Conceivability_What I Learned Exploring the Frontiers of Fertility

by Elizabeth L. Katkin

  The idea behind using Clomid to battle PCOS is simple: the suppression of estrogen is intended to force the struggling body to ovulate by artificially stimulating the necessary hormone production. However, despite its promise in theory, it is now known that Clomid is not the magic solution many hope it to be. In addition to the many women who fail to ovulate with Clomid, many others who do ovulate fail to conceive, likely because of poor egg quality—another challenge I, like a great many women with PCOS, later faced.

  Fortunately, women with PCOS facing the challenge of trying to conceive now have another potential option to pursue: a drug called letrozole. Letrozole, an aromatase inhibitor approved by the FDA for the treatment of breast cancer, seeks to achieve the same goal as Clomid—stimulating ovulation—through a different physiological mechanism. Letrozole blocks the production of estrogen, as opposed to preventing the estrogen from binding to the egg cell, as Clomid does.13 A study of 750 women, one of the largest to date examining infertility in women with PCOS, found letrozole to be more effective than Clomid, resulting in higher rates of ovulation, conception, pregnancy, and live birth rates.14 Women assigned to take letrozole experienced an ovulation rate of 61.7 percent and a live birth rate of 27.5 percent, as compared with 48.3 percent and 19.1 percent, respectively, for the Clomid group. Although some experts urge caution, wanting to see more safety data on letrozole,15 Dr. Richard Legro, the lead author of the study, said that the researchers were “extremely encouraged that letrozole could provide a new, oral, first line therapy for this common disorder . . . with a much lower risk of multiple pregnancy.”16

  Teen weight gain aside, I luckily suffered almost none of the other side effects of the syndrome—except the most emotionally painful effect: the cysts prevented me from ovulating, making it impossible to conceive without intervention.

  The nursery is the room I’ve been longing for . . . .

  Clara Andrews Williams,

  The House That Glue Built

  2

  Finding the Yellow Brick Road

  Navigating the Fertility Labyrinth

  While taking the 150 mg of Clomid, I started polling nearly every female friend and acquaintance I had in Washington, DC, asking for recommendations for a fertility specialist.

  “Dr. Sacks,” said Cori.

  “Preston Sacks,” said Katherine.

  “I don’t like my doctor,” said Melissa, “but I hear someone called Dr. Sacks is supposed to be great.”

  Dr. Sacks! Was there only one good fertility doctor in all of Washington, DC? It seemed that way. When I called to make an appointment, the first available date was more than three months away. It felt like an eternity.

  In the meantime, to my surprise and relief, I discovered that I was not alone with my fertility concerns. My friend Cori, from law school, provided not only a sympathetic ear but also a Clearblue Fertility Monitor. The Baby Computer, as we affectionately called it, goes far beyond a typical drugstore ovulation predictor kit. Rather than peeing on a stick for a few days to find out the one magic day that a woman might ovulate, the Baby Computer measures urine samples for many days of the cycle, indicating days of high fertility as well as two days of peak fertility, rendering a much broader window in which to potentially conceive.

  My daily routine of peeing on a stick and taking the Clomid kept me busy while waiting for Dr. Sacks. It was beginning to consume more and more of my time and energy. Little did I know that it was just the beginning, that I soon would be fighting the fight of my life, encountering and surmounting obstacle after obstacle.

  I realize now that at the start of my journey I had so little knowledge of not only the medical miracle of getting pregnant but also of the vast universe of fertility options that I was, without really knowing it, beginning to confront. Back then, as I followed my doctor’s advice blindly, and went from one failed course of action to another, I never fully understood why certain choices were being made. It would have been helpful to have known from the start why and how the treatment progresses from one stage to the next.

  In stark contrast to the notion of a baby made by nothing but one man, one woman, and pure love, evolution along the assisted-fertility spectrum is progressively less starry-eyed—and significantly more convoluted. Treatment options fall broadly into five, often overlapping, categories: non-invasive (Clomid and superovulatory drugs); complementary and alternative therapies (traditional Chinese medicine, acupuncture, nutrition, yoga); minimally invasive (intrauterine insemination, or IUI, also known as artificial insemination); invasive assisted reproductive technology (in vitro fertilization, or IVF, and its variations); and third-party parenting (sperm donation, egg donation, surrogacy).

  During the course of my journey, I had an opportunity to explore nearly every option.

  The First Visit with the Specialist

  Going to the initial visit with the fertility specialist already somewhat knowledgeable about the treatment options is a good way to start. First, the task is to determine the specific nature of particular problems. For men, this consists of determining sperm quality and quantity. For women, the process is more complex, and it begins with analyzing the reproductive organs and assessing hormone levels. During the “get to know you” phase of what may turn into a very long-term relationship, in addition to taking a detailed patient history, a good fertility doctor should conduct a physical exam, including a pelvic ultrasound, and blood tests. The ultrasound may reveal abnormalities in the uterus, fallopian tubes, or ovaries, and it might also shed light on ovarian reserve (essentially, egg quantity) through measurement of the number of antral follicles. Antral follicles are tiny follicles in the ovaries, each of which contains an immature egg that can potentially develop and be ovulated in the future. It is believed that higher numbers of follicles will translate into higher numbers of eggs, rendering more chances of conception.

  Blood tests to assess hormone levels can further help to get a sense of egg quantity and other ovulatory problems. Many doctors will want to start by analyzing levels of five hormones: FSH (follicle stimulating hormone), LH (luteinizing hormone), E2 (estradiol), AMH (anti-Mullerian hormone), and progesterone. Additional hormones, including prolactin (high levels of which may suppress the growth of egg follicles), testosterone (high levels likely indicate polycystic ovaries), and thyroid hormones (imbalances can result in ovulatory problems), may also be tested when there is reason to believe that they might come into play.

  While I know this sounds like a lot to take on board, there are two main hormones believed to be the culprit in many cases of the fertility challenged: FSH and AMH. Although LH, E2, and progesterone are useful in detecting the health and regularity of a woman’s cycle—whether a woman is ovulating, if the timing is correct, and if normal amounts of hormones were secreted in the process—doctors have historically turned to FSH levels, and are increasingly focusing on AMH levels, to determine whether a woman has a low ovarian reserve, meaning essentially that she has fewer eggs and presumably fewer chances to create a baby.

  FSH is one of the primary hormones involved in a natural menstrual cycle as well as in drug-induced stimulation of the ovaries. It is the main hormone promoting the production of mature eggs in the ovaries, essentially providing the fuel for each egg inside its tiny follicle to start its development. In women with large supplies of eggs, it doesn’t take much FSH to trigger the growth process. In women with fewer eggs, however, it takes a lot more FSH to stimulate an egg to grow, and the body will keep producing FSH until it gets one going. Testing a woman at the beginning of her menstrual cycle, typically on day two, three, or four of the cycle, gives an indication of how hard her body needs to work to produce an egg capable of ovulation. High levels of FSH indicate that a woman likely has a low ovarian reserve; in other words, not so many eggs left.

  But high FSH levels are not always the harbinger of doom that many doctors and patients assume. For starters, FSH levels can be hard to interpret accurately for a number of reasons. First, th
ey fluctuate. Second, they are measured by different diagnostic tests produced by different labs, resulting in a variety of “normal” ranges, making it difficult in certain cases to determine if a result is too high. Further, as noted by the respected fertility clinic Advanced Fertility Center of Chicago, while high baseline FSH “tends to be very predictive of low egg quantity, a normal result does not mean that the egg quantity is good.”1

  And while it flies in the face of conventional wisdom, the reverse can be true as well. Ilona, a thirty-eight-year-old African-American woman in Denver, was told that her odds of conception were very low due to her FSH level of 18 (on a scale in which less than 9 is considered normal, 9 to 11 is fair, 11 to 15 indicates a reduced ovarian reserve, 15 to 20 is a marked reduction, and more than 20 is a no go). After lowering her FSH to 14 following three months of acupuncture and traditional Chinese medicine (TCM), Ilona got pregnant naturally and gave birth to a healthy baby girl. Mary, a thirty-five-year-old with an FSH of 21.5 (a clear no go in the clinic’s eyes) similarly had a healthy baby, naturally conceived after a few months of TCM and acupuncture. And Marcy, with a poor-looking FSH level of 17.6, eventually got her FSH down to 9.7, below the critical number of 10, which was the bright-line test her insurance company used to determine whether to cover her treatment. Ironically, she didn’t require the expensive IVF she was so desperate for Aetna to cover, as Marcy too became pregnant the old-fashioned way.

  Interestingly, while FSH is widely used to measure egg quantity, recent research indicates that it may be a strong indicator of egg quality as well. Whereas traditional thinking holds that FSH levels do not affect the chromosomal makeup of the eggs they are stimulating into ovulation, new studies suggest that high FSH levels correlate with, and may in fact cause chromosomal abnormalities in developing eggs. Studies in mice have shown that when FSH levels decrease, chromosomal abnormalities also decrease. Although similar studies with humans are in their very early days, there are promising initial results of women lowering their FSH levels and producing higher numbers of chromosomally normal, healthy eggs. FSH levels are not necessarily static, and women like Ilona and Marcy have both successfully lowered their FSH, relying on acupuncture, TCM, and supplements, and gotten pregnant.

  Over the last five years, fertility clinics have increasingly turned toward testing AMH levels in addition to, or in some cases, instead of, FSH as the gold standard in predicting ovarian reserves, and assessing AMH is now a routine part of the initial fertility evaluation in many clinics. AMH is a hormone that is released during the growth of the antral follicles (those tiny follicles that each contain a developing egg). As a result, AMH levels correlate with the number of active antral follicles present; the higher the antral follicle count, the higher the AMH levels. Early studies are starting to show that it may be more accurate than FSH, due in part to the fact that AMH does not fluctuate significantly throughout the cycle as do FSH and other hormones, which also, conveniently, enables testing on any day of a woman’s cycle, as opposed to during a limited window.2 However, as a relatively new blood test, interpretation can be somewhat tricky as baseline “normal” levels (generally from 1.0 or 1.5 to 4.0) are not yet standardized and agreed on by all experts.3

  Another reason the level of AMH may be more accurate is that it reflects the number of active follicles in the ovaries—those follicles that are growing and have a developing egg inside. While not believed to be indicative of egg quality, AMH levels can shed light on the size of the remaining egg supply. This distinction has important implications for treatment, for although women with low numbers of eggs are not likely to be good candidates for traditional IVF, it does not necessarily mean that they do not have good-quality eggs.

  As with FSH, examples abound of women with alarmingly low AMH levels who have gone on to conceive healthy babies. Marcy, for example, was first told that her AMH was undetectable, and later told that it was .01, on a scale where 1.5 to 4.0 is considered normal and below 1.0 is considered worryingly low. She went on to conceive, without IVF. Ilona, similarly, had an AMH that was at first undetectable, and eventually rose to .5 and was discouraged from pursuing fertility treatments with her own eggs, yet she too conceived naturally. And Julia, a thirty-two-year-old woman with microscopic levels of AMH (.03), conceived and gave birth to a bouncing baby boy without assisted reproductive technology.

  And then, of course, there are plenty of cases like mine. Normal FSH, LH, and E2. Normal thyroid. Normal insulin. But no baby.

  So, while a patient can and should expect doctors to test hormone levels on that first visit, it is worth bearing in mind that they do not always provide definitive answers in and of themselves.

  An Infertility Road Map?

  While it would certainly be nice if all the testing I just described led to clear instructions, like those generated in mere seconds by the GPS in your phone or car, unfortunately, finding one’s way through the maze of infertility treatments more closely resembles navigating through the woods with a compass.

  In certain cases, the path will be clear. Many people facing infertility, for example, discover quickly that they have an identifiable issue, such as blocked tubes, or a low sperm count, which leads them down a specific treatment path. A woman with blocked tubes, for example, will be directed straight to IVF (which, by inserting the fertilized egg directly into the uterus, bypasses the need for the egg to travel through the fallopian tubes), while a man with a low sperm count is likely to be encouraged to undergo intracytoplasmic sperm injection (ICSI), a procedure that entails injecting the sperm directly into the egg, rather than taking the chance that the sperm and egg will find each other as nature intended.

  When the panoply of clearly identifiable problems is eliminated, however, one enters the rabbit hole of “unexplained infertility,” a world in which the culprit in the failure to conceive is generally assumed to be irreversibly poor egg quality, often coupled with irregular ovulation, or egg quantity—and frequently blamed on age. Yet contrary to conventional wisdom, research now shows that not all unexplained infertility is in fact due to advancing years.

  The treatment of unexplained fertility is anything but straightforward. It requires a trial-and-error approach—channeling a bit of Sherlock Holmes, a touch of Dr. Watson, and a healthy dose of Monty Python in the search for the Holy Grail of eggs capable of fertilization. It also requires tenacity on the parts of both doctor and patient. A woman who finds herself entering this rabbit hole would be wise to put a lot of thought and research into the choice of treatment clinic, as they will vary in their approach, knowledge of cutting edge protocols, and success rates over time. Yet, ironically, the vast majority of doctors start the process in the exact same way: they prescribe Clomid. And if that fails, next in the noninvasive chain often comes superovulatory drugs.

  Superovulatory Drugs

  When ready to move on from Clomid, or perhaps now letrozole, each intended to stimulate one or two eggs to ovulate, many doctors and patients turn to superovulatory drugs, known as gonadotropins (which contain FSH, LH, or both), which aim to stimulate the production of multiple eggs. Unlike Clomid and letrozole, almost all gonadotropins, sold under the brand names Gonal-f, Puregon, Follistim, Menopur, Menogon, and many others, are injectables. Getting the balance right here is key. The goal is to help produce one or two high-quality eggs, but not too many, for if the injectables work too well, having unprotected sex (or, of course, any insemination) bears a great risk of pregnancy with multiples, enhancing risk for the mother and babies. My conversations with several women who took gonadotropins illustrate the unpredictable course that may follow when stimulating many eggs.

  When Jessica and Ethan began their infertility treatment in North Carolina, their doctor suggested superovulatory drugs. With Jessica only twenty-seven years old, feeling like she was still very young, they did not plan to move to more invasive procedures such as IVF for some time. Facing extremely irregular periods, Jessica took superovulatory drugs during her first cycle a
t the clinic, but the drugs failed to stimulate any eggs. Switching drugs for a second cycle, Jessica forged ahead, to find that this time she was overstimulated and had too many eggs to safely proceed; the risk of becoming pregnant with multiples was too great. Jessica and Ethan faced a choice that needed an immediate answer: cancel the now high-risk cycle and try again with a lower dosage in an effort to stimulate fewer eggs, or harvest the eggs and convert to an IVF cycle. Forced to confront the IVF question much sooner than they anticipated, they uneasily opted to proceed. Her eggs were extracted and fertilized in the lab. They transferred their sole surviving embryo back to Jessica’s womb on day three. A beautiful baby girl was born nine months later.

  Paula and Derrick experienced the flip side of the equation. Having suffered a miscarriage and multiple failed attempts at conceptions, they turned to a treatment plan consisting of high levels of superovulatory drugs to be used in combination with IVF. Although the drugs did stimulate the production of eggs, there were not enough to proceed with IVF. Like Jessica and Ethan, they faced an immediate choice. Abandon the cycle altogether as they had the first time, or switch to IUI (intrauterine insemination)—essentially attempting fertilization with a “turkey baster”—which had a risk of multiples. Anxiously, they went ahead with the IUI and Paula became pregnant. Sadly, she miscarried at seven weeks.