IVF: A Personalized Step-by Step Approach

The ability to grow a healthy plant requires that a “good” seed be planted in a “fertile soil” and then be properly nurtured until it can thrive on its own….independent of intervention. Similarly, successful IVF requires the same relationship, only here, a “good seed” is a “competent, chromosomally normal (euploid) embryo and “fertile soil” is a “receptive” uterine lining (endometrium). You cannot expect success through planting a “bad seed” in a “fertile soil” any more than you could if you were to plant a good seed in “poor soil”. No…..in either case successful outcome requires that a “competent” embryo (seed) be located in a receptive uterus (“fertile soil”).

It follows that central to achieving a successful IVF outcome is the need:

1. At the very outset to define the variables that affect embryo quality and uterine receptivity

2. To avoid “one size fits all” protocols for controlled ovarian stimulation (COS). Instead it is necessary to individualize the protocol of the COS to fit the profile of each individual so as to establish an optimally nurturing environment for developing follicles, eggs and uterine lining.

3. To precisely time the egg retrieval (ER) and then safely extract, eggs from the woman’s ovary (ies).

4. To expertly transfer the best quality advanced embryo(s) [blastocyst(s)], gently and delicately to the uterus. To support early embryo implantation through optimal hormonal supplementation during most of the 1st trimester.

Controlled Ovarian Stimulation (COS): A woman undergoing IVF is given fertility drugs for two reasons: (1) to enhance the growth and development of her ovarian follicles in order to produce as many healthy eggs as possible and (2) to regulate the timing of ovulation so that her eggs can be surgically retrieved once they reach maturity and before they spontaneously ovulate.

In cases where the woman has previously received fertility drugs, the subsequent COS protocol is in part based upon her prior response to the most recent such treatment regime. If the cycle of COS the woman is to undergo is her first, the dosage and regimen of COS is determined by the biochemical measurement of her ovarian reserve (cycle day 3 basal blood FSH levels and measurement of antimullerian hormone (AMH) concentrations, any time in the cycle). The woman first undergoes a thorough general physical and Gynecologic evaluation before initiating COS. She will usually start by taking a balanced, monophasic birth control pill (BCP) within a few (5-6) days of her period starting. A base-line ultrasound examination is usually performed at the start of spontaneous or hormone-induced menstruation, to count antral follicles and to look for ovarian cysts, The duration of BCP therapy should in my opinion be at least 10 days, but this can be prolonged (cyclically) even for several months, without prejudice, if need be. The goal is to adjust the duration on the BCP so as to “orchestrate” that ovarian stimulation can commence on a set date.

At a predetermined time, while still taking BCP, the daily injection of a gonadotropin releasing hormone agonist (GnRHa); e.g., Lupron or Buserelin/Superfact etc., is initiated. A combination of agonist + BCP is then continued for another three days whereupon the BCP is abruptly stopped while agonist injections continue until menstruation ensues (usually within about 3 to 7 days). In this way we are able to schedule each cycle of IVF to the convenience of both the patient and the medical team. Additionally, the combined use of BCP + agonist reduces virtually eliminates the risk of the BCP suppressing subsequent response ovarian stimulation with gonadotropins, and well as the likelihood of ovarian cyst formation, thereby largely avoiding the need to delay or cancel the cycle of treatment.

As soon as menstruation begins, blood is drawn for measurement of estradiol [E2] concentration. Provided that the [E2] is under 70 pg/ml (or 200pmol/L) , the patient will be ready to initiate ovarian stimulation with gonadotropins. If the [E2] is greater than 70 pg/ml, a repeat ultrasound is done to look for one or more estrogen-producing functional ovarian cysts. If such a cyst is detected, it is my personal preference that (rather than wait for it to resolve on its own), that an immediate transvaginal ovarian cyst aspiration be performed (under local anesthesia) whereupon the [E2] will usually rapidly fall to below 70pg/ml within 24-72 hours. Within a few days of menstruation starting, COS with gonadotropins (e.g., Gonal F, Follistim,) is commenced. As soon as gonadotropin administration commences the agonist injections are either continued (at a reduced daily dosage) throughout the stimulation process, until the hCG trigger (i.e., The Long-Agonist Protocol) or in women with moderately or severely diminished ovarian reserve (DOR) where the AMH is <1.5 ng/ml, the protocol is modified to an agonist/antagonist conversion protocol A/ACP) where, coinciding with the onset of gonadotropin therapy, the agonist is supplanted by low-dosage GnRH antagonist (e.g., Ganirelix, Orgalutron or Cetrotide – the  A variation on the A/ACP theme is used in some women who have severely diminished ovarian reserve (DOR) where the basal AMH is <0.5ng/ml . Here, upon supplanting the agonist with an antagonist we add Estrogen Priming. The protocol is referred to as A/ACP with Estrogen Priming. With this protocol variation, the woman receives twice weekly intramuscular injections of estradiol valerate (Delestrogen) and/or vaginal estradiol suppositories beginning with the switch from the agonist to an antagonist at the time of the onset of bleeding ( about 8 days before commencing COS) with gonadotropins. This is continued until at least 50% of the follicles reach 14mm in diameter, whereupon estrogen priming it is stopped. The exact type of gonadotropin medication administered as well as the dosage/stimulation regime will vary from patient to patient. It is however my personal preference to prescribe recombinant DNA- FSH (e.g., Follistim, Puregon or Gonal-F), rather than urinary derived products, (e.g., Bravelle) which I believe to be more subject to batch-to batch variation in potency.

Two days after commencing gonadotropin therapy, I reduce the dosage of Follistim/Gonal F/Puregon and add 75U (1 vial) of Menopur daily. The FSH/LH therapy is maintained until at the point of optimal follicle development as determined by serial ultrasound examinations and blood [E2] measurements. Thereupon, 10,000U hCG (Profasi, Novarel or Pregnyl) is injected. I personally do not advocate supplanting this with 250mg of DNA recombinant hCG (Ovidrel) because, in my opinion, this dosage is too low to achieve optimal biological potency. If Ovidrel is to be used, the dosage should in my opinion be doubled. However, since this is much more expensive than Profasi, Novarel or Pregnyl, and there are no medical advantages, I do not use Ovidrel in my IVF patients. On occasion I do make adjustments to the dosage of gonadotropins, but not to the dosage of hCG.

Some people halve the trigger hCG dosage to 5,000U in very high responders, in the hope that this will reduce the risk of severe ovarian hyperstimulation syndrome (OHSS). In my opinion, it does not do so. Moreover, at such a low dosage, in the very patients that have a multitude of follicles, it does not achieve optimal receptor saturation in the follicle cells, and results in too many “immature” eggs being harvested at egg retrieval. Others favor the use of an agonist (rather than an hCG trigger). The intent is that the agonist, by causing LH to be expunged from the pituitary gland, will achieve a more “natural” maturation of eggs and reduce the risk of OHSS. I’m not convinced of such a benefit. Besides, it is hard to determine how much LH is released following the administration of such an “agonist trigger”.

Commencing 7-8 days after the initiation of gonadotropin therapy, the patient undergoes serial (usually daily) ultrasound and plasma estradiol evaluations to monitor her ovarian response. These assessments are aimed at determining the ideal day for administering the “hCG trigger”. Both the agonist/antagonist and gonadotropin injections are discontinued on the day of the trigger and the patient is scheduled for ER approximately 36-38 hours thereafter. Patients who because of immunologic implantation dysfunction (IID) require selective immunotherapy with a heparinoid (Clexane or Lovenox) plus corticosteroids (dexamethasone, prednisilone, prednisone). These are commenced with the initiation of Gonadotropin stimulation, followed by daily administration. Heparinoid injections are discontinued approximately 12 hours prior to the egg retrieval and re-started after the embryo transfer procedure.

I no longer advocate the use of aspirin for two reasons: First, it has no clear benefit. Second, by prolonging the bleeding time, it can result in excessive bleeding at egg retrieval and concealed intrauterine bleeding at embryo transfer (ET). The latter will often go undetected and could result in failed implantation. Those patients who have a thin endometrial lining receive sildenafil (Viagra) vaginal suppositories (four times daily) from the onset of gonadotropin therapy to the day of the hCG “trigger”, in an attempt to improve the thickness of their uterine linings. In some cases, where a deficient endometrium is detected a few days into the cycle of stimulation, the administration of Viagra can improve the lining within 48 hours.

Patients who have activated natural killer cells (NKa) as measured by a K-562 target cell test and/or cytokine uterine studies receive Intralipid (IL) therapy or IVIG by intravenous infusion 7-14 days prior to expected date of embryo transfer. In the event of a positive (and rising) blood beta hCG level (which suggests that implantation is in progress), the IL/IVIG infusions may be repeated once and then discontinued (in cases of autoimmune implantation dysfunction). In cases of alloimmune implantation dysfunction, Intralipid or IVIG should be administered every 2-4 weeks thereafter, until the 24th week of pregnancy. My IVF patients will almost always receive oral corticosteroids (dexamethasone, prednisilone or prednisone) daily, commencing with the start of ovarian stimulation and continuing until the first blood beta-hCG test (i.e., pregnancy test). Women who with rising blood hCG levels (a positive blood pregnancy test) 9-11 days after egg retrieval continue taking corticosteroid and heparin (as applicable) beyond the ultrasound confirmation of pregnancy, which is performed at the 6-7 gestational week until the 10th week of gestation.

In cases where the blood pregnancy test fails to reveal an appropriate increase in the quantitative beta hCG concentration, heparinoid (Clexane, Lovenox) therapy is discontinued, and the corticosteroid dosage is slowly tailed off and stopped over 1-2 weeks. Pregnant women continue on corticosteroid as well as heparinoid treatment until the 10th week of pregnancy, whereupon the heparin is discontinued and the corticosteroid is tapered off over 1-2 weeks and stopped. All patients receive an oral antibiotics beginning about seven days after the initiation of gonadotropin therapy and continuing for a few days after the embryo transfer procedure.

Egg Retrieval

Egg Retrieval (ER) involves a non-surgical procedure performed under conscious sedation. At SIRM, a qualified anesthesiologist is in attendance with the patient during the procedure. This is performed in a dedicated procedure room, where, under direct ultrasound guidance, a needle is passed along the side of a vaginal ultrasound probe through the top of the vagina into follicles (small fluid filled spaces that each contain an egg), within the ovary (ies). The follicular fluid is aspirated and collected in a test tube, which is promptly delivered to the embryologist(s) for analysis and processing. The procedure itself is relatively painless, however patients commonly experience some residual postoperative abdominal discomfort and /or cramping that rarely persists for more than a day or so. Postoperatively, all patients are given detailed instructions and are discharged within an hour or two with a prescription for analgesics (pain killers) and other medications as indicated.

Sperm Processing

A sperm specimen is usually obtained from the male partner through masturbation. On some occasions however, physical, medical and/or religious constraints demand that sperm be obtained through condom collection following intercourse, or by inserting a needle directly into the testicle(s) under local anesthesia and aspirating sperm. The two variations of this procedure are known as Testicular Sperm Extraction (TESE) and Percutaneous, Epididymal Sperm Aspiration (PESA). TESE and PESA are procedures of choice in cases where there is blockage of the sperm ducts (as occurs following vasectomy or following severe injury or infection), where the man is born without sperm ducts (congenital absence of the vas deferens), or in cases where as a result of testicular failure, sperm does not reach the ejaculatory ducts. Sometimes, in cases of retrograde ejaculation (seen after spinal injury, prostatectomy or advanced diabetes), sperm can be collected from the man’s bladder. Infrequently, in men with spinal cord injuries, ejaculation is facilitated by electrical stimulation (electro-ejaculation). Donor sperm, obtained from a sperm bank, can be used when indicated.

Fertilization in the Laboratory

Conventional IVF: In vitro fertilization literally means “fertilization in glass”. Fluid aspirated from ovarian follicles is examined in the embryology laboratory. The eggs are identified and extracted, and are placed in a specialized culture medium. Several hours later, approximately 50,000-100,000 processed sperm are placed around each of the eggs. The eggs and sperm are allowed to incubate together in a carefully controlled environment. Approximately 16-24 hours later, the eggs are inspected microscopically for fertilization as evidenced by the presence of two nuclear bodies. These binuclear unicellular bodies are referred to as “pro-nucleate embryos”.

Intracytoplasmic sperm injection (ICSI): Today, at SIRM, we perform virtually all IVF using ICSI. Studies have shown that there are really only advantages to this policy. The ICSI procedure involves the direct injection of a single sperm into each egg under direct microscopic vision. Initially, ICSI was used specifically to achieve fertilization in male infertility. When ICSI is employed in such cases, the IVF birth rate is unaffected by the presence and severity of the male factor. In fact, even when the absence of sperm in the ejaculate requires that ICSI be performed on sperm obtained through Testicular Sperm Extraction (TESE), the birth rate is no different than when IVF is performed for indications other than male infertility. Today, it is commonly used in conventional (non-male factor) cases. I personally advocate the use of ICSI in virtually all IVF.

Assisted Hatching: In selected cases where it is felt that the zona pellucida (the envelopment of the embryo/blastocyst) is unusually tough or thickened, a process known as assisted hatching (AH) may be employed. The process involves deliberately making a small aperture in the wall of the embryo (usually with a laser) so as to promote hatching (rupturing) and thereby facilitate implantation. It remains controversial as to whether AH actually improves pregnancy rates.

Selecting the Best Embryos for Transfer

Once embryo division (cleavage) has begun, the embryo will continue to divide at regular intervals. Embryos that divide the fastest are considered the healthiest and the most likely to implant.) The Graduated embryo scoring (GES) system which was developed by us in 2001. It provided a method whereby we score each individual embryo out of a maximum of 100 points. Embryos that on day 3 post fertilization have a GES of >70/100, are the ones that are most likely to develop into blastocysts and propagate healthy babies. However, we now grow almost all embryos to blastocysts so the GES scaring method has become somewhat redundant.

Microscopic Embryo and Blastocyst Grading: While embryos may be transferred 3 days after fertilization when they are divided to the 5-9 cell stage, it is my strong preference to wait until day 5-6 and then only transfer them if they reach the expanded blastocyst (100 cell+) stage of development. This is because embryos that fail to become blastocysts are almost always chromosomally abnormal (aneuploid) and are almost always incapable of propagating a healthy baby and are thus not worth transferring anyway. This does not mean that ALL those embryos that progress to blastocysts are chromosomally normal (euploid). They are not… but they do represent the ones that are most likely to be so. Blastocysts are graded on the basis of their cellularity, differentiation of their outer cellular layer (the trophectoderm), the inner core of aggregated cells (the inner cell mass) and the development of a demonstrable collection of fluid inside the blastocyst (an expanded blastocyst) Those blastocysts that contain more cells have a more expanded blastocele, a more prominent inner cell mass and have a well differentiated trophectoderm are the ones that are most likely to be “competent” (i.e. likely to propagate a viable pregnancy).

Preimplantation Genetic Testing (PGT) for the evaluation of eggs and embryos: In 2007, we became the first to report on the clinical value of counting all the embryo’s chromosomes (karyotyping) to identify those that had all 46 chromosomes (were euploid) and thuas the nes that were most likely to propagate viable pregnancies and the least likely to miscarry or result in chromosomal defects such as Down syndrome. We used a method known as metaphase CGH which now has largely been supplanted by next generation gene sequencing (NGS). NGS testing currently represents the most reliable method available to achieve this goal and is fast establishing a “new standard of care” in the field. In fact, the transfer of even a single CGH- normal embryo to a “receptive” uterus can yield a >50% chance of a live birth.

Embryo Banking

For older women and those with diminished ovarian reserve (DOR), repeated egg retrievals combined with CGH embryo selection will permit stockpiling of “competent embryos” over a number of cycles. This process of “Embryo Banking”, by allowing women to vitrify (freeze) and store their embryos for subsequent dispensation can stall the biological clock and prolong fertility potential.

The Embryo Transfer

Undoubtedly, embryo transfer (ET) is one of the rate limiting steps in IVF. It takes confidence, dexterity, skill and a soft touch to perform a good transfer. Of all the procedures in ART, this is arguably the most difficult to teach a training physician to conduct. It is a true art and we have seen many women fail to conceive simply because this procedure was not performed optimally. Shortly before the embryo transfer, the embryos/blastocysts are put together in a single laboratory dish containing growth medium. The laboratory staff informs the clinic coordinator that the embryos are ready for transfer, and the coordinator prepares the patient and informs the physician that a transfer is imminent.

Embryos/blastocysts are transferred to the uterus via a thin Teflon catheter. This procedure is conducted under ultrasound guidance with the woman on her back (in the lithotomy position) and with a full bladder. Today all embryo transfers should undoubtedly be performed under direct ultrasound guidance to ensure proper placement in the uterine cavity. This practice, properly conducted, will significantly enhance embryo implantation and pregnancy rates. We prefer to perform all embryo transfers when the woman has a full bladder. This facilitates the visualization of the uterus by abdominal ultrasound and causes reflex nervous suppression of uterine contractility. The patient is allowed to empty her bladder 10-15 minutes following the embryo transfer.

Transmyometrial Embryo Transfer (TMET): In rare cases where the shape or partial obstruction of the canal leading in to the uterus (i.e. the cervical canal) severely complicates conventional embryo transfer, this method can be used. The patient is first anesthetized, then, using sterile technique, a needle is passed along the side of a transvaginal ultrasound probe through the wall of the uterus, into the uterine cavity. A very thin catheter is then passed through the needle with its tip protruding into the uterine cavity. The needle is partially withdrawn and the blastocyst(s)/embryo(s) are injected. After the embryo transfer, the woman remains immobile for approximately one hour and is thereupon discharged with specific instructions.

Post Embryo Transfer Management

Immediately prior to being discharged following the embryo transfer procedure, an exit interview is conducted, wherein the patient/couple is/are given instructions on post-transfer care and follow-up.

Post-ET Hormonal Supplementation

This usually involves the administration of intramuscular injections of progesterone and/or vaginal suppositories (comprising estradiol valerate and micronized progesterone) until a blood pregnancy test is performed approximately eight days later (the chemical diagnosis of pregnancy). In selected cases, such progesterone treatment can be replaced with Crinone or Endometrin vaginal applications, once or twice daily. If the beta hCG pregnancy test is negative or the plasma hCG levels fail to rise appropriately in the ensuing days, all hormonal support is abruptly discontinued. An ultrasound examination is performed approximately 2-3 weeks after the chemical diagnosis of pregnancy is made by blood testing, at which time designated patients with viable pregnancies receive a final administration of Intralipid (in some cases additional monthly doses of Intralipid must be administered).

Embryo Freezing (Cryopreservation)

There have been dramatic advances in the technology of freezing and storing human embryos for future use. We freeze embryos as blastocysts. The recent introduction of an ultra-rapid freezing technique known as “vitrification” has revolutionized embryo freezing. This method, by freezing embryos faster than the blink of an eye, eliminates ice formation in the blastomeres. Now, very few chromosomally normal embryos are lost in the freeze/thaw process, and pregnancy rates with thawed pre-vitrified blastocysts are hardly different from that reported following the transfer of fresh blastocysts.

I do not intend, and it would indeed be presumptuous to suggest that the above approach should serve as a template for other RE’s to adopt. To the contrary, there are many alternative approaches that could well be equally efficacious, or perhaps even better. However after having been influential in the births of >18000 IVF babies, over the last 3 decades all I can say is that IVF is not a pure science nor a pure art. Rather it is an art-science blend, where experience and seasoning really counts. What is described above has resulted from my own prolonged trial and tribulation. Most importantly, it works.



Hi, why do you reduce the dosage of Follistim/Gonal F/Puregon after two days? What have been the results you see and do you reduce this dose for all patients of yours?

Dr. Geoffrey Sher

Yes I reduce the dosage for all my patients and have been doing his for > 2 decades. There is no merit in maintaining the dosage once you have launched follicular growth.

Geoff Sher


Thank you. I want to be an IVF nurse and I’m learning a lot from your blog. I’m 17 but women in my family go into menopause early. I’ve been reading this blog for 11 months. Do you do this for your patients that have diminished ovarian reserve too? Have you written any blogs about launching follicular growth? I want to read it please.

Dr. Geoffrey Sher

I would need much more information to be able to provide substantive advice.

Good luck!

Geoff Sher


Hi Dr Sher,
I am 40F and trying ivf for 3rd cycle now. I have normal AMH, FSH, LH and normal laparoscopy ie unexplained infertility( no obvious issue with my husband too). 1st cycle- GF 150 U from D2of my period+Cetrotide- 5 eggs retrieved on D13, only 1 fertilised. Transferred at D3 (8 cells),unsuccessful. Cycle2- same protocol with GF 225U+cetrotide- asynchronous follicles- 1 leading follicle of 22 mm and 3 other 12mm at D13, 2 more days of GF then leading follicle – 29 mm and the other 3 are 20 to 22 mm. My gynaecologist advised to cancel the collection. Now I just started 3rd cycle. Flare/boost I think. OC pills for 2 weeks then period came on D3. On D2 of my period- start GF 300U + Synarel. I am a medical doctor myself( haematologist) and from my understanding this is agonist cycle, different from first 2 which are anatagonist ones. I think for my age, 5 to 6 eggs are good numbers and I do think that there is a problem with my egg quality(poor fertilisation ). Do u think I am on right protocol for my age ?

Dr. Geoffrey Sher

Very respectfully,

While I need much more information in order to render an authoritative opinion, I want you to know that it is my opinion, that your issues likely relate to the protocol used for ovarian stimulation, and/or its implementation. Sedately, I do not agree with the use of ‘Flare” protocols in general and more specifically not in older women.

The potential for a woman’s eggs to undergo orderly development and maturation, while in large part being genetically determined can be profoundly influenced by the woman’s age, her “ovarian reserve” and proximity to menopause. It is also influenced by the protocol used for controlled ovarian stimulation (COH) which by fashioning the intra-ovarian hormonal environment, profoundly impacts egg development and maturation.

After the menarche (age at which menstruation starts) a monthly process of repeatedly processing eggs continues until the menopause, by which time most eggs will have been used up, and ovulation and menstruation cease. When the number of eggs remaining in the ovaries falls below a certain threshold, ovarian function starts to wane over a 5 to10-years. This time period is referred to as the climacteric. With the onset of the climacteric, blood Follicle Stimulating Hormone (FSH) and later also Luteinizing Hormone (LH) levels begin to rise…. at first slowly and then more rapidly, ultimately culminating in the complete cessation of ovulation and menstruation (i.e. menopause).

One of the early indications that the woman has entered the climacteric and that ovarian reserve is diminishing DOR) , is the detection of a basal blood FSH level above 9.0 MIU/ml and/ or an AMH level og <2.0ng/ml.

Prior to the changes that immediately precede ovulation, virtually all human eggs have 23 pairs (i.e. 46) of chromosomes. Thirty six to forty hours prior to ovulation, a surge occurs in the release of LH by the pituitary gland. One of the main e purposes of this LH surge is to cause the chromosomes in the egg to divide n half (to 23 in number) in order that once fertilized by a mature sperm ends up having 23 chromosomes) the resulting embryo will be back to having 46 chromosomes. A “competent” mature egg is one that has precisely 23 chromosomes, not any more or any less. It is largely the egg, rather than the sperm that determines the chromosomal integrity of the embryo and only an embryo that has a normal component of 46 chromosomes (i.e. euploid) is “competent” to develop into a healthy baby. If for any reason the final number of chromosomes in the egg is less or more than 23 (aneuploid), it will be incapable of propagating a euploid, “competent” embryo. Thus egg/embryo aneuploidy (“incompetence”) is the leading cause of human reproductive dysfunction which can manifest as: arrested embryo development and/or failed implantation (which often presents as infertility), early miscarriage or chromosomal birth defects (e.g. Down’s syndrome). While most aneuploid (“incompetent”) embryos often fail to produce a pregnancy, some do. However, most such pregnancies miscarry early on. On relatively rare occasions, depending on the chromosome pair involved, aneuploid embryos can develop into chromosomally defective babies (e.g. Down’s syndrome).

Up until a woman reaches her mid- thirties, at best, 1:2 of her eggs will likely be chromosomally normal. As she ages beyond her mid-thirties there will be a a progressive decline in egg quality such that by age 40 years only about 15%-20% of eggs are euploid and, by the time the woman reaches her mid-forties, less than 10% of her eggs are likely to be chromosomally normal. While most aneuploid embryos do appear to be microscopically abnormal under the light microscope, this is not invariably so. In fact, many aneuploid embryos a have a perfectly normal appearance under the microscope. This is why it is not possible to reliably differentiate between competent and incompetent embryos on the basis of their microscopic appearance (morphologic grade) alone.

The process of natural selection usually precludes most aneuploid embryos from attaching to the uterine lining. Those that do attach usually do so for such only a brief period of time. In such cases the woman often will not even experience a postponement of menstruation. There will be a transient rise in blood hCG levels but in most cases the woman will be unaware of even having conceived (i.e. a “chemical pregnancy”). Alternatively, an aneuploid embryo might attach for a period of a few weeks before being expelled (i.e. a “miscarriage”). Sometimes (fortunately rarely) an aneuploid embryo will develop into a viable baby that is born with a chromosomal birth defect (e.g. Down’s syndrome).
The fact that the incidence of embryo aneuploidy invariably increases with advancing age serves to explain why reproductive failure (“infertility”, miscarriages and birth defects), also increases as women get older.

It is an over-simplification to represent that diminishing ovarian reserve as evidenced by raised FSH blood levels (and other tests) and reduced response to stimulation with fertility drugs is a direct cause of “poor egg/ embryo quality”. This common misconception stems from the fact that poor embryo quality (“incompetence”) often occurs in women who at the same time, because of the advent of the climacteric also have elevated basal blood FSH/LH levels and reduced AMH. But it is not the elevation in FSH or the low AMH that causes embryo “incompetence”. Rather it is the effect of advancing age (the “biological clock”) resulting a progressive increase in the incidence of egg aneuploidy, which is responsible for declining egg quality. Simply stated, as women get older “wear and tear” on their eggs increases the likelihood of egg and thus embryo aneuploidy. It just so happens that the two precipitating factors often go hand in hand.

The importance of the IVF stimulation protocol on egg/embryo quality cannot be overstated. This factor seems often to be overlooked or discounted by those IVF practitioners who use a “one-size-fits-all” approach to ovarian stimulation. My experience is that the use of individualized/customized COS protocols can greatly improve IVF outcome in patients at risk – particularly those with diminished ovarian reserve (“poor responders”) and those who are “high responders” (women with PCOS , those with dysfunctional or absent ovulation, and young women under 25 years of age).

While no one can influence underlying genetics or turn back the clock on a woman’s age, any competent IVF specialist should be able to tailor the protocol for COS to meet the individual needs of the patient.

During the normal ovulation cycle, ovarian hormonal changes are regulated to avoid irregularities in production and interaction that could adversely influence follicle development and egg quality. As an example, small amounts of androgens (male hormones such as testosterone) that are produced by the ovarian stroma (the tissue surrounding ovarian follicles) during the pre-ovulatory phase of the cycle enhance late follicle development, estrogen production by the granulosa cells (cells that line the inner walls of follicles), and egg maturation.

However, over-production of testosterone can adversely influence the same processes. It follows that protocols for controlled ovarian stimulation (COS should be geared toward optimizing follicle growth and development (without placing the woman at risk from overstimulation), while at the same time avoiding excessive ovarian androgen production. Achievement of such objectives requires a very individualized approach to choosing the protocol for COS with fertility drugs as well as the precise timing of the “trigger shot” of hCG.

It is important to recognize that the pituitary gonadotropins, LH and FSH, while both playing a pivotal role in follicle development, have different primary sites of action in the ovary. The action of FSH is mainly directed towards the cells lining the inside of the follicle that are responsible for estrogen production. LH, on the other hand, acts primarily on the ovarian stroma to produce male hormones/ androgens (e.g. androstenedione and testosterone). A small amount of testosterone is necessary for optimal estrogen production. Over-production of such androgens can have a deleterious effect on granulosa cell activity, follicle growth/development, egg maturation, fertilization potential and subsequent embryo quality. Furthermore, excessive ovarian androgens can also compromise estrogen-induced endometrial growth and development.

In conditions such as polycystic ovarian syndrome (PCOS), which is characterized by increased blood LH levels, there is also increased ovarian androgen production. It is therefore not surprising that “poor egg/embryo quality” is often a feature of this condition. The use of LH-containing preparations such as Menopur further aggravates this effect. Thus we recommend using FSH-dominant products such as Follistim, Puregon, and Gonal-F in such cases. While it would seem prudent to limit LH exposure in all cases of COS, this appears to be more vital in older women, who tend to be more sensitive to LH

It is common practice to administer gonadotropin releasing hormone agonists (GnRHa) agonists such as Lupron, and, GnRH-antagonists such as Ganirelix and Orgalutron to prevent the release of LH during COS. GnRH agonists exert their LH-lowering effect over a number of days. They act by causing an initial outpouring followed by a depletion of pituitary gonadotropins. This results in the LH level falling to low concentrations, within 4-7 days, thereby establishing a relatively “LH-free environment”. GnRH Antagonists, on the other hand, act very rapidly (within a few hours) to block pituitary LH release, so as achieve the same effect.

Long Agonist (Lupron/Buserelin) Protocols: The most commonly prescribed protocol for Lupron/gonadotropin administration is the so-called “long protocol”. Here, Lupron is given, starting a week or so prior to menstruation. This results in an initial rise in FSH and LH level, which is rapidly followed by a precipitous fall to near zero. It is followed by uterine withdrawal bleeding (menstruation), whereupon gonadotropin treatment is initiated while daily Lupron injections continue, to ensure a “low LH” environment. A modification to the long protocol which I prefer using in cases of DOR, is the Agonist/Antagonist Conversion Protocol (A/ACP) where, upon the onset of a Lupron-induced bleed , this agonist is supplanted by an antagonist (Ganirelix/Cetrotide/Orgalutron) and this is continued until the hCG trigger. In many such cases I supplement with human growth hormone (HGH) to try and further enhance response and egg development.

Lupron Flare/Micro-Flare Protocol: Another approach to COS is by way of so-called “(micro) flare protocols”. This involves initiating gonadotropin therapy simultaneous with the administration of GnRH agonist (e.g. Lupron/Buserelin). The intent here is to deliberately allow Lupron to elicit an initial surge (“flare”) in pituitary FSH release in order to augment FSH administration by increased FSH production. Unfortunately, this “spring board effect” represents “a double edged sword” because while it indeed increases the release of FSH, it at the same time causes a surge in LH release. The latter can evoke excessive ovarian stromal androgen production which could potentially compromise egg quality, especially in older women and women with PCOS, whose ovaries have increased sensitivity to LH. I am of the opinion that by evoking an exaggerated ovarian androgen response, such “(micro) flare protocols” can harm egg/embryo quality and reduce IVF success rates, especially in older women, and in women with diminished ovarian reserve. Accordingly, I do not prescribe them at all.

Estrogen Priming – My approach for “Poor Responders” Our patients who have demonstrated reduced ovarian response to COS as well as those who by way of significantly raised FSH blood levels are likely to be “poor responders”, are treated using a “modified” long protocol. The approach involves the initial administration of GnRH agonist for a number of days to cause pituitary down-regulation. Upon menstruation and confirmation by ultrasound and measurement of blood estradiol levels that adequate ovarian suppression has been achieved, the dosage of GnRH agonist is drastically lowered and the woman is given twice-weekly injections of estradiol for a period of 8. COS is thereupon initiated using a relatively high dosage of FSH-(Follistim, Bravelle, Puregon or Gonal F) which is continued along with daily administration of GnRH agonist until the “hCG trigger.” By this approach we have been able to significantly improve ovarian response to gonadotropins in many of hitherto “resistant patients”.

The “Trigger”: hCG (Profasi/Pregnyl/Novarel) versus Lupron: With ovulation induction using fertility drugs, the administration of 10,000U hCGu (the hCG “trigger”) mimics the LH surge, sending the eggs (which up to that point are immature (M1) and have 46 chromosomes) into maturational division (meiosis) This process is designed to halve the chromosome number , resulting in mature eggs (M2) that will have 23 chromosomes rather that the 46 chromosomes it had prior to the “trigger”. Such a chromosomally normal, M2 egg, upon being fertilized by mature sperm (that following maturational division also has 23 chromosomes) will hopefully propagate embryos that have 46 chromosomes and will be “:competent” to propagate viable pregnancies. The key is to trigger with no less than 10,000U of hCGu (Profasi/Novarel/Pregnyl) and if hCGr (Ovidrel) is used, to make sure that 500mcg (rather than 250mcg) is administered. In my opinion, any lesser dosage will reduce the efficiency of meiosis, and increase the risk of the eggs being chromosomally abnormal. . I also do not use the agonist (Lupron) “trigger”. This approach which is often recommended for women at risk of overstimulation, is intended to reduce the risk of OHSS. The reason for using the Lupron trigger is that by inducing a surge in the release of LH by the pituitary gland it reduces the risk of OHSS. This is true, but this comes at the expense of egg quality because the extent of the induced LH surge varies and if too little LH is released, meiosis can be compromised, thereby increasing the percentage of chromosomally abnormal and of immature (M1) eggs. The use of “coasting” in such cases) can obviate this effect

.I strongly recommend that you visit www.SherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.

• The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• The Fundamental Requirements For Achieving Optimal IVF Success
• Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
• The “Biological Clock” and how it should Influence the Selection and Design of Ovarian Stimulation Protocols for IVF.
• A Rational Basis for selecting Controlled Ovarian Stimulation (COS) protocols in women with Diminished Ovarian Reserve (DOR)
• Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)
• Ovarian Stimulation in Women Who have Diminished Ovarian Reserve (DOR): Introducing the Agonist/Antagonist Conversion protocol
• Controlled Ovarian Stimulation (COS) in Older women and Women who have Diminished Ovarian Reserve (DOR): A Rational Basis for Selecting a Stimulation Protocol
• Optimizing Response to Ovarian Stimulation in Women with Compromised Ovarian Response to Ovarian Stimulation: A Personal Approach.
• Egg Maturation in IVF: How Egg “Immaturity”, “Post-maturity” and “Dysmaturity” Influence IVF Outcome:
• Commonly Asked Question in IVF: “Why Did so Few of my Eggs Fertilize and, so Many Fail to Reach Blastocyst?”
• Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
• The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
• Staggered IVF
• Staggered IVF with PGS- Selection of “Competent” Embryos Greatly Enhances the Utility & Efficiency of IVF.
• Staggered IVF: An Excellent Option When. Advancing Age and Diminished Ovarian Reserve (DOR) Reduces IVF Success Rate
• Embryo Banking/Stockpiling: Slows the “Biological Clock” and offers a Selective Alternative to IVF-Egg Donation
• Preimplantation Genetic Testing (PGS) in IVF: It should be Used Selectively and NOT be Routine.
• IVF: Selecting the Best Quality Embryos to Transfer
• Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
• PGS in IVF: Are Some Chromosomally abnormal Embryos Capable of Resulting in Normal Babies and Being Wrongly Discarded?
• PGS and Assessment of Egg/Embryo “competency”: How Method, Timing and Methodology Could Affect Reliability
• IVF outcome: How Does Advancing Age and Diminished Ovarian Reserve (DOR) Affect Egg/Embryo “Competency” and How Should the Problem be addressed.

Hitherto I have personally performed IVF- treatment and related procedures on patients who, elected to travel to Las Vegas to be managed by me. However, with the launching of Sher-Fertility Solutions (SFS) in April 2019, I have taken on a new and expanded role. Now, rather than having hands-on involvement I confine my services to providing hour-long online Skype consultations to an ever-growing number of patients (emanating from >40 countries), with complex Reproductive problems, who seek access to my input, advice and guidance. All Skype consultations are followed by a detailed written report that meticulously describes and explains my recommendations for treatment. All patients are encouraged to share this report with their personal treating doctor(s), with whom [subject to consent and a request from their doctor] I will, gladly discuss their case with the “treating Physician”.
Through SFS I am now able to conveniently provide those who because of geography, convenience and cost, prefer to be treated at home or elsewhere by their chosen Infertility Physician.
“I wish to emphasize to all patients with whom I consult, that in the final analyses, when it comes to management, strategy, protocol and implementation of treatment, my advice and recommendations are always superseded by that of the hands-on treating Physician”.

Anyone wishing to schedule a Skype consultation with me, can do so by: Calling my concierge (Patti Converse) at 1-800-780-7437 (in the U.S.A or Canada) or 702-533-2691, for an appointment. Patients can also enroll online on my website, http://www.SherIVF.com, or email Patti at concierge@SherIVF.com .
I was very recently greatly honored in receiving an award by the prestigious; International Association of Top Professionals (IAOTP). For more information, go to the press release on my website, http://www.sherIVF.com .


Geoff Sher


Thanks Dr Sher. It was very informative. I guess it is too late to do any changes for this cycle so I just have to go through with it. Now I am armed with more knowledge and information, I can discuss with my fertility specialist for other options for future cycles. Best regards


Dr Sher, in an older patient with DOR using your A/ACP protocol are there any detrimental effects in starting dexamethasone with the commencement of Lupron (3 days of Desogen overlap)? Or must dexamethasone only be started when stimulation starts? Thank you!

Dr. Geoffrey Sher

I do not see any real detrimental effects if you start with Lupron, but starting with the stimulation is quite adequate.

Good luck!

Geoff Sher


Dear Dr. Sher,
I am about to begin my 3rd IVF cycle, and am being prescribed Ganirelix instead of Lupron to down regulate, and am wondering if there would be any benefit to my using Ganirelix over Lupron. My 2 previous cycles were at a different clinic, and both were long lupron cycles. I am 38 years old, and became pregnant with twins from my first IVF cycle, but lost them in the second trimester 1 year ago. My AMH is currently 2.73 (it was 8.44 when I had my first IVF cycle). In my first IVF cycle I had 17 eggs retrieved, 11 were mature, 8 fertilized, and 4 made it to 5 day blast. My second IVF cycle was kind of a mess (I went directly from prepping for an FET to a fresh IVF without a break to get a period, had a lead follicle that was significantly larger than the rest, and the Dr. that performed my transfer took well over a minute to get the catheter through my cervix, and I ended up having spasms and cramps that reminded me of contractions 20 minutes after the transfer), and I had 16 eggs retrieved, 5 were mature, 3 fertilized, 1 made it to 5 day blast. In my first IVF, I also had mild to moderate OHSS. Also, for the second IVF, I was told to only take 5000 units HCG, rather than 10,000. In terms of my other hormone numbers (estrogen, progesterone, FSH, LH), they are all pretty much non-existent. I have a low functioning pituitary gland, and would not ovulate or menstruate without medication. I have always responded well to Gonal F, Menopur and Follistim (which I had to use for IUIs as well as IVF, since Clomid did nothing for me because of my pituitary issues). Do you think changing to Ganirelix makes sense here? Is there some potential benefit to taking it in terms of my egg quality (my current RE acknowledges that my 2nd IVF potentially should have been cancelled due to the lead follicle, but he’s still concerned about quality)?
Thank you for your time.

Dr. Geoffrey Sher

Since you are young and seem to have good ovarian reserve, While I [personally prefer to DR with an agonist (Lupron) coming off a BCP and avoiding the use of antagonists in high responders, I cannot really fault the idea of using an antagonist (Ganirelix). However inn my opinion, halviong the dosage of hCG for the trigger, is in my opinion, a mistake. A full dosage of hCG (10,000U) needed to promote optimal egg maturation. See belowfor my reasoning.

I strongly recommend that you visit http://www.DrGeoffreySherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.
• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
• The Fundamental Requirements For Achieving Optimal IVF Success
• Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the “Conventional” Antagonist Approach
• Ovarian Stimulation in Women Who have Diminished Ovarian Reserve (DOR): Introducing the Agonist/Antagonist Conversion protocol
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian
• Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
• A personalized, stepwise approach to IVF
• How Many Embryos should be transferred: A Critical Decision in IVF.
• The Role of Nutritional Supplements in Preparing for IVF
• “Triggering” Egg Maturation in IVF: Comparing urine-derived hCG, Recombinant DNA-hCG and GnRH-agonist:
Please call or email Julie Dahan, my patient concierge. She will guide you on how to set up an in-person or Skype consultation with me. You can reach Julie at on her cell phone or via email at any time:
Julie Dahan
• Email: Julied@sherivf.com
• Phone: 702-533-2691
 800-780-7437

Geoff Sher

I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.


Good morning Dr. i am going to do the AAcp Protocol here in Argentina , i am 43 , 3 kids, fsh 9 LH 4 E2. 72 but here in Argentina from were i am, my RE says he dont know that protocol and the quantities of Gonal we must use, could You tell me so we dont mess the treatment ? Also the antagonist in the stimulation is given every day in 125 mg form ? Thanks a lot for your help is unvaluabable!!

Dr. Geoffrey Sher

Sorry Cinthia, I cannot do this. The liability is too great. However, if your Dr wishes to call me directly and discuss this with me, I would be forthcoming. He/she could reach me by calling 702-533-2691.

Good luck!

Geoff Sher

Laurene Starkey

Our nurse practicioner adviser recommends that we ask for a data sheet for Dr. Sher’s clinic, that indicates ratio of number of actual patients [in the age and weight category of our family member who is hoping to conceive with Dr. Sher’s help] to number of conceptions and then to number of successful births. Is this data available? Could it be sent to me? Many thanks.

Dr. Geoffrey Sher

The 1st step should be to consult via Skype so that I can understand your specific set of circumstances. This would provide context to any representations that could/would be forthcoming and which I would provide during that consultation. Then you can decide how/whether or not to proceed.

Please call or email Julie Dahan, my patient concierge. She will guide you on how to set up an in-person or Skype consultation with me. You can reach Julie at on her cell phone or via email at any time:
Julie Dahan
• Email: Julied@sherivf.com
• Phone: 702-533-2691
 800-780-7437

Geoff Sher

I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.
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