IVF and Premature Ovarian Failure

Although it sounds unlikely, pregnancy is possible when one is in Premature Ovarian Failure (POF). Stories of women diagnosed with POF, “giving up,” and then suddenly conceiving naturally are not uncommon. However, pregnancies from IVF are significantly less common in women diagnosed with POF.

Why?

The most likely explanation is that traditional high stimulation treatments don’t work very well, if at all, so few women and their physicians attempt it. Even minimal stimulation protocols for women with POF may not produce results.

However, with expert clinical guidance, persistence and lots of luck, IVF can be successful in POF.

The most important determining factor is a proper diagnosis. POF indicates that few or no eggs are present in the ovarian reserve, resulting in an elevated FSH. It is critical to rule out conditions such as Hypogonadotropic Hypogonadism (HH), a rare syndrome in which the pituitary gland is unable to produce FSH to stimulate the ovaries. As a result, the ovaries appear inactive and antimulerian hormone (AMH) levels may be low. While FSH is elevated in POF, FSH is low or entirely absent in HH. The treatment for HH is completely different from the treatment for POF, so an accurate diagnosis is essential.

Another important determining factor is the severity of POF. Despite the fact that “failure” implies complete non-function of the ovary, the diagnosis of POF is often used when, in the presence of elevated FSH, the period still exists but is very irregular. The presence of a period indicates that there is still egg development and ovulation, and as long as there is ovulation, the possibility of pregnancy still exists. Perhaps a better description for this clinical state is the alternative term, Premature Ovarian Insufficiency (POI). In severe cases, when a period is not present, there may be still an opportunity for pregnancy. Follicle development may be possible when FSH reaches ideal levels for stimulation. It is also important to understand that the absence of a period may also indicate another condition: Ovarian Hyperstimulation Syndrome (OSS). OSS occurs in some women who receive high doses of fertility medication, causing an extreme elevation in their FSH levels. Their ovarian follicles subsequently develop an insensitivity to FSH.

The other major factor is age. As with all fertility treatments, the younger a patient is, the higher the chance of success. There are numerous studies that show there is very little difference in live birth rates from eggs retrieved from women with DOR vs women with normal reserve. This applies to POF as well. If a patient is still menstruating (and occasionally when she does not) and is “young enough,” baseline FSH or AMH will not determine outcome. Dr. Lyndon Chang, Medical Director of Hanabusa IVF, has had successful cases in his clinical practice whose FSH levels were as high as 166 pg/ml and AMH levels were imperceptible. Most of these patients were in their late 20s or early 30s.

So how does one proceed?

First, there must be a commitment to the cycle no matter how few ovarian follicles are present. Physicians who follow a traditional IVF protocol cancel cycles and convert to intrauterine insemination or intercourse when there is not an “acceptable” number of ovarian follicles.
In POF, there may never be an ‘acceptable” number of ovarian follicles, but this does not eliminate the possibility of success. Many practitioners will argue that they have attempted to continue these “inadequate” cycles in the past, but were unable to retrieve eggs or retrieved eggs that were of very poor quality.

However, at Hanabusa IVF, a leading fertility and IVF clinic in San Diego, we believe that this need not be the case.

There are circumstances when the best strategy is to skip an egg retrieval and wait for more optimal cycle. A patient’s estradiol may be too low, ovarian follicle growth too slow, and/or LH persistently too high.

In some cases, natural cycle IVF (NIVF) is the best option. When FSH levels are too high, follicles will no longer respond to fertility medication. In POF, even minimal stimulation may be too much stimulation, and in DOR, no stimulation is often the only option. For patients with severe POF, NIVF may take some time. FSH levels are often naturally over 30 mIU/ml and follicle recruitment is often delayed, resulting in a menstrual cycle that is significantly greater than 28 days. In these cases, FSH suppression may help in the recruitment and development of follicles. Certain medications or supplements can lower FSH from excessively high levels to ideal stimulation levels, thereby increasing the likelihood that ovarian follicles will develop. Estradiol is a well-known suppressor of FSH, but any substance that has estrogenic/progestational qualities will achieve similar effects, including estriol or progesterone. Supplements touted to improve fertility in POF/DOR such as DHEA may also suppress FSH, although to a much lesser degree.

Patients with POF/DOR who follow an NIVF protocol must receive frequent monitoring of both serum hormone levels and ovarian follicle growth. An ultrasound evaluation of the patient’s ovaries indicates ovarian follicle size, which helps a physician determine the optimal time for egg retrieval. The evaluation of serum hormones levels including FSH, LH, progesterone, and estradiol is also critically important. Here are a few points about hormone levels that the fertility specialists at Hanabusa IVF take into consideration when managing patients on an NIVF protocol:

  • An FSH level between 5 and 30 pg/ml is ideal; because assays vary from lab to lab, it is up to the physician to determine what level is optimal.
  • An elevated LH (>10 mIU/ml) during the follicular phase of a cycle can slow egg maturity.
  • Progesterone can be helpful in determining the time frame of the cycle (whether it is the follicular phase or the luteal phase)
  • Serum estradiol levels are indicative of ovarian follicle quality. A mature follicle produces about 200-250 pg/ml of estradiol; levels below this threshold suggest that the egg quality is sub-optimal. In this case, the best course of action is often to cancel the retrieval and wait for a more optimal cycle.

At Hanabusa IVF, we have developed a set of guidelines for egg retrievals that maximize success in our POF/DOR patients. Because retrievals involve few follicles, local anesthesia may be preferable to IVF sedation, a procedure that is both more invasive and more expensive. The use of a 20- or 21-gauge retrieval needle (as oppose to the 17-gauge needle typically used) minimizes patient discomfort. The retrieval technique our physicians use is follicle flushing, as opposed to the single aspiration technique that is typically used, which risks missing difficult-to-obtain eggs.

Once the egg is retrieved, we recommend ICSI for fertilization. Although blastocyst culture with Preimplantation Genetic Screening (PGS) has become the norm, because of the scarcity of opportunities in POF/DOR culturing to Day 2-3 may be prudent.

In conclusion, at Hanabusa IVF’s clinic in San Diego, our fertility specialists have developed a rigorous set of guidelines for the clinical management for our patients with POF/DOR. Patients with POF/DOR require expert clinical guidance, persistence and luck. The patient and the physician supply the persistence. The luck, we just have to hope and pray for.