IVF Ovarian Stimulation: The GnRH Agonist / Antagonist Protocol
702-892-9696
Fax:
702-892-9666
GnRH antagonists (e.g. Ganirelix, Cetrotide, Cetrorelix and Orgalutron) are currently used with many controlled ovarian hyperstimulation (COH) protocols. They are traditionally prescribed at the dosage of 250mcg daily from the 6th or 7th day of stimulation with gonadotropins. This is completely acceptable for younger patients (under 39 years) and for good responders to COH who have normal ovarian reserve (i.e. normal day 3 FSH, AMH, and Inhibin B blood levels). However, it can be disadvantageous in women who have elevated baseline luteinizing hormone (LH) levels (e.g. those with polycystic ovarian syndrome [PCOS], women over 40 years of age, and poor responders who have diminished ovarian reserve). In such cases, the abrupt pituitary suppression that rapidly follows administration of the GnRH antagonist, (when it is first administered several days after the COH begins), occurs too late in the cycle of stimulation to suppress LH before it begins adversely affect follicle and egg development
Background Information
One of the roles of LH is to promote male hormone (androgen) production through the connective tissue that surrounds follicles (the stroma or theca). The androgens (maily testosterone) represent the building blocks from which the follicle granulosa cells manufacture estrogen. While a small amount of stromal androgen is essential for optimal follicular growth and egg development, too much can compromise their development. Accordingly, unless the LH levels are regulated by the GnRH antagonist from early in the cycle of COH, the developing follicles and eggs of women who have chronically elevated LH levels can be overexposed to stromal androgens for several days before GnRH antagonist suppression is in effect. This can and does adversely influence egg/embryo quality and perhaps even endometrial proliferation in response to estrogen .
The “Premature LH Surge”
Presumably, the reason for the suggested mid-follicular initiation of high dose GnRH antagonist is to prevent the occurrence of the so called “premature LH surge”, a condition where high LH levels cause “follicular exhaustion” resulting in poor egg/embryo quality. But the term “premature LH surge” is a misnomer since it suggests a sudden unanticipated rise in LH that occurs as a “terminal event” or an isolated occurrence. In actuality, what happens is the result of a progressive escalation in LH (the so called “staircase effect”) that through a persistent rise in stromal androgens, ultimately exhausts the follicle and damages the egg irreparably.
A more accurate term might be “premature luteinization.” Against this background, trying to improve ovarian response and prevent follicular exhaustion through administration of GnRH antagonist initiated late in the cycle of COH is like shutting the gate after the horse has already left the stable.
As stated, the use of such “late–follicular” GnRH antagonist protocols in younger women or in women with normal LH and ovarian reserve will probably not produce such adverse effects. However, the more appropriate question might be: since such women are not at risk of premature luteinization, would they even require pituitary LH suppression? I doubt that they do! It is my position that some form of pituitary blockade, either in the form of a premenstrual GnRH agonist administration (e.g. Lupron, Buserelin, Nafarelin, Synarel. Decapeptyl) or GnRH antagonist (e.g. Cetrotide, Cetrorelix, Orgalutron, Ganirelix) is beneficial for older women, women with elevated LH, and for those with diminished ovarian reserve, undergoing COH for IVF. Only in this manner can the adverse effects of LH –induced ovarian androgen elevation on follicle/ egg development be averted.
With GnRH agonist (e.g Lupron) down-regulation protocols (where the pituitary gland is first largely exhausted of LH before COH begins) the residual amount of LH in the circulation is minimal by the time COH with gonadotropins is initiated. The above-mentioned adverse LH-induced androgen effect is thereby largely negated.
The agonist/antagonist conversion protocol
The downside of prolonged GnRHa (e.g. Lupron) administration throughout the cycle of COH is that the GnRHa, by competitively binding with ovarian follicle stimulating hormone (FSH) receptors, can suppress ovarian response to gonadotropins. To counter this effect, we introduced the Agonist/Antagonist Conversion Protocol (A/ACP).
With the A/ACP, only a low dosage (125mcg/day) of GnRH antagonist is injected daily. It is commenced at the onset of spontaneous menstruation, or after the onset of menstruation that follows the initiation of GnRH agonist (e.g. Lupron) therapy that is administered in a long-pituitary down-regulation protocol arrangement. We currently prescribe some form of the A/ACP for most of our IVF patients regardless of whether they are “normal responders” or “poor responders”. Results suggest a significant improvement in egg number, egg/embryo quality, as well as implantation and viable IVF pregnancy rates.
The A/ACP for poor responders
The A/ACP has, however, proven to be most advantageous in “poor responders” with diminished ovarian reserve, where additional enhancement of ovarian response to gonadotropins may be achieved through incorporation of “estrogen priming”. We have reported on the fact that the administration of intramuscular estradiol starting about a week prior to commencement of COH often markedly enhances ovarian response (presumably by enhancing the sensitivity of ovarian FSH-receptors), and improves egg/embryo quality. We refer to l this as the A/ACP+ E2V.
It is remarkable that while using the A/ACP + E2V in poor responders whose FSH levels were often well above threshold limits, the cycle cancellation has consistently been maintained below 10% (much lower than expected). Many such patients who previously were told that they should give up on using their own eggs and switch to ovum donation because of “poor ovarian reserve”, have subsequently gone on to achieve viable pregnancies using the A/ACP with “estrogen priming”.
What are the downsides of the A/ACP? There is one potential drawback to the use of the A/ACP, in that prolonged administration of GnRH antagonist throughout the stimulation phase of the cycle compromises the predictive use of serial plasma estradiol measurements as an indication of ovarian response to COH. The estradiol levels tend to be much lower in comparison with cases where GnRHa alone is used, or where a “conventional” GnRH antagonist protocol is commenced 6-8 days following initiation of gonadotropin stimulation. The reason for the lower blood concentration of estradiol seen with prolonged exposure to GnRH-antagonist could be the result of subtle, antagonist-induced alterations in the configuration of the estradiol molecule, such that currently available commercial test used to measure estradiol levels are rendered less sensitive/specific.
Accordingly, when the A/ACP protocols are employed, we rely much more heavily on the measurement of follicle growth by ultrasound than on the estradiol levels. Because of this downside, we confine the use of A/ACP protocols to normal and poor responders – refraining from using this approach in “high responders” who may be at risk of developing of severe ovarian hyperstimulation syndrome (OHSS) and in whom the accurate measurement of plasma estradiol plays a very important role in the safe management of their COH cycles.
38 Responses to “IVF Ovarian Stimulation: The GnRH Agonist / Antagonist Protocol”
Leave a Reply
Top Search Terms for In Vitro Fertilization
- Embryo Quality & Embryo “Competence” – Part III – Testing the Seed
- Embryo Quality & Embryo “Competence” – Part One: Planting a Good Seed
- The Needle vs. the Dish: Should ICSI Be Used in All IVF?
- Embryo Implantation: What Farmers Can Teach us About Growing Healthy Babies
- Acupuncture and IVF: Does it Improve Success?
Ask Our DoctorsA Question














Is there any Doctor that you know of that can grant this wish ?
Wisher:lawenforcementwife
Wish direct link :
http://wishuponahero.com/wishes/?id=313987
Hello Dr Sher, I came across this wish on WishUponAHero.com and I started to do some research to see if this wish could be granted. I googled and I came up with your site. If you can read this wish and know someone that could grant it please pass it on .Thanks!
I posted the wish at the bottom of this message and I posted the direct link over this message.
I WISH that we could find a good fertility doctor…
My husband and I have been married for almost 7 years. We spent the first 3 years of our marriage trying to have a child. We ended up spending over $50K in treatments & medications, but finally in 2006 were blessed with a beautiful baby girl. We would love for our daughter to have a sibling. My wish is that we could find a fertility doctor to discount the rates or donate his time so that we may be blessed with another child. We have so much love to give. I have faith that God will find a way to make this happen. If anyone knows of any good doctors in Missouri please share your information with us. Thank you & God Bless!
~ Kelly ~
Please contact the IVF support group the "InterNational Council on
Infertility Information Dissemination (INCIID) about their INCIID the Heart program that provides free IVF to qualifying couples. Talk to Nancy Hemenway Phone # 703-346-8402.
Good luck!
Geoff Sher
Would you suggest the A/ACP + E2V protocol for a patient with Factor V Leiden?
Thanks!
No reason not to! The thrombophilia is in no way related.
Geoff Sher
Dear Dr. Sher,
I am beginning my second round of IVF shortly, and my doctor has prescribed a protocol that sounds similar to what you've described above. I would take 3mg Centrotide on day 2 of my cycle and begin Follistim around day 7, adding more Centrotide once the follicles reached about 14mm.
I am 32, "lean" PCOS with insulin resistance, mild/subclinical hypothyroidism, and high DHEA-S levels. No male factor. With metformin and thyroid medication, I have begun ovulating normally but without pregnancy. We have had a year's worth of unsuccessful clomid/letrozole + IUI cycles and one IVF that resulted in a biochemical pregnancy (I responded well to that cycle, with 11 fertilized eggs but only one good quality blastocyst transferred on day 6). All my doctors have agreed that suppressing me prior to stimulation would be beneficial for egg quality, but I haven't come across a protocol that starts suppression on Day 2. Have you heard of this? Any ideas or suggestions as to a good approach?
Thanks for your thoughts.
Jenny
Dear Dr Sher, your A/ACP protocol is rather long, mostly u would start with BCP and GnRH agonist and wait for a period before starting on GnRH antagonist then Stim. Could it be possible to start GnRH antagonist right after spontaneous menstruation and then Stim? Will it work too? U mentioned this option in another entry but overall I see that you seem to advocate the long treatment with BCP.
I have failed two cycles so far with down regulation Agonist treatments, all embryos did not implant..seeming poor quality I assume. I am 37 and have lower ovarian reserve 6.0pmoL.
Would appreciate your comments. Thanks!
Dear Dr. Sher,
my protocol with Merional, Fostimon and Cetrotide injections brought 15 eggs, out of them 5 made it to the blastocyst stage after ICSI, 3 blastocysts were implanted and there was nothing to freeze. After the transfer I received the prescription for Progesteron 100 mg once daily but due to the mistake of pharmacy received only 50 mg daily. Blastocysts were transferred on 23/Jan/2013, BHCG on 01/Feb/2013 was less than 2. Until now (04/Feb/2013) I have no period. Is there a possibility that I am pregnant?
Wait a few days and repeat the beta. It can sometimes lag.
Good luck!
Geoff Sher
Hi Dr. Sher
I’m 42yo and here is my history:
1st IVF 2009 – 5 fert, d5et 2 blasts, bfn, Lupron, 225GF, 150M,
2nd IVF 2010 – 13 embrios, d5et 2 blasts, DS, 225 gf, 75M
3rd ivf 02/2012 – 2 embrios, chemical, 225 gf, 150M
4th IVF 10/2012 – d3et, 3 embrios, BFN, EPP, 300gf, 75M,
5th IVF 01/2013 – d3et, 4 embrios, BFN, BCP, MDL, 450gf, 150M,
Follicle Stimulating Hormone 7.06 mIU/mL
Anti-Mullerian Hormone (Quest 91000102) 1.74 ng/mL
For my next cycle my RE sufggested the following: 6th IVF 2013 – co-culture, EEP, clomid, 450gf, 150M, PIO + E, AH
What do you think of this protocol? Was protocol #5 what you would concider an Agonist / Antagonist protocol?
Thanks,
Anna
I personally never use clomiphene in IVF any longer.
Good luck!
Geoff Sher
Hello Sir,
Your blogs are great source of information. Unfortunately, I just found them a little late…so here is my question:
I am starting my 1st IVF, I am 32 and was identified with high prolactin( 50 ) last year which is now in control around 7 with the medication. My husband is 33 and has been identified with 2% morphology, We had two unsuccessful IUI’s (Clomid and ovirdrel) and are now moving ahead with IVF. Rest, we seem to have no issues from all the tests done.
My AMH- 2.04, FSH 6.1 and Estradiol 42.
Here are my stims, from your article it seems I am on long protocol but would appreciate if you could provide your thoughts on stimulation medicines.
BCP – Desogen – 3 weeks
Lupron – 10 units from 17th day of BCP and then BCP ends on 21st day.
Then I start 1 vial of menopur and 225 of follitism after 2 weeks of lupron. That day lupron goes down to 5 units and I continue all three till HCG shot…
Does this sound good to you?
Thank you!
DD
Sounds pretty good to me as long as all other bases have been covered such as implantation issues. You have normal ovarian reserve and I would anticipate that you will produce a good number of eggs. By the sound of things you have an excellent chance of being successful.
Please go to the home page of this blog, (www.IVFauthority.com). When you get there look for a “search bar” in the upper right hand column. Then type in the following subjects into the bar, click and this will take you to all the relevant articles I posted there.
1. “An Individualized Approach to Ovarian stimulation” (posted on November 22nd, 2010)
2. “Ovarian Stimulation in IVF: Why is it important to down-regulate LH?”
3. “Agonist/Antagonist Conversion Protocol”
4. “Immunologic Implantation Dysfunction” (posted on May, 10th and on May 16th respectively.
5. “Embryo Implantation………” (Part-1 and Part- 2—-Posted August 2012)
6.“A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)
8. “IVF success: Factors that influence outcome”
Good luck!
Geoff Sher
800-780-7437
Thank you so much for your quick response and kind words. I forgot to mention that we will be doing ICSI.
I have gone through all the articles you mentioned but I am not sure which tests I should be doing. I have done saline infusion sonogram already and everything looks fine. Also for mock transfer, my RE suggested since I have already IUI with her, there is no need to repeat that process.
Shall I ask to get done the blood work done for immunologic i.e. CTL and NK cell and should we do PGD?
Are there any other tests that you would think we should be doing for implantation checking?
Appreciate all your answers. They mean a lot!
DD
I cannot advise further. It would be intrusive. This is now between you and your RE.
Good luck!
Geoff Sher
The starting beta was very high so it could be that >1 took and is now in the process of spontaneously reducing. Time will tell.
Good luck!
Geoff Sher
AS I indicated,
I cannot immerse myself further. I would do those tests if I were you!
Geoff Sher
800-780-7437
Hi Dr Sher,
I am now on BCP and Lupron .5mg and I will be on this for a couple of days more when I will stop BCP and continue Lupron. My RE wants me to continue Lupron until i go to the clinic for the ultrasound scheduled for a specific day. Do you think this may work, continuing taking lupron even if i get my period until the day of ultrasound and then replace it with 125mcg antagonist the day of my ultrasound, same day when i start the gonadotropin therapy?
Because my u/s is scheduled for a specific it is a good idea continuing with lupron while on my period?
I understand you don’t intend to change my RE protocol but I would just like to know your opinion on this.
Thank you very much,
Emily
It will not do harm Emily!
Good luck!
Geoff Sher
Dear Dr Sher,
I live in Canada and I will start my treatment soon with my local RE. He will have me on birth control pill and .5ml buserelin instead of lupron. During the stims I will be on 125 orgalutran, 200 puregon and starting day 3 of stims on 37.5 menopur. In your opinion, do you think it is better to use a pure LH form as Luveris instead of menopur that is combined with FSH or it should be the same? ( as 237.5 puregon and 37.5 luveris versus 200 puregon and 37.5 menopur).
My FSH is 5.9 and LH 8.1 and I respond normal to the meds. Do you consider adding 37.5 menopur on day 3 of stims, a good choice or should I be just on puregon?
On the A/ACP protocol there is still a risk of oversuppression and not responding well during stims or because we switch to an antagonist, this will not happen?
Thank-you very much for your help,
Julia
Low dosage Menopur is as good as Luveris.
Good luck!
Geoff Sher
hi dr sher, I am 37 and ttc for 10 yrs, my fsh is 11 and amh is 8.3, i have no other issues.I have just had my 2nd 1vf cycle, no eggs were retrieved. on the first cycle i got 3 eggs out of 9 follicles, i had a chemical pregnancy from that cycle.i used a short protocol for each cycle with a higher dose of gonal on the 2nd cycle.my re has recommended three protocols for my next cycle.1. estrogen priming then using femara for 5 days at start of stimulation then menopur,gonal f and cetrotide on day 7. 2. long protocol or 3. short flare protocol using synarel, please can you advise which you would recommend i use
You are probably aware that I personally am against the use of short protocols for women who have diminished ovarian reserve because in my opinion, it causes increased LH which results in excessive ovarian testosterone which can adversely impact on egg/embryo quality. I prefer using the long pituitary down-regulation protocol referred to as the agonist/antagonist conversion protocol (A/ACP).
Please go to the home page of this blog, http://www.IVFauthority.com . When you get there, look for a “search bar” in the upper right hand corner. Type the following subjects into the bar, click on it and it will take you to all the relevant articles posted there.
1. “An Individualized Approach to Ovarian stimulation” (posted on November 22nd, 2010)
2. “Ovarian Stimulation in IVF: Why is it important to down-regulate LH?”
3. “Agonist/Antagonist Conversion Protocol”
Consider calling 800-780-7437 or 702-699-7437 to arrange a Skype consultation (free of charge to those who reside in the United States or Canada) with me so we can discuss your case in detail
Geoff Sher
Dear Dr Sher
Thank you for your reply. Do you think using femara is useful. I know you don’t use clomid at all, but would you recommend femara?
Thank you
Dear Dr Sher.
Thanks you so much for your informative articles.
I am 40 with a low amh of 4. My husband and I have had 2 failed cycles of icsi. I have responded poorly in both cycles to different protocols used.
The protocols I have responded poorly to were (i) the long protocol ( buserelin/ 300iu menopur) and (ii)’the short protocol (600iu gonal-f/ 75iu luveris followed by introduction of 0.25mg cetrotide 6 days after administration of gonal-f/ luveris). In both cases I had few weeks of combined pill first. In the case of the short protocol I was pre treated with dhea.
Although I did manage to have a top quality day 3 embryo transferred in both cases ( with negative result), I am anxious to see if protocol and my response can be improved.
I am interested in your A/ACP +E2V protocol but am concerned that I may experience ‘oversupression’ like I did in buserelin- long protocol.
My questions are as follows:
-Do you think I would be a suitable candidate for your protocol or is my ovarian reserve/ my response too poor to make much of a difference?
- With your protocol is it possible to lower dose of gonal-f/ luveris (or menopur) and still acheive better response?
Women like me tend to be hit with very high dose gonadotropins and I am concerned about the impact of same on egg quality. From your article, I am also concerned about dose of luveris used ( or LH contained in menopur) ie I am concerned re too much LH being used.
3. Do you do skype consult for international ( European) clients who are not in a position to travel to the states?!!!!
Many, many thanks.
No! In fact you would be an ideal candidate for the estrogen priming with an aggressive A/ACP stim. However, please expect it to take an additional few days to respond on the E2 priming approach .
Geoff Sher
Many thanks for that info Dr Sher.
Regarding my second icsi cycle ( short antagonist protocol) just looking at my bloods- my baseline serum LH was 0.9IU/L and 5 days into stimulating with 600iu gonal-f/ 75iu luveris, serum LH rose to 1.4IU/L . So, reflecting what you said in your article there was a LH surge.
By day 8, following cetrotide administration on day 6, the LH level dropped to 0.7IU/ ml.
Im concerned however, that overall, alll the serum LH levels measured are very low.
Are such low LH levels normal or typical with diminished ovarian reserve?
Does the kind of rise in serum LH I experienced with this protocol typify what you expect ?
Many thanks.
Frankly it does not look too bad…but I do not use short antagonist protocols in women with DOR.
Geoff Sher
Dear Dr Sher,
Please can you give your opinion.For my next ivf protocol the flare up protocol has been recommended. I responded poorly to previous cycles. the last one retrieved no eggs. my amh is 8.3 and fsh 11. The protocol uses synarel and gonal f and menopur. Do you think i will respond better to this protocol. would i benefit from estrogen priming before my next cycle? how long do you use estrogen priming treatment? Thank you
No! I am not a fan of the “flare protocol at all” (see below) and estrogen priming will have no benefit in your case.Please go to the home page of http://www.IVFauthority.com. When you get there look for a “search bar” in the upper right hand column. Then type in the following subjects into the bar, click and this will take you to all the relevant articles I posted there.
1. “An Individualized Approach to Ovarian stimulation” (posted on November 22nd, 2010)
2. “Ovarian Stimulation in IVF: Why is it important to down-regulate LH?”
3. “Embryo Implantation………” (Part-1 and Part- 2—-Posted August 2012)
4. “Traveling for IVF from Out of State/Country– The Process at SIRM-Las Vegas” (posted on March, 21st 2012)
5.“A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)
Consider calling 800-780-7437 or 702-699-7437 to arrange a Skype consultation (free of charge to those who reside in the United States or Canada) with me so we can discuss your case in detail
Geoff Sher
thank you Dr Sher, I’m just confused as to why you say that estrogen priming would have no benefit?
I did not imply that it will have no benefit, but it will not benefit everyone. It will in my opinion only benefit Very poor responders with severely diminished ovarian reserve.
Geoff Sher
I introduced estrogen priming but have found that it only benefits those with SEVERE DOR.
Geoff Sher
Greetings Dr. Sher,
Have you ever heard of a Ganirelix/Microflare protocol? It requires bcp for three weeks overlapped and followed by ganirelix. After 6 days on the ganirelix and after baseline info collected the stims start (Menopur 75 2x a day and Gonal-F 300 2x a day). What are your thoughts on this protocol? I thought it was the agonist/antagonist protocol, but it does seem like it is.
Ganirelix and other antagonists” do not cause a flare. It suppresses FSH and LH very rapidly. Lupron (and other agonists) by expunging FSH from the pituitary gland cause a “flare effect”. I respectfully do not agree with starting a stimulation coming off a BCP without 1st overlapping with an agonist such as Lupron or Buserelin. See the article I wrote on “use of the BCP in IVF” , elsewhere on this blog.
Feel free to call 800-780-7437 if you would like to discuss further via a Skype consultation with me.
Geoff sher
Hello. Is estrogen priming for women with DOR and low to mid-level response to gonadotropins harmful when there is also a diagnosis of Endometriosis?
Thank you,
Valerie
No it is not!
Geoff Sher
I have low Amh .10 and fsh in the last two years of 9 and 11. 2 resting follicles each side. 1st Ivf cancelled with only 2 produced from 225 menopur and glonal. Trying Seattle for 2nd try 8 months later would I benefit from estrogen priming and long pituitary down regulation protocol? I am 38.
Yes, you need a very aggressive agonist/antagonist conversion protocol with estrogen priming. You should also seriously consider Staggered IVF with embryo banking starting ASAP (see below).Please go to the home page of http://www.IVFauthority.com. When you get there look for a “search bar” in the upper right hand column. Then type in the following subjects into the bar, click and this will take you to all the relevant articles I posted there.
1. “An Individualized Approach to Ovarian stimulation” (posted on November 22nd, 2010)
2. “Ovarian Stimulation in IVF: Why is it important to down-regulate LH?”
3. “Agonist/Antagonist Conversion Protocol”
4. “Traveling for IVF from Out of State/Country– The Process at SIRM-Las Vegas” (posted on March, 21st 2012)
5. “A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)
6. “IVF success: Factors that influence outcome”
7. “Staggered IVF”
8.“Embryo Banking”
Consider calling 800-780-7437 or 702-699-7437 to arrange a Skype consultation (free of charge to those who reside in the United States or Canada) with me so we can discuss your case in detail