Oopause - poor ovarian response

One of the most frustrating problems in IVF today is that of poor ovarian response. This is also known as poor ovarian function, poor ovarian reserve, occult ovarian failure, or the oopause.

It’s well known that pregnancy rates in IVF are directly dependent upon the quality and number of embryos transferred, and the more the eggs a woman grows, the better the embryos we can select from. This is why women with a good ovarian response have much higher pregnancy rates than women with a poor ovarian response.

Usually, ovarian functions goes hand in hand with age, and as a women becomes older, her ovarian response starts declining. Every girl is born with a finite number of eggs, and their number progressively declines with age. A measure of the remaining number of eggs in the ovary is called the "ovarian reserve"; and as the woman ages, her ovarian reserve gets depleted. The infertility specialist is really not interested in the woman's calendar (or chronological age), but rather her biological age - or how many eggs are left in her ovaries.

Various tests have been described to measure ovarian reserve. The commonest test measures the level of FSH ( follicle stimulating hormone) in the blood - the basal ( day 3) FSH level. A high level suggests poor ovarian reserve; and a very high level ( more than 20 mIU/ml, though this varies from lab to lab ) is diagnostic of ovarian failure. A test that can provide earlier evidence of declining ovarian function is the clomiphene citrate challenge test ( CCCT).

This is similar to a " stress test " of the ovary; and involves measuring a basal Day 3 FSH level; and a Day 10 FSH level, after administering 100 mg of clomiphene citrate from Day 5 to Day 9. If the sum of the FSH levels is more than 25, then this suggests poor ovarian function, and predicts that the woman is likely to have a poor ovarian response ( she will most probably grow few eggs, of poor quality) when superovulated. Remember that a high FSH level does not mean that you cannot get pregnant - it just means that your chances are dropping because your egg quality is impaired.

Some women find it difficult to understand why FSH levels are high in women with poor quality eggs. Intuitively, more is better, so higher levels should mean better eggs, shouldn't it ? As one patient asked me, " If FSH stands for Follicle Stimulating Hormone, and I have high levels of FSH, then doesn't that mean that I have the ability to stimulate lots of follicles ? A high FSH should mean that I should have lots of eggs ! "

I had to explain the basic biology to her. Normally , FSH is produced by the pituitary, and this is the hormone which is responsible for the growth of the egg from the ovary every month. In young women with lots of good quality eggs, low levels of FSH are enough to grow the eggs. However, as the woman grows older and egg quality and quantity decline, the pituitary needs to produce more and more FSH to stimulate egg growth, because the FSH has to work harder to stimulate egg growth.

Another test which has been recently developed is the measurement of the level of the hormone, inhibin B, in the blood. Low levels of inhibin B ( which are produced by " good " follicles) suggest a poor ovarian reserve. However, just because a test result is normal does not mean that the quality or number of the eggs produced will be good - the final proof of the pudding is always in the eating ! This is why one of the most useful ways of making a diagnosis of poor ovarian reserve is when the patient gives a history of responding poorly to medications used for superovulation in the past.

Along with using biochemical tests to assess ovarian function, we can use biophysical markers to test these too. These biophysical tests use ultrasound technology to image the ovaries and the follicles. The most useful test is called an antral follicle count ( AFC) , in which the doctor counts the number of antral follicles ( also referred to as resting follicles) present in the ovary on Day 3 using vaginal ultrasound scanning.

Antral follicles are small follicles , usually about 2-8 mm in diameter. The number of antral follicles correlates well with ovarian response. A normal total antral count is between 15 and 30. If the count is less than 6, the prognosis is poor. You can read more about the antral follicle count and see ultrasound images of these at the www.advancedfertility.com website . The volume of the ovaries also correlates with ovarian response. The volume of each ovary is calculated using the formula ( length × width × height × 0.5 ) and the normal ovarian volume of both ovaries combined is 10 ml. Women with small ovaries ( volume of less than 4 ml) have a poor ovarian response.

While an older woman often expects to have poor ovarian reserve, and is prepared for the fact that she may respond poorly to superovulation, when a young woman finds out she is a poor ovarian responder, this comes as a rude blow. Most young women expect that their eggs will be fine, because they are young and have regular cycles, but this is not always true. Regular periods simply means that the eggs are good enough to produce enough hormones to have normal menstrual cycles; however, this does not mean that the egg quality is good enough to make a baby !

Ovarian reserve is a biological variable, and egg quantity and quality in an individual woman can be average for her age, better than average, or worse than average. Women with poor egg quality are said to have poor ovarian reserve , poor ovarian function, or occult ovarian failure; and Dr Jansen has coined the term , oopause, to describe this condition.

This diagram by Dr Norbert Gleicher illustrates the concept of a "fertility curve," which suggests there may be a "norm" for ovarian aging, and hence cases in which ovarian aging can be termed "premature."

Many women cannot understand why they will have a problem producing lots of eggs when they have regular menstrual cycles. " If I produce an egg every month, then why can't I produce a lot of eggs when you give me a lot of HMG injections for superovulation ? " I explain that just because a car goes at 10 mph when you drive it in 1st gear, this does not mean you can predict what it's speed will be when you drive it in 4th gear !

Many treatment strategies have been developed in order to treat women with poor ovarian reserve. Because time is at a premium for these women, treatment needs to be aggressive, in order to help them conceive before their eggs run out completely. IVF is usually their best option, as it offers the highest success rates. Superovulating these women can be quite tricky, and this is where the experience and the expertise of the doctor makes a critical difference !

While it is true that a skilled doctor will be able to design an optimal superovulation for women with poor ovarian reserve, it is also true that the results are still likely to be poor. While Michael Schumacher will drive your car much better than you will ever be able to, if you give him a broken-down lemon to drive , even his skills are likely to let him down !

They usually need much higher doses of gonadotropin injections ( HMG) for superovulation. We have used upto 750 IU of HMG ( 10 amp of 75 IU) daily for difficult women, in order to stimulate them to grow eggs. Unfortunately, this is like scraping the bottom of the barrel, and the quantity and quality of their eggs often still remains poor.

Recently, we have had extremely good results with the Letrozole-Antagon protocol for poor ovarian responders.

In this protocol, downregulation is not needed, and we use your own gonadotropins to improve follicular recruitment in order to help you grow more eggs.

For patient who are poor ovarian responders, we transfer all the embryos we get, to maximise the chances of implantation. In this group, the risk of a multiple pregnancy is very low.

After the transfer, luteal phase support is provided with daily Progynova ( estradiol valerate2 mg, 3 tab daily; and Uterogestan ( 200 mg), 6 vaginal suppositories daily. You can travel back 3 days after the embryo transfer.
14 days after the transfer, you need to do a blood test for beta HCG to confirm a pregnancy.

Other clinics have tried using rec FSH ( recombinant gonadotropins) or GnRH antagonists, but neither of these help. In the past, doctors tried adding growth hormone injections ( because of the “growth factors” this contained) , but this was of no use. Interestingly, some doctors have gone back to using the natural cycle, or trying gentle stimulation with clomiphene for these women, since they don’t see any benefit in spending hundreds of dollars just to get 2-3 more eggs for IVF.

Interestingly, we see a lot of women who are iatrogenic poor ovarian responders – who have a poor ovarian response because they have been badly superovulated. These are typically women who have PCOD ( polycystic ovarian disease), who are undergoing IVF in clinics which don’t have much experience with treating such patients. Because their doctors are so scared of ovarian hyperstimulation syndrome ( OHSS), in their anxiety to prevent this complication, they often trigger off ovulation and egg retrieval too early.

As a result of this mis-timing of the HCG shot, most of the eggs retrieved are immature, and fail to fertilise. These woman are then labeled as being poor ovarian responders , when in reality it is their doctors who are poor ovarian stimulators ! If they are superovulated properly in a good IVF clinic, their pregnancy rates are excellent.

What happens if you are young and find that you have a poor ovarian response in the middle of your first IVF cycle ? This is a very difficult problem, because it was not anticipated, and you are not emotionally prepared to deal with it. Options include: continuing the cycle with an increased dose of injections; or canceling this cycle and starting a new cycle later with a higher dose of injections. However, the prognosis remains poor, and there is no certainty that you will grow more eggs with a higher dose the next time around.

The option which offers the highest pregnancy rate for women with a poor ovarian response is to use donor eggs. While this is medically straight forward, it can be very hard for a young woman with regular cycles to accept this option. Often, it’s worth doing one cycle with your own eggs even if the chances are poor, so that you have peace of mind that you did your best. This also may make it easier to explore the option of donor eggs for the future.

Source: https://www.drmalpani.com/articles/highfsh

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Category: antral follicle counts, Clomid, Donor Egg, FSH, Hormones, infertility, IVF, medications, Old Eggs