FET Protocol Opinion

Question

Answer

This is an inordinate drop off from egg to “competent” embryo. In my opinion, , in spite of your borderline AMH (1.48ng/ml) which would suggest otherwise, you are a high responder to fertility drugs. The most likely explanation for your poor egg to “competent” embryo conversion has to do with the protocoil used for ovarian stimulation (see below).

The second issue is the relationship between endometriosis and immunologic implantation dysfunction (IID). This should also be examined because regardless of embryo quality, you cannot transfer to a “non-receptive endometrium.

1: Why so few “competent” Blastocysts?

One of the commonest questions asked by patients undergoing IVF relates to the likelihood of their eggs fertilizing and the likely “quality of their eggs and 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 intra-ovarian 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 (PCOS) 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.

2: The role of ovarian protocol selection on egg/embryo competency and IVF outcome

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  5^th -7^th 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.

Preferred Protocols for Controlled Ovarian Stimulation (COS):

• Long GnRH Agonist Protocols: The most prescribed protocol for agonist/gonadotropin administration is the so-called “long protocol”. An agonist (usually, Lupron) is given either in a natural cycle, starting 5-7 days prior to menstruation or is overlapped with the BCP for two days whereupon the latter is stopped and the Lupron, continued until menstruation ensues. The agonist precipitates a rapid rise in FSH and LH level, which is rapidly followed by a precipitous decline in the blood level of both, to near zero. This is followed by uterine withdrawal bleeding (menstruation) within 5-7 days of starting the agonist treatment, whereupon gonadotropin treatment is initiated (preferably within 7-10 days of the onset of menses) while daily Lupron injections continue, to ensure a relatively “low LH- environment”. Gonadotropin administration continues until the hCG trigger.
• Short (“Flare”) GnRH-agonist (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 “springboard 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
• Long-Agonist/Antagonist Conversion Protocol (A/ACP):With a few (notable) exceptions I preferentially advocate this protocol for many of my patients. With the A/ACP, as with the long protocol (see above) the woman again prepares to launch her stimulation cycle by taking a BCP for at least ten days before overlapping with an agonist such as Lupron. However, when about 5-7 days later her menstruation starts, she supplants the agonist with a with 250 mcg) of an antagonist (e.g. Ganirelix, Orgalutron or Cetrotide). Within a few days of this switch-over, gonadotropin stimulation is commenced. Both the antagonist and the gonadotropins are then continued until the hCG trigger. The purpose in switching from agonist to antagonist is to intentionally allow only a very small amount of the woman’s own pituitary LH to enter her blood and reach her ovaries, while at the same time preventing a large amount of LH from reaching her ovaries. This is because while a small amount of LH is essential to promote and optimize FSH-induced follicular growth and egg maturation, a large concentration of LH can trigger over-production of ovarian stromal testosterone, with an adverse effect of follicle/egg/embryo quality. Moreover, since testosterone also down-regulates estrogen receptors in the endometrium, an excess of testosterone can also have an adverse effect on endometrial growth. Also, since agonists might suppress some ovarian response to the gonadotropin stimulation, antagonists do not do so. It is for this reason that the A/ACP is so well suited to older women and those with some degree of diminished ovarian reserve.
• Agonist/antagonist conversion protocol with estrogen priming:Patients start their treatment cycle on a combined (monophasic) birth control pill-BCP (e.g., Marvelon, Desogen, Orthonovum 135; Low-Estrin…etc.)  for at least 8-10 days (depending on individual circumstances), before commencing controlled ovarian stimulation for IVF. With this approach, a GnRH agonist (e.g. Lupron/Superfact/Buserelin/Decapeptyl etc.) is continued until menstruation ensues (usually 5-7 days after commencement of the GnRH-agonist). At this point, the GnRH-agonist is SUPPLANTED with 250mcg GnRH antagonist (e.g. Ganirelix/Cetrotide, Orgalutron) and daily estradiol(E2) “priming” commences using either E2 skin-patches or intramuscular estradiol valerate (Delestrogen) injections, twice weekly while continuing the administration of the GnRH antagonist. Seven (7) days after commencing the E2 skin patches or intramuscular Delestrogen, daily injections of recombinant FSH-(e.g., Follistim/Gonal-F/Puregon)  + menotropin (e.g., Menopur)  therapy begins.. This is continued at a modified dosage, along with E2 patches or Delestrogen injections) until the “hCG trigger”. The egg retrieval is performed 36 hours later.

There are a few potential drawback to the use of the A/ACP. We have learned that prolonged use of a GnRH antagonist throughout the ovarian stimulation process can compromise the predictive value of serial plasma E2 measurements to evaluate follicle growth and development. It appears that when the antagonist is given throughout stimulation, the blood E2 levels tend to be significantly lower than when the agonist alone is used or where antagonist treatment is only commenced 5-7 days into the ovarian stimulation process. The reason for this is presently unclear. Accordingly, when the A/ACP is employed, we rely more on follicle size monitoring than on serial blood E2 trends to assess progress.

Also, younger women (under 30 years) and women with absent, irregular or dysfunctional ovulation, and those with polycystic ovarian syndrome are at risk of developing life-threatening Severe Ovarian Hyperstimulation Syndrome (OHSS). The prediction of this condition requires daily access to accurate blood E2 levels. Accordingly, we currently tend to refrain from prescribing the A/ACP in such cases, preferring instead use the “standard long-protocol” approach.

• Short-GnRH antagonist protocols:The use of GnRH antagonists as currently prescribed in ovarian stimulation cycles (i.e. the administration of 250mcg daily starting on the 6th or 7th day of stimulation with gonadotropins) may be problematic, especially in women over 39 yrs., women with diminished ovarian reserve (i.e. “poor responders” to gonadotropins), and women with PCOS. Such women tend to have higher levels of LH to start with and as such the initiation of LH suppression with GnRH antagonists so late in the cycle (usually on day 6-7) of stimulation fails to suppress LH early enough to avoid compromising egg development. This can adversely influence egg/embryo quality and endometrial development. As is the case with the “microflare” approach (see above) the use of GnRH antagonist protocols in younger women who have normal ovarian reserve, is acceptable. Again, for reasons of caution, and because I see no benefit in doing so, I personally never prescribe this approach for my patients. Presumably, the reason for the suggested mid-follicular initiation of high dose GnRH antagonist is to prevent the occurrence of the so called “premature LH surge”, which is known to be associated with “follicular exhaustion” and poor egg/embryo quality. However the term “premature LH surge” is a misnomer and the concept of this being a “terminal event” or an isolated insult is erroneous. In fact, the event is the culmination (end point) of the progressive escalation in LH (“a staircase effect”) which results in increasing ovarian stromal activation with commensurate growing androgen production. Trying to improve ovarian response and protect against follicular exhaustion by administering GnRH antagonists during the final few days of ovarian stimulation is like trying to prevent a shipwreck by removing the tip of an iceberg.
• Short-GnRH-agonist (“micro-flare”) protocols:Another approach to COH is by way of so-called “microflare protocols”. This involves initiating gonadotropin therapy simultaneously with the administration of GnRH agonist. The intent is to deliberately allow Lupron to affect an initial surge (“flare”) in pituitary FSH release to augment ovarian response to the gonadotropin medication. Unfortunately, this approach represents “a double-edged sword” as the resulting increased release of FSH is likely to be accompanied by a concomitant (excessive) rise in LH levels that could evoke excessive production of male hormone by the ovarian stroma. The latter in turn could potentially compromise egg quality, especially in women over 39 years of age, women with diminished ovarian reserve, and in women with polycystic ovarian syndrome (PCOS) – all of whose ovaries have increased sensitivity to LH. In this way, “microflare protocols” can potentially hinder egg/embryo development and reduce IVF success rates. While microflare protocols usually are not harmful in younger women and those with normal ovarian reserve, I personally avoid this approach altogether for safety’s sake. The follicles/eggs of women on GnRH-agonist “micro-flare protocols” can be exposed to exaggerated agonist-induced LH release, (the “flare effect”) while the follicles/eggs of women, who receive GnRH antagonists starting 6-8 days following the initiation of stimulation with gonadotropins can likewise be exposed to pituitary LH-induced ovarian male hormones (especially testosterone). While this is not necessarily problematic in younger women and those with adequate ovarian reserve (“normal responders”) it could be decidedly prejudicial in “poor responders” and older women where there is increased follicle and egg vulnerability to high local male hormone levels.
• The “Trigger Shot”- A Critical Decision:The egg goes through maturational division (meiosis) during the 36-hour period that precedes ovulation or retrieval. The efficiency of this process will determine the outcome of reproduction. It follows that when it comes to ovulation induction, aside from selecting a suitable protocol for COS one of the most important decisions the clinician has to make involves choosing and implementing with logic and precision, the “trigger shot” by which to facilitate meiosis.
  • Urinary versus recombinant hCG:Until quite recently, the standard method used to initiate the “trigger shot” was through the administration of 10,000 units of hCGu. More recently, a recombinant form of hCGr (Ovidrel) was introduced and marketed in 250 mcg doses. But clinical experience strongly suggests that 250 mcg of Ovidrel is most likely not equivalent in biological potency to 10,000 units of hCG. It probably at best only has 60%of the potency of a 10,000U dose of hCGu and as such might not be sufficient to fully promote meiosis, especially in cases where the woman has numerous follicles. For this reason, I firmly believe that when hCGr is selected as the “trigger shot” the dosage should be doubled to 500 mcg, at which dosage it will probably have an equivalent effect on promoting meiosis as would 10,000 units of hCGu.
  • The dosage of hCG used: Some clinicians, when faced with a risk of OHSS developing will deliberately elect to reduce the dosage of hCG administered as a trigger in the hope that by doing so, the risk of developing critical OHSS will be lowered. It is my opinion that such an approach is not optimal because a low dose of hCG (e.g., 5000 units hCGu or 25omcg hCGr) is likely inadequate to optimize the efficiency of meiosis, particularly when it comes to cases such as this where there are numerous follicles. In my opinion a far better approach is to use a method that I first described in 1989, known as “prolonged coasting”
  • Use of hCG versus a GnRHa(e.g., Lupron/Buserelin/Superfact) as the trigger shot: It has been suggested that the use of an “agonist ( Lupron) trigger” in women at risk of developing severe ovarian hyperstimulation syndrome (OHSS) could potentially reduce the risk of the condition becoming critical and thereby placing the woman at risk of developing life-endangering complications. It is for this reason that many RE’s prefer to trigger meiosis in this way (using an agonist-Lupron) rather than through the use of hCG. The agonist promptly causes the woman’s pituitary gland to expunge a large amount of LH over a short period of time and it is this LH “surge” that triggers meiosis. The problem with this approach, in my opinion, is that it is hard to predict how much LH will be released in by the pituitary gland of a given patient receiving an agonist trigger shot, especially if the woman was down-regulated using an agonist, or in cases where an antagonist was used to block pituitary LH release. For this reason, I personally prefer to use hCGu for the trigger, even in cases of ovarian hyperstimulation, with one important proviso…that she underwent “prolonged coasting” in order to reduce the risk of critical OHSS prior to the 10,000 unit hCGu “trigger”.
  • Combined use of hCG +GnRHa; This approach is preferable to the use of a GnRHa, alone. However, in my opinion is inferior to the appropriate and correct use of hCG, alone.
  • The timing of the trigger shot to initiate meiosis:This should coincide with the majority of ovarian follicles being >15 mm in mean diameter with several follicles having reached 18-22 mm. Follicles of larger than 22 mm will usually harbor overdeveloped eggs which in turn will usually fail to produce good quality eggs. Conversely, follicles less than 15 mm will usually harbor underdeveloped eggs that are more likely to be aneuploid and incompetent following the “trigger”.

Severe Ovarian Hyperstimulation Syndrome (OHSS) and prolonged Coasting”

OHSS is a life-endangering condition that usually occurs in women undergoing COS where the blood E2 level rises to above 4,000pg/ml. The risk escalates to greater than 80% in cases where the E2 level rises above 6,000pg/ml. It rarely occurs in normally ovulating women or older (>39Y) women and is more commonly encountered in:

• Young women (under 30y) who have a high ovarian reserve(based upon basal FSH and AMH.
• Women with polycystic Ovarian Syndrome (PCOS)
• Non-PCOS women who do not ovulate spontaneously

The treating physician should be alerted to the possibility of hyperstimulation when encountering a woman who develops >25 ovarian follicles of 14mm-16mm in mean diameter, in association with a blood E2 level of above 2,5000pg/ml prior to the hCG “trigger”.

OHSS is a self-limiting condition. Its development is linked to the effect of hCG and thus does not occur until the “hCG trigger” is administered. In fact, there is virtually no risk of OHSS until the hCG “trigger” is administered.

“Prolonged Coasting” is a procedure I introduced in 1991. It involves abruptly stopping gonadotropin therapy while continuing to administer the GnRH agonist (e.g. Lupron, Buserelin) deferring the hCG “trigger” until the woman is out of risk (as evidenced by a fall in plasma estradiol level to below 2,500pg/ml).

It is important that “prolonged coasting” be initiated as soon as two or more follicles have attained a greater diameter than 18mm with at least 50% of the remaining follicles having attained 14-16mm. To start the process of “prolonged coasting” any earlier or any later, while it would still protect against the development of OHSS, would almost certainly result in compromised egg and embryo quality with ultimate failure of the IVF cycle. Simply stated, the precise timing of initiating the process is critical. Proper implementation of PC will almost always prevent OHSS without seriously compromising egg/embryo quality.

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 Immunologic  Implantation Dysfunction (IID):

More than half of women who have endometriosis harbor antiphospholipid antibodies (APA) that can compromise development of the embryo’s root system (trophoblast). In addition and far more serious, is the fact that in about one third of cases endometriosis, regardless of its severity is associated with NKa and cytotoxic uterine lymphocytes (CTL) which can seriously jeopardize implantation. This immunologic implantation dysfunction (IID) is diagnosed by testing the woman’s blood for APA, for NKa (using the K-562 target cell test or by endometrial biopsy for cytokine activity) and, for CTL (by a blood immunophenotype). Activated NK cells attack the invading trophoblast cells (developing “root system” of the embryo/early conceptus) as soon as it tries to gain attachment to the uterine wall. In most cases, this results in rejection of the embryo even before the pregnancy is diagnosed and sometimes, in a chemical pregnancy or an early miscarriage. As such, many women with endometriosis, rather than being infertile, in the strict sense of the word, often actually experience repeated undetected “mini-miscarriages”.

Women who harbor APA’s often experience improved IVF birth rates when heparinoids (Clexane/Lovenox) are administered from the onset of ovarian stimulation with gonadotropins until the 10th week of pregnancy. NKa is treated with a combination of Intralipid (IL) and steroid therapy: Intralipid (IL) is a solution of small lipid droplets suspended in water. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, alpha-linolenic acid (ALA), an omega-3 fatty acid.IL is made up of 20% soybean oil/fatty acids (comprising linoleic acid, oleic acid, palmitic acid, linolenic acid and stearic acid) , 1.2% egg yolk phospholipids (1.2%), glycerin (2.25%)  and water (76.5%).IL exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating NKa.

The therapeutic effect of IL/steroid therapy is likely due to an ability to suppress pro-inflammatory cellular (Type-1) cytokines such as interferon gamma and TNF-alpha. IL/steroids down-regulates NKa within 2-3 weeks of treatment the vast majority of women experiencing immunologic implantation dysfunction. In this regard IL is just as effective as Intravenous Gamma globulin (IVIg) but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for 4-9 weeks when administered in early pregnancy.

The toxic pelvic environment caused by endometriosis, profoundly reduces natural fertilization potential. As a result normally ovulating infertile women with endometriosis and patent Fallopian tubes are much less likely to conceive naturally, or by using fertility agents alone (with or without intrauterine (IUI) insemination. The only effective way to bypass this adverse pelvic environment is through IVF. I am not suggesting here that all women who have endometriosis require IVF! Rather, I am saying that  in cases where  the condition is further compromised by an IID associated with NKa and/or for older women(over 35y)  who have  diminished ovarian reserve (DOR) where time is of the essence, it is my opinion that IVF is the treatment of choice.

4. Frozen Embryo Transfer (FET)

Until less than a decade ago, most women undergoing IVF would have embryos transferred to the uterus in the same cycle that the egg retrieval was performed (“Fresh” Embryo Transfer). This was because embryo cryopreservation (freezing) was a hazardous undertaking.  In fact, it resulted in about 30% not surviving the freezing process and those that did, having about one half the potential of “fresh embryos to implant and propagate a viable pregnancy. The main reason for the high attrition rate associated with embryo cryopreservation is that the “conventional” freezing” process that was done slowly and this resulted in ice forming within the embryo’s cells, damaging or destroying them. The introduction of an ultra-rapid cryopreservation process (vitrification) freezes the embryos so rapidly as to avoid ice crystals from developing. As a result, >90% survive the freeze/thaw process in as good a condition as they were prior to being frozen and thus without being compromised in their ability to propagate a viable pregnancy.

Recently, there have been several articles that have appeared in the literature suggest that an altered hormonal environment may be the reason for this effect.  There have also been reports showing that when singletons (pregnancy with one baby) conceived naturally are compared to singletons conceived through a “fresh” embryo transfers they tend to have a greater chance of low birth weight/prematurity. This difference was not observed in babies born following FET.  Hence, there is a suspicion that the altered hormonal environment during the fresh cycle may be the causative factor.

Available evidence suggests that FET (of pre-vitrified blastocysts) is at least as successful as is the transfer of “fresh” embryos and might even have the edge. The reason for this is certainly unlikely to have anything to do with the freezing process itself. It more than likely  has to do with two factors:

1. An ever increasing percentage of FET’s involve the transfer of PGS-tested, fully karyotyped, euploid blastocysts that have a greater potential to propagate viable pregnancies, than is the case with “fresh” ET’s where the embryos have rarely undergone prior PGS selection for “competency”…and,
2. With targeted hormone replacement therapy for FET, one is far better able to better to optimally prepare the endometrium for healthy implantation than is the case where embryos are transferre3d following ovarian stimulation with fertility drugs.

There are additional factors other than method used for embryo cryopreservation that influence outcome following FET. These include

• An emerging trend towards selective transferring only advanced (day 5-6) embryos (blastocysts).
•  (PGS) to allow for the selective transfer of genetic competent (euploid) embryos
• Addressing underlying causes of implantation dysfunction (anatomical and immunologic uterine factors) and
•  Exclusive use of ultrasound guidance for delivery of embryos transferred to the uterus.

Against this background, the use of FET has several decided advantages:

• The ability to cryostore surplus embryos left over after fresh embryo transfer
• The ability to safely hold embryos over for subsequent transfer in a later frozen embryo transfer (FET) cycle (i.e. Staggered IVF) in cases where:

• 1. Additional time is needed to perform preimplantation Genetic testing for embryo competency.
  2. In cases where ovarian hyperstimulation increases the risk of life-endangering complications associated with critically severe ovarian hyperstimulation syndrome (OHSS).
  3. To bank (stockpile) embryos for selective transfer of karyotypically normal embryos in older women or those who are diminished ovarian reserve
  4. The ability to store embryos in cases of IVF with third party parenting (Egg Donation; Gestational Surrogacy and Embryo donation) and so improve convenience for those couples seeking such services.

Preimplantation Genetic Sampling with FET:

The introduction of preimplantation genetic sampling (PGS) to karyotyping of embryos for selective transfer of the most “competent” embryos, requires in most cases that the tested blastocysts be vitribanked while awaiting test results and then transferred to the uterus at a later date. Many IVF programs have advocated the routine use of PGS in IVF purported to improve IVF outcome. But PGS should in my opinion should only be used selectively. I do not believe that it is needed for all women undergoing IVF. First there is the significant additional cost involved and second it will not benefit everyone undergoing IVF, in my opinion.

While PGS is a good approach for older women and those with diminished ovarian reserve (DOR) and also for woman who experience recurrent pregnancy loss (RPL) or “unexplained” recurrent IVF failure recent data suggests that it will not improve IVF success rates in  women under 36Y  who have normal ovarian reserve, who represent the majority of women seeking IVF treatment. Nor is it needed in women (regardless of their age) undergoing IVF with eggs donated by a younger donor.  This is because in such women about 1:2/3 of their eggs/embryos are usually chromosomally normal, and in most cases will upon fertilization produce multiple blastocysts per IVF attempt, anyway. Thus in such cases the transfer of 2 blastocysts will likely yield the same outcome regardless of whether the embryos had been subjected to PGS or not. The routine use of

It is another matter when it comes to women who have diminished ovarian reserve and/or DOR contemplating embryo banking and for women with unexplained recurrent IVF failure, recurrent pregnancy loss and women with alloimmune implantation dysfunction who regardless of their age or ovarian reserve require PGS for diagnostic reasons.

Embryo Banking: Some IVF centers are doing embryo banking cycles with Preimplantation Genetic Screening (PGS).  With Embryo Banking” several IVF cycles are performed sequentially (usually about 2 months apart), up to the egg retrieval stage. The eggs are fertilized and the resulting advanced embryos are biopsied. The biopsy specimens are held over until enough 4-8 blastocysts have been vitribanked, thus providing a reasonable likelihood that one or more will turn out to be PGS-normal. At this point the biopsy specimens (derived all banking cycles) are sent for PGS testing at one time (a significant cost-saver), the chromosomally normal blastocysts are identified and the women are scheduled for timed FET procedures….. with a good prospect of  a markedly improved chance of success as well as a reduced risk of miscarriage.

Standard (proposed) Regimen for preparing the uterus for frozen embryo transfer FET) is as follows:

The recipient’s cycle is initiated with an oral contraceptive-OC (e.g. Marvelon/Lo-Estrin; Lo-Ovral etc) for at least 10 days. This is later overlapped with 0.5 mg. (10 units) Lupron/Lucrin (or Superfact/Buserelin) daily for 3 days. Thereupon the OC is withdrawn and daily 0.25 mg (5 units) of Lupron/Lucrin/Superfact injections are continued. Menstruation will usually ensue within 1 week. At this point, an ultrasound examination is performed to exclude ovarian cyst(s) and a blood estradiol measurement is taken (it needs to be <70pg/ml) until daily progesterone administration is initiated some time later. The daily Lupron/Lucrin/Superfact is continued until the initiation of progesterone therapy (see below).

Four milligram (4mg) Estradiol valerate (Delestrogen) IM is injected SC, twice weekly (on Tuesday and Friday), commencing within a few days of Lupron/Lucrin/Superfact-induced menstruation. Blood is drawn on Monday and Thursday for measurement of blood [E2].  This allows for planned adjustment of the E2V dosage scheduled for the next day. The objective is to achieve a plasma E2 concentration of 500-1,000pg/ml and an endometrial lining of >8mm, as assessed by ultrasound examination done after 10 days of estrogen exposure i.e. a day after the 3^rd dosage of Delestrogen..  The twice weekly, final (adjusted) dosage of E2V is continued until pregnancy is discounted by blood testing or an ultrasound examination. Dexamethasone 0.75 mg is taken orally, daily with the start of the Lupron/Lucrin/Superfact. Oral folic acid (1 mg) is taken daily commencing with the first E2V injection and is continued throughout gestation. Patients also receive Ciprofloxin 500mg BID orally starting with the initiation of Progesterone therapy and continuing for 10 days.

Luteal support commences 6 days prior to the ET, with intramuscular progesterone in oil (PIO) at an initial dose of 50 mg (P4-Day 1).  Starting on progesterone administration-Day 2, PIO is increased to 100 mg daily continuing until the 10^th week of pregnancy, or until a blood pregnancy test/negative ultrasound (after the 6-7^th gestational week), discounts a viable pregnancy.

Also, commencing on the day following the ET, the patient inserts one (1) vaginal progesterone suppository (100 mg) in the morning + 2mg E2V vaginal suppository (in the evening) and this is continued until the 10^th week of pregnancy or until pregnancy is discounted by blood testing or by an ultrasound examination after the 6-7^th gestational week. Dexamethasone o.75mg is continued to the 10^th week of pregnancy (tailed off from the 8^th to 10^th week) or as soon as pregnancy is ruled out. With the obvious exception of the fact that embryo recipients do not receive an hCG injections, luteal phase and early pregnancy hormonal support and immuno-suppression is otherwise the same as for conventional IVF patients.  Blood pregnancy tests are performed 13 days and 15 days after the first P4 injection was given.

Note: One (1) vaginal application of Crinone 8% is administered on the 1^st day (referred to as luteal phase day 0 – LPO). On LP Day 1, they will commence the administration of Crinone 8% twice daily (AM and PM) until the day of embryo transfer.  Withhold Crinone on the morning of the embryo transfer and resume Crinone administration in the PM.   Crinone twice daily is resumed from the day after embryo transfer. Contingent upon positive blood pregnancy tests, and subsequently upon the ultrasound confirmation of a viable pregnancy, administration of Crinone twice daily are continued until the 10^th week of pregnancy.

Regime for Thawing and Transferring Cryopreserved Embryos/Morulae/Blastocysts:

Patients undergoing ET with cryopreserved embryos/morulas/blastocysts will have their embryos thawed and transferred by the following regimen.

Read the information above and once having done so, might I suggest you contact my assistant, Patti Converse (702-533-2691) and set up an online consultation with me. I think I can help you!

Geoff Sher