrated an excessive follicular response.

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