Question 9. What is ovarian reserve, and how is it tested?

Ovarian reserve is a very important but confusing topic. I would like to share an interesting story about ovarian reserve before getting to the Question of the Day on this day after Saint Patrick's Day. For those reading this blog on Fertile Grounds, feel free to skip to the Question if you have already read this story in my post.

DK is a 38 year old who came to see me in September 2008. She and her husband had undergone fertility treatment 3 years earlier at another center and conceived with CC/FSH/IUI but had a quintuplet pregnancy that ultimately ended up as twins. They were very worried about having another multiple pregnancy and wished to discuss options.

However, as part of the evaluation her FSH was found to be 14 with a normal E2 but an AMH of<0.1 and an antral follicle count of 2-3. Although they had originally considered stimulated IVF with single embryo transfer that option seemed unlikely given her diminished ovarian reserve. After failing a few natural cycle IUIs they decided to try Natural Cycle IVF in 2009. Their first Natural Cycle IVF was a biochemical pregnancy. They tried Natural Cycle IVF again in June 2009 and were successful. She was sent off to her Ob Gyn with a normal looking pregnancy.

But the roller coaster was just getting cranked up....

She underwent a CVS given her age and the results showed that some of the cells were normal but some were trisomy 9 (not compatible with life). Her Ob Gyn was suggesting a D&C so she called me just to let me know what was going on. I fired off an email to Dr Mark Hughes (the world's smartest geneticist). Since we know that the 8 cell human embryo can contain both normal and abnormal cells (limiting the usefulness of PGS) I was thinking that maybe the CVS results represented a case of placental mosaicism where the baby is normal but the placenta has both normal and abnormal cells. Dr. Hughes confirmed that was indeed possible.

The couple elected to continue the pregnancy and undergo amniocentesis. The amnio was totally normal and all sonograms were normal. She went full term and just went home from the hospital today after delivering a healthy 9 pound baby!

So this case demonstrates many interesting points. First of all, is Natural Cycle IVF appropriate in a couple with normal tubes, normal sperm and previous pregnancy? The answer was a resounding "yes" in this case. Secondly, can ovarian reserve drop dramatically in just a few years? The answer is "yes" and although this case is a bit unusual in that the patient went from quints to diminished ovarian reserve in just 3 years. Thirdly, this case does demonstrate again the limitations of PGD/PGS and even CVS in cases of mosaicism. Finally, this case shows how important it is to consider all options especially when confronted with an unexpected result (like mosaicism on CVS).

I am so happy for this family and considering that I am not a big lover of roller coasters, all I can say is a few more wild rides like that one and I probably wont have any hair left at all!

9. What is ovarian reserve, and how is it tested?

During a woman’s reproductive cycle, each month a single follicle is selected out of a group of potential follicles, reaches maturity, and ovulates a single egg. Many fertility treatments use medications to “rescue” other follicles from that group, so that multiple eggs are released during ovulation as opposed to just a single egg. If physicians could predict which patients would respond well to fertility treatments, then those women predicted to produce a low number of eggs with a poor chance of success with stimulated cycle IVF could defer this treatment and consider other options including unstimulated or Natural Cycle IVF. Those women who respond well to fertility medications are described as having normal ovarian reserve. Those patients who have a poor response to fertility medications are described as having diminished ovarian reserve. Although those patients with diminished ovarian reserve are likely to demonstrate suboptimal numbers of eggs during a stimulated IVF cycle, they may still conceive spontaneously, or with non-IVF treatments or with Natural cycle IVF.

Ovarian reserve consists of two separate components, both of which determine a woman’s chance of conceiving a child with IVF. The first component is the number of extra follicles that are available to undergo recruitment with treatment using fertility medications. This number depends on several factors, including the woman’s chronological age (as discussed below), previous ovarian surgery, genetics, and exposure to environmental toxins (most notably, tobacco usage).

The second component is the actual health of the follicles and the eggs within those follicles. First and foremost, egg quality is determined by a woman’s chronological age. Peak female fertility occurs when a woman is in her twenties and then drops significantly with age, especially following age 35. This fact has been conclusively demonstrated in many ways but is especially obvious when we look at IVF pregnancy rates. In patients who undergo IVF, studies have shown that around the age of 35 years old a marked decrease occurs in the chance of an embryo implanting successfully. In addition, the miscarriage rate rises with age, especially in those women older than age 40, in whom this rate exceeds 50%. Therefore, the age component of ovarian reserve is essentially immutable. In other words, unless she uses eggs from an egg donor, a woman cannot change her chronological age—and with increasing age, the number of normal eggs inevitably falls sharply. Although it is true that the percentage of normal eggs within an ovary is specific to the individual woman, even the most fertile women possess very few normal eggs after age 40.

The concept of ovarian reserve testing, therefore, represents a means by which the physician attempts to evaluate a woman’s reproductive potential both in terms of the number of follicles that remain and the health of those follicles. There are several ways in which one can assess ovarian reserve. First, the woman’s follicle-stimulating hormone (FSH) level can be measured on day 2 or 3 of a normal menstrual cycle. An estradiol level should be obtained at the same time, because the FSH level can be misleadingly low in women who have a high estrogen level early in the menstrual cycle. Alternatively, ovarian reserve can be assessed by performing a transvaginal ultrasound and counting the antral follicles present. In women with a slightly elevated FSH level, a transvaginal ultrasound may reveal a large number of follicles—somewhat reassuring the patient and her physician that perhaps her ovarian reserve is more normal than might otherwise be expected.

Unfortunately, normal FSH and estradiol levels do not guarantee a normal response to fertility medications. The clomiphene citrate challenge test (CCCT) was initially described as a means to identify those women with normal FSH and estradiol levels on day 3 of the menstrual cycle (day-3 hormones) who may demonstrate a suboptimal response to injectable fertility medications and poor IVF pregnancy rates. In the CCCT, the patient takes 100 mg of clomiphene citrate on cycle days 5 through 9. An FSH level is checked on days 3 and 10. If both of these levels are less than 10 IU/L (international units), then this represents a normal response. If the FSH level is greater than 10 IU on day 3 but less than 10 IU on day 10, then this represents a borderline situation, but potentially reassuring based on the response of the ovary to stimulation with clomiphene citrate. If the FSH level is normal on day 3 but more than 10 IU on day 10, however, the woman is likely to exhibit a suboptimal response to fertility medication, along with high IVF cancellation rates and poor pregnancy rates.

Antimullerian hormone (AMH) is another blood hormone test that is often used to assess ovarian reserve. Many experts believe that AHM is a better indicator of ovarian reserve than serum FSH as it has less cycle to cycle variability. See Question XX for more information on AMH.

A word of caution is in order regarding ovarian reserve testing, including the CCCT: Virtually all physicians have patients who have successfully delivered a child following an abnormal CCCT. An abnormal CCCT or elevated FSH levels on cycle day 3 do not preclude spontaneous pregnancy and delivery. Nevertheless, the miscarriage rate and the incidence of Down syndrome may be increased in such pregnancies. Patients with diminished ovarian reserve may have successful treatment with the combination of fertility drugs and intra-uterine insemination (IUI), or even with IUI alone. More recently, unstimulated or Natural Cycle IVF has gained increased popularity in treating patients with diminished ovarian reserve. A recent paper from Italy described 500 Natural Cycle IVF cycles in patients who had previously failed to respond to ovarian stimulation medications. In spite of having such a poor history, over 10% of the women under 40 years of age achieved a pregnancy. Considering that in the United States, most of these women would have only been offered donor egg IVF, we consider that pregnancy rate to be very remarkable.

The real benefit of the CCCT is its ability to identify often those patients in whom stimulated IVF is markedly less likely to be successful, allowing them to focus on other options such as unstimulated IVF, donor-egg IVF, adoption, or less invasive office-based fertility treatments. Overall, ovarian reserve testing represents an important factor when considering various fertility treatments and may be the final arbitrator in selecting the specific treatment plan.

Rebecca comments:

I first walked into my RE's office at the age of 39. I had just suffered the loss of a pregnancy that had taken me 8 months to conceive. I was very aware of the proverbial 'biological time clock' and was concerned that my husband and I may have run out of time. I was panic stricken about the tests that would evaluate my ovarian reserve, however my desire to have children was greater than the fear I had about the test results. Fortunately, we found an RE who did not rely solely on my chronological age when he discussed our treatment options with us. He reviewed all my medical tests with me and offered an individualized plan that included a number of family building options that might address my infertility issues (most likely age related). Looking back, I realize how important our choice of RE was. It is important for women of advanced maternal age (AMA) to quickly identify an RE that is willing to work with, and is experienced in working with, women of AMA. An AMA woman must find a fertility clinic that offers a variety of fertility treatment options; one size (or one treatment) does NOT fit all. And finally, an AMA woman must find an RE who is willing to be aggressive in her treatment, but is also capable of being honest about the limitations of those treatment options for an AMA woman.