Patients often feel victimized by and angry about their infertility condition, particularly when treatments fail or are associated with physical and emotional discomfort. Rather than providing useful, factual information, "Is This Any Way to Have a Baby?" merely serves to mislead and frighten already vulnerable women and undermine their trust in their healthcare providers. This type of fear-driven journalism does not support women or patients.

We look to Oprah and O Magazine for reliable information. As a leading patient advocate for the infertile and one-time guest on her talk show, I find that this article does not reflect the Oprah standard that so many have come to expect.

I welcome hearing your thoughts and concerns, and I hope you’ll join The AFA this month for more exciting Connections online educational events.

Connections Online
Sessions Schedule - February

February 4, 2004, Wednesday
Speaker: Benjamin Sandler, M.D. (Reproductive Medicine Associates of New York)
Topic: Blastocysts? Grading? How to Make Sense Out of the Language….
Time: 8-9 PM, EST (DST)

February 11, 2004, Wednesday
Speaker: Kaylen Silverberg, M.D. (Texas Fertility Center)
Topic: Surgical Procedures: What They Are and When They’re Necessary
Time: 8-9 PM, EST (DST)

February 17, 2004, Tuesday
Speaker: David Hoffman, M.D. (IVF Florida Reproductive Associates)
Topic: IVF Explained
Time: 8-9 PM, EST (DST)

February 24, 2004, Tuesday
Speaker: Peter Schlegel, M.D. (Cornell Institute for Reproductive Medicine; Center for Male Reproductive Medicine and Microsurgery)
Topic: When Male Factor is Part of Your Diagnosis
Time: 8-9 PM, EST (DST)

Click here for Connections Online

Jessica R. Brown, MD
Reproductive Medicine Associates of Brooklyn, LLP
A Satellite Office of NYU Medical Center, Program for IVF, Reproductive Surgery and Infertility
Clinical Assistant Professor of Obstetrics and Gynecology
NYU School of Medicine

UNEXPLAINED INFERTILITY

When a standard evaluation fails to reveal any abnormalities infertility is said to be “unexplained.” More than anything, those suffering from infertility desire children. But the desire to understand the reason for infertility can also be powerful. Those with a diagnosis of “unexplained infertility” suffer the added frustration of not knowing why they have been unable to conceive. Fortunately, many of those with unexplained infertility do eventually conceive, both with and without treatment. Which diagnostic tests are essential, and when can additional testing be beneficial? When is it time to move from diagnostic testing to treatment, and which treatments can be effective even when the cause of infertility remains a mystery? A thorough understanding of infertility testing and treatment options will help you to chart your own best course of action.

Causes of infertility/subfertility

About 15% of cases on infertility are unexplained. Well-recognized causes of infertility (inability to conceive) include failure to ovulate, absence of sperm, or complete tubal obstruction. Thus, a standard infertility evaluation includes testing to document ovulation, semen analysis, and a hysterosalpingogram to evaluate tubal patency. In many cases, what we call “infertility” is actually “subfertility”. Subfertile couples may be able to conceive, but they take longer to do so. Causes of subfertility include such varied conditions as advanced female age, infrequent ovulation (oligoovulation), luteal phase defect (inadequate progesterone production after ovulation), endometriosis, partial tubal obstruction, poor semen quality—such as low count, motility, and morphology (shape), abnormal (“hostile”) cervical mucus, and infections of the genital tract. Other conditions, such as uterine myomata (fibroids), are commonly seen in fertile women but are clearly responsible for infertility in some cases. Stress is also commonly implicated in infertility. Extreme stress can cause complete cessation of ovulation and menstruation, but the role of “everyday” stress is less clear. Some have conceived after utilizing techniques such as “mind/body” programs to help deal with stress.

The problem of “old eggs”

It is now recognized that many cases of subfertility can be attributed to “decreased ovarian reserve,” a term which describes the decreased capacity of the aging ovary to produce a healthy egg and a viable pregnancy. In fertile women, the average age of last birth is 41. Looked at another way, at least half of normal, fertile women will be infertile if they try to conceive at age 41 or over, and many will be infertile even at slightly younger ages. Decreased ovarian reserve is a normal phenomenon in older reproductive-aged women, who are typically subfertile. Many younger women who had been thought to have unexplained infertility will also be found to have decreased ovarian reserve. In one study, 38% of women with unexplained infertility actually had decreased ovarian reserve.

The easiest way to measure ovarian reserve is to draw blood during menstruation, usually on day 2 or 3, and measure levels of FSH and estradiol. High FSH levels, and, to a lesser extent, high estradiol levels, signify decreased ovarian reserve and a decreased fertility potential. More sophisticated tests, such as the “Clomid challenge,” are even more sensitive, revealing that some women with normal levels of FSH and estradiol on day 3 actually have decreased ovarian reserve. But it is important to remember that some women with decreased ovarian reserve do still get pregnant. Both increasing age and increasing FSH independently correlate with decreased fertility potential. While the prognosis for “older” (over 40) women with high FSH is indeed quite poor, younger women with high FSH should be advised to consider aggressive treatment early on in order to maximize their fertility potential with their own eggs. Great care must be taken in interpreting FSH levels, since the normal range varies greatly from lab to lab, as does the reliability of the test for predicting subsequent fertility.

Fertility rates in unexplained infertility

Studies show that when couples with unexplained infertility are followed for three more years 40-60% conceive on their own. The chance of conceiving is about 3% per cycle, far less than the normal cycle fecundity of about 20% in fertile couples. Unfortunately, no test exists to distinguish those couples who will conceive on their own from those who will still be childless three years later. Counseling for unexplained infertility should include assuring properly timed intercourse to maximize natural fertility potential. Periodic reevaluation is also important since problems that might benefit from specific treatment may develop over time. Without any “fertility crystal ball” to guide us, the age of the female partner remains the most important factor guiding the decision between watchful waiting and aggressive treatment. Younger women (in their 20s) who have normal ovarian reserve may have the luxury of time, since pregnancy rates with more aggressive treatments such as in vitro fertilization (IVF) remain high through the early 30s. Consideration of a woman’s current age and the magnitude of the drop in pregnancy rates with IVF over the next two to three years will help determine for how long a particular couple feels comfortable trying “on their own.” IVF pregnancy rates for couples with unexplained infertility are comparable to those for couples doing IVF for other reasons.

Why can’t we conceive?

How can you solve a problem if you don’t know what the problem is? Until recently, those with unexplained infertility typically spent a good deal of time and money undergoing extensive testing in search of “the cause.” With unexplained infertility, it is possible to overcome the infertility despite a lack of understanding of its causation (see below). But when the cause of infertility is known, treatment options also include targeted therapies aimed at overcoming a specific problem. For example, men who test positive for antisperm antibodies can be treated with immunosuppressive drugs, and couples with abnormal post-coital tests can be treated specifically with agents to improve cervical mucus quality. Until recently, women with infertility routinely underwent laparoscopy to detect conditions which could be treated surgically, such as endometriosis or pelvic adhesions. And many couples also routinely underwent more sophisticated laboratory testing, such as the sperm penetration assay (hamster test) and the hemizona assay, to more thoroughly assess sperm function. But since intracytoplasmic sperm injection (ICSI) now enables fertilization to occur in nearly all cases, the usefulness of these sperm function tests has been vastly diminished.

So when do you stop testing and begin treatment? For each recommended test you should ask “how will the result of this test affect my treatment options?” For women of older reproductive age it is generally unwise to delay the initiation of treatment by pursuing additional testing. On the other hand, younger women with unexplained infertility who would prefer to avoid IVF if possible are good candidates for a more thorough evaluation. The information derived from additional testing can sometimes suggest simpler, less expensive treatment options that may be effective.

How can we conceive?

Those with unexplained infertility must decide whether to continue the search for a cause or pursue “empiric” treatment (treatment which can boost the odds of conception whether or not the “cause” is ever found). Controlled ovarian hyperstimulation (giving fertility drugs to induce the ovulation of more than one egg per cycle) is most effective if combined with timed intrauterine insemination (IUI—the injection of washed sperm directly into the uterus). Fertility drugs can be given by mouth (clomiphene citrate) or by injection of either [1] human menopausal gonadotropins (HMG), a mixture of follicle stimulating hormone (FSH) and luteinizing hormone (LH) which is purified from postmenopausal women’s urine or [2] pure FSH, which is now generally a recombinant product, synthesized via genetic engineering).

Clomiphene with IUI is associated with few serious side effects but also lower pregnancy rates (no more than about 9% per cycle or 25% at three-to-four months).Women being treated with injectable fertility drugs must be monitored very closely to help avoid the risks of multiple birth and ovarian hyperstimulation syndrome, but pregnancy rates can be up to two to three times as high as with clomiphene. The highest pregnancy rates per cycle (about 30% nationwide for 1999, and as much as 50% per cycle for younger women in some programs) are seen with assisted reproductive technologies such as in vitro fertilization (IVF). IVF also provides information about fertilization rates and embryo development that can help explain the previously “unexplained.” For example, women may prove to be “poor responders” to fertility drugs despite previously normal testing for ovarian reserve. In other cases, embryos develop too slowly or are of poor quality, both of which correlate with decreased pregnancy rates. In rare cases, complete fertilization failure occurs despite normal appearing sperm and eggs. ICSI, a technique developed to achieve fertilization despite extremely poor semen quality, can also be effective in these cases, although interestingly, a majority of these couples will see fertilization occur “naturally” in subsequent cycles. Because ICSI is so effective in overcoming male infertility donor sperm is now rarely used for fertilization failure. But IVF with donor oocytes (“egg donation”) is highly effective at overcoming infertility related to poor egg quality or decreased ovarian reserve.

The dramatic rise in pregnancy rates for IVF has been associated with a trend away from extensive diagnostic testing and toward earlier utilization of empiric treatment. Women with decreased ovarian reserve or advanced age (beyond the early 30s) should be encouraged to consider aggressive treatment early on. Those wishing to avoid aggressive treatment if possible may benefit from a more thorough diagnostic evaluation. Because a significant number of couples with unexplained infertility will conceive on their own over time, some may reasonably choose to continue trying on their own a bit longer when no problem is found. And as with all infertility, psychological counseling may be helpful, especially in dealing with the added uncertainty associated with the label “unexplained.”