Oopause - poor ovarian response
Usually, ovarian function 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. In the past, the commonest test used was one which 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.
It's also useful to check your FSH:LH ratio. A normal FSH:LH ratio is 1. However, if your FSH level is much higher than your LH level, then this suggests poor ovarian reserve.
It's also a good idea to test your estradiol (E2) level on Day 3 at the time you check your FSH level. A high E2 level can artificially suppress the FSH back to normal, thus lulling you into a false sense of security. However , a high E2 level suggests poor ovarian reserve.
Another test which has been recently developed is the measurement of the level of the hormone AMH , in the blood. Low levels of AMH (which is 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 x width x height x 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.
Please do remember that doctors do not treat numbers - we treat patients, so don't obsess over just one number is isolation.
The final proof of the pudding is in the eating - and your response to superovulation is the best way of assessing your ovarian reserve. If you grow eggs well, then you should not worry about your "numbers" !
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. Dr Norbert Gleicher feels women have 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 !
Treatment for DOR ( diminished ovarian reserve)
Traditional teaching states that there is no treatment for a high FSH level. Once the ovarian reserve is depleted, the ovary cannot grow any new eggs. However, if you have a borderline high FSH levels, there are many alternative options you can explore to try to improve your ovarian reserve.
These include:
DHEA and wheat germ are now available in India from our clinic !
However, no clinical trials have been done to prove the efficacy of these interventions, so you need to understand that the results are unpredictable. However, you might want to explore these alternatives, so you have peace of mind you tried your best.
Read the book, Inconceivable, at http://www.amazon.com/Inconceivable-Womans-Triumph-Despair-Statistics/dp/0767908201
I had just advised a young woman who had oopause ( poor ovarian reserve) to try empirical therapy, with DHEA, wheat germ , yoga and acupuncture , before we started her IVF treatment.
She wanted to know the rationale behind my advise. " Doctor, on one hand you are saying that I have poor ovarian reserve, which means that I only have few eggs left in my ovaries. Women are born with all the eggs they will ever have and I cannot make any new eggs any more. In that case, how will taking all these medicines help me to grow more eggs during my IVF cycle ? "
This was my reply.
" Yes, it is true that we cannot make you grow new eggs. Your ovary contains all the eggs you will ever have. These eggs are in a resting phase, and are contained in primordial follicles. Each month some of these these follicles are selected and start growing. This group is called a cohort, and this is a response to the high FSH levels during the follicular phase. Of these follicles , only one will mature, while the others will die ( a process called atresia). It is our hypothesis that yoga and acupuncture will help us to recruit more of your follicles , so that if the cohort is larger, hopefully more follicles will mature when we superovulate you during your IVF treatment."
Some doctors prescribe estrogen tablets or birth control pills to women with high FSH levels. While this will artificially and temporarily suppress a high FSH level to the normal range, this will not improve your fertility, as these will not help you to grow eggs ! However, women take these tablets - and these create false hopes, because the FSH levels are now " in the normal range" !
Remember that the high FSH is NOT the cause of the infertility, which means that "treating the high FSH level" will NOT help. The high FSH level is just a marker of poor egg quality.
Check your own FSH and AMH levels
If you live in the USA, the good news is that you can now check your FSH levels yourself.
You can do this at MyMedLab !
Need help in interpreting the results ?
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. Remember that at the end of the day, we need just one good quality egg to create one good quality embryo to make one baby ! While it can be hard to find a needle in a haystack, it's worth making the effort !
Recently, we have had 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.
Typically, treatment starts from Day 2 of your cycle.
Day 1 = Day of bright red bleeding. If the bleeding starts after 6 pm count the next day as Day 1. Ignore the spotting.
On Day 2, you need to do an ultrasound scan to confirm there is no ovarian cyst, after which we start
your superovulation . This is done using a combination of Letrozole (which is also used for treating patients with breast cancer; and acts by boosting your own gonadotropin production) ; as well as gonadotropin injections.
Tab Letrozole (Femara), 5 mg daily from Day 2 - Day 6 with Inj Menogon (75 IU), 8 amp (600 IU ) daily from Day 2. The dose of HMG will depend upon your ovarian morphology and your antral follicle count.
From Day 7, you stop the Letrozole and start Inj Orgalutron/ Antagon, 0.25 mg daily . This is a GnRH antagonist which stops you from ovulating prematurely. The Menogon continues.
We do the next scan on Day 10, after which you would have to be in Bombay for about 10 days. Your husband is needed on Day 12-Day 14 (the day of the egg pickup). All the treatment is performed at our clinic, which means you never have to go elsewhere.
This is what the daily schedule would look like.
Day 1.
Day 2. Vaginal ultrasound scan to confirm there is no ovarian cyst. If there is no cyst, we can commence superovulation.
If there is a cyst, we aspirate (puncture) it and continue with the treatment.
Tab Letrozole (Femara), 5 mg daily . Inj Menogon (75 IU), 8 amp (600 IU ) daily
Day 3 Tab Letrozole (Femara), 5 mg daily . Inj Menogon (75 IU), 8 amp (600 IU ) daily
Day 4 Tab Letrozole (Femara), 5 mg daily .Inj Menogon (75 IU), 8 amp (600 IU ) daily
Day 5 Tab Letrozole (Femara), 5 mg daily . Inj Menogon (75 IU), 8 amp (600 IU ) daily
Day 6 Tab Letrozole (Femara), 5 mg daily . Inj Menogon (75 IU), 8 amp (600 IU ) daily
Day 7 . Inj Menogon (75 IU), 8 amp (600 IU ) daily. Inj Orgalutron, 0.25 mg daily
Day 8. Inj Menogon (75 IU), 8 amp (600 IU ) daily. Inj Orgalutron, 0.25 mg daily
Day 9. Inj Menogon (75 IU), 8 amp (600 IU ) daily. Inj Orgalutron, 0.25 mg daily
Day 10. Vaginal ultrasound scan to monitor follicular growth
The Menogon and Orgalutron injections continue until the follicles are mature (approx Day 12). Then the HCG injection is given, and eggs retrieved 36 hours after this.
Embryo transfer is performed 2 days later.
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 - those 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. We thouroughly enjoy treating such women in our clinic , because they get pregnant very easily when superovulated correctly !
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.
For some poor ovarian responders, we try empiric treatment with 75 mg DHEA daily for 12 weeks before trying a new IVF cycle. This can help to improve the ovarian response in some women, though results are unpredictable.
Interestingly, another option is doing natural cycle IVF or minimal stimulation IVF. This might seem paradoxical, but most women with poor ovarian reserve do have some good eggs in their ovaries ; and many of them do ovulate every month. However , aggressive superovulation does not help them to grow more follicles. This is why, instead of using high doses of HMG injections for superovulation ( which can be expensive !), we make use of the single follicle she grows in her natural cycle ( or supplement this with low doses of superovulation meds, so we can retrieve 2-3 mature eggs). The success rate with this approach is quite good !
This is the minimal stimulation IVF treatment plan we use.
Flow ( the day the period starts) = Day 1
Tab Letroz, 2.5 mg , 2 tab daily from Day 2 – Day 6
Inj Menogon, 75 IU, 2 amp IM daily from Day 2.
Scans every alternate day from Day 8
From Day 8, the Menogon will continue; and we will add Inj Cetrotide ( GnRh antagonist)
When the follicles are mature, we trigger with HCG and eggs retrieved after 36 hours. This is approximately Day 12 – 14.
Embryo transfer is performed 3 days later.
After the transfer, luteal phase support is provided with daily Progynova ( estradiol valerate2 mg, 3 tab daily; and Uterogestan ( 400 mg), 2 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.
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.