IVF and Diminished Ovarian Reserve

After months of failing to conceive on your own and countless tests and consultations, you have been told that you have Diminished Ovarian Reserve (DOR). Women receive this diagnosis when tests indicate that they have a low Antral Follicle Count (AFC), a low Anti-Mullerian Hormone (AMH) level and/or an elevated Follicle Stimulating Hormone (FSH) level.

What do you do?

First, do not panic. As long as you have a regular menstrual cycle (without the aid of medicine), the possibility of having a child with your own egg continues to exist. Even if you do not have a regular menstrual cycle, the possibility exists, but that is a different matter (i.e. IVF and Premature Ovarian Failure) and will be addressed elsewhere.

For those of you who have been told that DOR is the sole reason for your infertility, this is usually not the case. If you are cycling regularly, there is probably another reason for your infertility, and that needs to be explored.

Despite what you may have been told, IVF success is not impossible in the presence of DOR. There are numerous studies that show that there is very little difference in the rate of live births from eggs retrieved from women with DOR vs women with normal reserve. The younger you are, the more likely you will succeed, as is the case with all fertility treatments. The key challenge is accessing your eggs.

The traditional approach to IVF is not necessarily the optimal way to access your eggs if you have DOR. Traditional IVF protocols are designed to stimulate as many eggs as possible in the hope that some of these eggs will produce normal embryos.  The rationale for this approach is based on the observation that women who respond well to IVF medications and subsequently produce many eggs have higher live-birth success rates.

Unfortunately, women with DOR are at a significant disadvantage with traditional IVF protocols because they have fewer eggs available. IVF clinics routinely cancel cycles if patients do not demonstrate a minimum number of follicles during ultrasound examination. Therefore, women with DOR have a significant risk of IVF cycle cancellation at these clinics.

Reproductive endocrinologists and infertility specialists (REIs) use several techniques for their patients with DOR who are undergoing IVF. The most common technique is to compensate for fewer follicles by increasing the dosage of medications for stimulating follicle/egg development. (More is better!) Another common technique is to administer birth control pills or estrogen therapy to lower the FSH level prior to Day 1 of the cycle, then start stimulation. Another technique is to try to improve the quality of the egg reserve with various supplements and medications such as DHEA, CoQ10, human growth hormone (HGH), and corticosteroids. Unfortunately, none of these techniques work consistently and, in the case of using superstimulation protocols, numerous studies have shown that more medication is not better.

All of these traditional treatment options revolve around traditional super-stimulation protocols. It is not uncommon to hear stories of women with DOR whose follicles do not grow no matter how heavy the stimulation. Alternatively, too few follicles develop, and the cycle is canceled.  These women are then labeled “non-responders,” and it becomes a hopeless situation. It is also not uncommon to hear stories of women with DOR whose follicles started to develop when their stimulation medications were discontinued, or who produced comparatively more follicles when they received much lower  medication doses for an IUI cycle.

The tradionalist will argue that is not just an access issue. They will point out that when they do not cancel a cycle for a woman with DOR and proceed with the egg retrieval, the outcome was poor, which was the reason they were inclined to cancel in the first place.

Although natural cycle IVF and low stimulation protocols have been around since the advent of IVF (the first successful IVF pregnancy was a natural IVF cycle), these protocols only started to become more popular about 20 years ago in Japan. This rise in popularity was in response to the risks and complications associated with traditional superstimulation IVF. For quite some time, doctors who practiced minimal stimulation IVF observed that in cases of DOR, lower stimulation protocols were often superior to higher stimulation in gaining access to eggs.

Since these initial observations, we have found that follicles do not mature properly at very high levels of FSH. We don’t know why this happens, but Dr. Chang hypothesize that the receptors on the follicles eventually become insensitive to FSH, and sensitivity to FSH is necessary to mature the follicle properly. At Hanabusa IVF’s San Diego Fertility Center, we refer to this as “over-stimulation” syndrome. An interesting side note is that one definition of menopause is an FSH > 40 mIU/ml. The medications used in IVF to stimulate eggs are essentially pure FSH. These medications are essentially driving FSH closer and closer to (perhaps over) the level associated with menopause.  While there is no conclusive evidence concerning the effects of over-stimulation syndrome on fertility, we believe that the correlation between this phenomenon and sub-optimal access to eggs cannot be ignored, and is a salient reason that super-stimulation protocols are deleterious to women who wish to conceive a child.

Minimal stimulation can be effective for the following reasons:

  1. No cancellation. The basic foundation of minimal stimulation is that there is a natural progression with regard to egg quality. The lead follicle which occurs in nature is the egg that is most likely to result in a pregnancy for that particular month. Each additional egg that is stimulated in conjunction with the lead follicle is increasingly less likely to result in a normal pregnancy. There is no need to cancel due to low quantity since the quality of the eggs that develop in a minimal stimulation environment are most likely to be the best of the group.
  2. No overstimulation syndrome. Less medication means lower FSH levels, so over-stimulation is less of an issue.
  3. Preservation of the dominant follicle. This is an esoteric concept, but an important one. In minimalist philosophy, the lead follicle is the best one. It may not be the only egg that could result in a healthy pregnancy, but it is the most likely one. A common practice in traditional IVF protocols is to “sacrifice” the lead follicle (i.e., let it over-grow and over-mature) in order to allow more follicles to reach maturity. This practice may be fine for a woman in her early thirties with a normal egg reserve, but it is risky for a woman with DOR. It is also a poor treatment strategy for women over 40 years old. but, once again, that will be addressed elsewhere.

At Hanabusa, we achieve optimal results in the setting of DOR by:

  1. Using less medication than traditional IVF protocols
  2. Following a protocol that does not over-mature the lead follicle
  3. Aiming to retrieve eggs (regardless of the number) rather than cancel cycles
  4. Flushing the follicle during egg retrieval. There is a small chance that an egg will not be retrieved using the typical single aspiration technique. This may not be an issue when there are a dozen follicles, but it is a major issue when there are only one or two.
  5. Utilizing ICSI for fertilization
  6. Egg/embryo banking. DOR rarely improves. If you have a successful cycle, it will only get more difficult later on. Embryo freezing is very reliable now.  Collect your eggs and embryos now to optimize your chances for success by preparing for the future.

In DOR, success is often a matter of opportunity. Unfortunately, the traditional IVF approach often limits those opportunities. By following a minimalist protocol, patients with DOR have many more opportunities for success.