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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Metformin and PCOS

There is an adage in medicine that “like treats like.” So if you have a hormonal problem, then treat with hormones. If it is an anatomic problem, then treat with surgery…etc. In the case of PCOS, if this is an insulin related problem, then treat with a medication that addresses insulin issues. At Dominion, our preference has been for all patients with PCOS to take metformin. The majority of the patients tolerate the medicine and many resume normal cycles and conceive. For those patients in whom metformin alone is not sufficient, then we can induce ovulation with clomiphene or fertility injections (gonadotropins). Although an article in the New England Journal of Medicine suggested that starting with clomid is better, it is our opinion that starting with metformin first and then adding clomid if cycles fail to resume in 6 weeks makes the most sense.


So in continuing along in our PCOS theme, here is the “Question of the Day” from the book that patients at Dominion can get free of charge (with only a little bit of begging), but that the rest of the US will have to wait a few more weeks to get at Amazon.com.




24. If I have PCOS, why do I need to take metformin? Isn’t that a drug for diabetics?


The role of insulin resistance as the probable initiating factor in PCOS has important clinical implications. Because of the pioneering work done by Drs. John Nestler and Andrea Dunaif, the treatment of patients with PCOS has now shifted toward addressing the underlying issue of insulin resistance. Patients with PCOS are often treated with an insulin-sensitizing medication such as metformin (Glucophage). Approximately 20% to 50% of patients with PCOS and irregular cycles will experience a restoration of their normal cycles with metformin treatment. Because most patients who take metformin experience a diminished appetite, they may also benefit from weight loss with this therapy. Patients with PCOS also have increased rates of first-trimester miscarriage, and preliminary data suggest that there is a reduced rate of miscarriage in patients with PCOS who are treated with metformin. The dose of metformin is increased gradually. Many physicians initially prescribe 500 mg a day of the extended-releasepreparation of metformin, to be taken at dinner. After 1 week, the dose is increased to 1000 mg; after another week, the dose is increased to the maximum of 1500 mg. Most patients can tolerate the medication, although severe gastrointestinal side effects (mainly diarrhea) arise in 10% to 15% of patients. Patients who fail to resume predictable cycles with metformin therapy alone will need to consider ovulation induction with fertility medications.

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Where does PCOS come from?

Years ago the field of Gynecology was actually a subspecialty within Surgery and many surgeons were trained in Gynecology since it was not a separate medical specialty. My father was one such surgeon and he still loves to tell me how he was better at hysterectomies than any Gyn physician. Since I never do hysterectomies as a fertility physician, I never took this comment as an insult. In any case, one day we were discussing fertility problems and I mentioned PCOS. I was surprised to hear from my Dad that he was quite familiar with PCOS and had performed many ovarian wedge resections to treat PCOS. Although this approach has been more or less abandoned with better ovulation induction medications, it may still have a place in some patients.

So what is our current understanding of where PCOS comes from? Well read the following excerpt from "100 Questions and Answers About Infertility" and find out. And while you are at Barnes and Noble at Midnight tonight be sure to order a copy of this book while you wait for Harry Potter!


23. Where does PCOS come from?

The topic of PCOS can fill an entire book. In fact, several books have been devoted to this subject. Although this condition was originally described by Drs. Stein and Leventhal in 1935, our understanding of PCOS has advanced significantly in the last decade. Originally, PCOS was thought to be an anatomical problem in which a thickened coating around the ovary prevented ovulation. It is now agreed that PCOS represents a hormonal imbalance. At the heart of this disorder is insulin resistance.

Insulin is a hormone secreted by the pancreas that induces your body to store the sugar circulating in the bloodstream. Individuals who fail to produce insulin as a result of an autoimmune disorder require insulin therapy to maintain normal blood sugar levels. These patients are referred to as having insulin-dependent diabetes (also known as type 1 diabetes). The majority of patients with impaired glucose metabolism actually suffer from insulin resistance rather than insulin deficiency. That is, the cells of their bodies are not sensitive to the effects of insulin, so they require ever-increasing amounts of insulin to be released from the pancreas until appropriate blood levels of glucose are obtained. These patients are commonly referred to as having non-insulin-dependent diabetes (also known as type 2 diabetes or adult-onset diabetes). Despite the name of the disease, persons with type 2 diabetes may require insulin injections to maintain normal glucose levels depending on their degree of insulin resistance.

Insulin resistance is often a genetic disorder. This explains why adult-onset type 2 diabetes is so prevalent in certain families and in certain ethnic groups. In patients who are insulin resistant, the excessive levels of insulin affect not only their metabolism, but also their reproductive system.

Insulin directly affects the release of reproductive hormones from the pituitary gland and directly stimulates ovarian production of male hormones. Thus the presence of excess insulin results in a local environment that is not conducive to follicle growth. When multiple follicles fail to grow, they release excessive male hormones, resulting in the acne and abnormal hair growth commonly encountered in women with PCOS.

Obesity itself also increases insulin resistance, so patients can find themselves trapped in a vicious cycle of irregular cycles and worsening weight gain. Women who have always had regular periods during their entire life but suddenly gain significant weight can find themselves resembling patients with PCOS. In these cases weight loss by itself may restore normal cycles and improve fertility

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What is PCOS?

Certain reproductive problems are more common than others and PCOS is one of the most common fertility problems that we deal with in clinical practice. When lecturing the medical students and residents I spend a lot of time talking about PCOS because this is a problem that all Ob Gyn physicians should understand and manage. That being said, it sometimes seems to me that the patients understand a lot more about PCOS than their doctor.

Before I go any further let me set the record straight – polycystic ovaries are not like polycystic kidneys. In PCOS the cysts are just undeveloped follicles waiting for the signal to grow. The cysts in PCOS do not rupture leading to Emergency Room visits and they do not become cancerous.

So let’s start out with some basics about PCOS and then move to more specific questions. Of course, if you already have a copy of “100 Questions and Answers about Infertility” then turn to page 34 at the bottom and read along.

22. What is polycystic ovarian syndrome?

Polycystic ovarian syndrome (PCOS) is an exceedingly common reproductive disorder, affecting an estimated 10% to 15% of reproductive-age women. The diagnosis of PCOS is a clinical one. In 2003, the ESHRE/ASRM consensus conference redefined PCOS as the presence of at least two out of the three following clinical criteria:

1. Irregular menstrual cycles
2. Evidence of extra male hormones, as determined either by clinical examination or by blood tests
3. Ultrasound demonstrating ovaries with numerous small follicles (PCO-appearing ovaries)

Previously, only patients with irregular menstrual cycles were thought to have PCOS, so the expansion of this definition has led to some confusion among healthcare providers. Other features commonly associated with PCOS include obesity, insulin resistance, borderline diabetes, skin tags, and a velvety discoloration on the nape of the neck and inner thighs called acanthosis nigricans.

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"There be books here..."

Well the blessed moment has arrived as Jennifer, our office manager and I, unloaded 44 boxes of books at the local Storage USA facility here in Arlington. It is always exciting to tear open that first carton and see the books sitting there...kinda like Christmas morning.

The road to this point was tough going at times. DrD and I had to balance the usual responsibilities at the office and at home, but we believed in the project and the folks at Jones and Bartlett were very supportive.

One of the most amusing issues was picking the cover color scheme. The initial cover looked like this:


Although DrD liked the brown, we had a straw poll here in the office and then went through pink, peach and mauve before settling on the blue which everyone seemed pretty happy with in the end.

So now it is up to you, dear reader, to go forth and purchase this book or just keep reading this blog and spend your $17.95 at Starbucks instead. It wont hurt my feelings, although I don't know how my Mother will take the news and at age 84 she is getting a bit frail...

I remain open to all comments and suggestions. If there are questions that were not included, please feel free to post them at the INCIID bulletin board and I will chime in with my $0.02 worth...just remember that free advice is worth what you pay for it...


DrG

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Egg Donor Screening

Several years ago I attended a conference about legal issues in reproduction. It was a great meeting and a lot of very interesting topics were addressed. At that meeting the following cartoon was presented.

Clearly, there are different ways to screen your donors. However, the FDA has now become involved in egg donation to ensure that no diseases are transmitted through the process. Fortunately, even before the FDA became involved there had never been a case of transmission of an infectious disease from egg donor to recipient.

Psychological screening is where most donors fail the process in our clinic. These young women may sometimes have a lot of issues that give pause when considering using them as a donor. The Hippocratic Oath stipulates a key rule in medicine: Primum Non Nocere—Above All, Do No Harm! So when screening donors this must be kept in mind. In our clinic we will not use donors on anti-depressants or those with a history of sexual abuse.

So how about those screening tests? Well, that is the “Question of the Day.”

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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Where Do Donors Come From?

When the media is not foaming at the mouth over a sextuplet pregnancy, the next most likely sensationalistic topic is egg donation. The focus is usually on the compensation paid to the donors with $50 thousand to $100 thousand for Ivy League eggs often reported. As a Princeton grad, I can tell you that my wife, for one, would never pay that much for Ivy League gametes (eggs or sperm). In fact, after meeting my college buddies for the first time in 1985 she probably immediately had 2nd thoughts about my suitability as a future spouse. Fortunately, our kids may take after her (especially my oldest son, Seth, who plans on being an engineer just like his Mom http://www.connectionnewspapers.com/article.asp?article=83736&cat=104).

In any case, being an egg donor is a wonderful opportunity to perform an altruistic act but it is not a great way to get out of debt or buy a new car. Undergoing IVF is a lot of work. It is inconvenient. It interferes with your life. The drugs can have unpleasant side effects and you have to be available for many days out of the month for blood tests and sonograms. I tell all the donors that there are a lot of other ways to make money that do not involve this level of commitment. In addition, psychological studies suggest that donors who donate for the sake of the money alone, do not have as good an experience as those who are doing it as an altruistic act.

So why be a donor? That is the topic of today’s “Question of the Day” from 100 Questions and Answers about Infertility….


83. Where do egg donors come from, and why do they want to be a donor?


The typical egg donor is a healthy, young female in her twenties who desires to help others in having a baby. In our experience, egg donors tend to be intelligent, altruistic, sincere women who are knowledgeable about the difficulties that many couples face with their infertility. Most egg donors come from the local community near the infertility practice. They have learned about infertility from their friends, family, the Internet, and the media. Most of the donors whom we recruit for our practice have a college degree or are actively pursuing one. Most anonymous donors are reimbursed for their time and the expenses involved in the screening and treatment process. The screening usually takes 2 to 3 months to complete and the IVF treatment takes 4 to 6 weeks. In our experience, women who donate their eggs are very responsible individuals and genuinely concerned about carefully completing their role in the IVF treatment process to achieve a successful outcome.

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