Best Ovarian Stimulation Protocols for IVF with guest Dr. Geoffrey Sher
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This article originally appeared on The Egg Whisperer Show, hosted by Dr. Aimee Eyvazzadeh. You can find her site, along with other episodes like this one at her website: https://draimee.org/blog
Dr. Geoffrey Sher joins Dr. Aimee again to talk about his approach to care when it comes to IVF. They are discussing how he individualizes ovarian stimulation protocols to optimize egg embryo quality, giving his patients the best chance of IVF pregnancy.
Dr. Sher helped fashion the entire field of ART. After training under the fathers of IVF, Doctors Patrick Steptoe and Robert Edwards, he established the first private IVF program in the United States in 1982 with his partner Dr. Ghanima Maassarani. He then went on to open 10 more IVF centers throughout the U.S., most recently culminating in Sher Fertility Solutions, with offices in Las Vegas and New York City. He’s authored more than 200 articles and several books.
Dr. Aimee: What are your favorite ovarian stimulation protocols?
Dr. Geoffrey Sher: This is probably the most important aspect of the entire IVF process. There is no “one-size-fits-all” approach. You must individualize protocols.
Protocol selection is based upon a few basic physiological principles. These are that the ovary comprises two compartments. Follicles are the dark areas that are seen on ultrasound and stroma or theca which is a white perimeter surrounding the follicle. The stroma produces androgens such as androstenedione and testosterone. The latter is the most important because it is the “building block” from which the follicle will form estrogen (estradiol-E2).
Testosterone is carried from the ovarian stroma/theca in a bucket brigade fashion to the Granulosa cells that line the inside of the follicle. There, under the effect of FSH, it is enzymatically (desmolase and aromatase activity), converted to E2. As this happens, the granulosa cells multiply, the follicle stretches, and secretions pour into the inside of the follicle which distends while the granulosa cells that line the follicle, multiply. We measure the size of the follicles by ultrasound, and we measure the estradiol in the bloodstream, to assess follicle development.
It’s important to have some testosterone present or no follicles will grow, and no eggs will develop. Thus, the emphasis is upon there being some testosterone delivered to the Granulosa cells…. but not too much. Studies have shown that too much intrafollicular testosterone reaching the follicular fluid has the reverse effect. It compromises egg and follicle development and promotes premature luteinization such that the follicle stops growing and the egg often does not develop properly. This can be a serious problem. In biology, if a system fails to develop properly, it won’t ripen or “mature” optimally. If this happens, the “LH/hCG trigger” will be less likely to affect the orderly “maturation” of the eggs and a greater percentage of them will end up being chromosomally abnormal (aneuploid) and “incompetent”. This problem is further magnified in older women and those that have “diminished ovarian reserve” (DOR).
It is the “hCG/LH trigger” that sends the egg into a reproductive (maturational) division known as “meiosis.” Up until the “LH/hCG “trigger”, virtually all eggs contain 46 chromosomes…. two pairs of 23, (one from the mother and one from the father). The purpose of meiosis is to divide the chromosomes down the middle, shed half of the chromosomes to the periphery of the egg as a “polar body”, and so facilitate the chromosome number in the egg being reduced to 23 (half their original number). Each spermatozoon goes through a similar process, also ending up with 23 chromosomes. Only, when it comes to the sperm, it divides into 2 mature spermatozoa…each with 23 chromosomes. Thus, the resulting healthy embryo goes back to comprising the normal human genomic number of 46 chromosomes.
If an embryo has more or less than that normal genomic number of 46 chromosomes, that particular embryo is “incompetent,” (aneuploid) and it will either not continue to divide, will divide but it won’t attach in the uterus; will attach and be lost in very early pregnancy (chemical pregnancy or miscarriage) or will propagate and aneuploid conceptus (e.g. Down syndrome). The bottom line is that it is the egg rather than the sperm that is primarily responsible for whether the embryo is going to be chromosomally normal or euploid and an egg that has developed abnormally during the initial phase of stimulation and is then subjected to the “LH/hCG trigger” will invariably propagate and become an incompetent/aneuploid embryo.
The objective of ovarian stimulation is to get the egg to the point of the “LH/hCG trigger” without it being adversely affected by overexposure to testosterone.
So, what makes the woman’s ovary produce testosterone? Primarily, it is the hormone LH (from the pituitary gland or medication administered) that causes the ovarian stroma/theca to produce testosterone. Overproduction of LH by the pituitary is usually seen in older women, women who have a condition called polycystic ovarian disease and in women with diminished ovarian reserve (DOR), or in cases where a woman with DOR is given clomiphene or letrozole and /or too much menotropins (e.g., Menopur), which contain LH. In my opinion, over-administration of DHEA (which is a precursor of androgens), especially to older women and/or those with DOR, can also compromise egg/embryo “competency. Over-production of stromal testosterone can also result from “space-occupying lesions in the ovary (e.g., an endometrioma or ovarian cyst/tumor). It rarely can occur due to the adrenal gland over-producing male hormones). Therefore we often see poor egg/embryo “competency” in women with these conditions.
The bottom line for optimizing egg/embryo “competency” is to regulate follicle exposure to ovarian stimulation testosterone. This requires that the protocol used for ovarian stimulation be individualized and custom-designed to fit the needs of each patient. In my opinion, this is by far the most important consideration when it comes to optimizing IVF outcomes, especially in older women and those with DOR.
There are different ways of achieving this goal: What I do is I put most of my patients on a birth control pill (BCP) to launch their IVF stimulation cycles. This suppresses pituitary LH within a couple of days. I usually advocate the use of a balanced, monophasic BCP such as Low-Estrin; Orthonovum-135, or Desogen/ Marvelon for at least 10 days.
Often people will tell you, “But I’ve been told by my doctor that the pill suppresses ovarian response to stimulation.” Yes, it does,… but only if used “incorrectly”. The BCP is likely to suppress women, only if it is taken without overlapping with a GnRH agonist (see later) up to the start of the ovarian stimulation with gonadotropins. stimulation. The reason is that the BCP suppresses both FSH and LH. Early exposure of preantral follicles to FSH in the 5-7 days is essential to convert them to antral follicles. Only Antral Follicles can respond optimally to stimulation (preantral follicles will not). If the BCP is administered up to the menstrual bleed, it can so suppress FSH that antral follicle development is impeded. Preantral follicles look the same as antral follicles under ultrasound scrutiny but they don’t have the required receptors that will allow them to respond to FSH. Accordingly, they often fail to develop, and/or they’ll take far longer to develop into optimally developing follicles.
To achieve the optimal development of antral follicles, I overlap the birth control pill for 3 days with a GnRH agonist such as Lupron, Superfact, Buserelin; Decapeptyl, etc. . Then, I stop the BCP. The GnRH agonist expunges FSH from the pituitary gland. This converts the preantral to antral follicles. If this approach is followed, there will rarely (if ever) be BCP-induced suppression of follicular development.
The BCP, by suppressing LH, gives the ovaries a “breather” in preparation for the upcoming stimulation. It also serves another purpose: By lengthening or shortening the duration of time on the BCP it is possible to regulate precisely when the GnRH agonist-induced menstrual period will occur. As soon as this starts, we schedule a baseline ultrasound examination and a blood estradiol measurement (in the patient’s home setting). By shortening or lengthening the time on the BCP, the exact start date of ovarian stimulation can be fixed. This allows patients to schedule their travel arrangements to and from our IVF center in NY. Moreover, since I only do four batches of IVF cycles per year in Manhattan in New York and all of my patients start their cycle on the same day, it facilitates that everyone arrives at the NY center on time. The total time spent at the clinic is rarely >7-10 days, total.
The gonadotropin stimulation begins with predominantly FSH products, (Follistim, Gonal-f, Puregon, Menopur). The woman starts on a designated dosage for two days on the third day, I drop the dose of the FSH in and double the dosage of Menopur to 75u. This continues along with the GnRHa (daily) until the follicles are adequately developed whereupon the “hCG/LH trigger” is administered (the dosage of hCGu [Pregnyl/Profasi/Novarel] is 10,000U or hCGr [Ovidrel] is 500mcg).
Dr. Aimee: What you’re saying is you’re giving them two Ovidrel then, so they’re getting 500.
Dr. Geoffrey Sher: Correct. One shot with Ovidrel 5,000U, or one shot with hCGu 10,000
Now, that is the standard for women who have normal ovarian reserve. For women that are older (>40y) or for those who have diminished ovarian reserve (DOR) where the AMH level is under 1.5ng/ml (<10pmol/L). I modify the approach. Here, the woman continues the GnRH agonist, 10 units, until her menstrual period occurs. The moment her period starts, I switch to a GnRH antagonist such as Orgalutron, Cetrotide, or Ganirelix. The reason I switch them is that the former can sometimes competitively inhibit the action of FSH, and suppress the response in such patients.
In women who are exceptionally resistant and who have very low ovarian reserve (AMH=<0.2ng/ml), I often use “estrogen priming”. Such women, either use daily estrogen skin patches or they receive estradiol; valerate (Delestrogen) injections twice weekly starting at the point that the post-GnRH agonist-induced period begins. Estrogen priming continues for 7-8 days at which point gonadotropin stimulation starts. The “estrogen priming” then continues until the hCG/LH trigger.
I never give my IVF patients clomiphene or Letrozole because clomiphene is an antiestrogen. It has the effect of increasing pituitary LH output and thereby, potentially lowering egg quality. Both clomiphene and Letrozole increase the release of GnRH agonist by the hypothalamus, increasing pituitary LH and FSH. Once again, too much LH, especially in older women and women with diminished ovarian reserve, is not a good idea.
I don’t do mini-IVF or natural cycle IVF or Natural Cycle IVF. The results are too poor.
I offer my patients access to EZ-IVF where I use low doses of gonadotropins (every other day). This works well if patients are properly selected.
Dr. Aimee: Do you have patients take supplements during the cycle at all, like DHEA?
Dr. Geoffrey Sher: As previously stated, I’m against the use of DHEA. Although, I know that there are people who feel differently, and I respect their opinion. The reason for that is that DHEA is a precursor of androgens and testosterone. If you give it to the wrong woman, you’re going to increase her ovarian testosterone, and this could result in poorer quality eggs developed. But I do give most of my patients human growth hormone, which I start with the Lupron and continue all the way through to the trigger.
Dr. Aimee: So, you’re giving them HGH even before their stimulation starts.
Dr. Geoffrey Sher: So, about a week before.
Dr. Aimee: Perfect. I know that not all of our readers are going to understand everything that you’re saying because there’s a lot of terminology involved. Just hearing the words and knowing that every doctor has their own tools in their toolbox that they use and that they feel comfortable with. I hope that maybe some of the things that you’re suggesting could be things that maybe patients can learn from and bring to their doctor.
When a patient is going through IVF, how does she know that the protocol that the doctor is choosing for her is the right protocol? If you were a patient and you were going through an IVF cycle, what would you ask to make sure that the protocol is being customized for you?
Dr. Geoffrey Sher: There are two factors that help determine this: The first is the age of the woman. The second is her ovarian reserve. I reserve the protocol where I supplant the GnRH agonist with an GnRH antagonist (i.e. the Agonist-Antagonist Conversion Protocol – A/ACP) for women who have diminished reserve. Women where the AMH is under 1.5 (<10pmol/L).
I use the regular long down-regulation protocol where I give GnRH agonist throughout the cycle for women who have normal ovarian reserve.
In the case of women who are very high responders, I often recommend EZ-IVF. But there is a problem with such “high responders”. If a woman has a very high AMH, or if she has polycystic ovarian syndrome, she is at risk of developing severe ovarian hyperstimulation syndrome (OHSS), a dreaded condition that we in the field, try to avoid, because it puts the patient at risk, especially if it’s wrongly treated.
There are methods for preventing OHSS. One of the ways you often hear doctors talk about is the use of a GnRH agonist (e.g., Lupron) trigger instead of an hCG trigger. This is not a good approach because, while it protects the woman and reduces the risk and effects of OHSS, this often comes at the expense of egg quality. hCG “aggravates” and compounds the risk of OHSS developing so that by giving a GnRH agonist you partially avoid this problem. The GnRH agonist promotes meiosis by triggering a surge in pituitary gland LH output. However, you can’t control how much LH is released. You can’t regulate it. If not enough LH is produced, which especially applies to women who have large numbers of follicles) egg quality will suffer. So, I don’t use it.
I use a process that I first described in 1990, called prolonged coasting. It works very well, but it takes some doing to know how to use it. If you use it incorrectly, you’ll make matters worse. You have to start “coasting” early enough and not wait too long before you trigger. It’s a whole different category to discuss (for another time).
Many REs when treating high responders who they deem to be most at risk of developing OHSS will “trigger” early to harvest the eggs before the follicles grow too much and put the woman at greater. That is wrong and can be avoided by doing “prolonged coasting” where you stop the gonadotropin medication while continuing the administration of the GnRH agonist and allow the estradiol level to peak and then come down to a safe level before you “trigger”. If you do it correctly, you will rarely end up with poor-quality eggs.
Dr. Aimee: I think the agonist antagonist should probably be named “The Sher cycle.” You call it EZ on your website.
Dr. Geoffrey Sher: It’s for women with normal ovarian reserve who want to receive fewer fertility drugs. It’s far better than mini-IVF, which is bad for the very people that it’s given to. Mini-IVF doesn’t work well in women already older and producing large amounts of LH. You would be making matters worse, and by adding clomiphene you are promoting even more LH production.
Dr. Aimee: I imagine, like me, you probably have patients who bank embryos and do more than one cycle. Then sometimes you do a cycle for someone, and you say, “I want to make a change.” How do you decide what to change in a protocol? I’ll give you an example…
Let’s say I have a patient who has three beautiful blastocysts that are genetically normal. I’ve seen other doctors still change the protocol from one cycle to the next and I’m just wondering, “Why did you do that? She had high-quality embryos.” I’m just wondering what is the decision-making that you go through to change the protocol or stay the same in your patients from one to the next?
Dr. Geoffrey Sher: That’s a very good question. I think there comes a point where if you give too much, you’re not going to get any benefit anyway. This is usually encountered in women with diminished ovarian reserve who have fewer antral follicles. If a woman has a low antral follicle count and you give a certain dosage of gonadotropins and she’s producing eggs and embryos that turn out to be euploid by PGT testing, I don’t think there is any justification in just randomly increasing the dosage.
Conversely, if a woman has large numbers of antral follicles and she produces few eggs, you can often increase the number of eggs, therefore potentially the number of embryos and the number of blastocysts that you get, by upping the dose.
You also have to look at the history and how the patient responded in the previous cycle, and what her age and her ovarian reserve are.
Now, a woman in her early 30s does not need a lot of follicles. If you get eight or nine follicles, you’re in a fat city. If you have an older woman, you will want more. More eggs would increase her chances, provided you use an individualized protocol for stimulation.
It’s very much based upon previous response, age, ovarian reserve, and how many follicles.
Dr. Aimee: Thank you for sharing all of your wisdom with us about ovarian stimulation protocols for IVF. But I want to ask you one question. Do you have any special sperm tricks that you want to teach our listeners to get the best sperm for the day of the egg retrieval? What do you tell your patients?
Dr. Geoffrey Sher: This is one of the toughest problems of all. Obviously, in men that have low counts and have low motility, you must look at things like the FSH, the LH, the testosterone, and get an ultrasound done to see if there is a varicocele, which by the way is rarely associated with low sperm counts.
The bottom line is an assessment of sperm count, motility, and morphology. The morphology is very difficult to assess. The guy that developed the “Kruger classification of sperm morphology (The Kruger Classification) is a friend of mine. I went to medical school with him. His name is Dr. Thinus Kruger. But even this classification is not exact. As long as the sperm are moving, they could still propagate viable embryos.
I think it’s helpful to some men to put them on low dosage clomiphene for 90 days or so if their FSH is low and they have low or normal testosterone levels. In about 40–50% of the time, there will be a marked improvement.
I think it’s helpful to put men on supplements. There are many male fertility blends out there. The one I advocate is Proceptin. You can buy it online at www.proceptin.com. In my opinion, it is the best male fertility blend that’s out there.
Some people will tell you that if there’s very poor-quality sperm it is better to go in and surgically extract sperm directly from the testicles by doing testicular sperm extraction (TESE). If there are any moving sperm in the ejaculate, this rarely has any value.
Dr. Aimee: Unless you hate your husband. I’m just kidding, obviously, I’m trying to make light of something very serious.
Dr. Geoffrey Sher: TESE works very well in certain cases. When there is an obstructive uropathy in the man, where the ducts are blocked or damaged and closed. But it doesn’t help much in men where sperm production is poor. The results using sperm obtained are poor, but if that’s the only hope of using the man’s sperm, it is perhaps worth a try.
Dr. Aimee: I use a chip, the micro sorting chip ZyMōt, on my cases.
Dr. Geoffrey Sher: We also use it. We think it has a great advantage. Of course, the sperm DNA fragmentation assay, also known as the sperm chromatin structure assay (SCSA), is helpful because the DNA fragmentation index may be helpful. But I’ve seen men with very elevated DFIs (DNA fragmentation indices) father children. I don’t think an elevated DFI should ever be a reason for not proceeding.
Dr. Aimee: Right. I feel like the ZyMōt chip has leveled the playing field.
Dr. Geoffrey Sher: I agree.
Dr. Aimee: Before ZyMōt, I would do the DFIs. Now I’m like, unless you’re not my patient and you’re a center that doesn’t have ZyMōt, go ahead and do a DFI. Then if it’s high, make sure that they add ZyMōt to your protocol.
Dr. Geoffrey Sher: Absolutely. We do that all the time.
Dr. Aimee: Thank you for coming on again as a guest.
Dr. Geoffrey Sher: Thank you so much for having me.
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