19,771 Comments

1. Jessica on December 19, 2019 at 6:39 am

   Hi dr. Sher, I’m given flare protocol by my RE because of my failed antagonist protocol. I know you don’t like to use this one.
   My question is, my stim Meds are 450iu Follistim and 75iu menopur. I’m not comfortable with the added menopur after I read your blog abt how LH can comprise the egg quality. But my RE said I still need a little bit of LH for eggs maturity. Thoughts? Thank you!

   • Dr. Geoffrey Sher on December 19, 2019 at 7:54 pm

     While I do not agree with the use of “flare protocols” (especially when it comes to older women and those with Diminished Ovarian Reserve -DOR), I do agree with your RE that 75U of Menopur during stimulation is appropriate.

     Good luck!

     Geoff Sher

2. Mary on December 19, 2019 at 12:01 am

   Hi!
   First of all I have to thank You for very interesting views and information about an important topic. Through your articles I`ve become aware of some factors to IVF that I did`nt know about. I will come back to them after I have told You a little about myself.
   I am a woman who recently turned 41 years old. I had a child (naturally conceived) 8 years ago. Now I try for one more. I have done 3 egg retrievals in the last 1,5 years. I have been stimulated with injections of 225-300 IU of menopur pr day from day 2 in every of the 3 IVF cycles, and cetrotide from day 5-6. Ovitrelle 250 µg has been the triggershot.
   Here is my day 2-3 bloodtest results a few months ago:
   11-deoxycortisol1,1 nmol/L
   17-OH progesterone1,0 nmol/L
   DHEA-sulphate3,4 µmol/L
   LH9,0 IE/L
   FSH4,8 IE/L
   Prolactin166 mIE/L
   SHBG62 nmol/L
   Testosterone0,6 nmol/L
   Free testosterone index0,1
   Estradiol118 pmol/L
   Progesterone<1,0 nmol/L
   AMH20,5 pmol/L
   25-OH vitamine D48 nmol/L
   No inherited thrombophilia. Both ovaries seems fine and uterus also fine. My uterus lining is always fine at transfer and transfer of the freezed embryos/blastocysts has been done based on my own report from urine LH ovulation test strips at home. In my opinion it is best to have a transfer in a natural cycle, though it can sometimes be difficult to predict ovulation. I have tests that is LH-positive (LH line darker than control line) 3-4 days but I always report the first day as “positive test day” and have been pregnant (MA) twice as a outcome of this method.
   My partner have perfectly good sperm.
   In the first IVF cycle I injected 300 IU of menopur. I got 20 eggs out, 11 fertilized and only 1 egg that looked morphologically normal on day 3. I was showing signs of OHSS an the egg was freezed. Later I got pregnant with this egg, but it resulted in MA probably between week 4-7.
   Second IVF cycle I injected 225 IU of menopur. I got 11 eggs out, 7 fertilized and 4 of them made it to day 5. 3 were freezed and I had a fresh transfer of one of them. This and the second transfer (freeze transfer) did not result in pregnancy but the third freeze transfer did. But same thing happened again,- early MA. Fetus only 3 mm and no heartbeat in week 7.
   Third IVF cycle I injected 225 IU of menopur since we had 4 good blastocysts last cycle. This time I got 10 eggs out, 9 fertilized with ICSI and 4 of them made it to day 5. This time we wanted to perform a PGS test on all 4 blastocysts. The biopsy was performed on day 5, freezed and sent to another country for PGS testing. Here are the results:
   #1 missing one chromosome 16 and one X
   #5 missing one chromosome 21, one extra chromosome 22 and a duplication on chromosome 13
   #7 missing one chromosome 19
   #8 one extra chromosome 3, 18, 19, 20, 21 and 22
   After a lot of reading in Your blog I have some questions:
   1: Do You think my long LH surge means that I am producing too much LH that could be fatal for my eggs either in the cycle I retrieve eggs or in the cycle I have the transfer?
   2: You have mentioned several times that Menopur may not be the optimal choice for older women. If I have too much LH in advance, and then injecting Menopur on top of that, can this be fatal for my eggs? Can You explain this in detail and would You suggest another alternative for me?
   3: I am very interested in Your articles about triggershots and their effects on meiosis. Besides my age, could ovitrelle be a reason for so many aneuploide blastocysts? What would You suggest?
   4: Do my hormone tests look fine to You?
   5: What is Your opinion on the PGS results? Is it terrible results or are they “hopeful”? I am aware aneuploidy is aneuploidy, but 1 defect chromosome must be better than 10?
   6: We have talked about donor egg but would like to try one more time with my eggs. Which IVF regime do You think would be best for us?
   This was a lot of information but we are quite desperate now before our last IVF attempt. I hope You`ve got time to look at it. Have a nice day!

   • Dr. Geoffrey Sher on December 19, 2019 at 1:52 am

     1: Do You think my long LH surge means that I am producing too much LH that could be fatal for my eggs either in the cycle I retrieve eggs or in the cycle I have the transfer?I

     A: Very possibly, depending when the surge begins.
     Premature luteinization (“premature LH surge”) occurs when prior to the planned initiation of the hCG trigger, a progressive rise in LH, irreversibly compromises follicle and egg development and maturation. It is not a sporadic isolated event. It comes as a culmination of a series ovarian events, occurring mostly in susceptible women (i.e. usually older women and those with diminished ovarian reserve. It is more likely to occur when the protocol used for ovarian stimulation has failed to maintain LH activity at a low level prior to and throughout the ovarian stimulation process. Once it occurs in any given stimulation cycle it cannot be switched off by changing the stimulation in progress or by administering GnRH antagonists (e.g. Ganirelix/Cetrotide/Orgalutron) midway in the cycle in the hope that this could rescue the eggs under development. It is my opinion, once premature luteinization commences, the cycle is doomed and outcome is doomed to fail. The condition increases the likelihood of premature ovulation, failed release of eggs during needle-guided egg retrieval (so called “empty follicle syndrome” and the incidence of egg/embryo “incompetence” (chromosomal aneuploidy).
     This situation is most commonly seen in older women and in women who have severely diminished ovarian reserve. In many cases its effect can be prevented through implementation of strategic and individualized protocols for controlled ovarian stimulation (COS) coupled with optimizing the type, timing and dosage of the “hCG trigger shot.”
     Normally, following optimal ovarian stimulation, the “trigger shot” is given for the purpose of it initiating meiosis (reproductive division) that is intended to halve the number of chromosomes from 46 to 23 within 32-36 hours. The hCG trigger also enables the egg to signal the “cumulus cells” that bind it firmly to the inner wall of the follicle (through enzymatic activity), to loosen or disperse, so that the egg can detach and readily be captured at egg retrieval (ER).
     Older women, and women with diminished ovarian reserve, tend to have more biologically active LH in circulation. LH causes production of male hormone (androgens, predominantly testosterone), by ovarian connective tissue (stroma/theca). A little testosterone is needed for optimal follicle development and for FSH-induced ovogenesis (egg development). Too much LH activity compromises the latter, and eggs so affected are far more likely to be aneuploid following meiosis.
     Women with the above mentioned conditions often have increased LH activity and are thus more likely to produce excessive ovarian testosterone. It follows that sustained, premature elevations in LH or premature luteinization (often referred to as a “premature LH surge”) will prejudice egg development. Such compromised eggs are much more likely to end up being complex aneuploid following the administration of the hCG trigger, leading to fruitless attempts at retrieval and the so called “empty follicle syndrome.”
     The developing eggs of women who have increased LH activity (older women, and women with diminished ovarian reserve) are inordinately vulnerable to the effects of protracted exposure to LH-induced ovarian testosterone. Because of this, the administration of medications that provoke further pituitary LH release (e.g., clomiphene and Letrozole), drugs that contain LH or hCG (e.g., Menopur), or protocols of ovarian stimulation that provoke increased exposure to the woman’s own pituitary LH (e.g., “flare-agonist protocols”) and the use of “late pituitary blockade” (antagonist) protocols can be prejudicial.

     The importance of individualizing COS protocol selection, precision with regard to the dosage and type of hCG trigger used, and the timing of its administration in such cases cannot be overstated. The ideal dosage of urinary-derived hCG (hCG-u) such as Novarel, Pregnyl and Profasi is 10,000U. When recombinant DNA-derived hCG (hCG-r) such as Ovidrel is used, the optimal dosage is 500mcg. A lower dosage of hCG or Ovidrel can, by compromising meiosis, increase the risk of egg aneuploidy, and thus of IVF outcome.

     2: You have mentioned several times that Menopur may not be the optimal choice for older women. If I have too much LH in advance, and then injecting Menopur on top of that, can this be fatal for my eggs? Can You explain this in detail and would You suggest another alternative for me?

     A: Menopur contains an equal amount of FSH and LH/CG. The latter increases production of ovarian androgen/male hormone (especially testosterone) which if in excess can adversely affect egg/follicular development and ultimately the percentage of eggs that are chromosomally abnormal (aneuploid). This is most damaging in my opinion in older women (>40Y) and/or those who regardless of age have diminished ovarian reserve who already have increased ovarian testosterone production.
     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

     3: I am very interested in Your articles about triggershots and their effects on meiosis. Besides my age, could ovitrelle be a reason for so many aneuploid blastocysts? What would You suggest?

     A:Until quite recently, the standard method used to “trigger” egg maturation was through the administration of 10,000 units of hCGu. Subsequently,, a DNA 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 only has 50%-70%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 best 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. Failure to “trigger” with 10,000U hCGu or 500mcg hCGr, will in my opinion increase the likelihood of disorderly meiosis, “incompetent (aneuploid) eggs” and the risk of follicles not yielding eggs at egg retrieval (“empty follicles”). Having said this, it is my personal opinion that it is unnecessary to supplant hCGu with hCGr since the latter is considerably more expensive and is probably no more biopotent than the latter.

     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”.

     4: Do my hormone tests look fine to You?

     A: They look OK

     5: What is Your opinion on the PGS results? Is it terrible results or are they “hopeful”? I am aware aneuploidy is aneuploidy, but 1 defect chromosome must be better than 10?

     A: Single or double autosomal aneuploidies can sometimes point to embryo “mosaicism”, which means that some cells in the embryo are aneuploid and others are euploid. Mosaic embryos can autocorrect. However, the older the woman, the more the likelihood that cause is due to “meiotic aneuploid which cannot “autocorrect in thge uterus and the smaller the likelihood that that an aneuploid embryo will be “mosaic” (the result of mitotic aneuploidy-see below) and thus be able to autocorrect in-utero. This is because the older the woman, the greater the incidence of meiotic aneuploidy.
     Human embryo development occurs through a process that encompasses reprogramming, sequential cleavage divisions and mitotic chromosome segregation and embryonic genome activation. Chromosomal abnormalities may arise during germ cell and/or preimplantation embryo development and represents a major cause of early pregnancy loss. About a decade ago, I and my associate, Levent Keskintepe PhD were the first to introduce full embryo karyotyping (identification of all 46 chromosomes) through preimplantation genetic sampling (PGS) as a method by which to selectively transfer only euploid embryos (i.e. those that have a full component of chromosomes) to the uterus. We subsequently reported on a 2-3-fold improvement in implantation and birth rates as well as a significant reduction in early pregnancy loss, following IVF. Since then PGS has grown dramatically in popularity such that it is now widely used throughout the world.

     MOSAICISM: Many IVF programs that offer PGS services, require that all participating patients consent to all their aneuploid embryos (i.e. those with an irregular quota of chromosomes) be disposed of. However, growing evidence suggests that following embryo transfer, some aneuploid embryos will in the process of ongoing development, convert to the euploid state (i.e. “autocorrect”) and then go on to develop into chromosomally normal offspring. In fact, I am personally aware of several such cases having occurred in my own practice. So clearly, summarily discarding all aneuploid embryos as a matter of routine we are sometimes destroying some embryos that might otherwise have “autocorrected” and gone on to develop into normal offspring. Thus by discarding aneuploid embryos the possibility exists that we could be denying some women the opportunity of having a baby. This creates a major ethical and moral dilemma for those of us that provide the option of PGS to our patients. On the one hand, we strive “to avoid knowingly doing harm” (the Hippocratic Oath) and as such would prefer to avoid or minimize the risk of miscarriage and/or chromosomal birth defects and on the other hand we would not wish to deny patients with aneuploid embryos, the opportunity to have a baby.

     The basis for such embryo “autocorrection” lies in the fact that some embryos found through PGS-karyotyping to harbor one or more aneuploid cells (blastomeres) will often also harbor chromosomally normal (euploid) cells (blastomeres). The coexistence of both aneuploid and euploid cells coexisting in the same embryo is referred to as “mosaicism.”

     It is against this background, that an ever-increasing number of IVF practitioners, rather than summarily discard PGS-identified aneuploid embryos are now choosing to cryobanking (freeze-store) certain of them, to leave open the possibility of ultimately transferring them to the uterus. In order to best understand the complexity of the factors involved in such decision making, it is essential to understand the causes of embryo aneuploidy of which there are two varieties:

     1.Meiotic aneuploidy” results from aberrations in chromosomal numerical configuration that originate in either the egg (most commonly) and/or in sperm, during preconceptual maturational division (meiosis). Since meiosis occurs in the pre-fertilized egg or in and sperm, it follows that when aneuploidy occurs due to defective meiosis, all subsequent cells in the developing embryo/blastocyst/conceptus inevitably will be aneuploid, precluding subsequent “autocorrection”. Meiotic aneuploidy will thus invariably be perpetuated in all the cells of the embryo as they replicate. It is a permanent phenomenon and is irreversible. All embryos so affected are thus fatally damaged. Most will fail to implant and those that do implant will either be lost in early pregnancy or develop into chromosomally defective offspring (e.g. Down syndrome, Edward syndrome, Turner syndrome).

     2.Mitotic aneuploidy (“Mosaicism”) occurs when following fertilization and subsequent cell replication (cleavage), some cells (blastomeres) of a meiotically normal (euploid) early embryo mutate and become aneuploid. This is referred to as “mosaicism”. Thereupon, with continued subsequent cell replication (mitosis) the chromosomal make-up (karyotype) of the embryo might either comprise of predominantly aneuploid cells or euploid cells. The subsequent viability or competency of the conceptus will thereupon depend on whether euploid or aneuploid cells predominate. If in such mosaic embryos aneuploid cells predominate, the embryo will be “incompetent”). If (as is frequently the case) euploid cells prevail, the mosaic embryo will likely be “competent” and capable of propagating a normal conceptus.

     Since some mitotically aneuploid (“mosaic”) embryos can, and indeed do “autocorrect’ while meiotically aneuploid embryos cannot, it follows that an ability to reliably differentiate between these two varieties of aneuploidy would potentially be of considerable clinical value. The recent introduction of a variety of preimplantation genetic screening (PGS) known as next generation gene sequencing (NGS) has vastly improved the ability to reliably and accurately karyotype embryos and thus to diagnose embryo “mosaicism”.

     Most complex aneuploidies are meiotic in origin and will thus almost invariably fail to propagate viable pregnancies. The ability of mosaic embryos to autocorrect is influenced by stage of embryo development in which the diagnosis is made, which chromosomes are affected, whether the aneuploidy involves a single chromosome (simple) or involves 3 or more chromosomes (complex), and the percentage of cells that are aneuploid. Many embryos diagnosed as being mosaic prior to their development into blastocysts (in the cleaved state), subsequently undergo autocorrection to the euploid state (normal numerical chromosomal configuration) as they develop to blastocysts in the Petri dish. This is one reason why “mosaicism” is more commonly detected in early embryos than in blastocysts. Embryos with segmental mosaic aneuploidies, i.e. the addition (duplication) or subtraction (deletion), are also more likely to autocorrect. Finally, the lower the percentage of mitotically aneuploid (mosaic) cells in the blastocyst the greater the propensity for autocorrection and propagation of chromosomally normal (euploid) offspring. A blastocyst with <30% mosaicism could yield a 30% likelihood of a healthy baby rate with 10-15% miscarriage rate, while with >50% mosaicism the baby rate is roughly halved and the miscarriage rate double. As stated above, the transfer of embryos with autosomal meiotic trisomy, will invariably result in failed implantation, early miscarriage or the birth of a defective child. Those with autosomal mitotic (“mosaic”) trisomies, while having the ability to autocorrect in-utero and result in the birth of a healthy baby can, depending on the percentage of mosaic (mitotically aneuploid) cells present, the number of aneuploid chromosomes and the type of mosaicism (single or segmental) either autocorrect and propagate a normal baby, result in failed implantation, miscarry or cause a birth defect (especially with trisomies 13, 18 or 21). This is why when it comes to giving consideration to transferring trisomic embryos, suspected of being “mosaic”, I advise patients to undergo prenatal genetic testing once pregnant and to be willing to undergo termination of pregnancy in the event of the baby being affected. Conversely, when it comes to meiotic autosomal monosomy, there is almost no chance of a viable pregnancy. in most cases implantation will fail to occur and if it does, the pregnancy will with rare exceptions, miscarry. “Mosaic” (mitotically aneuploid) autosomally monosomic embryos where a chromosome is missing), can and often will “autocorrect” in-utero and propagate a viable pregnancy. It is for this reason that I readily recommend the transfer of such embryos, while still (for safety sake) advising prenatal genetic testing in the event that a pregnancy results.

     Given our ability to recognize “mosaicism” through karyotyping of embryos, the question arrases as to which “mosaic” embryos are capable of auto-correcting in-utero and propagating viable pregnancies. Research suggests that that virtually no autosomal monosomy embryos will propagate viable pregnancies. Thus, the transfer of such mosaic embryos is virtually risk free. Needless to say however, in any such cases, it is essential to make full disclosure to the patient (s), and to insure the completion of a detailed informed consent agreement which would include a commitment by the patient (s) to undergo prenatal genetic testing (amniocentesis/CVS) aimed at excluding a chromosomal defect in the developing baby and/or a willingness to terminate the pregnancy should a serious birth defect be diagnosed.

     6: We have talked about donor egg but would like to try one more time with my eggs. Which IVF regime do You think would be best for us?

     A: As I stated above, 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.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.

     3.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.

     USE OF BIRTH CONTROL PILLS (BCP) TO LAUNCH IVF OVARIAN STIMULATION:

     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 hope this helps!
     __________________________________________________________________________________________
     Please visit my Blog on this very site, 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)
     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 recommend

3. Sarah on December 18, 2019 at 6:35 pm

   Hi

   I am a 30 year old woman who has been trying to conceive for over almost 3 years with unexplained infertility. Low-ish AMH for age (9.6pmol/l) but no other abnormalities detected from day 3 or day 21 bloods or saline ultrasound.

   In the past year I have had 3 x IUIs all unsuccessful, short protocol ivf 12 eggs collected resulting in 1 embryos transferred day 5 (4AB- miscarriage at 6 weeks) one frozen day 6 (4bb- no pregnancy) a second cycle 9 eggs collected resulted in 3 day 5 embryos a 4AA and 3AB transferred resulting in chemical pregnancy, one left frozen.

   I am at a loss of what to do next. I’m reluctant to go through another cycle if there is something impacting my outcomes. I have not been tested for endometriosis. Are there any further tests you’d recommend I pursue?

   • Dr. Geoffrey Sher on December 18, 2019 at 8:18 pm

     You do have diminished ovarian reserve and in such cases, the protocol used for ovarian stimulation is very 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 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

4. Kristen on December 18, 2019 at 2:15 pm

   Hi Dr. Sher.

   I’m 39 years old. I have a 19mm, 13mm and a 12mm follicle. I am on day 10 in my cycle. I am doing a timed intercourse cycle with menopur. In your opinion, should I continue to stimulate to grow the 12 and 13mm follicles? Would I risk jeopardising the 19mm if I continue to take menopur?

   • Dr. Geoffrey Sher on December 18, 2019 at 8:19 pm

     Kristen, my recommendation would be to trigger now. The 12 and 13mm follicles are notgoiung to catch up.

     Geoff Sher

5. Ariel on December 18, 2019 at 1:51 pm

   HI Dr, Sher,
   I will try and be as concise why my question as possible. I am Hypothyroid and take Levothyroxine for it. I have been taking it for several years.

   My husband and I have had 6 miscarriages. The first was natural at 40years old. The next one was at 9weeks through IVF and the testing on the products of conception showed a chromosomal normal male. The next 2 were chemicals back to back. These were all with my own eggs, 5 days blasts. Next we did a donor egg round which resulted in no blasts only an embryo which was a full day behind. I did not have high hopes for it. Yet I still got pregnant and miscarried. Just a month ago we did another donor egg round in Europe (we just moved to Belgium) our donor is 23 we got 5 perfect blasts, transferred 2 and froze the other three. My first beta at 14dpo was 531 and 4 days later it was 2200. So a really good doubling rate. Out of nowhere, a week later I miscarried. At this point I am led to believe this is something going on with me. I have had all of the traditional RPL testing, hysteroscopy etc. While they found very mild scarring they removed it and a follow-up hysteroscopy showed my uterus was completely clear. I do not have blood clotting disorder though I was on baby aspirin anyways.

   I am wondering if because I am Hypothyroid that my losses are autoimmune related? Would I benefit form taking low dose prednisone and or intralipids if we decide to do another transfer? Or is this just a case where I can t carry a baby? I seem to get pregnant very easily. I have had only one transfer where it was a negative.

   I really appreciate your first thoughts on how to tackle this problem,
   Ariel

   • Dr. Geoffrey Sher on December 18, 2019 at 8:23 pm

     PLEASE SEE BELOW!

     Thyroid autoimmunity and IVF Outcome:

     Between 2% and 5% of women of the childbearing age have reduced thyroid hormone activity (hypothyroidism). Women with hypothyroidism often manifest with reproductive failure i.e. infertility, unexplained (often repeated) IVF failure, or recurrent pregnancy loss (RPL). The condition is 5-10 times more common in women than in men. In most cases hypothyroidism is caused by damage to the thyroid gland resulting from of thyroid autoimmunity (Hashimoto’s disease) caused by damage done to the thyroid gland by antithyroglobulin and antimicrosomal auto-antibodies.
     The increased prevalence of hypothyroidism and thyroid autoimmunity (TAI) in women is likely the result of a combination of genetic factors, estrogen-related effects and chromosome X abnormalities. This having been said, there is significantly increased incidence of thyroid antibodies in non-pregnant women with a history of infertility and recurrent pregnancy loss and thyroid antibodies can be present asymptomatically in women without them manifesting with overt clinical or endocrinologic evidence of thyroid disease. In addition, these antibodies may persist in women who have suffered from hyper- or hypothyroidism even after normalization of their thyroid function by appropriate pharmacological treatment. The manifestations of reproductive dysfunction thus seem to be linked more to the presence of thyroid autoimmunity (TAI) than to clinical existence of hypothyroidism and treatment of the latter does not routinely result in a subsequent improvement in reproductive performance.
     It follows, that if antithyroid autoantibodies are associated with reproductive dysfunction they may serve as useful markers for predicting poor outcome in patients undergoing assisted reproductive technologies.
     Some years back, I reported on the fact that 47% of women who harbor thyroid autoantibodies, regardless of the absence or presence of clinical hypothyroidism, have activated uterine natural killer cells (NKa) cells and cytotoxic lymphocytes (CTL) and that such women often present with reproductive dysfunction. We demonstrated that appropriate immunotherapy with IVIG or intralipid (IL) and steroids, subsequently often results in a significant improvement in reproductive performance in such cases.
     The fact that almost 50% of women who harbor antithyroid antibodies do not have activated CTL/NK cells suggests that it is NOT the antithyroid antibodies themselves that cause reproductive dysfunction. The activation of CTL and NK cells that occurs in half of the cases with TAI is probably an epiphenomenon with the associated reproductive dysfunction being due to CTL/NK cell activation that damages the early “root system” (trophoblast) of the implanting embryo. We have shown that treatment of those women who have thyroid antibodies + NKa/CTL using IL/steroids, improves subsequent reproductive performance while women with thyroid antibodies who do not harbor NKa/CTL do not require or benefit from such treatment.

     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
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     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!