39 Yr Old TTC With Previous Miscarriage: Clomid Vs. Gonadotropins? Flare Vs. Antagonist Protocol?

Question:

Dear Doctor,

I am from India. I am 39. I had two missed abortions at 36 and 37 both in the eighth week and after the heart beat was felt.After leaving a gap of four months I have been trying to conceive naturally for 14 months without any result.

Subsequently I started Clomid 100 mg (day 3-7) at the advice of doctor.I did 3 cycles with Clomid out of which I got two follicles of ovulatory size (more than 18mm) in two of the cycles and one follicle (20mm) in one of the cycles.I did not conceive. My FSH and other hormones are normal.

I consulted a IVF specialist who examined me and said that my ovary volume is good and said that she will go for two cycles of IUI, if they are not successful she will go for IVF.

In my first cycle of IUI, the doctor did a trans-vaginal ultra sound on day 2 and gave the following medications from day 2 to day 5 (1) Suprefact 10 markings in the insulin syringe with 100 markings (BD 100 mark syringe) (between 1 to 2 pm daily)(2) GMH (human menopausal Gonadotropins (FSH+LH)) 225 IU (between 7-9 pm daily)

On day 6 she checked and told me that there is no response and the follicles have not grown.She changed the medication to GMH 375 IU per day on day 6 and day7 (between 7-9 pm daily) (She stopped Suprefact)

On day 8, she checked and told me that the follicles have not grown and advised cancellation of the cycle.Further she said that my follicles are not good enough for future trials of IVF or IUI and advised IVF with donor egg.

I asked her how I could get two ovulatory sized follicles (above 18mm) with Clomid in two of my three monitored cycles but nothing in this cycle and she is ruling out the possibility of the future trials. Her answer was that with Clomid or Letrozole even empty follicles grow and give a false impression that the follicles are growing and ovulating. But with Gonadotropins only follicles with good eggs will grow and that is the reason why my follicles did not grow with Gonadotropins. Is the above statement about Clomid and Gonadotropins correct. I will be grateful for your answer. R. from India

Answer:

Hello R. from India,

The simple answer is "NO. Her explanation is NOT correct." The gonadotropins are more effective than Clomid or Letrozole in recruiting and growing follicles because it IS the hormone the brain sends to the ovary for that purpose. Clomid and Letrozole work by an indirect method to cause the brain to increse its FSH output.

Also, she is NOT correct that gonadotropins only grow "good" follicles whereas Clomid grows "false" follicles. This explanation is made up and not scientific at all. In fact, no such thing exists. Sorry.I am not sure why your doctor cancelled your cycle. If the CD#8 ultrasound (which is early) or Estradiol level are showing a low response, the proper protocol is to continue going. Sometimes the follicle can grow slower. I have had patients get up to 21 days before ovulation occurs. In addition, the FSH should be increased if the stimulation is slow. I do not expect to have ovulatory sized follicles until at least CD#12.

I agree with you that since you stimulated with Clomid previously, you should readily stimulate with Gonadotropins as well. Maybe you should find a new IVF specialist. One thing to keep in mind, however, although your chances are still good at 39 years old, your previous miscarriage show what part of the problem is, which is that the eggs have aged and more and more of them are not of good quality. As a result, there is a higher chance of abnormal embryos which increases the miscarriage rate. IVF should help that because it increases the amount of eggs that are retrieved which in turn increases the possibility of finding an egg that is still good quality. You probably will need a high dose protocol using up to 600IU of FSH. IVF is definitely the way to go!

Follow-Up Question:

Dear Doctor,Thanks for your kind advice.The IVF specialist said the protocol given to me is the flare protocol meant for poor responders. Is that so? Then I do not understand why I did not respond to the protocol.

During my Clomid cycles my follicles reach ovulatory size by day 12. Do you think the poor response in the Gonadotropins cycle could be due the Suprefact Injection which was given from day 2 to day 5 along with Gonadotropins? Also kindly advise if it is necessary to add Suprefact or lupron early in the cycle or giving only FSH will help. Besides doctors here give Gonadotropins (FSH+LH) not Recombinant FSH. Is it better to give Recombinant FSH?

Kindly advise. R.

Follow-Up Answer:

Hello Again,

I do not like to comment on protocol specifics because there is no one way to do things. Please keep that in mind as I answer your questions. The "flare" protocol is one type of protocol used to stimulate the ovaries with IVF. It has no advantage over other protocols, but sometimes is used in patients that are designated as "poor responders". Studies have not shown it to be any better. I personally do not use the flare protocol. My preference is to use an antogonist protocol so that there is no suppression of the ovaries during the initial recruit phase, but I am in the minority in terms of centers that use this type of protocol.

In terms of your stimulation, I still think that a higher amount of medication may be warranted.

Both Suprefact and Lupron are medications called "gonadotropin agonists" and what they do is suppress the brain from producing FSH and LH.Gonadotropins are either pure FSH, pure LH or mixed FSH/LH. This is the name for that class of medications. Some IVF clinics only use FSH, some will use a mixed protocol of FSH and FSH/LH. Examples are Follistim (pure FSH) and Menopur (FSH/LH). My preference is the mixed protocol but many clinics will use FSH only protocols and some will use only the mixed FSH/LH medications. Studies have not show a necessary benefit of any of these protocols so they cannot be compared or criticized. Each doctor and/or clinic has their preferences. The most important aspect is how much FSH is being given because FSH (follicle stimulating hormone) is the hormone that stimulates follicle growth in the ovaries. Also, Natural vs Recombinant forms are equal. There is no difference.

Wishing you good luck with your TTC journey,

Dr. Edward J. Ramirez, M.D., FACOG
Executive Medical Director
The Fertility and Gynecology Center
Monterey Bay IVF Program
www.montereybayivf.com
Monterey, California, U.S.A.