Why Did so Few of my Eggs Fertilize into Embryos, and so Many More Fail to Reach Blastocyst?

One of the most common questions asked by patients undergoing IVF relates to the likelihood of their eggs fertilizing and the likely “quality” of their embryos. This is also one of the most difficult questions to answer. On the one hand many factors that profoundly influence egg quality; such as the genetic recruitment of eggs for use in an upcoming cycle, the woman’s age and her ovarian reserve, are our outside of our control.

On the other hand the protocol for controlled ovarian stimulation (COS) can also profoundly influence egg/embryo development and this is indeed chosen by the treating physician.

First, it should be understood that the most important determinant of fertilization potential, embryo development and blastocyst generation, is “competency” of the embryo that is mostly affected by the numerical chromosomal integrity (ploidy) of the egg. While sperm quality does play a role, in the absence of moderate to severe sperm dysfunction this is (moderate or severe male factor infertility a relatively small one). Human eggs have the highest rate of numerical chromosomal irregularities (aneuploidy) of all mammals.

In fact only about half the eggs of women in their twenties or early thirties, have the required number of chromosomes (euploid), without which upon fertilization they cannot propagate a normal pregnancy. As the woman advances into and beyond her mid-thirties, the percentage of eggs euploid eggs declines progressively such that by the age of 40 years, only about one out of six are likely to be chromosomally normal. By her mid-only about forties one in ten of her eggs will be euploid and by 4r years of age, fewer than one in twenty will be euploid.

Second; embryos that fail to develop into blastocysts are almost always aneuploid and not worthy of being transferred to the uterus because they will either not implant, will miscarry or could even result in a chromosomally abnormal baby (e.g. Down syndrome). However, it is incorrect to assume that all embryos reaching the blastocyst stage are will be euploid (“competent”). It is true that since many aneuploid embryos are lost during development and that those failing to survive to the blastocyst stage are far more likely to be competent than are earlier (cleaved) embryos.  What is also true is that the older the woman who produced the eggs, the less likely it is that a given blastocyst will be “competent”. As an example, a morphologically pristine blastocyst derived from the egg of a 30 year old woman would have about a 50:50 chance of being euploid and such a microscopically normal embryo would have 25%-30% chance of propagating a healthy, normal baby, while a microscopically comparable blastocyst derived through fertilization of the eggs from a 40 year old, would be about half as likely to be euploid and/or propagate a healthy baby and by 45 years of age – less than 5%. .

While the effect of species on the potential of eggs to be euploid at ovulation is genetically preordained and nothing we do can alter this equation, there is unfortunately a lot we can (often unwittingly) do to worsen the situation by selecting a suboptimal protocol of controlled ovarian stimulation (COS). This, by creating an adverse intraovarian hormonal environment will often disrupt normal egg development and lead to a higher incidence of egg aneuploidy than otherwise might have occurred.  Older women, women with diminished ovarian reserve (DOR) and those with polycystic ovarian syndrome are especially vulnerable in this regard.

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 (tissue surrounding ovarian follicles) during the pre-ovulatory phase of the cycle enhance late follicle development, estrogen production by the granulosa 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 COS protocols should be individualized and geared toward optimizing follicle growth and development time while avoiding excessive ovarian androgen (testosterone) production and that the hCG “trigger shot” should be carefully timed.

In summary it is important to understand the influence species, age of the woman as well as the effect of the protocol used for ovarian stimulation, on the chromosomal integrity of the egg (“competency) on, fertilization potential, blastocyst generation, and thus on IVF outcome. With the exception of, the hormonal ovarian environment created by the protocol used for ovarian stimulation, all other factors are inherent and unavoidable. This is why selection of the protocol used for ovarian stimulation is by far the most important decision that the RE has to make when it comes to trying to influence IVF outcome. This becomes even more relevant when dealing with older women, those with DOR and women with polycystic ovarian syndrome (PCOS) who are the most vulnerable in this regard.

42 Comments

Johanna

Dear Dr. Sher,
I’m turning 41 in a few months, and since the age of 37, I’ve been trying to retrieve eggs for a future embryo transfer, given that at age 34 I was operated for quite severe endometriosis. I managed to collect 3 embryos in a time span of 1 year, but all transfers have failed. The last embryo was a 1AA blastocyst. My AMH was very low since the first time I was tested for it, and the last test (in Sept. 2019) showed it was 0.34 ng/mL.
I’ve been trying to give it one more go, and my doc has suggested natural cycles. I’ve had two attempts at egg retrieval. The first time I had two eggs (one was immature) and the second, one egg. In both cases, eggs failed to fertilize. I’m using a sperm donor – so I suppose the issue is with my eggs – and the ICSI method.
My doc suggested that we could perhaps try (just once) Clomifene next time, and I’m wondering: is this a good strategy? Can I try anything else? Worse still, but it’s a question I’m asking myself every day: is there any point in still trying?
Thanks in advance!

reply
Dr. Geoffrey Sher

Johanna,
There are several issues to be considered here:

1. AGE AND DIMINISHED OVARIAN RESERVE

The older a woman becomes, the more likely it is that her eggs will be chromosomally/genetically “incompetent” (not have the potential upon being fertilized and transferred, to result in a viable pregnancy). That is why, the likelihood of failure to conceive, miscarrying and of giving birth to a chromosomally defective child (e.g. with Down Syndrome) increases with the woman’s advancing age. In addition, as women age beyond 35Y there is commonly a progressive diminution in the number of eggs left in the ovaries, i.e. diminished ovarian reserve (DOR). So it is that older women as well as those who (regardless of age) have DOR have a reduced potential for IVF success. Much of this is due to the fact that such women tend to have increased production of LH biological activity which can result in excessive LH-induced ovarian male hormone (predominantly testosterone) production which in turn can have a deleterious effect on egg/embryo “competency”.
While it is presently not possible by any means, to reverse the age-related effect on the woman’s “biological clock, certain ovarian stimulation regimes, by promoting excessive LH production (e.g. short agonist/Lupron- “flare” protocols, clomiphene and Letrozole), can make matters worse. Similarly, the amount/dosage of certain fertility drugs that contain LH/hCG (e.g. Menopur) can have a negative effect on the development of the eggs of older women and those who have DOR and should be limited.
I try to avoid using such protocols/regimes (especially) in older women and those with DOR, favoring instead the use of the agonist/antagonist conversion protocol (A/ACP), a modified, long pituitary down-regulation regime, augmented by adding supplementary human growth hormone (HGH). I further recommend that such women be offered access to embryo banking of PGS (next generation gene sequencing/NGS)-selected normal blastocysts, the subsequent selective transfer of which by allowing them to capitalize on whatever residual ovarian reserve and egg quality might still exist and thereby “make hay while the sun still shines” could significantly enhance the opportunity to achieve a viable pregnancy

2.THE EFFECT OF THE PROTOCOL USED FOR OVARIAN STIMULATION ON EGG/EMBRYO QUALITY.

The importance of the IVF stimulation protocol on egg/embryo quality cannot be overstated. This factor seems often to be overlooked or discounted by t 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. 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.
Gonadotropins (LH and FSH), whether produced by the pituitary gland or administered by way of fertility drugs, have different “targeted” sites of action in the ovary. FSH targets cells that line the inner wall of the follicle (granulosa cells) and also form the cumulus cells that bind the egg to the inner surface of the follicle. Granulosa cells are responsible for estrogen production.
LH, on the other hand, targets the ovarian connective tissue (stroma/theca) that surrounds ovarian follicles resulting in the production of male hormones such as testosterone (predominantly), androstenedione and DHEA. These androgens are then transported to the granulosa cells of the adjacent follicles in a “bucket brigade fashion”. There FSH converts testosterone to estradiol, causing granulosa cells to multiply (proliferate) and produce estradiol, follicles to grows and eggs to develop (ovogenesis) It follows that ovarian androgens (mainly testosterone) is absolutely indispensable to follicle/ egg growth and development.
However, the emphasis is on a “normal” amount of testosterone. Over-exposure of the follicle to testosterone can in my opinion, compromise egg development and lead to an increased likelihood of chromosomal irregularities (aneuploid) following LH/hCG-induced egg maturational division (meiosis) and compromise embryo “competency/quality.
Ovarian androgens can also reach the uterine lining where they sometimes will compromise estrogen receptor -induced endometrial growth and development.
A significant percentage of older women and those who have diminished ovarian reserve (DOR) have increased LH activity is increased. Such women either over-produce LH and/or the LH produced is far more biologically active. Chronically increased LH activity leads to overgrowth of ovarian connective tissue (stroma/theca). This condition, which is often referred to as Stromal Hyperplasia or hyperthecosis can result in excessive ovarian androgen/testosterone production and poorer egg-embryo quality/competency, Similarly, women with polycystic ovarian syndrome (PCOS), also characteristically have Stromal hyperplasia/hyperthecosis due to chronically increased LH activity. Thus they too often manifest with increased ovarian androgen production. It is therefore not surprising that “poor egg/embryo quality” is often also a feature of PCOS.
In my opinion, the over-administration of LH-containing menotropins such as Menopur, [which is comprised of roughly equal amount of FSH and hCG ,which acts similar to LH)], to older women, women with DOR and those who have PCOS can also lead to reduced egg/embryo competency . Similarly, drugs such as clomiphene or Letrozole that cause the pituitary gland to release excessive amounts of LH, are also potentially harmful to egg development and in my opinion, are best omitted from IVF COS protocols. This is especially the case when it comes to older women and those with DOR, who in my opinion should preferably be stimulated using FSH-dominant products such as Follistim, Puregon, Fostimon and Gonal-F.
Gonadotropin releasing hormone agonists (GnRHa): GnRHa such as Lupron, Buserelin, Superfact, Gonopeptyl etc. are often used to launch ovarian stimulation cycles. They act by causing an initial outpouring followed by a depletion of pituitary gonadotropins. This results in LH levels falling to low concentrations, within 4-7 days, thereby establishing a relatively “LH-free environment”. When GnRHa are administered for about 7 days prior to initiating gonadotropin stimulation (“long” pituitary down-regulation”), the LH depletion that will exist when COS is initiated, will usually be protective of subsequent egg development. In contrast, when the GnRHa administration commences along with the initiation of gonadotropin therapy, there will be a resultant immediate surge in the release of pituitary LH with the potential to increase ovarian testosterone to egg-compromising levels , from the outset of COS. This, in my opinion could be particularly harmful when undertaken in older women and those who have DOR.
GnRH-antagonists such as Ganirelix, Cetrotide and Orgalutron, on the other hand, act very rapidly (within hours) to block pituitary LH release. The purpose in using GnRH antagonists is to prevent the release of LH during COS. In contrast, the LH-lowering effect of GnRH agonists develops over a number of days.
GnRH antagonists are traditionally given, starting after 5th -7th day of gonadotropin stimulation. However, when this is done in older women and those (regardless of age) who have DOR, LH-suppression might be reached too late to prevent the deleterious effect of excessive ovarian androgen production on egg development in the early stage of ovarian stimulation. This is why, it is my preference to administer GnRH-antagonists, starting at the initiation of gonadotropin administration.
My preferred Protocols for Controlled Ovarian Stimulation (COS):
1. “Long” GnRHa (Lupron/Buserelin/Superfact/Gonopeptyl) Pituitary Down-regulation Protocol: The most commonly prescribed protocol for GnRHa/gonadotropin administration is the so-called “long protocol”. Here, GnRHa is given, starting a week or so prior to menstruation. This results in an initial rise in FSH and LH , which is rapidly followed by a precipitous fall to near zero. It is followed by a withdrawal bleed (menstruation), whereupon gonadotropin treatment should commence, while daily Lupron injections continue, to ensure a “low LH” environment. A modification to the “long protocol” which I prefer prescribing for older women and in cases of DOR, is the Agonist/Antagonist Conversion Protocol (A/ACP) where, upon the onset of a GnRHa-induced bleed, the agonist is supplanted by an antagonist (Ganirelix/Cetrotide/Orgalutron) and this is continued until the hCG trigger. In many such cases I often supplement with human growth hormone (HGH) in such cases in an attempt to enhance egg mitochondrial activity and so enhance egg development. This approach is often augmented with preimplantation genetic screening (PGS) of all embryos that reach the expanded blastocyst stage of development by day 5-6 post-fertilization. I also commonly recommend blastocyst banking to many such patients.
2.
3. Short (“Flare”) GnRHa Protocol: Another GnRHa usage for COS is the so called “(micro) flare protocol”. This involves initiating gonadotropin therapy commensurate with initiation of gonadotropin administration. The supposed objective 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” constitutes “a double-edged sword”. 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/thecal androgen production which could potentially compromise egg quality, especially when it comes to older women and women with DOR. 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 when it comes to COS in older women, and in women with diminished ovarian reserve. Accordingly, I do not prescribe such protocols to my IVF patients.
4. Estrogen Priming – This is the approach I sometimes prescribe for my patients who have virtually depleted ovarian reserve , as determined by very low blood anti-Mullerian hormone AMH levels (<0.2ng/ml or 2 pmol/L) and are thus likely to be very “poor responders”. It involves a modified A/ACP. We start with estrogen skin patches applied every 2nd day (or with the BCP) for 10 days or longer, overlap it for 3 days with a GnRHa whereupon the estrogen priming is stopped. Th GnRHa is continued until the onset of menstruation (usually 5-7 days later) to cause pituitary LH, down-regulation. Upon menstruation and confirmation by ultrasound and measurement of blood estradiol levels that adequate ovarian suppression has been achieved, The patient is given twice-weekly injections of estradiol valerate (Delestrogen) for a period of 7-8 days whereupon COS is initiated using a relatively high dosage FSH-(Follistim, Fostimon, Puregon or Gonal F), which is continued along with daily administration of GnRH antagonist until the “hCG “trigger.” This approach is often augmented with HGH administration throughout the process of COS and by preimplantation genetic screening (PGS) of all embryos that reach the expanded blastocyst stage of development by day 5-6 post-fertilization. I also commonly recommend blastocyst banking to many such patients.
Estrogen Priming has succeeded in significantly enhancing ovarian response to gonadotropins in many of otherwise very poor responders.
Triggering egg Maturation prior to egg Retrieval: hCG versus GnRHa
With ovulation induction using fertility drugs, the administration of 10,000U hCGu (Pregnyl; Profasi, Novarel) or 500mcg hCGr (Ovidrel/Ovitrel) “trigger”) sends the eggs (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 they had prior to the “trigger”. Such a chromosomally numerically normal (euploid), mature (MII) eggs, upon being fertilized will (hopefully) propagate euploid embryos that have 46 chromosomes and will be “: competent” to propagate viable pregnancies. In my opinion, the key is to always “trigger” with no less than 10,000U of hCGu or 500mcg hCGr (Ovidrel/Ovitrel). Any lesser dosage often will reduce the efficiency of meiosis and increase the risk of the eggs being aneuploid. I personally do not use the agonist (Lupron) “trigger”, unless it is combined with (low dosage) hCG. The supposed reason for using the agonist, (Lupron) “trigger” is that by inducing meiosis through compelling a surge in the release of LH by the pituitary gland, the risk it reduces the risk of OHSS. This may be true, but it 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 likelihood of aneuploid and immature (MI) eggs. And there are other better approaches to preventing OHSS (e.g. “prolonged coasting”), in my opinion.
Use of the Birth Control Pill (BCP) to launch IVF-COS.
In natural (unstimulated) as well as in cycles stimulated with fertility drugs, the ability of follicles to properly respond to FSH stimulation is dependent on their having developed FSH-responsive receptors. Pre-antral follicles (PAF) do not have such primed FSH receptors and thus cannot respond properly to FSH stimulation with gonadotropins. The acquisition of FSH receptor responsivity requires that the pre-antral follicles be exposed to FSH, for a number of days (5-7) during which time they attain “FSH-responsivity” and are now known as antral follicles (AF). These AF’s are now able to respond properly to stimulation with administered FSH-gonadotropins. In regular menstrual cycles, the rising FSH output from the pituitary gland insures that PAFs convert tor AF’s. The BCP (as well as prolonged administration of estrogen/progesterone) suppresses FSH. This suppression needs to be countered by artificially causing blood FSH levels to rise in order to cause PAF to AF conversion prior to COS commencing, otherwise pre-antral-to –antral follicle conversion will not take place in an orderly fashion, the duration of ovarian stimulation will be prolonged and both follicle and egg development may be compromised. GnRH agonists cause an immediate surge in release of FSH by the pituitary gland thus causing conversion from PAF to SAF. This is why women who take a BCP to launch a cycle of COS need to have an overlap of the BCP with an agonist. By overlapping the BCP with an agonist for a few days prior to menstruation the early recruited follicles are able to complete their developmental drive to the AF stage and as such, be ready to respond appropriately to optimal ovarian stimulation. Using this approach, the timing of the initiation of the IVF treatment cycle can readily and safely be regulated and controlled by varying the length of time that the woman is on the BCP.
Since optimizing follicular response to COS requires that prior to stimulation with gonadotropins, FSH-induced conversion from PAF to AF’s first be completed and the BCP suppresses FSH, it follows when it comes to women launching COS coming off a BCP something needs to be done to cause a rise in FSH for 5-7 days prior to menstruation heralding the cycle of CO S. This is where overlapping the BCP with a GnRHa comes in. The agonist causes FSH to be released by the pituitary gland and if overlapped with the BCP for several days and this will (within 2-5 days) facilitate PAF to AF conversion…. in time to start COS with the onset of menstruation. Initiating ovarian stimulation in women taking a BCP, without doing this is suboptimal.

3. ENDOMETRIOSIS AND IVF.

When women with infertility due to endometriosis seek treatment, they are all too often advised to first try ovarian stimulation (ovulation Induction) with intrauterine insemination (IUI) ………as if to say that this would be just as likely to result in a baby as would in vitro fertilization (IVF). Nothing could be further from reality It is time to set the record straight. And hence this communication!
Bear in mind that the cost of treatment comprises both financial and emotional components and that it is the cost of having a baby rather than cost of a procedure. Then consider the fact that regardless of her age or the severity of the condition, women with infertility due to endometriosis are several fold more likely to have a baby per treatment cycle of IVF than with IUI. It follows that there is a distinct advantage in doing IVF first, rather than as a last resort.
So then, why is it that ovulation induction with or without IUI is routinely offered proposed preferentially to women with mild to moderately severe endometriosis? Could it in part be due to the fact that most practicing doctors do not provide IVF services but are indeed remunerated for ovarian stimulation and IUI services and are thus economically incentivized to offer IUI as a first line approach? Or is because of the often erroneous belief that the use of fertility drugs will in all cases induce the release (ovulation) of multiple eggs at a time and thereby increase the chance of a pregnancy. The truth however is that while normally ovulating women (the majority of women who have mild to moderately severe endometriosis) respond to ovarian stimulation with fertility drugs by forming multiple follicles, they rarely ovulate > 1 (or at most 2) egg at a time. This is because such women usually only develop a single dominant follicle which upon ovulating leaves the others intact. This is the reason why normally ovulating women who undergo ovulation induction usually will not experience improved pregnancy potential, nor will they have a marked increase in multiple pregnancies. Conversely, non-ovulating women (as well as those with dysfunctional ovulation) who undergo ovulation induction, almost always develop multiple large follicles that tend to ovulate in unison. This increases the potential to conceive along with an increased risk multiple pregnancies.

So let me take a stab at explaining why IVF is more successful than IUI or surgical correction in the treatment of endometriosis-related infertility:
1. The toxic pelvic factor: Endometriosis is a condition where the lining of the uterus (the endometrium) grows outside the uterus. While this process begins early in the reproductive life of a woman, with notable exceptions, it only becomes manifest in the 2ndhalf of her reproductive life. After some time, these deposits bleed and when the blood absorbs it leaves a visible pigment that can be identified upon surgical exposure of the pelvis. Such endometriotic deposits invariably produce and release toxins” into the pelvic secretions that coat the surface of the membrane (the peritoneum) that envelops all abdominal and pelvic organs, including the uterus, tubes and ovaries. These toxins are referred to as “the peritoneal factor”. Following ovulation, the egg(s) must pass from the ovary (ies), through these toxic secretions to reach the sperm lying in wait in the outer part the fallopian tube (s) tube(s) where, the sperm lie in waiting. In the process of going from the ovary(ies) to the Fallopian tube(s) these eggs become exposed to the “peritoneal toxins” which alter s the envelopment of the egg (i.e. zona pellucida) making it much less receptive to being fertilized by sperm. As a consequence, if they are chromosomally normal such eggs are rendered much less likely to be successfully fertilized. Since almost all women with endometriosis have this problem, it is not difficult to understand why they are far less likely to conceive following ovulation (whether natural or induced through ovulation induction). This “toxic peritoneal factor impacts on eggs that are ovulated whether spontaneously (as in natural cycles) or following the use of fertility drugs and serves to explain why the chance of pregnancy is so significantly reduced in normally ovulating women with endometriosis.
2. The Immunologic Factor: About one third of women who have endometriosis will also have an immunologic implantation dysfunction (IID) linked to activation of uterine natural killer cells (NKa). This will require selective immunotherapy with Intralipid infusions, and/or heparinoids (e.g. Clexane/Lovenox) that is much more effectively implemented in combination with IVF.
3. Surgical treatment of mild to moderate endometriosis does not usually improve pregnancy potential:. The reason is that endometriosis can be considered to be a “work in progress”. New lesions are constantly developing. So it is that for every endometriotic seen there are usually many non-pigmented deposits that are in the process of evolving but are not yet visible to the naked eye and such evolving (non-visible) lesions can also release the same “toxins that compromise fertilization. Accordingly, even after surgical removal of all visible lesions the invisible ones continue to release “toxins” and retain the ability to compromise natural fertilization. It also explains why surgery to remove endometriotic deposits in women with mild to moderate endometriosis usually will fail to significantly improve pregnancy generating potential. In contrast, IVF, by removing eggs from the ovaries prior to ovulation, fertilizing these outside of the body and then transferring the resulting embryo(s) to the uterus, bypasses the toxic pelvic environment and is therefore is the treatment of choice in cases of endometriosis-related infertility.
4. Ovarian Endometriomas: Women, who have advanced endometriosis, often have endometriotic ovarian cysts, known as endometriomas. These cysts contain decomposed menstrual blood that looks like melted chocolate…hence the name “chocolate cysts”. These space occupying lesions can activate ovarian connective tissue (stroma or theca) resulting in an overproduction of male hormones (especially testosterone). An excess of ovarian testosterone can severely compromise follicle and egg development in the affected ovary. Thus there are two reasons for treating endometriomas. The first is to alleviate symptoms and the second is to optimize egg and embryo quality. Conventional treatment of endometriomas involves surgical drainage of the cyst contents with subsequent removal of the cyst wall (usually by laparoscopy), increasing the risk of surgical complications. We recently reported on a new, effective and safe outpatient approach to treating endometriomas in women planning to undergo IVF. We termed the treatment ovarian Sclerotherapy. The process involves; needle aspiration of the “chocolate colored liquid content of the endometriotic cyst, followed by the injection of 5% tetracycline hydrochloride into the cyst cavity. Such treatment will, more than 75% of the time result in disappearance of the lesion within 6-8 weeks. Ovarian sclerotherapy can be performed under local anesthesia or under conscious sedation. It is a safe and effective alternative to surgery for definitive treatment of recurrent ovarian endometriomas in a select group of patients planning to undergo IVF

I am not suggesting that all women with infertility-related endometriosis should automatically resort to IVF. Quite to the contrary…. In spite of having reduced fertility potential, many women with mild to moderate endometriosis can and do go on to conceive on their own (without treatment). It is just that the chance of this happening is so is much lower than normal.
IN SUMMARY: For young ovulating women (< 35 years of age ) with endometriosis, who have normal reproductive anatomy and have fertile male partners, expectant treatment is often preferable to IUI or IVF. However, for older women, women who (regardless of their age) have any additional factor (e.g. pelvic adhesions, ovarian endometriomas, male infertility, IID or diminished ovarian reserve-DOR) IVF should be the primary treatment of choice. 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.
• The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
• 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
• 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 Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 1-Background
• Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 2- Making a Diagnosis
• Immunologic Dysfunction (IID) & Infertility (IID): PART 3-Treatment
• Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
• Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management: (Case Report)
• Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
• Intralipid (IL) Administration in IVF: It’s Composition; how it Works; Administration; Side-effects; Reactions and Precautions
• Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
• Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas
• Should IVF Treatment Cycles be provided uninterrupted or be Conducted in 7-12 Pre-scheduled “Batches” per Year
• A personalized, stepwise approach to IVF

reply
Atiye

Hi Dr Sher,

I’m 34 with regular cycles and started the fertility treatment more than a year ago, had laparoscopy to check whether it is endo which was negative.
6 rounds of failed IUI (as Dutch protocol) and recently one round of IVf failed٫ 7 eggs retrieved of which 4 fertilized and one embryo day 3.

What confused me was that my reaction to medicine for IUI was great, I would get lowest dose as my doctor said I would ever prescribed and still 3 follicle. But IVF totally different. We are now speaking about 2nd round but I’m worried as the results was so bad in the first round.
they told us that it is unexplained fertility as no issue also found with my husband. Only 2 month ago they found my thyroid is low like borderlines low and I’m not overweight.

reply
Dr. Geoffrey Sher

For about 10% of all infertile couples, the cause of the infertility cannot be readily determined using conventional diagnostic methods. Such cases are often referred to as “unexplained infertility.” The truth however is that in most such cases, the diagnosis of “unexplained infertility is in fact “presumptive because a more in-depth evaluation would have revealed a cause. This having been said, people diagnosed with so called “unexplained infertility” fall into two broad groups: a)those couples who don’t have any biological problems interfering with pregnancy and, b) those who do but the reason cannot be found due to insufficient medical information or technology. It is in this latter group that improved testing techniques have made infertility easier to diagnose and treat.
In order to make even a presumptive diagnosis of “unexplained infertility” the answers to the following questions must be in the affirmative.
 Is the woman ovulating normally?
 Is the couple having intercourse regularly in the periovulatory phase of the cycle?
 Are the fallopian tubes normal and open?
 Can endometriosis be excluded?
 Does the male partner have normal semen parameters (most specifically with regard to sperm count and motility?
 Is the post coital (Huhner) test (periovulatory examination of cervical mucous, done 6-18 hours after intercourse) normal?
The definitive diagnosis of “unexplained infertility” has a lot to do with the thoroughness of the health care provider in excluding all possible causes. The fewer tests performed, the more likely a presumptive diagnosis
For Example:
 Abnormalities of the fallopian tubes (adhesions or developmental defects) of the finger-like “petals” at their outer ends of the tubes that help sweep eggs inside (i.e. fimbriae). can prevent eggs from being collected and transported to the awaiting sperm
 Chromosomal abnormalities of eggs or embryos: Eggs must be euploid (contain the right number of chromosomes) to be successfully fertilized and embryos must also be euploid in order to implant successfully in the uterine lining. Until recently there was no reliable method for determining whether eggs and embryos were euploid. The recent introduction of genetic tests such as comparative genomic hybridization (CGH) now allows for identification of all chromosomes in the egg and embryo. As such CGH represents an important addition to the “infertility” diagnostic armamentarium.
 Luteinized Unruptured Follicle (LUF)Syndrome: Here, the eggs can become trapped in the follicle and not be released (trapped ovulation) In such cases routine tests done to detect ovulation ((temperature charting, Urine LH testing, Blood progesterone levels) may be normal resulting in false interpretation that ovulation is actually occurring.
 Ovulation (hormonal) Dysfunction: Abnormalities in ovarian hormone production in the preovulatory phase of the cycle (follicular phase defect) and/or in the postovulatory phase (luteal phase defect) can negatively affect preparation of the uterine lining (endometrium), thus thwarting normal implantation.
 Immunologic implantation dysfunction (IID): Sometimes, the woman’s or the man’s own immune system can attack sperm cells, killing them or causing them to become immobilized. Also, immunologic dysfunction involving the uterine lining can cause the implanting embryo to be rejected so early that the woman does not even recognize that she in fact had conceived.
 Cervical infection; Ureaplasma urealyticum infection of the cervical glands can prevent sperm from migrating through the cervix and uterus to reach the egg(s) in the fallopian tube(s). Such infection will usually not be detectable through routine examination and/or cervical culturing methods.
 Mild or Moderate Endometriosis: Endometriosis is in 100% of cases associated with the production of “pelvic toxins” that reduce the fertilization potential of otherwise normal eggs by a factor of 3-5. In addition, about 1/3 of woman with endometriosis (regardless of its severity) have immunologic implantation dysfunction (IID). Furthermore mild and often even moderately severe endometriosis can only be accurately diagnosed by direct visualization of the lesions through laparoscopy or laparotomy and, the detection of IID requires highly sophisticated tests that can only be adequately performed by a handful of Reproductive Immunology Reference Laboratories in the United States. Finally, a condition called nonpigmented endometriosis, in which the endometrium may be growing inside the pelvic cavity with many of the same deleterious effects as overt endometriosis, cannot be detected even by direct vision (at laparoscopy/laparotomy). The fertility of these patients may be every bit as compromised as if they had detectable endometriosis.
 Psychological Factors: The entire reproductive process is governed by the brain. Thus it should come as no surprise that stress and negativity can interfere with hormonal balance and decrease the ability to conceive.
 Mild Male Factor
 Antisperm antibodies in the man or woman.
Management:
Successful management of “Unexplained Infertility” requires that a very individualized approach be taken. Wherever possible the underlying cause should first be identified. Problems that involve ovulation dysfunction (hormonal imbalance) require ovulation induction with oral or injectible fertility drugs. Cervical mucous hostility due to infection with ureaplasma (which is transferred back and forth sexually to both partners) requires specific and concurrent antibiotic therapy. In other cases involving younger women (under 39 years) where there is a problem with sperm migration via the cervix and uterus to the fallopian tube(s) intrauterine insemination (IUI) with or without ovulation induction, is indicated. When these treatments fail, in cases, women over the age of 39 years, in women with IID, in men or women who harbor antisperm antibodies in significant concentrations and in cases associated with tubal abnormalities, in vitro fertilization (IVF) is needed. All cases of intractable, moderate or severe male infertility call for injecting sperm directly into the egg to achieve forced fertilization (intracytoplasmic sperm injection-ICSI).
It is an indisputable fact that most causes of infertility can be diagnosed and it is a great pity that the diagnosis of “unexplained infertility” is often used as an excuse for not having performed a full and detailed evaluation of the problem. Couples should not simply accept a diagnosis of “unexplained infertility” at face value since treatment is most likely to be successful when the specific cause of the problem can be fully identified
I strongly recommend that you visit http://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.

• A Fresh Look at the Indications for IVF
• The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
• 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
• Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
• Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
• IVF and the use of Supplementary Human Growth Hormone (HGH) : Is it Worth Trying and who needs it?
• The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
• Blastocyst Embryo Transfers Should be the Standard of Care in IVF
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
• IVF: Approach to Selecting the Best Embryos for Transfer to the Uterus.
• Fresh versus Frozen Embryo Transfers (FET) Enhance IVF Outcome
• Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
• Genetically Testing Embryos for IVF
• Staggered IVF
• Staggered IVF with PGS- Selection of “Competent” Embryos Greatly Enhances the Utility & Efficiency of IVF.
• 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
• Endometrial Receptivity Array (ERA): Is There an actual “There, There”?
• IVF Failure and Implantation Dysfunction:
• Diagnosing and Treating Immunologic Implantation Dysfunction (IID)
• The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 1-Background
• Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 2- Making a Diagnosis
• Immunologic Dysfunction (IID) & Infertility (IID):PART 3-Treatment
• Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
• Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management:(Case Report
• Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
• Intralipid (IL) Administration in IVF: It’s Composition; How it Works; Administration; Side-effects; Reactions and Precautions
• Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
• Endometrial Thickness, Uterine Pathology and Immunologic Factors
• Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
• A Thin Uterine Lining: Vaginal Viagra is Often the Answer (update)
• Cervical Ureaplasma Urealyticum Infection: How can it Affect IUI/IVF Outcome?
• The Role of Nutritional Supplements in Preparing for IVF
• The Basic Infertility Work-Up
• Defining and Addressing an Abnormal Luteal Phase
• Male Factor Infertility
• Routine Fertilization by Intracytoplasmic Sperm Injection (ICSI): An Argument in Favor
• Hormonal Treatment of Male Infertility
• Hormonal Treatment of Male Infertility
• Antisperm Antibodies, Infertility and the Role of IVF with Intracytoplasmic Sperm Injection (ICSI)
• Endometriosis and Infertily
• Endometriosis and Immunologic Implantation Dysfunction (IID) and IVF
• Endometriosis and Infertility: Why IVF Rather than IUI or Surgery Should be the Treatment of Choice.
• Endometriosis and Infertility: The Influence of Age and Severity on Treatment Options
• Early -Endometriosis-related Infertility: Ovulation Induction (with or without Intrauterine Insemination) and Reproductive Surgery Versus IVF
• Deciding Between Intrauterine Insemination (IUI) and In Vitro Fertilization (IVF).
• Intrauterine Insemination (IUI): Who Needs it & who Does Not: Pro’s & Con’s!IUI-Reflecting upon its Use and Misuse: Time for a Serious “Reality Check
• Mode of Action, Indications, Benefits, Limitations and Contraindications for its ue
• Clomiphene Induction of Ovulation: Its Use and Misuse!

ADDENDUM: PLEASE READ!!
INTRODUCING SHER FERTILITY SOLUTIONS (SFS)
Founded in April 2019, Sher Fertility Solutions (SFS) offers online (Skype/FaceTime) consultations to patients from > 40 different countries. All consultations are followed by a detailed written report presenting my personal recommendations for treatment of what often constitute complex Reproductive Issues.

If you wish to schedule an online consultation with me, please contact my assistant (Patti Converse) by phone (800-780-7437/702-533-2691), email (concierge@SherIVF.com) or, enroll online on then home-page of my website (www.SherIVF.com).

PLEASE SPREAD THE WORD ABOUT SFS!

Geoff Sher

reply
Karen

Hello
Very interesting article, very informative
I would like to ask you something. I am 43 and just had an IVF cycle with 10 follicles, 5 matures but only one fertilized.
We use menopur 150, gonal 300 and garinelix after one week of the other 2, we did the triggers with lupron and chorionic gonadotropin after around 13 days.

Is there anything you would do different?. I noticed some increase of hair this time, that since you mentioned the “testosterone” factor.

Thanks for your time and all this useful information.

reply
Dr. Geoffrey Sher

Respectfully, I would not use this protocol and I would “trigger differently. Perhaps we should discuss this (see below).

The older a woman becomes, the more likely it is that her eggs will be chromosomally/genetically “incompetent” (not have the potential upon being fertilized and transferred, to result in a viable pregnancy). That is why, the likelihood of failure to conceive, miscarrying and of giving birth to a chromosomally defective child (e.g. with Down Syndrome) increases with the woman’s advancing age. In addition, as women age beyond 35Y there is commonly a progressive diminution in the number of eggs left in the ovaries, i.e. diminished ovarian reserve (DOR). So it is that older women as well as those who (regardless of age) have DOR have a reduced potential for IVF success. Much of this is due to the fact that such women tend to have increased production of LH biological activity which can result in excessive LH-induced ovarian male hormone (predominantly testosterone) production which in turn can have a deleterious effect on egg/embryo “competency”.
While it is presently not possible by any means, to reverse the age-related effect on the woman’s “biological clock, certain ovarian stimulation regimes, by promoting excessive LH production (e.g. short agonist/Lupron- “flare” protocols, clomiphene and Letrozole), can make matters worse. Similarly, the amount/dosage of certain fertility drugs that contain LH/hCG (e.g. Menopur) can have a negative effect on the development of the eggs of older women and those who have DOR and should be limited.
I try to avoid using such protocols/regimes (especially) in older women and those with DOR, favoring instead the use of the agonist/antagonist conversion protocol (A/ACP), a modified, long pituitary down-regulation regime, augmented by adding supplementary human growth hormone (HGH). I further recommend that such women be offered access to embryo banking of PGS (next generation gene sequencing/NGS)-selected normal blastocysts, the subsequent selective transfer of which by allowing them to capitalize on whatever residual ovarian reserve and egg quality might still exist and thereby “make hay while the sun still shines” could significantly enhance the opportunity to achieve a viable pregnancy

Please visit my Blog on this very site, http://www.DrGeoffreySherIVF.com, find the “search bar” and 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
• 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)
• Controlled Ovarian Stimulation (COS) in Older women and Women who have Diminished Ovarian Reserve (DOR): A Rational Basis for Selecting a Stimulation Protocol
• 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?
• Blastocyst Embryo Transfers Should be the Standard of Care in IVF
• Frozen Embryo Transfer (FET) versus “Fresh” ET: How to Make the Decision
• Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting 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.
• 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
• Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
• Traveling for IVF from Out of State/Country–
• 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
• Premature Luteinization (“the premature LH surge): Why it happens and how it can be prevented.
• IVF Egg Donation: A Comprehensive Overview

______________________________________________________
ADDENDUM: PLEASE READ!!
INTRODUCING SHER FERTILITY SOLUTIONS (SFS)
Founded in April 2019, Sher Fertility Solutions (SFS) offers online (Skype/FaceTime) consultations to patients from > 40 different countries. All consultations are followed by a detailed written report presenting my personal recommendations for treatment of what often constitute complex Reproductive Issues.

If you wish to schedule an online consultation with me, please contact my assistant (Patti Converse) by phone (800-780-7437/702-533-2691), email (concierge@SherIVF.com) or, enroll online on then home-page of my website (www.SherIVF.com).

PLEASE SPREAD THE WORD ABOUT SFS!

Geoff Sher

reply
Ashleigh

Hi Dr Sher,
I have completed 4 full stim IVF cycles. I am 30 years old, slightly lower AMH but good AFC. My husband has poor sperm (low count/concentration but decent motility with poor DNA frag).
We have terrible fertilisation results! We average 25% fertilisation with ICSI a summary of our cycles.
#1- 13 eggs, 8 mature, 1 fertilised. Transfer on day 3 (6 cell C grade)- BFN
#2- 10 eggs, 6 mature, 1 fertilised (6 cell C grade on day 3 chose not to transfer) didn’t progress past day 3
#3- 16 eggs, 9 mature, 3 fertilised (9 & 8 cell grade A&B transfered on day 3) 3rd embryo didn’t grow past day 3. We did get pregnant but miscarried (blighted ovum)
#4- 8 eggs, 8 mature, 3 fertilised- I’m awaiting day 3 results now.

So from 32 mature eggs in total we have had 8 fertilise with ICSI. My husbands sperm generally ranges between 1-3% normal morphology, 70% motility and between 2-12 million in count. He has normal karotype testing with no deleted chromosomes.
Why do we experience such poor fertilisation results? Embryologists have always said my eggs look fine but there are no tests we can do to check this out.
What do you suggest I do?

reply
Dr. Geoffrey Sher

Thank for your post.
Here are a few concepts to consider!

WHY DOES IVF FAIL?

Whenever a patient fails to achieve a viable pregnancy following embryo transfer (ET), the first question asked is why! Was it simply due to, bad luck?, How likely is the failure to recur in future attempts and what can be done differently, to avoid it happening next time?.
It is an indisputable fact that any IVF procedure is at least as likely to fail as it is to succeed. Thus when it comes to outcome, luck is an undeniable factor. Notwithstanding, it is incumbent upon the treating physician to carefully consider and address the causes of IVF failure before proceeding to another attempt:
1. Age: The chance of a woman under 35Y of age having a baby per embryo transfer is about 35-40%. From there it declines progressively to under 5% by the time she reaches her mid-forties. This is largely due to declining chromosomal integrity of the eggs with advancing age…”a wear and tear effect” on eggs that are in the ovaries from birth.
2. Embryo Quality/”competency (capable of propagating a viable pregnancy)”. As stated, the woman’s age plays a big role in determining egg/embryo quality/”competency”. This having been said, aside from age the protocol used for controlled ovarian stimulation (COS) is the next most important factor. It is especially important when it comes to older women, and women with diminished ovarian reserve (DOR) where it becomes essential to be aggressive, and to customize and individualize the ovarian stimulation protocol.
We used to believe that the uterine environment is more beneficial to embryo development than is the incubator/petri dish and that accordingly, the earlier on in development that embryos are transferred to the uterus, the better. To achieve this goal, we used to select embryos for transfer based upon their day two or microscopic appearance (“grade”). But we have since learned that the further an embryo has advanced in its development, the more likely it is to be “competent” and that embryos failing to reach the expanded blastocyst stage within 5-6 days of being fertilized are almost invariably “incompetent” and are unworthy of being transferred. Moreover, the introduction into clinical practice about 15y ago, (by Levent Keskintepe PhD and myself) of Preimplantation Genetic Sampling (PGS), which assesses for the presence of all the embryos chromosomes (complete chromosomal karyotyping), provides another tool by which to select the most “competent” embryos for transfer. This methodology has selective benefit when it comes to older women, women with DOR, cases of unexplained repeated IVF failure and women who experience recurrent pregnancy loss (RPL).
3. The number of the embryos transferred: Most patients believe that the more embryos transferred the greater the chance of success. To some extent this might be true, but if the problem lies with the use of a suboptimal COS protocol, transferring more embryos at a time won’t improve the chance of success. Nor will the transfer of a greater number of embryos solve an underlying embryo implantation dysfunction (anatomical molecular or immunologic).Moreover, the transfer of multiple embryos, should they implant, can and all too often does result in triplets or greater (high order multiples) which increases the incidence of maternal pregnancy-induced complications and of premature delivery with its serious risks to the newborn. It is for this reason that I rarely recommend the transfer of more than 2 embryos at a time and am moving in the direction of advising single embryo transfers …especially when it comes to transferring embryos derived through the fertilization of eggs from young women.

4. Implantation Dysfunction (ID): Implantation dysfunction is a very common (often overlooked) cause of “unexplained” IVF failure. This is especially the case in young ovulating women who have normal ovarian reserve and have fertile partners. Failure to identify, typify, and address such issues is, in my opinion, an unfortunate and relatively common cause of repeated IVF failure in such women. Common sense dictates that if ultrasound guided embryo transfer is performed competently and yet repeated IVF attempts fail to propagate a viable pregnancy, implantation dysfunction must be seriously considered. Yet ID is probably the most overlooked factor. The most common causes of implantation dysfunction are:

a. A“ thin uterine lining”
b. A uterus with surface lesions in the cavity (polyps, fibroids, scar tissue)
c. Immunologic implantation dysfunction (IID)
d. Endocrine/molecular endometrial receptivity issues
e. Ureaplasma Urealyticum (UU) Infection of cervical mucous and the endometrial lining of the uterus, can sometimes present as unexplained early pregnancy loss or unexplained failure following intrauterine insemination or IVF. The infection can also occur in the man, (prostatitis) and thus can go back and forth between partners, with sexual intercourse. This is the reason why both partners must be tested and if positive, should be treated contemporaneously.
Certain causes of infertility are repetitive and thus cannot readily be reversed. Examples include advanced age of the woman; severe male infertility; immunologic infertility associated with alloimmune implantation dysfunction (especially if it is a “complete DQ alpha genetic match between partners plus uterine natural killer cell activation (NKa).

WHY SO FEW EMBRYOS REACHING BLASTOCYST?

One of the commonest questions asked by patients undergoing IVF relates to the likelihood of their eggs fertilizing and the likely “quality of their embryos. This is also one of the most difficult questions to answer. On the one hand many factors that profoundly influence egg quality; such as the genetic recruitment of eggs for use in an upcoming cycle, the woman’s age and her ovarian reserve, are our outside of our control. On the other hand the protocol for controlled ovarian stimulation (COS) can also profoundly influence egg/embryo development and this is indeed chosen by the treating physician.
First; it should be understood that the most important determinant of fertilization potential, embryo development and blastocyst generation, is the numerical chromosomal integrity of the egg (While sperm quality does play a role, in the absence of moderate to severe sperm dysfunction this is (moderate or severe male factor infertility a relatively small one). Human eggs have the highest rate of numerical chromosomal irregularities (aneuploidy) of all mammals. In fact only about half the eggs of women in their twenties or early thirties, have the required number of chromosomes (euploid), without which upon fertilization they cannot propagate a normal pregnancy. As the woman advances into and beyond her mid-thirties, the percentage of eggs euploid eggs declines progressively such that by the age of 40 years, only about one out of seven or eight are likely to be chromosomally normal and by the time she reaches her mid-forties less than one in ten of her eggs will be euploid.
Second; embryos that fail to develop into blastocysts are almost always aneuploid and not worthy of being transferred to the uterus because they will either not implant, will miscarry or could even result in a chromosomally abnormal baby (e.g. Down syndrome). However, it is incorrect to assume that all embryos reaching the blastocyst stage will be euploid (“competent”). ). It is true that since many aneuploid embryos are lost during development and that those failing to survive to the blastocyst stage are far more likely to be competent than are earlier (cleaved) embryos. What is also true is that the older the woman who produces the eggs, the less likely it is that a given blastocyst will be “competent”. As an example, a morphologically pristine blastocyst derived from the egg of a 30-year-old woman would have about a 50:50 chance of being euploid and a 30% chance of propagating a healthy, normal baby, while a microscopically comparable blastocyst-derived through fertilization of the eggs from a 40-year-old, would be about half as likely to be euploid and/or propagate a healthy baby.
While the effect of species on the potential of eggs to be euploid at ovulation is genetically preordained and nothing we do can alter this equation, there is, unfortunately, a lot we can (often unwittingly) do to worsen the situation by selecting a suboptimal protocol of controlled ovarian stimulation (COS). This, by creating an adverse intraovarian hormonal environment will often disrupt normal egg development and lead to a higher incidence of egg aneuploidy than otherwise might have occurred. Older women, women with diminished ovarian reserve (DOR) and those with polycystic ovarian syndrome are especially vulnerable in this regard.

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 (tissue surrounding ovarian follicles) during the pre-ovulatory phase of the cycle enhance late follicle development, estrogen production by the granulosa 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 COS protocols should be individualized and geared toward optimizing follicle growth and development time while avoiding excessive ovarian androgen (testosterone) production and that the hCG “trigger shot” should be carefully timed.

OVARIAN STIMULATION AND ITS EFFECT ON EGG/EMBRYO COMPETYENCY:

The importance of the IVF stimulation protocol on egg/embryo quality cannot be overstated. This factor seems often to be overlooked or discounted by t 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. 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.
Gonadotropins (LH and FSH), whether produced by the pituitary gland or administered by way of fertility drugs, have different “targeted” sites of action in the ovary. FSH targets cells that line the inner wall of the follicle (granulosa cells) and also form the cumulus cells that bind the egg to the inner surface of the follicle. Granulosa cells are responsible for estrogen production.
LH, on the other hand, targets the ovarian connective tissue (stroma/theca) that surrounds ovarian follicles resulting in the production of male hormones such as testosterone (predominantly), androstenedione and DHEA. These androgens are then transported to the granulosa cells of the adjacent follicles in a “bucket brigade fashion”. There FSH converts testosterone to estradiol, causing granulosa cells to multiply (proliferate) and produce estradiol, follicles to grows and eggs to develop (ovogenesis) It follows that ovarian androgens (mainly testosterone) is absolutely indispensable to follicle/ egg growth and development.
However, the emphasis is on a “normal” amount of testosterone. Over-exposure of the follicle to testosterone can in my opinion, compromise egg development and lead to an increased likelihood of chromosomal irregularities (aneuploid) following LH/hCG-induced egg maturational division (meiosis) and compromise embryo “competency/quality.
Ovarian androgens can also reach the uterine lining where they sometimes will compromise estrogen receptor -induced endometrial growth and development.
A significant percentage of older women and those who have diminished ovarian reserve (DOR) have increased LH activity is increased. Such women either over-produce LH and/or the LH produced is far more biologically active. Chronically increased LH activity leads to overgrowth of ovarian connective tissue (stroma/theca). This condition, which is often referred to as Stromal Hyperplasia or hyperthecosis can result in excessive ovarian androgen/testosterone production and poorer egg-embryo quality/competency, Similarly, women with polycystic ovarian syndrome (PCOS), also characteristically have Stromal hyperplasia/hyperthecosis due to chronically increased LH activity. Thus they too often manifest with increased ovarian androgen production. It is therefore not surprising that “poor egg/embryo quality” is often also a feature of PCOS.
In my opinion, the over-administration of LH-containing menotropins such as Menopur, [which is comprised of roughly equal amount of FSH and hCG ,which acts similar to LH)], to older women, women with DOR and those who have PCOS can also lead to reduced egg/embryo competency . Similarly, drugs such as clomiphene or Letrozole that cause the pituitary gland to release excessive amounts of LH, are also potentially harmful to egg development and in my opinion, are best omitted from IVF COS protocols. This is especially the case when it comes to older women and those with DOR, who in my opinion should preferably be stimulated using FSH-dominant products such as Follistim, Puregon, Fostimon and Gonal-F.
Gonadotropin releasing hormone agonists (GnRHa): GnRHa such as Lupron, Buserelin, Superfact, Gonopeptyl etc. are often used to launch ovarian stimulation cycles. They act by causing an initial outpouring followed by a depletion of pituitary gonadotropins. This results in LH levels falling to low concentrations, within 4-7 days, thereby establishing a relatively “LH-free environment”. When GnRHa are administered for about 7 days prior to initiating gonadotropin stimulation (“long” pituitary down-regulation”), the LH depletion that will exist when COS is initiated, will usually be protective of subsequent egg development. In contrast, when the GnRHa administration commences along with the initiation of gonadotropin therapy, there will be a resultant immediate surge in the release of pituitary LH with the potential to increase ovarian testosterone to egg-compromising levels , from the outset of COS. This, in my opinion could be particularly harmful when undertaken in older women and those who have DOR.
GnRH-antagonists such as Ganirelix, Cetrotide and Orgalutron, on the other hand, act very rapidly (within hours) to block pituitary LH release. The purpose in using GnRH antagonists is to prevent the release of LH during COS. In contrast, the LH-lowering effect of GnRH agonists develops over a number of days.
GnRH antagonists are traditionally given, starting after 5th -7th day of gonadotropin stimulation. However, when this is done in older women and those (regardless of age) who have DOR, LH-suppression might be reached too late to prevent the deleterious effect of excessive ovarian androgen production on egg development in the early stage of ovarian stimulation. This is why, it is my preference to administer GnRH-antagonists, starting at the initiation of gonadotropin administration.
My preferred Protocols for Controlled Ovarian Stimulation (COS):
1. “Long” GnRHa (Lupron/Buserelin/Superfact/Gonopeptyl) Pituitary Down-regulation Protocol: The most commonly prescribed protocol for GnRHa/gonadotropin administration is the so-called “long protocol”. Here, GnRHa is given, starting a week or so prior to menstruation. This results in an initial rise in FSH and LH , which is rapidly followed by a precipitous fall to near zero. It is followed by a withdrawal bleed (menstruation), whereupon gonadotropin treatment should commence, while daily Lupron injections continue, to ensure a “low LH” environment. A modification to the “long protocol” which I prefer prescribing for older women and in cases of DOR, is the Agonist/Antagonist Conversion Protocol (A/ACP) where, upon the onset of a GnRHa-induced bleed, the agonist is supplanted by an antagonist (Ganirelix/Cetrotide/Orgalutron) and this is continued until the hCG trigger. In many such cases I often supplement with human growth hormone (HGH) in such cases in an attempt to enhance egg mitochondrial activity and so enhance egg development. This approach is often augmented with preimplantation genetic screening (PGS) of all embryos that reach the expanded blastocyst stage of development by day 5-6 post-fertilization. I also commonly recommend blastocyst banking to many such patients.
2.
3. Short (“Flare”) GnRHa Protocol: Another GnRHa usage for COS is the so called “(micro) flare protocol”. This involves initiating gonadotropin therapy commensurate with initiation of gonadotropin administration. The supposed objective 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” constitutes “a double-edged sword”. 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/thecal androgen production which could potentially compromise egg quality, especially when it comes to older women and women with DOR. 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 when it comes to COS in older women, and in women with diminished ovarian reserve. Accordingly, I do not prescribe such protocols to my IVF patients.
4. Estrogen Priming – This is the approach I sometimes prescribe for my patients who have virtually depleted ovarian reserve , as determined by very low blood anti-Mullerian hormone AMH levels (<0.2ng/ml or 2 pmol/L) and are thus likely to be very “poor responders”. It involves a modified A/ACP. We start with estrogen skin patches applied every 2nd day (or with the BCP) for 10 days or longer, overlap it for 3 days with a GnRHa whereupon the estrogen priming is stopped. Th GnRHa is continued until the onset of menstruation (usually 5-7 days later) to cause pituitary LH, down-regulation. Upon menstruation and confirmation by ultrasound and measurement of blood estradiol levels that adequate ovarian suppression has been achieved, The patient is given twice-weekly injections of estradiol valerate (Delestrogen) for a period of 7-8 days whereupon COS is initiated using a relatively high dosage FSH-(Follistim, Fostimon, Puregon or Gonal F), which is continued along with daily administration of GnRH antagonist until the “hCG “trigger.” This approach is often augmented with HGH administration throughout the process of COS and by preimplantation genetic screening (PGS) of all embryos that reach the expanded blastocyst stage of development by day 5-6 post-fertilization. I also commonly recommend blastocyst banking to many such patients.
Estrogen Priming has succeeded in significantly enhancing ovarian response to gonadotropins in many of otherwise very poor responders.
Triggering egg Maturation prior to egg Retrieval: hCG versus GnRHa
With ovulation induction using fertility drugs, the administration of 10,000U hCGu (Pregnyl; Profasi, Novarel) or 500mcg hCGr (Ovidrel/Ovitrel) “trigger”) sends the eggs (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 they had prior to the “trigger”. Such a chromosomally numerically normal (euploid), mature (MII) eggs, upon being fertilized will (hopefully) propagate euploid embryos that have 46 chromosomes and will be “: competent” to propagate viable pregnancies. In my opinion, the key is to always “trigger” with no less than 10,000U of hCGu or 500mcg hCGr (Ovidrel/Ovitrel). Any lesser dosage often will reduce the efficiency of meiosis and increase the risk of the eggs being aneuploid. I personally do not use the agonist (Lupron) “trigger”, unless it is combined with (low dosage) hCG. The supposed reason for using the agonist, (Lupron) “trigger” is that by inducing meiosis through compelling a surge in the release of LH by the pituitary gland, the risk it reduces the risk of OHSS. This may be true, but it 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 likelihood of aneuploid and immature (MI) eggs. And there are other better approaches to preventing OHSS (e.g. “prolonged coasting”), in my opinion.
Use of the Birth Control Pill (BCP) to launch IVF-COS.
In natural (unstimulated) as well as in cycles stimulated with fertility drugs, the ability of follicles to properly respond to FSH stimulation is dependent on their having developed FSH-responsive receptors. Pre-antral follicles (PAF) do not have such primed FSH receptors and thus cannot respond properly to FSH stimulation with gonadotropins. The acquisition of FSH receptor responsivity requires that the pre-antral follicles be exposed to FSH, for a number of days (5-7) during which time they attain “FSH-responsivity” and are now known as antral follicles (AF). These AF’s are now able to respond properly to stimulation with administered FSH-gonadotropins. In regular menstrual cycles, the rising FSH output from the pituitary gland insures that PAFs convert tor AF’s. The BCP (as well as prolonged administration of estrogen/progesterone) suppresses FSH. This suppression needs to be countered by artificially causing blood FSH levels to rise in order to cause PAF to AF conversion prior to COS commencing, otherwise pre-antral-to –antral follicle conversion will not take place in an orderly fashion, the duration of ovarian stimulation will be prolonged and both follicle and egg development may be compromised. GnRH agonists cause an immediate surge in release of FSH by the pituitary gland thus causing conversion from PAF to SAF. This is why women who take a BCP to launch a cycle of COS need to have an overlap of the BCP with an agonist. By overlapping the BCP with an agonist for a few days prior to menstruation the early recruited follicles are able to complete their developmental drive to the AF stage and as such, be ready to respond appropriately to optimal ovarian stimulation. Using this approach, the timing of the initiation of the IVF treatment cycle can readily and safely be regulated and controlled by varying the length of time that the woman is on the BCP.
Since optimizing follicular response to COS requires that prior to stimulation with gonadotropins, FSH-induced conversion from PAF to AF’s first be completed and the BCP suppresses FSH, it follows when it comes to women launching COS coming off a BCP something needs to be done to cause a rise in FSH for 5-7 days prior to menstruation heralding the cycle of CO S. This is where overlapping the BCP with a GnRHa comes in. The agonist causes FSH to be released by the pituitary gland and if overlapped with the BCP for several days and this will (within 2-5 days) facilitate PAF to AF conversion…. in time to start COS with the onset of menstruation. Initiating ovarian stimulation in women taking a BCP, without doing this is suboptimal.
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.

______________________________________________________
ADDENDUM: PLEASE READ!!
INTRODUCING SHER FERTILITY SOLUTIONS (SFS)
Founded in April 2019, Sher Fertility Solutions (SFS) offers online (Skype/FaceTime) consultations to patients from > 40 different countries. All consultations are followed by a detailed written report presenting my personal recommendations for treatment of what often constitute complex Reproductive Issues.

If you wish to schedule an online consultation with me, please contact my assistant (Patti Converse) by phone (800-780-7437/702-533-2691), email (concierge@SherIVF.com) or, enroll online on then home-page of my website (www.SherIVF.com).

PLEASE SPREAD THE WORD ABOUT SFS!

Geoff Sher

reply
Ashleigh

Thanks Dr Sher, but my question was aimed at fertilisation- not at why IVF/transfers has not worked.
We are a unique case and you simply copy and pasted an article I’d already read on your site.
I was looking more specifically at why you think we would average a 25% fertilisation rate with ICSI. Given my age 30- with egg retrievals between ages 28-30 age ‘should’ not play a factor.
I would be interested in having a Skype consult but worry your generic respond to my question like presented here will not be helpful or individualised.

reply
Dr. Geoffrey Sher

IT is possible that this has in large part to do with the protocol used for ovarian stimulation. As I have repeatedly professed, this, other than age and ovarian reserve, is by far the most important consideration. Call Patti (my assistant) at 702-533-2691 so we can set up a one-on-one, online consultation to discuss!

Geoff Sher

reply
Mary

Hello Dr Sher,

I’m just coming to term with my failed round and would love some advice as I need to know what my
options are going forward, I have also lost faith in my current Dr.

This was our second IVF round and our odds weren’t too great from the start. I suffered from Ovary
torsion during a previous IVF pregnancy with my daughter and lost the use of my right ovary. So going into this, I went in relying on one ovary. As well as that, we discovered my AMH had dropped from 32 pmol/l to 5.6 pmol/l, most likely due to my right ovary now not working. My FSH is also slightly raised and I’ve just turned 40.

Considering the circumstances, my left ovary responded well to the short protocol which involved 375 units of Menopur, Fermydale from day 6 and the trigger shot. During my final scan before egg collection, there were 0 follicles in my right (as expected) but 14 follicles in my left ovary albeit all different sizes. They managed to collect 8 eggs but 3 were immature and out of the 5, 4 fertilised. By day 5 however, I was left with a 3BC blastocyst and a morula. We were told our chances of a pregnancy were very low and yesterday that became a reality.

In comparison, during my first round with my two functioning ovaries and a long protocol, I had 28 follicles. 14 eggs collected, 11 fertilised and 3 blastocysts. 5AA miscarried at 10 weeks, 3BB turned into my gorgeous girl and 4AB was a chemical a few months ago.

I have reason to believe I have egg quality issues although this has not been suggested to me by my doctor yet. Out of interest, what would you do differently if I came to you with a single ovary, good AFC but low AMH? Also, is it possible that my AMH is only on the low side due to having one functioning ovary and not because I have DOR?

Your thoughts would be welcome as I really need guidance on how to approach my situation going forward.

Mary

reply
Mary

I should add, I suffered from OHSS during during my first round with a long protocol and I’m pretty certain it was what lead to my ovary torsion during an FET pregnancy with my daughter.

Mary

reply
Mary

Thanks for your reply Dr Sher. I will look into an online consultation. In the meantime, can you please delete my last post as it shows my email address instead of name. Thank you

reply
Dr. Geoffrey Sher

I will try, but I do not know how tom reaccess your last post!

Geoff Sher

reply
Dr. Geoffrey Sher

The older a woman becomes, the more likely it is that her eggs will be chromosomally/genetically “incompetent” (not have the potential upon being fertilized and transferred, to result in a viable pregnancy). That is why, the likelihood of failure to conceive, miscarrying and of giving birth to a chromosomally defective child (e.g. with Down Syndrome) increases with the woman’s advancing age. In addition, as women age beyond 35Y there is commonly a progressive diminution in the number of eggs left in the ovaries, i.e. diminished ovarian reserve (DOR). So it is that older women as well as those who (regardless of age) have DOR have a reduced potential for IVF success. Much of this is due to the fact that such women tend to have increased production of LH biological activity which can result in excessive LH-induced ovarian male hormone (predominantly testosterone) production which in turn can have a deleterious effect on egg/embryo “competency”.
While it is presently not possible by any means, to reverse the age-related effect on the woman’s “biological clock, certain ovarian stimulation regimes, by promoting excessive LH production (e.g. short agonist/Lupron- “flare” protocols, clomiphene and Letrozole), can make matters worse. Similarly, the amount/dosage of certain fertility drugs that contain LH/hCG (e.g. Menopur) can have a negative effect on the development of the eggs of older women and those who have DOR and should be limited.
I try to avoid using such protocols/regimes (especially) in older women and those with DOR, favoring instead the use of the agonist/antagonist conversion protocol (A/ACP), a modified, long pituitary down-regulation regime, augmented by adding supplementary human growth hormone (HGH). I further recommend that such women be offered access to embryo banking of PGS (next generation gene sequencing/NGS)-selected normal blastocysts, the subsequent selective transfer of which by allowing them to to capitalize on whatever residual ovarian reserve and egg quality might still exist and thereby “make hay while the sun still shines” could significantly enhance the opportunity to achieve a viable pregnancy

Please visit my Blog on this very site, http://www.DrGeoffreySherIVF.com, find the “search bar” and 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
• 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)
• Controlled Ovarian Stimulation (COS) in Older women and Women who have Diminished Ovarian Reserve (DOR): A Rational Basis for Selecting a Stimulation Protocol
• 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?
• Blastocyst Embryo Transfers Should be the Standard of Care in IVF
• Frozen Embryo Transfer (FET) versus “Fresh” ET: How to Make the Decision
• Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting 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.
• 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
• Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
• Traveling for IVF from Out of State/Country–
• 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
• Premature Luteinization (“the premature LH surge): Why it happens and how it can be prevented.
• IVF Egg Donation: A Comprehensive Overview

______________________________________________________
ADDENDUM: PLEASE READ!!
INTRODUCING SHER FERTILITY SOLUTIONS (SFS)
Founded in April 2019, Sher Fertility Solutions (SFS) offers online (Skype/FaceTime) consultations to patients from > 40 different countries. All consultations are followed by a detailed written report presenting my personal recommendations for treatment of what often constitute complex Reproductive Issues.

Patients are encouraged to share the information I provide, with their treating Physicians and/or to avail themselves of my personal hands-on services, provided through batched IVF cycles that I conduct every 3 months at Los Angeles IVF (LAIVF) Clinic, Century City, Los Angeles, CA.

If you wish to schedule an online consultation with me, please contact my assistant (Patti Converse) by phone (800-780-7437/702-533-2691), email (concierge@SherIVF.com) or, enroll online on then home-page of my website (www.SherIVF.com).

PLEASE SPREAD THE WORD ABOUT SFS!

Geoff Sher

reply
Dalia

Dr. Sher,

After one stillbirth at 30 weeks and 3 early miscarriages, we decided to pursue a cycle of ivf. I am 35 and have low amh (0.5) and fsh of 13. During my baseline ultrasound my doctor counted about 7 follicles. My ivf protocol began with 7 days of ocp followed by 9 days of stims which included gonal-f (300 iu) and menopur (150 iu). I also took cetrotide for several days towards the end of my cycle. I did one dose of an hcg trigger and Lupron on the last two days of the cycle. My doctor saw 4 maturing eggs prior to retrieval but was only able to retrieve 3 and only 2 made it to fertilization. We are now awaiting to see which ones make it to blasts. In your opinion, what would you do differently (if anything) to stimulate more follicle growth without comprising egg quality. I understand my fsh level is a contributing factor to poor responding follicles, however, I’ve seen various protocols used when there is an elevated level of fsh and DOR.

reply
Dr. Geoffrey Sher

You clearly have diminished ovarian reserve.

Women who (regardless of age) have diminished ovarian reserve (DOR) have a reduced potential for IVF success. Much of this is due to the fact that such women tend to have increased production, and/or biological activity, of LH. This can result in excessive ovarian male hormone (predominantly testosterone) production. This in turn can have a deleterious effect on egg/embryo “competency”.
While it is presently not possible by any means, to reverse the effect of DOR, certain ovarian stimulation regimes, by promoting excessive LH production (e.g. short agonist/Lupron- “flare” protocols, clomiphene and Letrozole), can in my opinion, make matters worse. Similarly, the amount/dosage of certain fertility drugs that contain LH/hCG (e.g. Menopur) can have a negative effect on the development of the eggs of older women and those who have DOR and should be limited.
I try to avoid using such protocols/regimes (especially) in women with DOR, favoring instead the use of the agonist/antagonist conversion protocol (A/ACP), a modified, long pituitary down-regulation regime, augmented by adding supplementary human growth hormone (HGH). I further recommend that such women be offered access to embryo banking of PGS (next generation gene sequencing/NGS)-selected normal blastocysts, the subsequent selective transfer of which by allowing them to capitalize on whatever residual ovarian reserve and egg quality might still exist and thereby “make hay while the sun still shines” could significantly enhance the opportunity to achieve a viable pregnancy

RECURRENT PREGNANCY LOSS:

When it comes to reproduction, humans are the poorest performers of all mammals. In fact we are so inefficient that up to 75% of fertilized eggs do not produce live births, and up to 30% of pregnancies end up being lost within 10 weeks of conception (in the first trimester). RPL is defined as two (2) or more failed pregnancies. Less than 5% of women will experience two (2) consecutive miscarriages, and only 1% experience three or more.
Pregnancy loss can be classified by the stage of pregnancy when the loss occurs:
• Early pregnancy loss (first trimester)
• Late pregnancy loss (after the first trimester)
• Occult “hidden” and not clinically recognized, (chemical) pregnancy loss (occurs prior to ultrasound confirmation of pregnancy)
• Early pregnancy losses usually occur sporadically (are not repetitive).

In more than 70% of cases the loss is due to embryo aneuploidy (where there are more or less than the normal quota of 46 chromosomes). Conversely, repeated losses (RPL), with isolated exceptions where the cause is structural (e.g., unbalanced translocations), are seldom attributable to numerical chromosomal abnormalities (aneuploidy). In fact, the vast majority of cases of RPL are attributable to non-chromosomal causes such as anatomical uterine abnormalities or Immunologic Implantation Dysfunction (IID).
Since most sporadic early pregnancy losses are induced by chromosomal factors and thus are non-repetitive, having had a single miscarriage the likelihood of a second one occurring is no greater than average. However, once having had two losses the chance of a third one occurring is double (35-40%) and after having had three losses the chance of a fourth miscarriage increases to about 60%. The reason for this is that the more miscarriages a woman has, the greater is the likelihood of this being due to a non-chromosomal (repetitive) cause such as IID. It follows that if numerical chromosomal analysis (karyotyping) of embryonic/fetal products derived from a miscarriage tests karyotypically normal, then by a process of elimination, there would be a strong likelihood of a miscarriage repeating in subsequent pregnancies and one would not have to wait for the disaster to recur before taking action. This is precisely why we strongly advocate that all miscarriage specimens be karyotyped.
There is however one caveat to be taken into consideration. That is that the laboratory performing the karyotyping might unwittingly be testing the mother’s cells rather than that of the conceptus. That is why it is not possible to confidently exclude aneuploidy in cases where karyotyping of products suggests a “chromosomally normal” (euploid) female.
Late pregnancy losses (occurring after completion of the 1st trimester/12th week) occur far less frequently (1%) than early pregnancy losses. They are most commonly due to anatomical abnormalities of the uterus and/or cervix. Weakness of the neck of the cervix rendering it able to act as an effective valve that retains the pregnancy (i.e., cervical incompetence) is in fact one of the commonest causes of late pregnancy loss. So also are developmental (congenital) abnormalities of the uterus (e.g., a uterine septum) and uterine fibroid tumors. In some cases intrauterine growth retardation, premature separation of the placenta (placental abruption), premature rupture of the membranes and premature labor can also causes of late pregnancy loss.
Much progress has been made in understanding the mechanisms involved in RPL. There are two broad categories:
1. Problems involving the uterine environment in which a normal embryo is prohibited from properly implanting and developing. Possible causes include:
• Inadequate thickening of the uterine lining
• Irregularity in the contour of the uterine cavity (polyps, fibroid tumors in the uterine wall, intra-uterine scarring and adenomyosis)
• Hormonal imbalances (progesterone deficiency or luteal phase defects). This most commonly results in occult RPL.
• Deficient blood flow to the uterine lining (thin uterine lining).
• Immunologic implantation dysfunction (IID). A major cause of RPL. Plays a role in 75% of cases where chromosomally normal preimplantation embryos fail to implant.
• Interference of blood supply to the developing conceptus can occur due to a hereditary clotting disorder known as Thrombophilia.

2. Genetic and/or structural chromosomal abnormality of the embryo.Genetic abnormalities are rare causes of RPL. Structural chromosomal abnormalities are slightly more common but are also occur infrequently (1%). These are referred to as unbalanced translocation and they result from part of one chromosome detaching and then fusing with another chromosome. Additionally, a number of studies suggest the existence of paternal (sperm derived) effect on human embryo quality and pregnancy outcome that are not reflected as a chromosomal abnormality. Damaged sperm DNA can have a negative impact on fetal development and present clinically as occult or early clinical miscarriage. The Sperm Chromatin Structure Assay (SCSA) which measures the same endpoints are newer and possibly improved methods for evaluating.

IMMUNOLOGIC IMPLANTATION DYSFUNCTION
Autoimmune IID: Here an immunologic reaction is produced by the individual to his/her body’s own cellular components. The most common antibodies that form in such situations are APA and antithyroid antibodies (ATA).
But it is only when specialized immune cells in the uterine lining, known as cytotoxic lymphocytes (CTL) and natural killer (NK) cells, become activated and start to release an excessive/disproportionate amount of TH-1 cytokines that attack the root system of the embryo, that implantation potential is jeopardized. Diagnosis of such activation requires highly specialized blood test for cytokine activity that can only be performed by a handful of reproductive immunology reference laboratories in the United States.
Alloimmune IID, i.e., where antibodies are formed against antigens derived from another member of the same species, is believed to be a relatively common immunologic cause of recurrent pregnancy loss.
Autoimmune IID is often genetically transmitted. Thus it should not be surprising to learn that it is more likely to exist in women who have a family (or personal) history of primary autoimmune diseases such as lupus erythematosus (LE), scleroderma or autoimmune hypothyroidism (Hashimoto’s disease), autoimmune hyperthyroidism (Grave’s disease), rheumatoid arthritis, etc. Reactionary (secondary) autoimmunity can occur in conjunction with any medical condition associated with widespread tissue damage. One such gynecologic condition is endometriosis. Since autoimmune IID is usually associated with activated NK and T-cells from the outset, it usually results in such very early destruction of the embryo’s root system that the patient does not even recognize that she is pregnant. Accordingly the condition usually presents as “unexplained infertility” or “unexplained IVF failure” rather than as a miscarriage.
Alloimmune IID, on the other hand, usually starts off presenting as unexplained miscarriages (often manifesting as RPL). Over time as NK/T cell activation builds and eventually becomes permanently established the patient often goes from RPL to “infertility” due to failed implantation. RPL is more commonly the consequence of alloimmune rather than autoimmune implantation dysfunction.
However, regardless, of whether miscarriage is due to autoimmune or alloimmune implantation dysfunction the final blow to the pregnancy is the result of activated NK cells and CTL in the uterine lining that damage the developing embryo’s “root system” (trophoblast) so that it can no longer sustain the growing conceptus. This having been said, it is important to note that autoimmune IID is readily amenable to reversal through timely, appropriately administered, selective immunotherapy, and alloimmune IID is not. It is much more difficult to treat successfully, even with the use of immunotherapy. In fact, in some cases the only solution will be to revert to selective immunotherapy plus using donor sperm (provided there is no “match” between the donor’s DQa profile and that of the female recipient) or alternatively to resort to gestational surrogacy.
DIAGNOSING THE CAUSE OF RPL
In the past, women who miscarried were not evaluated thoroughly until they had lost several pregnancies in a row. This was because sporadic miscarriages are most commonly the result of embryo numerical chromosomal irregularities (aneuploidy) and thus not treatable. However, a consecutive series of miscarriages points to a repetitive cause that is non-chromosomal and is potentially remediable. Since RPL is most commonly due to a uterine pathology or immunologic causes that are potentially treatable, it follows that early chromosomal evaluation of products of conception could point to a potentially treatable situation. Thus I strongly recommend that such testing be done in most cases of miscarriage. Doing so will avoid a great deal of unnecessary heartache for many patients.
Establishing the correct diagnosis is the first step toward determining effective treatment for couples with RPL. It results from a problem within the pregnancy itself or within the uterine environment where the pregnancy implants and grows. Diagnostic tests useful in identifying individuals at greater risk for a problem within the pregnancy itself include:

Karyotyping (chromosome analysis) both prospective parents
• Assessment of the karyotype of products of conception derived from previous miscarriage specimens
• Ultrasound examination of the uterine cavity after sterile water is injected or sonohysterogram, fluid ultrasound, etc.)
• Hysterosalpingogram (dye X-ray test)
• Hysteroscopic evaluation of the uterine cavity
• Full hormonal evaluation (estrogen, progesterone, adrenal steroid hormones, thyroid hormones, FSH/LH, etc.)
• Immunologic testing to include:
a) Antiphospholipid antibody (APA) panel
b) Antinuclear antibody (ANA) panel
c) Antithyroid antibody panel (i.e., antithyroglobulin and antimicrosomal antibodies)
d) Reproductive immunophenotype
e) Natural killer cell activity (NKa) assay (i.e., K562 target cell test)
f) Alloimmune testing of both the male and female partners

TREATMENT OF RPL
Treatment for Anatomic Abnormalities of the Uterus: This involves restoration through removal of local lesions such as fibroids, scar tissue, and endometrial polyps or timely insertion of a cervical cerclage (a stitch placed around the neck of the weakened cervix) or the excision of a uterine septum when indicated.
Treatment of Thin Uterine Lining: A thin uterine lining has been shown to correlate with compromised pregnancy outcome. Often this will be associated with reduced blood flow to the endometrium. Such decreased blood flow to the uterus can be improved through treatment with sildenafil and possibly aspirin.
Sildenafil (Viagra) Therapy. Viagra has been used successfully to increase uterine blood flow. However, to be effective it must be administered starting as soon as the period stops up until the day of ovulation and it must be administered vaginally (not orally). Viagra in the form of vaginal suppositories given in the dosage of 25 mg four times a day has been shown to increase uterine blood flow as well as thickness of the uterine lining. To date, we have seen significant improvement of the thickness of the uterine lining in about 70% of women treated. Successful pregnancy resulted in 42% of women who responded to the Viagra. It should be remembered that most of these women had previously experienced repeated IVF failures.
Use of Aspirin: This is an anti-prostaglandin that improves blood flow to the endometrium. It is administered at a dosage of 81 mg orally, daily from the beginning of the cycle until ovulation.

Treating Immunologic Implantation Dysfunction with Selective Immunotherapy: Modalities such as IL/IVIg, heparinoids (Lovenox/Clexane), and corticosteroids (dexamethasone, prednisone, prednisolone) can be used in select cases depending on autoimmune or alloimmune dysfunction.
The Use of IVF in the Treatment of RPL
In the following circumstances, IVF is the preferred option:
1. When in addition to a history of RPL, another standard indication for IVF (e.g., tubal factor, endometriosis, and male factor infertility) is superimposed.
2. In cases where selective immunotherapy is needed to treat an immunologic implantation dysfunction.
The reason for IVF being a preferred approach in such cases is that in order to be effective, the immunotherapy needs to be initiated well before spontaneous or induced ovulation. Given the fact that the anticipated birthrate per cycle of COS with or without IUI is at best about 15%, it follows that short of IVF, to have even a reasonable chance of a live birth, most women with immunologic causes of RPL would need to undergo immunotherapy repeatedly, over consecutive cycles. Conversely, with IVF, the chance of a successful outcome in a single cycle of treatment is several times greater and, because of the attenuated and concentrated time period required for treatment, IVF is far safer and thus represents a more practicable alternative
Since embryo aneuploidy is a common cause of miscarriage, the use of preimplantation genetic diagnosis (PGD), with tests such as CGH, can provide a valuable diagnostic and therapeutic advantage in cases of RPL. PGD requires IVF to provide access to embryos for testing.
There are a few cases of intractable alloimmune dysfunction due to absolute DQ alpha matching where Gestational Surrogacy or use of donor sperm could represent the only viable recourse, other than abandoning treatment altogether and/or resorting to adoption. Other non-immunologic factors such as an intractably thin uterine lining or severe uterine pathology might also warrant that last resort consideration be given to gestational surrogacy.
The good news is that if a couple with RPL is open to all of the diagnostic and treatment options referred to above, a live birthrate of 70%–80% is ultimately achievable.
I strongly recommend that you visit http://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
• 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 Stimulation (COS) in IVF.
• 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?
• Blastocyst Embryo Transfers Should be the Standard of Care in IVF
• IVF: How Many Attempts should be considered before Stopping?
• “Unexplained” Infertility: Often a matter of the Diagnosis Being Overlooked!
• IVF Failure and Implantation Dysfunction:
• The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 1-Background
• Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 2- Making a Diagnosis
• Immunologic Dysfunction (IID) & Infertility (IID):PART 3-Treatment
• Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
• Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management:(Case Report
• Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
• Intralipid (IL) Administration in IVF: It’s Composition; How it Works; Administration; Side-effects; Reactions and Precautions
• Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
• Endometrial Thickness, Uterine Pathology and Immunologic Factors
• Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
• 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

______________________________________________________
ADDENDUM: PLEASE READ!!
INTRODUCING SHER FERTILITY SOLUTIONS (SFS)
Founded in April 2019, Sher Fertility Solutions (SFS) offers online (Skype/FaceTime) consultations to patients from > 40 different countries. All consultations are followed by a detailed written report presenting my personal recommendations for treatment of what often constitute complex Reproductive Issues.

Patients are encouraged to share the information I provide, with their treating Physicians and/or to avail themselves of my personal hands-on services, provided through batched IVF cycles that I conduct every 3 months at Los Angeles IVF (LAIVF) Clinic, Century City, Los Angeles, CA.

If you wish to schedule an online consultation with me, please contact my assistant (Patti Converse) by phone (800-780-7437/702-533-2691), email (concierge@SherIVF.com) or, enroll online on then home-page of my website (www.SherIVF.com).

PLEASE SPREAD THE WORD ABOUT SFS!

Geoff Sher

reply
Sharon

I have just had egg retrieval and we got 8 eggs although I got a call today to say that only 2 fertilised. I’m 37 years of age. What is the likelihood of these 2 making it to day 5 blastocyst? I am so gutted at the lack of fertilised eggs.

reply
Dr. Geoffrey Sher

It is not possible to predict. However, in my opinion, in the absence of severe male factor infertility and severely diminished ovarian reserve, it is the protocol for ovarian stimulation which in my opinion is most important.

The importance of the IVF stimulation protocol on egg/embryo quality cannot be overstated. This factor seems often to be overlooked or discounted by t 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. 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.
Gonadotropins (LH and FSH), whether produced by the pituitary gland or administered by way of fertility drugs, have different “targeted” sites of action in the ovary. FSH targets cells that line the inner wall of the follicle (granulosa cells) and also form the cumulus cells that bind the egg to the inner surface of the follicle. Granulosa cells are responsible for estrogen production.
LH, on the other hand, targets the ovarian connective tissue (stroma/theca) that surrounds ovarian follicles resulting in the production of male hormones such as testosterone (predominantly), androstenedione and DHEA. These androgens are then transported to the granulosa cells of the adjacent follicles in a “bucket brigade fashion”. There FSH converts testosterone to estradiol, causing granulosa cells to multiply (proliferate) and produce estradiol, follicles to grows and eggs to develop (ovogenesis) It follows that ovarian androgens (mainly testosterone) is absolutely indispensable to follicle/ egg growth and development.
However, the emphasis is on a “small” amount of testosterone. Over-exposure of the follicle to testosterone can compromise egg development and lead to an increased likelihood of chromosomal irregularities (aneuploid) following LH/hCG-induced egg maturational division (meiosis) and compromise embryo “competency/quality.
Ovarian androgens can also reach the uterine lining where they sometimes will compromise estrogen receptor -induced endometrial growth and development.
Many older women and those who have diminished ovarian reserve (DOR) have increased LH activity is increased. Such women either over-produce LH and/or the LH produced is far more biologically active. Chronically increased LH activity leads to overgrowth of ovarian connective tissue (stroma/theca). This condition, which is often referred to as Stromal Hyperplasia or hyperthecosis can result in excessive ovarian androgen/testosterone production and poorer egg-embryo quality/competency, Similarly, women with polycystic ovarian syndrome (PCOS), also characteristically have Stromal hyperplasia/hyperthecosis due to chronically increased LH activity. Thus they too often manifest with increased ovarian androgen production. It is therefore not surprising that “poor egg/embryo quality” is often also a feature of PCOS.
In my opinion, the over-administration of LH-containing menotropins such as Menopur, [which is comprised of roughly equal amount of FSH and hCG ,which acts similar to LH)], to older women, women with DOR and those who have PCOS can also lead to reduced egg/embryo competency . Similarly, drugs such as clomiphene or Letrozole that cause the pituitary gland to release excessive amounts of LH, are also potentially harmful to egg development and in my opinion, are best omitted from IVF COS protocols. This is especially the case when it comes to older women and those with DOR, who in my opinion should preferably be stimulated using FSH-dominant products such as Follistim, Puregon, Fostimon and Gonal-F.
Gonadotropin releasing hormone agonists (GnRHa): GnRHa such as Lupron, Buserelin, Superfact, Gonopeptyl etc. are often used to launch ovarian stimulation cycles. They act by causing an initial outpouring followed by a depletion of pituitary gonadotropins. This results in LH levels falling to low concentrations, within 4-7 days, thereby establishing a relatively “LH-free environment”. When GnRHa are administered for about 7 days prior to initiating gonadotropin stimulation (“long” pituitary down-regulation”), the LH depletion that will exist when COS is initiated, will usually be protective of subsequent egg development. In contrast, when the GnRHa administration commences along with the initiation of gonadotropin therapy, there will be a resultant immediate surge in the release of pituitary LH with the potential to increase ovarian testosterone to egg-compromising levels , from the outset of COS. This, in my opinion could be particularly harmful when undertaken in older women and those who have DOR.
GnRH-antagonists such as Ganirelix, Cetrotide and Orgalutron, on the other hand, act very rapidly (within hours) to block pituitary LH release. The purpose in using GnRH antagonists is to prevent the release of LH during COS. In contrast, the LH-lowering effect of GnRH agonists develops over a number of days.
GnRH antagonists are traditionally given, starting after 5th -7th day of gonadotropin stimulation. However, when this is done in older women and those (regardless of age) who have DOR, LH-suppression might be reached too late to prevent the deleterious effect of excessive ovarian androgen production on egg development in the early stage of ovarian stimulation. This is why, it is my preference to administer GnRH-antagonists, starting at the initiation of gonadotropin administration.
My preferred Protocols for Controlled Ovarian Stimulation (COS):
1. “Long” GnRHa (Lupron/Buserelin/Superfact/Gonopeptyl) Pituitary Down-regulation Protocol: The most commonly prescribed protocol for GnRHa/gonadotropin administration is the so-called “long protocol”. Here, GnRHa is given, starting a week or so prior to menstruation. This results in an initial rise in FSH and LH , which is rapidly followed by a precipitous fall to near zero. It is followed by a withdrawal bleed (menstruation), whereupon gonadotropin treatment should commence, while daily Lupron injections continue, to ensure a “low LH” environment. A modification to the “long protocol” which I prefer prescribing for older women and in cases of DOR, is the Agonist/Antagonist Conversion Protocol (A/ACP) where, upon the onset of a GnRHa-induced bleed, the agonist is supplanted by an antagonist (Ganirelix/Cetrotide/Orgalutron) and this is continued until the hCG trigger. In many such cases I often supplement with human growth hormone (HGH) in such cases in an attempt to enhance egg mitochondrial activity and so enhance egg development. This approach is often augmented with preimplantation genetic screening (PGS) of all embryos that reach the expanded blastocyst stage of development by day 5-6 post-fertilization. I also commonly recommend blastocyst banking to many such patients.
2.
3. Short (“Flare”) GnRHa Protocol: Another GnRHa usage for COS is the so called “(micro) flare protocol”. This involves initiating gonadotropin therapy commensurate with initiation of gonadotropin administration. The supposed objective 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” constitutes “a double-edged sword”. 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/thecal androgen production which could potentially compromise egg quality, especially when it comes to older women and women with DOR. 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 when it comes to COS in older women, and in women with diminished ovarian reserve. Accordingly, I do not prescribe such protocols to my IVF patients.
4. Estrogen Priming – This is the approach I sometimes prescribe for my patients who have virtually depleted ovarian reserve , as determined by very low blood anti-Mullerian hormone AMH levels (<0.2ng/ml or 2 pmol/L) and are thus likely to be very “poor responders”. It involves a modified A/ACP. We start with estrogen skin patches applied every 2nd day (or with the BCP) for 10 days or longer, overlap it for 3 days with a GnRHa whereupon the estrogen priming is stopped. Th GnRHa is continued until the onset of menstruation (usually 5-7 days later) to cause pituitary LH, down-regulation. Upon menstruation and confirmation by ultrasound and measurement of blood estradiol levels that adequate ovarian suppression has been achieved, The patient is given twice-weekly injections of estradiol valerate (Delestrogen) for a period of 7-8 days whereupon COS is initiated using a relatively high dosage FSH-(Follistim, Fostimon, Puregon or Gonal F), which is continued along with daily administration of GnRH antagonist until the “hCG “trigger.” This approach is often augmented with HGH administration throughout the process of COS and by preimplantation genetic screening (PGS) of all embryos that reach the expanded blastocyst stage of development by day 5-6 post-fertilization. I also commonly recommend blastocyst banking to many such patients.
Estrogen Priming has succeeded in significantly enhancing ovarian response to gonadotropins in many of otherwise very poor responders.
Triggering egg Maturation prior to egg Retrieval: hCG versus GnRHa
With ovulation induction using fertility drugs, the administration of 10,000U hCGu (Pregnyl; Profasi, Novarel) or 500mcg hCGr (Ovidrel/Ovitrel) “trigger”) sends the eggs (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 they had prior to the “trigger”. Such a chromosomally numerically normal (euploid), mature (MII) eggs, upon being fertilized will (hopefully) propagate euploid embryos that have 46 chromosomes and will be “: competent” to propagate viable pregnancies. In my opinion, the key is to always “trigger” with no less than 10,000U of hCGu or 500mcg hCGr (Ovidrel/Ovitrel). Any lesser dosage often will reduce the efficiency of meiosis and increase the risk of the eggs being aneuploid. I personally do not use the agonist (Lupron) “trigger”, unless it is combined with (low dosage) hCG. The supposed reason for using the agonist, (Lupron) “trigger” is that by inducing meiosis through compelling a surge in the release of LH by the pituitary gland, the risk it reduces the risk of OHSS. This may be true, but it 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 likelihood of aneuploid and immature (MI) eggs. And there are other better approaches to preventing OHSS (e.g. “prolonged coasting”), in my opinion.
Use of the Birth Control Pill (BCP) to launch IVF-COS.
In natural (unstimulated) as well as in cycles stimulated with fertility drugs, the ability of follicles to properly respond to FSH stimulation is dependent on their having developed FSH-responsive receptors. Pre-antral follicles (PAF) do not have such primed FSH receptors and thus cannot respond properly to FSH stimulation with gonadotropins. The acquisition of FSH receptor responsivity requires that the pre-antral follicles be exposed to FSH, for a number of days (5-7) during which time they attain “FSH-responsivity” and are now known as antral follicles (AF). These AF’s are now able to respond properly to stimulation with administered FSH-gonadotropins. In regular menstrual cycles, the rising FSH output from the pituitary gland insures that PAFs convert tor AF’s. The BCP (as well as prolonged administration of estrogen/progesterone) suppresses FSH. This suppression needs to be countered by artificially causing blood FSH levels to rise in order to cause PAF to AF conversion prior to COS commencing, otherwise pre-antral-to –antral follicle conversion will not take place in an orderly fashion, the duration of ovarian stimulation will be prolonged and both follicle and egg development may be compromised. GnRH agonists cause an immediate surge in release of FSH by the pituitary gland thus causing conversion from PAF to SAF. This is why women who take a BCP to launch a cycle of COS need to have an overlap of the BCP with an agonist. By overlapping the BCP with an agonist for a few days prior to menstruation the early recruited follicles are able to complete their developmental drive to the AF stage and as such, be ready to respond appropriately to optimal ovarian stimulation. Using this approach, the timing of the initiation of the IVF treatment cycle can readily and safely be regulated and controlled by varying the length of time that the woman is on the BCP.
Since optimizing follicular response to COS requires that prior to stimulation with gonadotropins, FSH-induced conversion from PAF to AF’s first be completed and the BCP suppresses FSH, it follows when it comes to women launching COS coming off a BCP something needs to be done to cause a rise in FSH for 5-7 days prior to menstruation heralding the cycle of CO S. This is where overlapping the BCP with a GnRHa comes in. The agonist causes FSH to be released by the pituitary gland and if overlapped with the BCP for several days and this will (within 2-5 days) facilitate PAF to AF conversion…. in time to start COS with the onset of menstruation. Initiating ovarian stimulation in women taking a BCP, without doing this is suboptimal.
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.

______________________________________________________
ADDENDUM: PLEASE READ!!
INTRODUCING SHER FERTILITY SOLUTIONS (SFS)
Founded in April 2019, Sher Fertility Solutions (SFS) offers online (Skype/FaceTime) consultations to patients from > 40 different countries. All consultations are followed by a detailed written report presenting my personal recommendations for treatment of what often constitute complex Reproductive Issues.

Patients are encouraged to share the information I provide, with their treating Physicians and/or to avail themselves of my personal hands-on services, provided through batched IVF cycles that I conduct every 3 months at Los Angeles IVF (LAIVF) Clinic, Century City, Los Angeles, CA.

If you wish to schedule an online consultation with me, please contact my assistant (Patti Converse) by phone (800-780-7437/702-533-2691), email (concierge@SherIVF.com) or, enroll online on then home-page of my website (www.SherIVF.com).

PLEASE SPREAD THE WORD ABOUT SFS!

Geoff Sher

reply
Dalia

Dr. Sher, thank you for your response. I did not mention this but it’s important to note that I did naturally conceive a healthy baby 2.5 years ago (no complications and full-term). I’m not sure if this changes your response in regards to recurrent miscarriages. I did the full recurrent miscarriage work up and everything came back normal, including karyotype for myself and husband. The only thing they could find was an mthfr mutation.

reply
Dr. Geoffrey Sher

No Dalia,

It does not change my opinion. I strongly urge you to take my recommendations to heart!

Good luck!

Geoff Sher

reply
SW

Hi Dalia,
I just had a similar outcome. 18 eggs retrieved, only 6 fertilised! I go in on Saturday for the transfer but am so nervous. What was the outcome of yours?

reply
Dr. Geoffrey Sher

Hope you don’t mind my input here, SW!

One of the commonest questions asked by patients undergoing IVF relates to the likelihood of their eggs fertilizing and the likely “quality of their embryos. This is also one of the most difficult questions to answer. On the one hand many factors that profoundly influence egg quality; such as the genetic recruitment of eggs for use in an upcoming cycle, the woman’s age and her ovarian reserve, are our outside of our control. On the other hand the protocol for controlled ovarian stimulation (COS) can also profoundly influence egg/embryo development and this is indeed chosen by the treating physician.
First; it should be understood that the most important determinant of fertilization potential, embryo development and blastocyst generation, is the numerical chromosomal integrity of the egg (While sperm quality does play a role, in the absence of moderate to severe sperm dysfunction this is (moderate or severe male factor infertility a relatively small one). Human eggs have the highest rate of numerical chromosomal irregularities (aneuploidy) of all mammals. In fact only about half the eggs of women in their twenties or early thirties, have the required number of chromosomes (euploid), without which upon fertilization they cannot propagate a normal pregnancy. As the woman advances into and beyond her mid-thirties, the percentage of eggs euploid eggs declines progressively such that by the age of 40 years, only about one out of seven or eight are likely to be chromosomally normal and by the time she reaches her mid-forties less than one in ten of her eggs will be euploid.
Second; embryos that fail to develop into blastocysts are almost always aneuploid and not worthy of being transferred to the uterus because they will either not implant, will miscarry or could even result in a chromosomally abnormal baby (e.g. Down syndrome). However, it is incorrect to assume that all embryos reaching the blastocyst stage will be euploid (“competent”). ). It is true that since many aneuploid embryos are lost during development and that those failing to survive to the blastocyst stage are far more likely to be competent than are earlier (cleaved) embryos. What is also true is that the older the woman who produces the eggs, the less likely it is that a given blastocyst will be “competent”. As an example, a morphologically pristine blastocyst derived from the egg of a 30-year-old woman would have about a 50:50 chance of being euploid and a 30% chance of propagating a healthy, normal baby, while a microscopically comparable blastocyst-derived through fertilization of the eggs from a 40-year-old, would be about half as likely to be euploid and/or propagate a healthy baby.
While the effect of species on the potential of eggs to be euploid at ovulation is genetically preordained and nothing we do can alter this equation, there is, unfortunately, a lot we can (often unwittingly) do to worsen the situation by selecting a suboptimal protocol of controlled ovarian stimulation (COS). This, by creating an adverse intraovarian hormonal environment will often disrupt normal egg development and lead to a higher incidence of egg aneuploidy than otherwise might have occurred. Older women, women with diminished ovarian reserve (DOR) and those with polycystic ovarian syndrome are especially vulnerable in this regard.

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 (tissue surrounding ovarian follicles) during the pre-ovulatory phase of the cycle enhance late follicle development, estrogen production by the granulosa 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 COS protocols should be individualized and geared toward optimizing follicle growth and development time while avoiding excessive ovarian androgen (testosterone) production and that the hCG “trigger shot” should be carefully timed.
In summary, it is important to understand the influence species, age of the woman as well as the effect of the COS protocol can have on egg/embryo quality and thus on IVF outcome. The selection of an individualized protocol for ovarian stimulation is one of the most important decisions that the RE has to make and this becomes even more relevant when dealing with older women, those with DOR and women with PCOS. Such factors will in large part determine fertilization potential, the rate of blastocyst generation and indeed IVF outcome.
I strongly recommend that you visit http://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.

______________________________________________________
ADDENDUM: PLEASE READ!!
INTRODUCING SHER FERTILITY SOLUTIONS (SFS)
Founded in April 2019, Sher Fertility Solutions (SFS) offers online (Skype/FaceTime) consultations to patients from > 40 different countries. All consultations are followed by a detailed written report presenting my personal recommendations for treatment of what often constitute complex Reproductive Issues.

If you wish to schedule an online consultation with me, please contact my assistant (Patti Converse) by phone (800-780-7437/702-533-2691), email (concierge@SherIVF.com) or, enroll online on then home-page of my website (www.SherIVF.com).

PLEASE SPREAD THE WORD ABOUT SFS!

Geoff Sher

reply
Jjfn

Hi just finished a are 1st cycle of ICSI, I have server oligospermia 1.2 million has been my highest sample and 200 the lowest, I have also small Testicle than normal,
On are ICSI cycle we fertilised 7 eggs but on day 3 we got the phone call to say none have progressed, what could be the out come of this because I know it is very uncommon, and my fertility unit are quite shocked by this, I have a follow up appointment next week, is there any questions I could ask them or tests taken so this doesn’t happen again thanks

reply
Dr. Geoffrey Sher

I would need much more information to respond authoritatively. I suggest you call my assistant, Patti Converse at 702-533-2691 and set up a Skype/FaceTime consultation with me to discuss.

Geoff Sher

reply
Mykela

The same thing just happened to me. They are going to do a more aggressive round. Also she had me start taking 600 of CoQ10. It is a vitamin you can find anywhere. Please keep me updated on what happens. I’m hoping this time goes better. But at all unknown.

reply
Jennifer

Hi-
I just turned 36 years old and have a high normal AMH (charts I’ve seen have me closer to women who are 31). After 2 failed IUIs we moved on to IVF. Our first IVF I hyperstimulated terribly but only had 11 eggs, 9 fertilized but only 2 made it to blastocyst stage on day 7 and were low quality. One was genetically normal DC quality and is on ice.
For our 2nd retrieval, we did a more detailed test on my husband’s sperm and saw that he had a borderline issue. The doctor ordered him to take vitamins, added a human growth hormone to my shots and switched my trigger to avoid hyperstim. This time we only had 2 more eggs, 13 total, even though I had 18 follicles. The lab used a zymot to make sure we got the strongest sperm. I had 11 mature eggs, 10 fertilized and while we did get 2 day-5 blastocysts that are great quality & one day-7 low-quality blastocyst there are just 3 total. Would love your opinion on why I’m not producing more eggs and why our fertilization to blastocyst ratio continues to be so low. I am a bit overweight (not obese, but could stand to drop 15-20lbs) but the months it would take to drop the weight vs. the months on my age and egg age is a tradeoff and all doctors say my weight is fine. Thanks for reading!

reply
Dr. Geoffrey Sher

Hi Jennifer. There can be many reasons why sometimes far fewer eggs are harvested than originally suggested by the # of follicles seen and why some women produce incompetent eggs (immature, dysmature or post-mature). However, in my opinion, the commonest cause is linked to the the protocol chosen for ovarian stimulation and its implementation. This needs to be carefully reviewed and possibly modified.

The importance of the IVF stimulation protocol on egg/embryo quality cannot be overstated. This factor seems often to be overlooked or discounted by t 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. 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.
Gonadotropins (LH and FSH), whether produced by the pituitary gland or administered by way of fertility drugs, have different “targeted” sites of action in the ovary. FSH targets cells that line the inner wall of the follicle (granulosa cells) and also form the cumulus cells that bind the egg to the inner surface of the follicle. Granulosa cells are responsible for estrogen production.
LH, on the other hand, targets the ovarian connective tissue (stroma/theca) that surrounds ovarian follicles resulting in the production of male hormones such as testosterone (predominantly), androstenedione and DHEA. These androgens are then transported to the granulosa cells of the adjacent follicles in a “bucket brigade fashion”. There FSH converts testosterone to estradiol, causing granulosa cells to multiply (proliferate) and produce estradiol, follicles to grows and eggs to develop (ovogenesis) It follows that ovarian androgens (mainly testosterone) is absolutely indispensable to follicle/ egg growth and development.
However, the emphasis is on a “small” amount of testosterone. Over-exposure of the follicle to testosterone can compromise egg development and lead to an increased likelihood of chromosomal irregularities (aneuploid) following LH/hCG-induced egg maturational division (meiosis) and compromise embryo “competency/quality.
Ovarian androgens can also reach the uterine lining where they sometimes will compromise estrogen receptor -induced endometrial growth and development.
Many older women and those who have diminished ovarian reserve (DOR) have increased LH activity is increased. Such women either over-produce LH and/or the LH produced is far more biologically active. Chronically increased LH activity leads to overgrowth of ovarian connective tissue (stroma/theca). This condition, which is often referred to as Stromal Hyperplasia or hyperthecosis can result in excessive ovarian androgen/testosterone production and poorer egg-embryo quality/competency, Similarly, women with polycystic ovarian syndrome (PCOS), also characteristically have Stromal hyperplasia/hyperthecosis due to chronically increased LH activity. Thus they too often manifest with increased ovarian androgen production. It is therefore not surprising that “poor egg/embryo quality” is often also a feature of PCOS.
In my opinion, the over-administration of LH-containing menotropins such as Menopur, [which is comprised of roughly equal amount of FSH and hCG ,which acts similar to LH)], to older women, women with DOR and those who have PCOS can also lead to reduced egg/embryo competency . Similarly, drugs such as clomiphene or Letrozole that cause the pituitary gland to release excessive amounts of LH, are also potentially harmful to egg development and in my opinion, are best omitted from IVF COS protocols. This is especially the case when it comes to older women and those with DOR, who in my opinion should preferably be stimulated using FSH-dominant products such as Follistim, Puregon, Fostimon and Gonal-F.
Gonadotropin releasing hormone agonists (GnRHa): GnRHa such as Lupron, Buserelin, Superfact, Gonopeptyl etc. are often used to launch ovarian stimulation cycles. They act by causing an initial outpouring followed by a depletion of pituitary gonadotropins. This results in LH levels falling to low concentrations, within 4-7 days, thereby establishing a relatively “LH-free environment”. When GnRHa are administered for about 7 days prior to initiating gonadotropin stimulation (“long” pituitary down-regulation”), the LH depletion that will exist when COS is initiated, will usually be protective of subsequent egg development. In contrast, when the GnRHa administration commences along with the initiation of gonadotropin therapy, there will be a resultant immediate surge in the release of pituitary LH with the potential to increase ovarian testosterone to egg-compromising levels , from the outset of COS. This, in my opinion could be particularly harmful when undertaken in older women and those who have DOR.
GnRH-antagonists such as Ganirelix, Cetrotide and Orgalutron, on the other hand, act very rapidly (within hours) to block pituitary LH release. The purpose in using GnRH antagonists is to prevent the release of LH during COS. In contrast, the LH-lowering effect of GnRH agonists develops over a number of days.
GnRH antagonists are traditionally given, starting after 5th -7th day of gonadotropin stimulation. However, when this is done in older women and those (regardless of age) who have DOR, LH-suppression might be reached too late to prevent the deleterious effect of excessive ovarian androgen production on egg development in the early stage of ovarian stimulation. This is why, it is my preference to administer GnRH-antagonists, starting at the initiation of gonadotropin administration.
My preferred Protocols for Controlled Ovarian Stimulation (COS):
1. “Long” GnRHa (Lupron/Buserelin/Superfact/Gonopeptyl) Pituitary Down-regulation Protocol: The most commonly prescribed protocol for GnRHa/gonadotropin administration is the so-called “long protocol”. Here, GnRHa is given, starting a week or so prior to menstruation. This results in an initial rise in FSH and LH , which is rapidly followed by a precipitous fall to near zero. It is followed by a withdrawal bleed (menstruation), whereupon gonadotropin treatment should commence, while daily Lupron injections continue, to ensure a “low LH” environment. A modification to the “long protocol” which I prefer prescribing for older women and in cases of DOR, is the Agonist/Antagonist Conversion Protocol (A/ACP) where, upon the onset of a GnRHa-induced bleed, the agonist is supplanted by an antagonist (Ganirelix/Cetrotide/Orgalutron) and this is continued until the hCG trigger. In many such cases I often supplement with human growth hormone (HGH) in such cases in an attempt to enhance egg mitochondrial activity and so enhance egg development. This approach is often augmented with preimplantation genetic screening (PGS) of all embryos that reach the expanded blastocyst stage of development by day 5-6 post-fertilization. I also commonly recommend blastocyst banking to many such patients.
2.
3. Short (“Flare”) GnRHa Protocol: Another GnRHa usage for COS is the so called “(micro) flare protocol”. This involves initiating gonadotropin therapy commensurate with initiation of gonadotropin administration. The supposed objective 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” constitutes “a double-edged sword”. 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/thecal androgen production which could potentially compromise egg quality, especially when it comes to older women and women with DOR. 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 when it comes to COS in older women, and in women with diminished ovarian reserve. Accordingly, I do not prescribe such protocols to my IVF patients.
4. Estrogen Priming – This is the approach I sometimes prescribe for my patients who have virtually depleted ovarian reserve , as determined by very low blood anti-Mullerian hormone AMH levels (<0.2ng/ml or 2 pmol/L) and are thus likely to be very “poor responders”. It involves a modified A/ACP. We start with the birth control pill (BCP) for 10 days or longer, overlap it for 3 days with a GnRHa whereupon the BCP is stopped. Th GnRHa is continued until the onset of menstruation (usually 5-7 days later) to cause pituitary LH, down-regulation. Upon menstruation and confirmation by ultrasound and measurement of blood estradiol levels that adequate ovarian suppression has been achieved, the dosage of GnRHa is stopped and is immediately supplanted by daily administration of GnRH antagonist. The patient is given twice-weekly injections of estradiol valerate (Delestrogen) for a period of 8 days whereupon COS is initiated using a relatively high dosage FSH-(Follistim, Fostimon, Puregon or Gonal F), which is continued along with daily administration of GnRH antagonist until the “hCG “trigger.” This approach is often augmented with HGH administration throughout the process of COS and by preimplantation genetic screening (PGS) of all embryos that reach the expanded blastocyst stage of development by day 5-6 post-fertilization. I also commonly recommend blastocyst banking to many such patients.
Estrogen Priming has succeeded in significantly enhancing ovarian response to gonadotropins in many of otherwise very poor responders.
Triggering egg Maturation prior to egg Retrieval: hCG versus GnRHa
With ovulation induction using fertility drugs, the administration of 10,000U hCGu (Pregnyl; Profasi, Novarel) or 500mcg hCGr (Ovidrel/Ovitrel) “trigger”) sends the eggs (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 they had prior to the “trigger”. Such a chromosomally numerically normal (euploid), mature (MII) eggs, upon being fertilized will (hopefully) propagate euploid embryos that have 46 chromosomes and will be “: competent” to propagate viable pregnancies. In my opinion, the key is to always “trigger” with no less than 10,000U of hCGu or 500mcg hCGr (Ovidrel/Ovitrel). Any lesser dosage often will reduce the efficiency of meiosis and increase the risk of the eggs being aneuploid. I personally do not use the agonist (Lupron) “trigger”, unless it is combined with (low dosage) hCG. The supposed reason for using the agonist, (Lupron) “trigger” is that by inducing meiosis through compelling a surge in the release of LH by the pituitary gland, the risk it reduces the risk of OHSS. This may be true, but it 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 likelihood of aneuploid and immature (MI) eggs. And there are other better approaches to preventing OHSS (e.g. “prolonged coasting”), in my opinion.
Use of the Birth Control Pill (BCP) to launch IVF-COS.
In natural (unstimulated) as well as in cycles stimulated with fertility drugs, the ability of follicles to properly respond to FSH stimulation is dependent on their having developed FSH-responsive receptors. Pre-antral follicles (PAF) do not have such primed FSH receptors and thus cannot respond properly to FSH stimulation with gonadotropins. The acquisition of FSH receptor responsivity requires that the pre-antral follicles be exposed to FSH, for a number of days (5-7) during which time they attain “FSH-responsivity” and are now known as antral follicles (AF). These AF’s are now able to respond properly to stimulation with administered FSH-gonadotropins. In regular menstrual cycles, the rising FSH output from the pituitary gland insures that PAFs convert tor AF’s. The BCP (as well as prolonged administration of estrogen/progesterone) suppresses FSH. This suppression needs to be countered by artificially causing blood FSH levels to rise in order to cause PAF to AF conversion prior to COS commencing, otherwise pre-antral-to –antral follicle conversion will not take place in an orderly fashion, the duration of ovarian stimulation will be prolonged and both follicle and egg development may be compromised. GnRH agonists cause an immediate surge in release of FSH by the pituitary gland thus causing conversion from PAF to SAF. This is why women who take a BCP to launch a cycle of COS need to have an overlap of the BCP with an agonist. By overlapping the BCP with an agonist for a few days prior to menstruation the early recruited follicles are able to complete their developmental drive to the AF stage and as such, be ready to respond appropriately to optimal ovarian stimulation. Using this approach, the timing of the initiation of the IVF treatment cycle can readily and safely be regulated and controlled by varying the length of time that the woman is on the BCP.
Since optimizing follicular response to COS requires that prior to stimulation with gonadotropins, FSH-induced conversion from PAF to AF’s first be completed and the BCP suppresses FSH, it follows when it comes to women launching COS coming off a BCP something needs to be done to cause a rise in FSH for 5-7 days prior to menstruation heralding the cycle of CO S. This is where overlapping the BCP with a GnRHa comes in. The agonist causes FSH to be released by the pituitary gland and if overlapped with the BCP for several days and this will (within 2-5 days) facilitate PAF to AF conversion…. in time to start COS with the onset of menstruation. Initiating ovarian stimulation in women taking a BCP, without doing this is suboptimal.
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.

___________________________________________________________
ADDENDUM: PLEASE READ!!
INTRODUCING SHER FERTILITY SOLUTIONS (SFS)
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 .

PLEASE HELP SPREAD THE WORD ABOUT SFS!

Geoff Sher

reply
Amy

Hi I’m 35 and my husband and I completed one round of IVF with two embryos implanted in day 2 that ended in failure. I had 10 mature eggs retrieved but only 5 fertilized with ICSI. My husband has minor elevated levels of morphed sperm. Should I be concerned that only half fertilized with ICSI? Also, should I worry about the day 2 transfer? Thanks!

reply
Dr. Geoffrey Sher

I am not a proponent of a day 2 transfer.. A 50% fertilization rate is also not great!

Whenever a patient fails to achieve a viable pregnancy following embryo transfer (ET), the first question asked is why! Was it simply due to, bad luck?, How likely is the failure to recur in future attempts and what can be done differently, to avoid it happening next time?.
It is an indisputable fact that any IVF procedure is at least as likely to fail as it is to succeed. Thus when it comes to outcome, luck is an undeniable factor. Notwithstanding, it is incumbent upon the treating physician to carefully consider and address the causes of IVF failure before proceeding to another attempt:
1. Age: The chance of a woman under 35Y of age having a baby per embryo transfer is about 35-40%. From there it declines progressively to under 5% by the time she reaches her mid-forties. This is largely due to declining chromosomal integrity of the eggs with advancing age…”a wear and tear effect” on eggs that are in the ovaries from birth.
2. Embryo Quality/”competency (capable of propagating a viable pregnancy)”. As stated, the woman’s age plays a big role in determining egg/embryo quality/”competency”. This having been said, aside from age the protocol used for controlled ovarian stimulation (COS) is the next most important factor. It is especially important when it comes to older women, and women with diminished ovarian reserve (DOR) where it becomes essential to be aggressive, and to customize and individualize the ovarian stimulation protocol.
We used to believe that the uterine environment is more beneficial to embryo development than is the incubator/petri dish and that accordingly, the earlier on in development that embryos are transferred to the uterus, the better. To achieve this goal, we used to select embryos for transfer based upon their day two or microscopic appearance (“grade”). But we have since learned that the further an embryo has advanced in its development, the more likely it is to be “competent” and that embryos failing to reach the expanded blastocyst stage within 5-6 days of being fertilized are almost invariably “incompetent” and are unworthy of being transferred. Moreover, the introduction into clinical practice about a decade ago, (by Levent Keskintepe PhD and myself) of Preimplantation Genetic Sampling (PGS), which assesses for the presence of all the embryos chromosomes (complete chromosomal karyotyping), provides another tool by which to select the most “competent” embryos for transfer. This methodology has selective benefit when it comes to older women, women with DOR, cases of unexplained repeated IVF failure and women who experience recurrent pregnancy loss (RPL).
3. The number of the embryos transferred: Most patients believe that the more embryos transferred the greater the chance of success. To some extent this might be true, but if the problem lies with the use of a suboptimal COS protocol, transferring more embryos at a time won’t improve the chance of success. Nor will the transfer of a greater number of embryos solve an underlying embryo implantation dysfunction (anatomical molecular or immunologic).Moreover, the transfer of multiple embryos, should they implant, can and all too often does result in triplets or greater (high order multiples) which increases the incidence of maternal pregnancy-induced complications and of premature delivery with its serious risks to the newborn. It is for this reason that I rarely recommend the transfer of more than 2 embryos at a time and am moving in the direction of advising single embryo transfers …especially when it comes to transferring embryos derived through the fertilization of eggs from young women.
4. Implantation Dysfunction (ID): Implantation dysfunction is a very common (often overlooked) cause of “unexplained” IVF failure. This is especially the case in young ovulating women who have normal ovarian reserve and have fertile partners. Failure to identify, typify, and address such issues is, in my opinion, an unfortunate and relatively common cause of repeated IVF failure in such women. Common sense dictates that if ultrasound guided embryo transfer is performed competently and yet repeated IVF attempts fail to propagate a viable pregnancy, implantation dysfunction must be seriously considered. Yet ID is probably the most overlooked factor. The most common causes of implantation dysfunction are:
a. A“ thin uterine lining”
b. A uterus with surface lesions in the cavity (polyps, fibroids, scar tissue)
c. Immunologic implantation dysfunction (IID)
d. Endocrine/molecular endometrial receptivity issues
Certain causes of infertility are repetitive and thus cannot readily be reversed. Examples include advanced age of the woman; severe male infertility; immunologic infertility associated with alloimmune implantation dysfunction (especially if it is a “complete DQ alpha genetic match between partners plus uterine natural killer cell activation (NKa).
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.

• The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
• 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
• Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
• 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 Stimulation (COS) in IVF.
• 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?
• Blastocyst Embryo Transfers should be the Standard of Care in IVF
• IVF: How Many Attempts should be considered before Stopping?
• “Unexplained” Infertility: Often a matter of the Diagnosis Being Overlooked!
• IVF Failure and Implantation Dysfunction:
• The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 1-Background
• Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 2- Making a Diagnosis
• Immunologic Dysfunction (IID) & Infertility (IID): PART 3-Treatment
• Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
• Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management 🙁 Case Report)
• Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
• Intralipid (IL) Administration in IVF: It’s Composition; how it Works; Administration; Side-effects; Reactions and Precautions
• Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
• Endometrial Thickness, Uterine Pathology and Immunologic Factors
• Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
• 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
If you are interested in my advice or medical services, I urge you to contact my patient concierge, ASAP to set up a Skype or an in-person consultation with me. You can also set this up by emailing concierge@sherivf.com or by calling 702-533-2691 and/or 800-780-743. You can also enroll for a consultation with me, online at http://www.SherIVF.com.
Also, my book, “In Vitro Fertilization, the ART of Making Babies” is available as a down-load through http://www.Amazon.com .

Geoffrey Sher MD

reply
Sarah

Dear Dr. Sher,
I am 35 year old and have a 3.5 year old kid through 2 cycles of IUI using fresh donor sperm in 2014. This year I am planning to have a second child, but after 2 cycles of non-medicated IUI and 1 cycle of IVF with PGS using the same donor’s frozen sperm, I totally lost confidence in myself. In the recent IVF cycle, 13 eggs retrieved, 8 of 13 were mature and all fertilized via ICSI, 6 embryos made it into day 3 but only 1 made it a 3CC blastocyst on day 6. With all other embryos stopped growing, this only one day-6 blastocyst was diagnosed as aneuploid by PGS. So, my FET was canceled. My Dr. said the my donor’s older age (60 when he donated the sperm) might be a reason although the post-thaw sperm’s statistics look totally fine.

Should I be concerned about the lab culture condition and my own egg quality, in addition to donor’s sperm quality? FYI, I was on 300 follistim + 75 menopur for 8 days, triggered on day 8 with Lupron and 2500 IU HCG and on day 9 with another Lupron. My AMH is 2.2 and all other hormone numbers are normal. 5’5” and 150 lbs.

Thank you!

reply
Dr. Geoffrey Sher

Whenever a patient fails to achieve a viable pregnancy following embryo transfer (ET), the first question asked is why! Was it simply due to, bad luck?, How likely is the failure to recur in future attempts and what can be done differently, to avoid it happening next time?.
It is an indisputable fact that any IVF procedure is at least as likely to fail as it is to succeed. Thus when it comes to outcome, luck is an undeniable factor. Notwithstanding, it is incumbent upon the treating physician to carefully consider and address the causes of IVF failure before proceeding to another attempt:
1. Age: The chance of a woman under 35Y of age having a baby per embryo transfer is about 35-40%. From there it declines progressively to under 5% by the time she reaches her mid-forties. This is largely due to declining chromosomal integrity of the eggs with advancing age…”a wear and tear effect” on eggs that are in the ovaries from birth.
2. Embryo Quality/”competency (capable of propagating a viable pregnancy)”. As stated, the woman’s age plays a big role in determining egg/embryo quality/”competency”. This having been said, aside from age the protocol used for controlled ovarian stimulation (COS) is the next most important factor. It is especially important when it comes to older women, and women with diminished ovarian reserve (DOR) where it becomes essential to be aggressive, and to customize and individualize the ovarian stimulation protocol.
We used to believe that the uterine environment is more beneficial to embryo development than is the incubator/petri dish and that accordingly, the earlier on in development that embryos are transferred to the uterus, the better. To achieve this goal, we used to select embryos for transfer based upon their day two or microscopic appearance (“grade”). But we have since learned that the further an embryo has advanced in its development, the more likely it is to be “competent” and that embryos failing to reach the expanded blastocyst stage within 5-6 days of being fertilized are almost invariably “incompetent” and are unworthy of being transferred. Moreover, the introduction into clinical practice about a decade ago, (by Levent Keskintepe PhD and myself) of Preimplantation Genetic Sampling (PGS), which assesses for the presence of all the embryos chromosomes (complete chromosomal karyotyping), provides another tool by which to select the most “competent” embryos for transfer. This methodology has selective benefit when it comes to older women, women with DOR, cases of unexplained repeated IVF failure and women who experience recurrent pregnancy loss (RPL).
3. The number of the embryos transferred: Most patients believe that the more embryos transferred the greater the chance of success. To some extent this might be true, but if the problem lies with the use of a suboptimal COS protocol, transferring more embryos at a time won’t improve the chance of success. Nor will the transfer of a greater number of embryos solve an underlying embryo implantation dysfunction (anatomical molecular or immunologic).Moreover, the transfer of multiple embryos, should they implant, can and all too often does result in triplets or greater (high order multiples) which increases the incidence of maternal pregnancy-induced complications and of premature delivery with its serious risks to the newborn. It is for this reason that I rarely recommend the transfer of more than 2 embryos at a time and am moving in the direction of advising single embryo transfers …especially when it comes to transferring embryos derived through the fertilization of eggs from young women.
4. Implantation Dysfunction (ID): Implantation dysfunction is a very common (often overlooked) cause of “unexplained” IVF failure. This is especially the case in young ovulating women who have normal ovarian reserve and have fertile partners. Failure to identify, typify, and address such issues is, in my opinion, an unfortunate and relatively common cause of repeated IVF failure in such women. Common sense dictates that if ultrasound guided embryo transfer is performed competently and yet repeated IVF attempts fail to propagate a viable pregnancy, implantation dysfunction must be seriously considered. Yet ID is probably the most overlooked factor. The most common causes of implantation dysfunction are:
a. A“ thin uterine lining”
b. A uterus with surface lesions in the cavity (polyps, fibroids, scar tissue)
c. Immunologic implantation dysfunction (IID)
d. Endocrine/molecular endometrial receptivity issues
Certain causes of infertility are repetitive and thus cannot readily be reversed. Examples include advanced age of the woman; severe male infertility; immunologic infertility associated with alloimmune implantation dysfunction (especially if it is a “complete DQ alpha genetic match between partners plus uterine natural killer cell activation (NKa).
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.

• The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
• 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
• Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
• 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 Stimulation (COS) in IVF.
• 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?
• Blastocyst Embryo Transfers should be the Standard of Care in IVF
• IVF: How Many Attempts should be considered before Stopping?
• “Unexplained” Infertility: Often a matter of the Diagnosis Being Overlooked!
• IVF Failure and Implantation Dysfunction:
• The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 1-Background
• Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 2- Making a Diagnosis
• Immunologic Dysfunction (IID) & Infertility (IID): PART 3-Treatment
• Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
• Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management 🙁 Case Report)
• Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
• Intralipid (IL) Administration in IVF: It’s Composition; how it Works; Administration; Side-effects; Reactions and Precautions
• Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
• Endometrial Thickness, Uterine Pathology and Immunologic Factors
• Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
• 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
If you are interested in seeking my advice or services, I urge you to contact my concierge, Julie Dahan ASAP to set up a Skype or an in-person consultation with me. You can also contact Julie by phone or via email at 702-533-2691/ Julied@sherivf.com You can also apply online at http://www.SherIVF.com .

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

Geoffrey Sher MD

reply
Brittany

Hi Dr. Sher! Congrats on your impending retirement.
My husband and I just went through our first IVF (Denmark mini protocol) 3 weeks ago. I’m 29 (hx of 2 ectopics and stage I endometriosis no lesions on ovaries and PCOS mild and normal body condition), he’s 30 and we only had one day 5 blast make it with 12 eggs retrieved. We are distraught by those results. We were told that it could be an egg or sperm problem but not sure. My husband’s semen analysis came back as above average in every category. His part was collected at 7:15am and the lab didn’t come get the specimen until 8:30-8:45 with my retrieval at 9:45. I kept it under my coat until they got it. Would that have anything to do with our results? My medical mind is trying to process everything before going through with another cycle in the future.

reply
Dr. Geoffrey Sher

I doubt the egg/embryo issuer was due to mishandling of sperm. The most common reason relates to the protocl used for ovarian stimulation. However since you do have endometriosis which (regardless of its severity) is associated with an immunologic implantation dysfunction linked to natural killer cell activation (NKa), I advise that you also be tested for the latter. This is done by doing the K-562 target cell, blood test and/or uterine biopsy for cytokines.

Whenever a patient fails to achieve a viable pregnancy following embryo transfer (ET), the first question asked is why! Was it simply due to, bad luck?, How likely is the failure to recur in future attempts and what can be done differently, to avoid it happening next time?.
It is an indisputable fact that any IVF procedure is at least as likely to fail as it is to succeed. Thus when it comes to outcome, luck is an undeniable factor. Notwithstanding, it is incumbent upon the treating physician to carefully consider and address the causes of IVF failure before proceeding to another attempt:
1. Age: The chance of a woman under 35Y of age having a baby per embryo transfer is about 35-40%. From there it declines progressively to under 5% by the time she reaches her mid-forties. This is largely due to declining chromosomal integrity of the eggs with advancing age…”a wear and tear effect” on eggs that are in the ovaries from birth.
2. Embryo Quality/”competency (capable of propagating a viable pregnancy)”. As stated, the woman’s age plays a big role in determining egg/embryo quality/”competency”. This having been said, aside from age the protocol used for controlled ovarian stimulation (COS) is the next most important factor. It is especially important when it comes to older women, and women with diminished ovarian reserve (DOR) where it becomes essential to be aggressive, and to customize and individualize the ovarian stimulation protocol.
We used to believe that the uterine environment is more beneficial to embryo development than is the incubator/petri dish and that accordingly, the earlier on in development that embryos are transferred to the uterus, the better. To achieve this goal, we used to select embryos for transfer based upon their day two or microscopic appearance (“grade”). But we have since learned that the further an embryo has advanced in its development, the more likely it is to be “competent” and that embryos failing to reach the expanded blastocyst stage within 5-6 days of being fertilized are almost invariably “incompetent” and are unworthy of being transferred. Moreover, the introduction into clinical practice about a decade ago, (by Levent Keskintepe PhD and myself) of Preimplantation Genetic Sampling (PGS), which assesses for the presence of all the embryos chromosomes (complete chromosomal karyotyping), provides another tool by which to select the most “competent” embryos for transfer. This methodology has selective benefit when it comes to older women, women with DOR, cases of unexplained repeated IVF failure and women who experience recurrent pregnancy loss (RPL).
3. The number of the embryos transferred: Most patients believe that the more embryos transferred the greater the chance of success. To some extent this might be true, but if the problem lies with the use of a suboptimal COS protocol, transferring more embryos at a time won’t improve the chance of success. Nor will the transfer of a greater number of embryos solve an underlying embryo implantation dysfunction (anatomical molecular or immunologic).Moreover, the transfer of multiple embryos, should they implant, can and all too often does result in triplets or greater (high order multiples) which increases the incidence of maternal pregnancy-induced complications and of premature delivery with its serious risks to the newborn. It is for this reason that I rarely recommend the transfer of more than 2 embryos at a time and am moving in the direction of advising single embryo transfers …especially when it comes to transferring embryos derived through the fertilization of eggs from young women.
4. Implantation Dysfunction (ID): Implantation dysfunction is a very common (often overlooked) cause of “unexplained” IVF failure. This is especially the case in young ovulating women who have normal ovarian reserve and have fertile partners. Failure to identify, typify, and address such issues is, in my opinion, an unfortunate and relatively common cause of repeated IVF failure in such women. Common sense dictates that if ultrasound guided embryo transfer is performed competently and yet repeated IVF attempts fail to propagate a viable pregnancy, implantation dysfunction must be seriously considered. Yet ID is probably the most overlooked factor. The most common causes of implantation dysfunction are:
a. A“ thin uterine lining”
b. A uterus with surface lesions in the cavity (polyps, fibroids, scar tissue)
c. Immunologic implantation dysfunction (IID)
d. Endocrine/molecular endometrial receptivity issues
Certain causes of infertility are repetitive and thus cannot readily be reversed. Examples include advanced age of the woman; severe male infertility; immunologic infertility associated with alloimmune implantation dysfunction (especially if it is a “complete DQ alpha genetic match between partners plus uterine natural killer cell activation (NKa).
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.

• The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
• 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
• Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
• 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 Stimulation (COS) in IVF.
• 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?
• Blastocyst Embryo Transfers should be the Standard of Care in IVF
• IVF: How Many Attempts should be considered before Stopping?
• “Unexplained” Infertility: Often a matter of the Diagnosis Being Overlooked!
• IVF Failure and Implantation Dysfunction:
• The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 1-Background
• Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 2- Making a Diagnosis
• Immunologic Dysfunction (IID) & Infertility (IID): PART 3-Treatment
• Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
• Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management 🙁 Case Report)
• Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
• Intralipid (IL) Administration in IVF: It’s Composition; how it Works; Administration; Side-effects; Reactions and Precautions
• Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
• Endometrial Thickness, Uterine Pathology and Immunologic Factors
• Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
• 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

If you are interested in seeking my advice or services, I urge you to contact my concierge, Julie Dahan ASAP to set up a Skype or an in-person consultation with me. You can also contact Julie by phone or via email at 702-533-2691/ Julied@sherivf.com You can also apply online at http://www.SherIVF.com .

*FYI
The 4th edition of my newest book ,”In Vitro Fertilization, the ART of Making Babies” is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

Geoffrey Sher MD

reply
Jennifer Smith

Hi Dr Sher, Congrats on retirement. I am a bit lost on what to do next. I am 36. AMh is 3 and Fsh is normal. I have had four IVF cycles. First was local clinic with fresh transfer of two day 3 embryos (we retreived 6 on gonal f and menopur). Second at same clinic had 12 retrevied and they all arrested by day 3 (however, I was told there was a lab issue and got a full refund). Third was at IVF Michigan (which I loved) got 18 eggs, 9 fertilized and 2 sent for genetic testing both abnormal. We primed w testosterone and did gonal and menopure. My husband did a sperm aspiration because he has fragmentation. Fourth cycle at ccrm was primed with testosterone and estrace. Got 28 eggs, 21 mature, 19 fertilized, 6 sent for genetic testing and all abnormal. My husband fragmentation improved to less than 7% from 30%. Genetic issues are all over the board. Have been told I need a donor egg but no real reason why except I can’t make normal babies. I haven’t been checked for endo but am not sure that is effecting our ability to create normal embryos. I am open to ideas

reply
Dr. Geoffrey Sher

Hi Jennifer Still have a year or so before I occupy a rocking chair. Much to be done before then.

In my opinion, given your age and obviously adequate ovarian reserve , I believe your embryo “competency issue” to be related to the protocol being used for ovarian stimulation and/or its implementation. I do not believe that it is a lab issue or likely to be due to MF. In my opinion the protocol used needs to be critically reviewed and likely, revised.

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.
• The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
• 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
• 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.
• 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?
• Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas
• Should IVF Treatment Cycles be provided uninterrupted or be Conducted in 7-12 Pre-scheduled “Batches” per Year
• A personalized, stepwise approach to IVF
• Male Factor Infertility
• Routine Fertilization by Intracytoplasmic Sperm Injection (ICSI): An Argument in Favor
• Hormonal Treatment of Male Infertility
• Antisperm Antibodies, Infertility and the Role of IVF with Intracytoplasmic Sperm Injection (ICSI)
• Testicular Sperm Extraction (TESE) and Testicular Sperm Aspiration (TESA): Surgical Approaches for Accessing Sperm from men who have no sperm in their ejaculates (Azoospermia)
• Varicocele and Male Infertility: When and how should it be treated?
• The Sperm Chromatin Structure Assay (SCSA): A Measure of the Potential of Sperm to Help Propagate a Viable Pregnancy

ANNOUNCEMENTS:
1. About my Retirement by mid-2018:
After > 30 years in the field of Assisted Reproduction (AR), the time has finally come for me to plan on retiring from full-time clinical medicine within a year. If you are interested in my medical services prior to my retirement, I urge you to contact my concierge, Julie Dahan ASAP to set up a Skype or an in-person consultation with me. You can also contact Julie by phone or via email at 702-533-2691/ Julied@sherivf.com. You can also apply online at http://www.SherIVF.com.

2. The 4th edition of my newest book ,
“In Vitro Fertilization, the ART of Making Babies” is now available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

Geoffrey Sher MD

reply
Timmy

Helo dr sher. I often read your posts and find them very informative. i am 27..Well last year i underwent ivf. Long protocol. Produced 8 follicles 5 were mature 4 fertilized and only 2 reached blast of which we transferred one and failed to conceive. The max my bhcg went was 11.4
My eggs had thickened zona pellucida. Can you or do you recommend any supplements ro improve egg quality or acupuncture perhaps. I was given max dose of stimulation i.e is 600 of stim med thats some combination med. And is there a likely hood of better response in next cycle

reply
Dr. Geoffrey Sher

The only real thing of potential value is to review and then revise the stimulation. It is not so much dosage as it is composition and timing…i.e. implementation.

Whenever a patient fails to achieve a viable pregnancy following embryo transfer (ET), the first question asked is why! Was it simply due to, bad luck?, How likely is the failure to recur in future attempts and what can be done differently, to avoid it happening next time?.
It is an indisputable fact that any IVF procedure is at least as likely to fail as it is to succeed. Thus when it comes to outcome, luck is an undeniable factor. Notwithstanding, it is incumbent upon the treating physician to carefully consider and address the causes of IVF failure before proceeding to another attempt:
1. Age: The chance of a woman under 35Y of age having a baby per embryo transfer is about 35-40%. From there it declines progressively to under 5% by the time she reaches her mid-forties. This is largely due to declining chromosomal integrity of the eggs with advancing age…”a wear and tear effect” on eggs that are in the ovaries from birth.
2. Embryo Quality/”competency (capable of propagating a viable pregnancy)”. As stated, the woman’s age plays a big role in determining egg/embryo quality/”competency”. This having been said, aside from age the protocol used for controlled ovarian stimulation (COS) is the next most important factor. It is especially important when it comes to older women, and women with diminished ovarian reserve (DOR) where it becomes essential to be aggressive, and to customize and individualize the ovarian stimulation protocol.
We used to believe that the uterine environment is more beneficial to embryo development than is the incubator/petri dish and that accordingly, the earlier on in development that embryos are transferred to the uterus, the better. To achieve this goal, we used to select embryos for transfer based upon their day two or microscopic appearance (“grade”). But we have since learned that the further an embryo has advanced in its development, the more likely it is to be “competent” and that embryos failing to reach the expanded blastocyst stage within 5-6 days of being fertilized are almost invariably “incompetent” and are unworthy of being transferred. Moreover, the introduction into clinical practice about a decade ago, (by Levent Keskintepe PhD and myself) of Preimplantation Genetic Sampling (PGS), which assesses for the presence of all the embryos chromosomes (complete chromosomal karyotyping), provides another tool by which to select the most “competent” embryos for transfer. This methodology has selective benefit when it comes to older women, women with DOR, cases of unexplained repeated IVF failure and women who experience recurrent pregnancy loss (RPL).
3. The number of the embryos transferred: Most patients believe that the more embryos transferred the greater the chance of success. To some extent this might be true, but if the problem lies with the use of a suboptimal COS protocol, transferring more embryos at a time won’t improve the chance of success. Nor will the transfer of a greater number of embryos solve an underlying embryo implantation dysfunction (anatomical molecular or immunologic).Moreover, the transfer of multiple embryos, should they implant, can and all too often does result in triplets or greater (high order multiples) which increases the incidence of maternal pregnancy-induced complications and of premature delivery with its serious risks to the newborn. It is for this reason that I rarely recommend the transfer of more than 2 embryos at a time and am moving in the direction of advising single embryo transfers …especially when it comes to transferring embryos derived through the fertilization of eggs from young women.
4. Implantation Dysfunction (ID): Implantation dysfunction is a very common (often overlooked) cause of “unexplained” IVF failure. This is especially the case in young ovulating women who have normal ovarian reserve and have fertile partners. Failure to identify, typify, and address such issues is, in my opinion, an unfortunate and relatively common cause of repeated IVF failure in such women. Common sense dictates that if ultrasound guided embryo transfer is performed competently and yet repeated IVF attempts fail to propagate a viable pregnancy, implantation dysfunction must be seriously considered. Yet ID is probably the most overlooked factor. The most common causes of implantation dysfunction are:
a. A“ thin uterine lining”
b. A uterus with surface lesions in the cavity (polyps, fibroids, scar tissue)
c. Immunologic implantation dysfunction (IID)
d. Endocrine/molecular endometrial receptivity issues
Certain causes of infertility are repetitive and thus cannot readily be reversed. Examples include advanced age of the woman; severe male infertility; immunologic infertility associated with alloimmune implantation dysfunction (especially if it is a “complete DQ alpha genetic match between partners plus uterine natural killer cell activation (NKa).
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.

• The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
• 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
• Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
• 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 Stimulation (COS) in IVF.
• 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?
• Blastocyst Embryo Transfers Should be the Standard of Care in IVF
• IVF: How Many Attempts should be considered before Stopping?
• “Unexplained” Infertility: Often a matter of the Diagnosis Being Overlooked!
• IVF Failure and Implantation Dysfunction:
• The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 1-Background
• Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 2- Making a Diagnosis
• Immunologic Dysfunction (IID) & Infertility (IID):PART 3-Treatment
• Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
• Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management:(Case Report
• Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
• Intralipid (IL) Administration in IVF: It’s Composition; How it Works; Administration; Side-effects; Reactions and Precautions
• Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
• Endometrial Thickness, Uterine Pathology and Immunologic Factors
• Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
• 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

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.

reply

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