Ask Our Doctors

Dear Patients,

I created this forum to welcome any questions you have on the topic of infertility, IVF, conception, testing, evaluation, or any related topics. I do my best to answer all questions in less than 24 hours. I know your question is important and, in many cases, I will answer within just a few hours. Thank you for taking the time to trust me with your concern.

– Geoffrey Sher, MD

Fill in the following information and we’ll get back to you.

Name: Jessi W

Hello! I was wondering what requirements you have for the surrogates that your patients might work with if they choose the gestational surrogacy route. Is there an age limit or BMI limit? Would a surrogate who had diet-controlled gestational diabetes be someone that can be reviewed and approved? Is there a limit on the number of deliveries or c-sections they’ve had? Any sort of guidelines that your patients need to keep in mind for potential surrogates would be super helpful. Thank you so much!

Answer:

Of course all the factors you mention and many more are part of the screening process. Also, I advocate that you meet with the surrogate.

IVF surrogacy involves the transfer of one or more embryos into the uterus of a surrogate, who provides a host womb and carries the baby to term, but does not contribute genetically to the baby. Typically, the intended mother provides the eggs and her partner (the intended father) provides the sperm. However, at times eggs and/or sperm may be derived from gamete donors. While ethical, moral, and medico‑legal issues still apply, IVF surrogacy appears to have gained social acceptance. We offer IVF surrogacy as an option at Sher Fertility Solutions (SFS().

Candidates for IVF surrogacy can be divided into two groups: (1) women who are not capable of carrying a pregnancy to full term due to: their uterus having been surgically removed (hysterectomy), disease, or developmental absence of the uterus (from birth) and (2) women who have been advised against undertaking a pregnancy because of systemic illnesses such as diabetes, heart disease, hypertension, etc.

As in preparation for other assisted reproductive techniques, the biological/intended parents, the surrogate and/or donors undergo a thorough clinical, psychological, and laboratory assessment prior to embarking on the process. The purpose is to exclude sexually transmitted diseases that might damage eggs, sperm and embryos, or be carried to the surrogate with embryo transfer. They are also counseled on issues faced by all IVF participants such as the possibility of multiple gestation, miscarriage and ectopic pregnancy.

All legal issues pertaining to custody and the rights of the biological parents and the surrogate should be discussed in detail and the appropriate consent forms completed following full disclosure. We recommend that the surrogate and biological/intended parents get separate legal counsel to avoid any conflict of interest that could arise were one attorney to counsel both parties.

Selecting a Surrogate

Couples with the necessary financial resources will usually retain a surrogacy agency to find a suitable IVF surrogacy candidate. We direct our patients to reputable surrogacy agencies who have access to quality surrogates. Because the surrogate gives birth, it is rarely possible or even realistic for her to remain anonymous.

Since recruiting a gestational surrogate from an agency can be very expensive, many infertile couples who qualify for IVF surrogate parenting solicit the assistance of empathic friends or family members to act as surrogates.

Other couples independently seek surrogates by advertising in the media.

Screening the Surrogate

Once the surrogate has been selected, she will undergo thorough medical and psychological evaluations, including:

  1. Cervical cultures and/or blood tests to screen for infection with sexually transmitted bacteria such chlamydia, ureaplasma, gonococcus and syphilis or viruses such as cytomegalic virus, HIV, HTLV, and hepatitis.
  2. A variety of blood‑hormone tests, such as the measurement of plasma prolactin and thyroid‑stimulating hormone (TSH) and tests to ensure that the surrogate is immune to the development of rubella (German measles).
  3. Physical evaluation
  4. Psychological assessment

When friends or family members serve as IVF surrogates they should be be carefully assessed to ascertain whether they might have been coerced to participate. This is especially important when a young family member is being recruited.

The surrogate should also be counseled on issues such as risks and consequences of multiple pregnancies. Such discussions should include agreement on the number of embryos to be transferred and the delicate issue of selective pregnancy reduction , in the event of a high order multiple pregnancy (triplets or greater).

The surrogate should visit with her designated IVF physician who should take her medical history and perform a thorough physical examination. Thereupon she should have a full consultation with the nurse coordinator charged with oversight of her treatment. The coordinator will outline the exact IVF-surrogacy process step by step, will make certain that the surrogate understands that she has full right of access to the clinic staff and that her concerns will be addressed promptly at all times. The surrogate should also be informed that if pregnancy occurs, she will be referred to a qualified obstetrician or perinatologist for prenatal care and delivery.

Once a viable pregnancy is confirmed by ultrasound recognition of a fetal heartbeat (at the 6th-7th week), there is a better than 85% chance that the pregnancy will proceed normally to term. Once the pregnancy has progressed beyond the 12th week, the chance of a healthy baby being born is upward of 95%.

At Sher Fertility Solutions (SFS), depending on the age of the egg provider (under 39 years) and her having normal ovarian reserve, we would anticipate approximately a 40%-50% birthrate every time good quality advanced embryos (expanded blastocysts) are transferred. The birthrate falls with further advancement in the age of the egg provider and with diminishing ovarian reserve. It is important to note that there is no convincing evidence to suggest an increase in the incidence of spontaneous miscarriage or birth defects as a direct result of IVF surrogacy.

If the surrogate’s blood pregnancy tests are negative, treatment with estrogen, progesterone and corticosteroids is discontinued, and she can expect to menstruate within four to 10 days. In the event that the pregnancy test is positive, estrogen, progesterone and steroid therapy are continued till the 10th week of pregnancy.

After the evaluation and counseling of both the couple and the surrogate has been completed, the three parties should meet. And, once all the evaluations have been completed, the intended parents will select a date to begin treatment.

Synchronizing the Cycles of Surrogate and Aspiring Mother

Both the surrogate and the egg provider are placed on monophasic birth control pills (BCP) for 10-25 days. The objective ist to insure that they both start menstruating around the same date so as to launch their cycle of treatment together. Thus the duration that each would remain on the BCP will depend on the desired timing of the start of the IVF treatment cycle. At some point while taking the BCP, both parties will overlapped the BCP with a GnRH agonist (GnRHa) such as Lupron for a period of approximately 2-3 days, whereupon the BCP will be stopped and the Lupron continued. Menstruation will follow (in both) within a few days.

At this point the egg provider begins controlled ovarian stimulation (COS) with gonadotropins while the IVF surrogate commences corticosteroid (dexamethasone or prednisone) therapy and either, twice weekly injections of estradiol valerate (Delestrogen) or daily estradiol skin patches. Blood estradiol measurements are taken twice weekly and the dosage of administered estradiol is adjusted so as to attain a blood estradiol level of between 500 and 1,000pg/ml. Then, as soon as the egg provider (based on hormonal testing and ultrasound follicle assessment) receives the hCG “trigger shot” the surrogate starts receiving daily intramuscular progesterone injections ( while continuing estradiol therapy). In the case of day 3 embryo transfers, this continues for 4 days prior to the embryo transfer and in the case of blastocyst transfers, for 6 days.

Preimplantation Genetic Sampling (PGS) Selection-the Ideal Approach for Gestational Surrogacy

PGS of embryos via next generation gene sequencing (NGS) requires that the woman’s IVF cycle be broken into two parts – the first involving stimulation, egg retrieval, fertilization, and removal of a cell from the embryo for testing. Because CGH testing requires 4-5 weeks to obtain results, the embryos are frozen while the testing is performed on the removed cell. The woman then returns at a later date for her embryo transfer. We call this process “Staggered IVF “. The same approach to ET can be used with gestational surrogacy and the same 60+% birth rate can be anticipated when CGH-normal embryos are transferred. In fact, Staggered IVF lends itself to Gestational Surrogacy because it is possible in this way to completely segregate the ovarian stimulation process from the ET. This allows couples seeking gestational surrogacy to delay identifying and recruiting a surrogate until they are assured of having “competent” embryos available for transfer.

Management and Follow‑up after the Embryo Transfer

Following embryo transfer, the surrogate will be given daily progesterone injections and bi-weekly estradiol valerate injections and/or suppositories in order to sustain an optimal environment for implantation. Approximately 10 days after the embryo transfer, she will undergo a pregnancy test. A positive test indicates that implantation is taking place. In such an event, the hormone injections will be continued for an additional four to six weeks. In the interim, an ultrasound examination will be performed to definitively diagnose a clinical pregnancy. If the test is negative, all hormonal treatment is discontinued, and menstruation will ensue within three to 10 days. If the surrogate does not conceive, the aspiring mother may have her remaining embryos frozen, to be thawed and transferred to the uterus of the surrogate at a later date. If, in spite of both the initial attempt and subsequent transfer of thawed embryos the surrogate does not conceive, the infertile couple may schedule a new cycle of treatment.

Toward the Bioethics of IVF Surrogacy

The determination of ethical guidelines has not kept pace with the exploding growth and development in IVF. However, some leaders in the field are working together, sharing experiences and advice, in an attempt to formulate a code of ethics.

The genetic combination of the male and the female provide two of the essential elements which, along with gestation, are necessary to produce a human being. The two‑out‑of‑three rule basically looks at these three elements: the egg, the sperm, and the gestational component. If at all possible, I recommend that at least two of these three components be contributed by the intended parents. If they can only contribute one, it is important to make every effort not to have the other two contributed by the same person (i.e., the egg provider should not also be the surrogate) as this can cause a variety of problems.

 PH: 702-533-2691 for online consultation with me.

Name: Cassidy C

Just wondering if you see any pitfalls in doing a simple oestrogen/progesterone protocol. I asked about adding in prednisolone, as a precaution. But the clinic is not keen using steroid medications- such as prednisolone, in patients who do not necessarily need it can cause more harm than good and also due to the nature of steroid medications there is a lot of side effects of these medications so would not be a light decision to start them. Its strikes me that approach can vary so much from clinic to clinic… my approach would be to throw everything at it now, minimise the number of collections/transfers needed and cost, i.e take the steroids in case you body see the embryo as an alien object it needs to reject. Would you mind confirming that the oestrogen/progesterone approach stands a good chance of working… I ovulate, produced some euploids and no known issues.

Many thanks & best wishes to you!!!

Answer:

Perhaps we should talk!

702-533-2691

Name: Olga M

Good afternoon dear doctor! I am 42 years old, after 8 hormonal stimulations, I have a single mosaic embryo. Blastocyst 7 days. I need to decide an important question whether to transfer it or not. Embryo seq(3)x1~2,(6)x1~2. Mosaic monosomy of chromosome 3 (mosaic level 40%) and chromosome 6 (mosaic level 30%). Female. Doctor, please help. Thank you!

Answer:

I would not advise using this embryo!

 

 

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. More than 15 years ago, we 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.

Many IVF programs that offer PGS/PGT-A 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, a  growing  body of 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/PGT-A 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/PGT-A-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, 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’s sake) advising prenatal genetic testing in the event that a pregnancy results.

What should be done with “mosaic embryos? While the ability to identify “mosaicism” through karyotyping of embryos has vastly improved, it is far from being absolutely reliable. In fact, I personally have witnessed a number of healthy/normal babies born after the transfer of aneuploid embryos, previously reported on as revealing no evidence of “mosaicism”.  However, the question arises as to which “mosaic” embryos are capable of autocorrecting in-utero and propagating viable pregnancies. Research suggests that that embryos with autosomal monosomy very rarely will propagate viable pregnancies. Thus, it is in my opinion virtually risk-free to transfer embryos with monosomies involving up to two (2) autosomes. The same applies to the transfer of trisomic embryos where up to 2 autosomes are involved. Only here, there is a risk of birth defects (e.g. trisomy 21/18, etc.) and any resulting pregnancies need to be carefully assessed and if needed/desired, be ended. Regardless, it is essential to make full disclosure to the patient (s), and to ensure 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. Blastocysts with aneuploidies involving > 2 autosomes  are complex abnormal and should in my opinion, be discarded.

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.

  • A Fresh Look at the Indications for IVF
  • The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
  • Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
  • IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
  • The Fundamental Requirements For Achieving Optimal IVF Success
  • Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
  • Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
  • 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.
  • Hereditary Clotting Defects (Thrombophilia)
  • Blastocyst Embryo Transfers done 5-6 Days Following Fertilization are Fast Replacing Earlier day 2-3 Transfers of Cleaved Embryos.
  • Embryo Transfer Procedure: The “Holy Grail in IVF.
  • Timing of ET: Transferring Blastocysts on Day 5-6 Post-Fertilization, Rather Than on Day 2-3 as Cleaved Embryos.
  • IVF: Approach to Selecting the Best Embryos for Transfer to the Uterus.
  • Fresh versus Frozen Embryo Transfers (FET) Enhance IVF Outcome
  • Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
  • 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 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.

 

 

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ADDENDUM: PLEASE READ!!

INTRODUCING SHER FERTILITY SOLUTIONS (SFS)

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

 

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

 

PLEASE SPREAD THE WORD ABOUT SFS!

 

Geoff Sher

 

Name: Cassidy C

Hello Dr Sher!

I’ve taken this drug to treat thrush, 150mg.

I’m getting my period is 8 days and am planning to start FET protocol – but I’ve since read that it’s not a safe drug to take when trying to conceive.
It can stay in the system up to 7 days, does that mean I should be ok to start FET next cycle / should I wait another month?

Many thanks!!

Answer:

THERE WOULD IN MY OPINION BE NO PROBLEM!

Name: tammy S

i’m 40 years old,my AHM is 0.89. i was undergoing an ivf which failed. they got 6 eggs,5 mature,i embryo was slowly groing ending up not sticking after transfering.
later the doctir told me they examined my eggs and came to conclusion that they were post mature.
i was stimmed from the second day of my cycle with gonal-f (225) at mirning,and gonal f (225) and Luveris (225) at evening for 6 days, then gonal f 4450 one shot and luverus 225 at tge 7th day,day 8 triggered ,orgalutran 250 at morning and burselin 1000 and ovidrel 250 at night. next day no med.
day 10 was retrieval
what do you suggest,i found you very informative regarding the best protocol for my cases.

thanks alot

Answer:

It is primarily the egg (rather than the sperm) that determines the chromosomal integrity (karyotype) of the embryo, the most important determinant of egg/embryo competency”. A “competent” egg is therefore one that has a normal karyotype and has the best potential to propagate a “competent” embryo. In turn, a “competent embryo is one that possesses the highest potential to implant and develop into a normal, healthy, baby.

When it comes to reproductive performance, humans are the least efficient of all mammals. Even in young women under 35y, at best only 2 out of 3 eggs are chromosomally numerically normal (euploid). The remainder will have an irregular number of chromosomes (aneuploid) and are thus “incompetent”. The incidence of egg aneuploidy increases with age such by age 39 years, 3 in 4 are “competent”, and by the mid-forties, at best one in 10 are likely to be aneuploid. The fertilization of an aneuploid egg will inevitably lead to embryo aneuploidy (“incompetence”). As previously stated,   an aneuploid embryo cannot propagate a normal pregnancy

Within 38-42 hours of the initiation of the spontaneous pre-ovulatory luteinizing hormone (LH) surge (and also following administration of the human chorionic gonadotropin (hCG) “trigger” shot, given to induce egg maturation after ovarian stimulation with fertility drugs), the egg embarks on a rapid maturational process that involves halving of its 46 chromosomes to 23. During this process, (known as meiosis) 23 chromosomes are retained within the nucleus of the egg while the remaining 23 chromosomes are expelled in a membrane envelopment, from the egg nucleus. This small structure known as the polar body, comes to lie immediately below the “shell” of the egg (the zona pellucida) and is known as the 1st polar body or PB-1. The sperm, in the process of its maturation also undergoes meiosis divides into two separate functional gametes, each containing 23 chromosomes (half its original number of 46 chromosomes).  With subsequent fertilization, the 23 chromosomes of the egg now fuse with the 23 chromosomes of the mature sperm resulting in the development of an embryo with  46 chromosomes (the normal human genome) comprising a combination of the genetic material from both partners. For the embryo to have exactly 46 chromosomes (the euploid number), both the mature egg and mature spermatozoon must contain exactly 23 chromosomes. Only such euploid embryos are “competent” (capable of developing into healthy babies). Those with an irregular number of chromosomes (aneuploid embryos) are “incompetent” and are incapable of propagating healthy babies. While embryo “incompetence” can result from either egg or sperm aneuploidy, it usually stems from egg aneuploidy. However, in cases of moderate or severe male factor infertility, the sperm’s contribution to aneuploidy of the embryo can be significantly greater.

While embryo ploidy (numerical chromosomal integrity) is not the only determinant of its “competency, it is by far the most important and in fact is a rate-limiting factor in human reproduction. It is causal in the vast majority of cases of “failed nidation which in turn is responsible for most cases of a failed pregnancy (natural or assisted) and causes most sporadic early pregnancy losses (both chemical gestations and miscarriages) as well as  many chromosomal birth defects such as Turner syndrome (X-monosomy ) Down syndrome (trisomy 21) and Edward syndrome (trisomy 18) .

In most cases, embryos that develop too slowly as well as those that grow too fast (i.e. ones that by day 3 post-fertilization comprise fewer than 6 cells or more than 9 cells) and/or embryos that contain cell debris or “fragments” are usually aneuploid and are thus unable to propagate a healthy pregnancy (“incompetent”). Additionally, embryos that fail to survive in culture to the blastocyst stage are also almost always aneuploid/”incompetent”.

At a certain point in the later stage of a woman’s reproductive career, the number of remaining eggs in her ovaries falls below a certain threshold, upon which she is unable to respond optimally to fertility drugs. Often times this is signaled by a rising day 3 basal blood follicle stimulating hormone (FSH) level (>9.0MIU/ml) and a falling blood anti-Mullerian hormone (AMH) level (<2.0ng/ml or <15nmol/L). Such women who have  diminished ovarian reserve (DOR) produce fewer eggs in response to ovarian stimulation. While DOR is most commonly encountered in women over 40 years of age it can and indeed also can occur in much younger women.

A few important (but often overlooked concepts should be considered in this regard:

  • Age: It is advancing chronologic age and NOT declining ovarian reserve (as evidenced by abnormal blood AMH or FSH that results in an increased incidence of egg/embryo “incompetence” due to aneuploidy
  • The ovaries and developing eggs of women with DOR (regardless of age) are highly susceptible to the adverse effect of excessive Luteinizing Hormone (LH)-induced, ovarian overproduction of male hormones (e,g. testosterone and androstenedione). While a little testosterone produced by the ovary promotes normal follicle growth and orderly egg development excessive testosterone has a converse effect. That is why in older women and those who regardless of their age have DOR (and thus excessive LH bioavailability and increased ovarian testosterone production), the use of ovarian stimulation protocols that fail to down-regulate LH activity prior to initiating ovarian stimulation with gonadotropins, often prejudices egg/embryo quality and IVF outcome.
  • Simply stated, while age is certainly the most important factor in determining the incidence of egg/embryo aneuploidy, women with DOR (regardless of their age), are less likely to propagate euploid (competent) eggs/embryos. While virtually nothing can be done to lower the incidence of age related aneuploidy, it is indeed possible to avoid a further decrease in egg/embryo “competency”  by individualizing the protocols of ovarian stimulation used.
  • My preferred protocols for women who have relatively normal ovarian reserve:
  • The conventional long pituitary down regulation protocol: BCP are commenced early in the cycle and continued for at least 10 days. Starting 3 days before the BCP is to be discontinued, it is overlapped with an agonist such as Lupron 10U daily for three (3) days and continued until menstruation begins (which should ensue within 5-7 days of stopping the BCP). At that point an US examination is done along with a baseline measurement of blood estradiol to exclude a functional ovarian cyst. Daily Lupron (10U) is continued and an FSH-dominant gonadotropin such as Follistim, Puregon or Gonal-f daily is administered daily falong with 37.5U of Menopur (an FSH/LH combination) for 2 days. On the 3rd day the gonadotropin dosage is reduced by about one half and the dosage of Menopur is increased to 75U daily. Daily ultrasound and blood estradiol measurements are conducted starting on the 7th or 8th day of gonadotropin administration and continued until daily ultrasound follicle assessments indicate that most follicles have fully developed. At this point egg maturation is “triggered” using an intramuscular injection of a recombinant hCGr (Ovidrel) 500mcg or urinary derived hCGu (Pregnyl/Profasi/Novarel) 10,000U. And an egg retrieval is scheduled for 36h later.
  • The agonist/antagonist conversion protocol (A/ACP): This is essentially the same as the conventional long down regulation protocol (see “a”-as above), except that with the onset of post-BCP menstruation, the agonist is supplanted by daily administration of a GnRH antagonist (e.g. Ganirelix, Cetrotide or Orgalutron) at a dosage of 125-250mcg daily until the day of the “trigger”. When it comes to women who have DOR I favor the use of the A/ACP, adding supplementary human growth hormone (HGH). In cases where the DOR is regarded as severe (AMH=<0.2), I often augment  the AACP protocol by using estrogen priming for 7-9 days prior to or with the commencement of gonadotropin therapy; For this I prescribe E2 skin patches  or intramuscular  estradiol valerate (Delestrogen), prior to or sometimes concurrent with, the  commencement of the GnRH antagonist administration.
  • The following Ovarian stimulation protocols are in my opinion best avoided in stimulating olderf women and /or thosed who regardless of age , have  DOR :
  1. Microdose agonist (e.g. Lupron) “flare” protocols which result in an out-pouring of pituitary-LH at the critical time that ovarian follicles and eggs start developing/growing.
  2. High dosages of LH -containing fertility drugs (e.g. Menopur).
  3. Supplementation with preparations that are testosterone-based
  4. Supplementation with DHEA (which is converted to testosterone in the ovaries.
  5. Clomiphene citrate or Letrozole which cause increased release of LH and thus increase ovarian male hormone (testosterone and androstenedione output.
  6. “Triggering” egg maturation using too low a dosage of hCG (e.g. 5,000U rather than 10,000U) or Ovidrel (e.g. 250mcg of Ovidrel rather than 500mcg)
  7. “Triggering” women who have DOR, with an agonist (alone)such as Lupron Superfact/ Buserelin/Aminopeptidyl/Decapeptyl.
  • Preimplantation Genetic Screening (PGS):

The introduction of preimplantation genetic testing/screening (PGT/PGS) for e permits identification of all the chromosomes in the egg and embryo (full karyotyping) allowing for the  identification of the most “competent” (euploid) embryos for selective transfer to the uterus. This vastly improves the efficiency and success of the IVF process and renders us fare better equipped us to manage older women and those who regardless of their age, have DOR.

Name: Katharine C

Dear Dr. Sher,
I’ve been following your comments for years. Thanks for the info. on 2 shots of Ovidrel. I’m interested in what you say here about Hoshimoto’s and what you call “Immunologic Implantation Dysfunction.” You mention that 50% of women (with or without Hoshimoto’s/full-blown hypothyroidism) will have this IDD due to the thyroid anti-bodies. Is this your hypothesis or is this based on a study you have done or data that you are aware of? Do you have any material I could see apart from this one case? How did you arrive at the 50%? Is speculative wisdom from what you’ve witnessed at your own practice? I’m a huge admirer, but I’m honestly confused as to where this information is coming from. Would love to know! Many thanks, Katharine

Answer:

I published on this 25y ago.

Sher G, Maassarani G, Zouves C, Feinman M, Sohn S, Matzner W, Chong P, Ching W. “The use of Combined Heparin/Aspirin and Immunoglobulin G. Therapy in the Treatment of IVF Patients with Antithyroid Antibodies” Am J Repr Immunol, 1998; 39:223-5.

Name: Isma B

Hi Dr Sher

I have been trying to conceive for 3 years now with no success. I’ve recently had 1 failed ivf cycle where I began bleeding 7 days post embryo transfer. Which I believe is implantation failure.

I have a history of heavy painful periods, stomach problems such as diarrhea and bloating, mid cycle bleeding (i spot randomly at any point during the cycle and it feels like having a mini period as i spot and have pain at the same time), painful ovulation. I suspect that I have endometriosis however my doctor refused to investigate further and said I only have hormonal imbalance. However, I have heard that endometriosis and estrogen dominance go hand in hand.

A year before pursuing ivf, I had a hysteroscopy which showed that I didn’t have any polyps and my uterus is normal. My question to you is that can you detect endometriosis with hysteroscopy and should I continue to push my doctor for endometriosis diagnosis.

I also want to ask you that I suffer from allergies such as hayfever, does this make my immune system overactive and creates more natural killer cells?

Answer:

often advised to first try ovarian stimulation (ovulation Induction) with intrauterine insemination (IUI) ………as if to say that this would be just as likely to result in a baby as would in vitro fertilization (IVF). Nothing could be further from reality It is time to set the record straight. And hence this communication!

Bear in mind that the cost of treatment comprises both financial and emotional components and that it is the cost of having a baby rather than cost of a procedure. Then consider the fact that regardless of her age or the severity of the condition, women with infertility due to endometriosis are several fold more likely to have a baby per treatment cycle of IVF than with IUI. It follows that there is a distinct advantage in doing IVF first, rather than as a last resort.

So then, why is it that ovulation induction with or without IUI is routinely offered proposed preferentially to women with mild to moderately severe endometriosis? Could it in part be due to the fact that most practicing doctors do not provide IVF services but are indeed remunerated for ovarian stimulation and IUI services and are thus economically incentivized to offer IUI as a first line approach? Or is because of the often erroneous belief that the use of fertility drugs will in all cases induce the release (ovulation) of multiple eggs at a time and thereby increase the chance of a pregnancy. The truth however is that while normally ovulating women (the majority of women who have mild to moderately severe endometriosis) respond to ovarian stimulation with fertility drugs by forming multiple follicles, they rarely ovulate > 1 (or at most 2) egg at a time. This is because such women usually only develop a single dominant follicle which upon ovulating leaves the others intact. This is the reason why normally ovulating women who undergo ovulation induction usually will not experience improved pregnancy potential, nor will they have a marked increase in multiple pregnancies. Conversely, non-ovulating women (as well as those with dysfunctional ovulation) who undergo ovulation induction, almost always develop multiple large follicles that tend to ovulate in unison. This increases the potential to conceive along with an increased risk multiple pregnancies.

 

So let me take a stab at explaining why IVF is more successful than IUI or surgical correction in the treatment of endometriosis-related infertility:

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

 

 

 I am not suggesting that all women with infertility-related endometriosis should automatically resort to IVF. Quite to the contrary…. In spite of having reduced fertility potential, many women with mild to moderate endometriosis can and do go on to conceive on their own (without treatment). It is just that the chance of this happening is so is much lower than normal.

IN SUMMARY: For young ovulating women (< 35 years of age ) with endometriosis, who have normal reproductive anatomy and have fertile male partners, expectant treatment is often preferable to IUI or IVF. However, for older women, women who (regardless of their age) have any additional factor (e.g. pelvic adhesions, ovarian endometriomas, male infertility, IID or diminished ovarian reserve-DOR) IVF should be the primary treatment of choice.

 

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

  • The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
  • Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
  • IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation (COS)
  • The Fundamental Requirements For Achieving Optimal IVF Success
  • Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
  • Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF:
  • The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 1-Background
  • Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 2- Making a Diagnosis
  • Immunologic Dysfunction (IID) & Infertility (IID): PART 3-Treatment
  • Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
  • Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management: (Case Report)
  • Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
  • Intralipid (IL) Administration in IVF: It’s Composition; how it Works; Administration; Side-effects; Reactions and Precautions
  • Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
  • Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas
  • Should IVF Treatment Cycles be provided uninterrupted or be Conducted in 7-12 Pre-scheduled “Batches” per Year
  • A personalized, stepwise approach to IVF
  • How Many Embryos should be transferred: A Critical Decision in IVF?
  • Endometriosis and Immunologic Implantation Dysfunction (IID) and IVF
  • Endometriosis and Infertility: Why IVF Rather than IUI or Surgery Should be the Treatment of Choice.
  • Endometriosis and Infertility: The Influence of Age and Severity on Treatment Options
  • Early -Endometriosis-related Infertility: Ovulation Induction (with or without Intrauterine Insemination) and Reproductive Surgery Versus IVF
  • Treating Ovarian Endometriomas with Sclerotherapy.
  • Effect of Advanced Endometriosis with Endometriotic cysts (Endometriomas) on IVF Outcome & Treatment Options.
  • Deciding Between Intrauterine Insemination (IUI) and In Vitro Fertilization (IVF).
  • Intrauterine Insemination (IUI): Who Needs it & who Does Not: Pro’s &
  • Induction of Ovulation with Clomiphene Citrate: Mode of Action, Indications, Benefits, Limitations and Contraindications for its use
  • Clomiphene Induction of Ovulation: Its Use and Misuse!

 

 

 

______________________________________________________

ADDENDUM: PLEASE READ!!

INTRODUCING SHER FERTILITY SOLUTIONS (SFS)

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

 

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

 

PLEASE SPREAD THE WORD ABOUT SFS!

 

Geoff Sher

 

Name: Charlotte D

Dear Dr Sher,

I recently had a baseline scan and oestrogen and progesterone blood tests for an upcoming FET cycle. The scan and blood tests identified a 2.5cm hormone-producing simple cyst on my left ovary. I have been prescribed 21 days of Provera (2 x 10mg tablets daily), which I’m told usually resolves these cysts. How long does it normally take for simple cysts of this size to resolve? Is this course of Provera likely to resolve the cyst within 3 weeks?

Thank you!

Answer:

Yes! It is likely to cause the functional cyst to absorb by the next period!

An ovarian cyst is any collection of fluid, surrounded by a very thin wall, within an ovary. An ovarian follicle that is larger than 22mm is termed a functional follicular cyst. They are non-malignant (benign) and harmless and in most cases, don’t even cause symptoms, however, in some cases, rapid distention of the cyst , or rupture with bleeding , can lead to sudden and severe pain and in some cases, a disruption in hormone balance leads to vaginal bleeding.

 

There are 2 varieties of “functional ovarian cysts:

  1. Follicle Cysts: In menstruating women, a follicle containing the unfertilized egg will rupture during ovulation. If this does not occur, a follicular cyst of more than 2.5 cm diameter may result. These cysts develop in response to stimulation with follicle stimulating hormone that is either self-produced (by the woman’s own pituitary gland (endogenous) or is induced by agonists (e.g. Lupron/Decapeptyl/Buserelin) that sometimes propagate increased and sustained pituitary FSH release.
  2. Corpus luteum cysts: These appear after ovulation or egg retrieval. The corpus luteum is the remnant of the follicle after the ovum has moved to the fallopian tubes. It usually degrades within 5-9 days. A corpus luteum of > 3 cm is regarded as being cystic.

 

A:Follicular cysts: These lesions have special relevance in women about to undergo controlled ovarian stimulation (COS) with gonadotropins for IVF where they can literally, “throw a spanner in the works”, causing a delay, postponement and sometimes even cancellation of the cycle of treatment.

 

Functional Ovarian cysts must be distinguished from “non-functional or cystic ovarian tumors”. By definition, “tumors are capable of independent growth.  Thus “cystic ovarian tumors do not develop as a result of exposure to gonadotropin stimulation and it is this feature that distinguishes them from “functional” ovarian cysts.

 

Aside from sometimes causing pain and dysfunctional uterine bleeding, unruptured follicular cysts are usually relatively non-problematic. As stated above, in some cases, functional “cysts” undergo rapid distention (often as a result of a minor degree of bleeding inside the cyst itself). In such cases the woman will often experience a sharp or aching pain on one or other side of her lower abdomen and/or deep seated pain during intercourse. The cysts may even rupture, causing sudden lower abdominal pain that exacerbates and may even simulate an attack of acute appendicitis or a ruptured ectopic (tubular) pregnancy. While very unpleasant, a ruptured “functional cyst” seldom produces a degree of internal bleeding that warrants surgical intervention. The pain, typically is made worse by movement. It stabilizes within a number of days but subsides progressively to disappear within about four to seven days.

 

Whenever an ovarian cyst is detected (usually by ultrasound examination), the first consideration should be to determine whether it is a “functional cyst or a “cystic ovarian tumor”. The reason for this is that tumors are subject to a variety of complications such as twisting (torsion), hemorrhage, infection and even malignant change, all of which usually will require surgical intervention.

 

Gonadotropin releasing hormone agonists (GnRHa) such as Lupron, Buserelin, Nafarelin and Synarel, administered daily, starting a few days prior to menstruation, all elicit an initial and rapid, out-pouring (“surge”) in pituitary LH and FSH release. This “surge” lasts for a day or two. Then as the pituitary reservoir of FSH and LH becomes depleted, the blood FSH and LH levels fall rapidly reaching near undetectable blood levels within a day or two. At the same time, the declining FSH result in a drop in blood E2 concentration leading to a withdrawal bleed (menstruation). The progressive exhaustion of Pituitary FSH/LH along with the decline in blood E2, is referred to as ” down-regulation” The continued daily administration of GnRHa or its replacement (supplanting)  with a GnRH antagonist (e.g. Ganirelix, Cetrotide or Orgalutron) results in blood LH concentrations being sustained at a very low level throughout the ensuing cycle of controlled ovarian hyperstimulation (COH) with gonadotropins, thereby optimizing follicular maturation and promoting E2 induced endometrial proliferation.

 

Functional follicular cysts resulting from controlled ovarian stimulation (COS), can occur regardless of whether down regulation with GnRHa (Lupron/Buserelin/Decapeptyl) is initiated in cases where the cycle of stimulation is launched with the woman coming off  a BCP or when the agonist is initiated on day 20-23  (the mid luteal phase) of a natural cycle. When this happens it is due to the initial agonist-induced FSH “surge” sometimes so accelerating follicular growth that it leads to the development of one or more “functional follicular cysts”. These cysts release E2 and cause the blood E2 often to remain elevated (>70pg/ml). Depending on the extent of this effect, it sometimes leads to a delay in the onset of menstruation and thus also to deferment in the initiation of COS.

 

Failure of menstruation to commence within 4-7 days of initiating treatment with GnRHa suggestive of an underlying “functional ovarian cyst” and calls for an ultrasound examination to make the diagnosis. Once diagnosed, depending upon the number and size of cysts detected. There are two therapeutic options:

  • Wait for the cyst to absorb spontaneously and for menstruation to ensue: While it at first might seem that this approach of continuing GnRHa therapy in order to cause absorption of the cyst(s) within a week or two might be a good approach , it often has unintended consequences. First there is the real possibility that prolonged uninterrupted GnRHa therapy might blunt subsequent ovarian follicular response to gonadotropin therapy and second, if menstruation does not follow within 10-14 days, the cycle will usually need to be cancelled.
  • Immediate needle aspiration of the cyst(s) under local anesthesia. I personally favor needle aspiration, sooner rather than later in such cases. Menstruation will usually follow a successful aspiration within 2-4 days. Upon menstruation a blood E2 level is measured and as soon as it drops below 70pg/ml COS can be initiated.

 

  1. Corpus Luteum cysts: As with follicular cysts, so at times do Corpus Luteum cysts also bleed, distend and cause fain. They often delay onset of spontaneous menstruation by a week or longer (Halban syndrome”.). In isolated cases, internal bleeding within the cyst substance causes pain, rapid enlargement of the lesion and by ultrasound examination reveals local areas of absorption causing it to appear as a “complex” cystic lesion that simulates a tumor, prompting surgical intervention. Sadly, there are countless cases where women have had an entire ovary removed due to this happening.

 

“Functional ovarian cysts” rarely present as a serious health hazard. In the vast majority of cases they spontaneously resolve within 2-4 weeks while “cystic tumors” will not. Accordingly, the persistence of any ovarian cyst that persists for longer than 4 weeks should raise suspicion of it being a tumor rather than with a “functional cyst”. Since ovarian tumors can be (or become) malignant, all ovarian cysts that persist for longer than 6 weeks (whether occurring in non-pregnant or pregnant women), should be considered for surgical removal and this should be followed by pathological analysis.

Good luck!

 

Geoff Sher

Name: Patrick R

We have an extra embryo to donate to another couple or science. What are our options?

Answer:

Please call 646-792–7476 and ask for Bushra Sudal RN. She will be glad to assist you.

Name: Jimena A

Good day Dr. Geoffrey,
I salute you from Mexico City. I’m in the mieddle of the preparatios for the FET, and I want to know what should the maximium estradiol levels be at the day before my FET. Today I’m on day 13 of my cycle and my endometrium is meassuring 9 mm.
Thank you very much for your time. Best regards,
Jimena

Answer:

I prescribe twice weekly injections of estradiol valerate (Delestrogen). Using this approach, I aim for peak E2 values ranging between 500 and 1000pg/ml!

Good luck!

 

 

Name: Jacqueline S

Hello. I am writing today to inquire about your services. I am 36 years old. I have 2 healthy boys (4 years old and 2 years old). I have had 2 miscarriages in a row while trying to get pregnant with my 2nd son. I seemingly do not have fertility issues. However, my husband and I are interested in IVF for our third so that we can better balance our family and reduce our risk of miscarrying again. I know you typically help patients with fertility issues, so I wanted to inquire about whether or not you would be able to help families like ours and the cost to do so. Thank you.

Name: Esther L

Hi Dr. Sher, I am asking this question after first egg retrieval. I am 40 years old, first time doing this IVF. I saw about 23 follicles during ultrasound and was on 21 days lupron protocol ended with 20 eggs, 13 matured, 10 fertilized and 6 became 6 days blastocysts. After pgta I got results as follows: one low level mosaic trisomy 22, 1 high level complex mosaic, three abnormal and one chaos. I currently have 7 years old daughter and trying for the 2nd baby. My first child was conceived naturally. My amh was 4.2. I am preparing for the 2nd egg retrieval. Can do anything differently. I eat healthy, taking all coq10, vit D, prenatal, calcim magnesium, dha, dhea(25mg only one pill) vit c and nac. I walk every other day. Do I have a hope to have good embryos next cycle. I am very healthy no disease illnesses in the past. Thank u.

Answer:

The importance of the IVF stimulation protocol on egg/embryo quality cannot be overstated. This factor seems often to be overlooked or discounted by t IVF practitioners who use a “one-size-fits-all” approach to ovarian stimulation. My experience is that the use of individualized/customized COS protocols can greatly improve IVF outcome. While no one can influence underlying genetics or turn back the clock on a woman’s age, any competent IVF specialist should be able to tailor the protocol for COS to meet the individual needs of the patient.

Gonadotropins (LH and FSH), whether produced by the pituitary gland or administered by way of fertility drugs, have different “targeted” sites of action in the ovary. FSH targets cells that line the inner wall of the follicle (granulosa cells) and also form the cumulus cells that bind the egg to the inner surface of the follicle. Granulosa cells are responsible for estrogen production.

LH, on the other hand, targets the ovarian connective tissue (stroma/theca) that surrounds ovarian follicles resulting in the production of male hormones such as testosterone (predominantly), androstenedione and DHEA. These androgens are then transported to the granulosa cells of the adjacent follicles in a “bucket brigade fashion”. There FSH converts testosterone to estradiol, causing granulosa cells to multiply (proliferate) and produce estradiol, follicles to  grows and eggs to develop (ovogenesis) It follows that  ovarian androgens (mainly testosterone) is absolutely indispensable to follicle/ egg growth and development.

However, the emphasis is on a “normal” amount of testosterone. Over-exposure of the follicle to testosterone can in my opinion,  compromise egg development and lead to an increased likelihood of chromosomal irregularities (aneuploid) following LH/hCG-induced egg maturational division (meiosis) and compromise embryo “competency/quality.

Ovarian androgens can also reach the uterine lining where they sometimes will compromise estrogen receptor -induced endometrial growth and development.

A significant percentage of  older women and those who have diminished ovarian reserve (DOR) have increased LH activity is increased. Such women either over-produce LH and/or the LH produced is far more biologically active. Chronically increased LH activity leads to overgrowth of ovarian connective tissue (stroma/theca). This condition, which is often referred to as Stromal Hyperplasia or hyperthecosis can result in  excessive ovarian androgen/testosterone production and poorer egg-embryo quality/competency, Similarly, women with polycystic ovarian syndrome (PCOS), also characteristically have Stromal hyperplasia/hyperthecosis due to chronically increased LH activity. Thus they too often manifest with increased ovarian androgen production. It is therefore not surprising that “poor egg/embryo quality” is often also a feature of PCOS.

In my opinion, the over-administration of LH-containing menotropins such as Menopur, [which is comprised of roughly equal amount of FSH and   hCG ,which acts similar to LH)], to older women, women with DOR and those who have PCOS can also lead to reduced egg/embryo competency . Similarly, drugs such as clomiphene or Letrozole that cause the pituitary gland to release excessive amounts of LH, are also potentially harmful to egg development and in my opinion, are best omitted from IVF COS protocols. This is especially the case when it comes to older women and those with DOR, who in my opinion should preferably be stimulated using FSH-dominant products such as Follistim, Puregon, Fostimon and Gonal-F. 

Gonadotropin releasing hormone agonists (GnRHa): GnRHa such as Lupron, Buserelin, Superfact, Gonopeptyl etc. are often used to launch ovarian stimulation cycles. They act by causing an initial outpouring followed by a depletion of pituitary gonadotropins. This results in LH levels falling to low concentrations, within 4-7 days, thereby establishing a relatively “LH-free environment”. When GnRHa are administered for about 7 days prior to initiating gonadotropin stimulation (“long” pituitary down-regulation”), the LH depletion that will exist when COS is initiated, will usually be protective of subsequent egg development. In contrast, when the GnRHa administration commences along with the initiation of gonadotropin therapy, there will be a resultant immediate surge in the release of pituitary LH with  the potential to increase ovarian testosterone to egg-compromising levels , from the outset of COS. This, in my opinion could be particularly harmful when undertaken in older women and those who have DOR.

GnRH-antagonists such as Ganirelix, Cetrotide and Orgalutron, on the other hand, act very rapidly (within hours) to block pituitary LH release. The purpose in using GnRH antagonists is to prevent the release of LH during COS. In contrast, the LH-lowering effect of GnRH agonists develops over a number of days.

GnRH antagonists are traditionally given, starting after  5th -7th day of gonadotropin stimulation. However, when this is done in older women and those (regardless of age) who have DOR, LH-suppression might be reached too late to prevent the deleterious effect of excessive ovarian androgen production on egg development in the early stage of ovarian stimulation. This is why, it is my preference to administer GnRH-antagonists, starting at the initiation of gonadotropin administration.

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.

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

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

 

 

______________________________________________________

ADDENDUM: PLEASE READ!!

INTRODUCING SHER FERTILITY SOLUTIONS (SFS)

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

 

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

 

PLEASE SPREAD THE WORD ABOUT SFS!

 

Geoff Sher

 

 

 

 

Name: Elona K

Hi Dr. Sher,

Just following up from my last question regarding my 14mm follicle on day 15 when I had a LH surge… isn’t this too small of a follicle for a surge to happen meaning an immature/eggless follicle? I thought a mature follicle must reach a minimum of 17mm in order for a surge to occur. Mine was only 14mm. We did try but I want to be realistic with my expectations. Is there any way to treat this going forward if this continues to happen? Thanks!

Answer:

My response was based upon he suspicion that this 14mm follicle was actually 18mm + a day or so before and the reduction in size was due to partial ovulation.

 

 

Name: Elona K

Hi Dr.Sher,

I am doing an investigative cycle through my fertility clinic this month. Yesterday was my day 15 and on ultrasound I had a dominant follicle measuring 14mm. It was growing at a rate of 1mm per day since day 10. The nurse informed me that based on the size of the follicle that I should expect my lh to surge later this week. I got home a few hours after doing my ultrasound (and bloodwork) and the nurse called to say that my bloodwork results just came in and I was having a surge.
I am of course devastated as everything I have read states that the follicle must be at least 18 mm in order for a surge to happen. And as mine was only 14mm at the time of the surge, the follicle most likely did not contain an egg or if it did it was immature. My husband and I tried last night anyway. Any insight or advice would be greatly appreciated. I am 39, have PCOS and have had RPL (all very early before 6 weeks). Are there any drugs to help with this?

Answer:

The most likely explanation is that when (on day 15 the 14mm follicle was seen, ovulation had already commenced!

 

 

Name: Maryam F

Im looking to have a girl for my third pregnancy after having 2 boys. I have had no fertility issue and for both my kids I got pregnant in my first try. Do you have any gender selection service? Like IUI or IVF?

Answer:

Couples have for centuries sought to influence the gender of their offspring. More than seven centuries ago the ancient Chinese developed a birth calendar said to be able to predict gender on the basis of when conception occurred. Later, the ancient Greeks suggested that by lying on her right side during intercourse, a woman could improve the likelihood of having a male child. And 300 years ago, the French suggested that placing a ligature around the right testicle would improve the chance of having a male child.

More recently in the U.S., methods such as timing intercourse, assuming different positions during sex, and (relatively recently) employing rapid sperm centrifugation in an attempt to separate male chromosome-bearing sperm from female sperm prior to artificial insemination were proposed. The fact is that none of these (as well as many other) such anecdotal assertions have been shown to have any real validity.

Currently, in spite of several well described medical approaches, the indisputable fact has emerged that it is only by way of IVF that reliable sex selection can be achieved. This allows for embryos to be screened for gender through preimplantation genetic diagnosis prior to transferring the embryo(s) of the desired gender to the uterus.

Nevertheless, it is an inescapable reality that the very idea of medical sex selection challenges moral and ethical beliefs at their very foundation. Many hold that the growing popularity of gender selection solely for the convenience of altering a family’s gender balance represents an unwanted example of how assisted reproductive technology is subject to abuse…and thus it should be outlawed. They also see it as an example of a disturbing trend towards “designer babies” where genetic engineering could be used to manipulate the intellect, body configuration, build, height, and the talents of future offspring. This assertion is commonly followed by the tantalizing question as to where all this would end and whether we as a society “would really want to live in such a world.”

 

There is, however, one clear exception to the apparent across-the-board opposition to sex selection that is well worthy of mention. This applies in cases where sex selection is used to avoid the occurrence of a serious medical disorder that selectively affects one gender or the other (e.g., Hemophilia, a life threatening bleeding disorder that selectively affects male offspring).

 

EVALUATING CURRENTLY USED METHODS FOR SEX SELECTION

 

SPERM GRADIENT METODOLOGY (discredited because of a lack of reliability)

 

This is one of the simplest methods that still (unfortunately) remains in widespread use. Here sperm is rapidly spun down (centrifuged) in the hope of separating the male sperm (those with Y-chromosomes) from the female sperm (those with X-chromosomes). It relies on the assumption that the X chromosome makes sperm heavier, allowing for separation of male from female chromosome-bearing sperm. Though this method is often touted as a low cost method for sex selection, the truth is that it simply does not work!

 

LOW CYTOMETRIC TESTING BY THE MICROSORT METHOD (discredited because of a lack of reliability)

This method which is now somewhat discredited by the FDA  employedthe use of a fluorescent dye that adheres to genetic material within the sperm. It was based on the premise that because X-bearing sperm contain more genetic material, these sperm were supposed to pick up more dye than Y-bearing sperm. Thereupon, X and Y bearing sperm are then separated into two groups and used for intrauterine insemination (IUI) or IVF. This method was touted as yielding a 60% to 70% accuracy rate with IUI. This has not been adequately confirmed and in my personal experience its reliability in the IVF setting has been questionable to say the least. The Microsort technique is to my knowledge not presently being offered in the United States.

IVF using PREIMPLANTATION GENETIC DIAGNOSIS (PGD)

Preimplantation Genetic Diagnosis (PGD) involves the removal of one or more cells from an embryo, for chromosomal or genetic analysis.  The most widely used and he most reliable PGD method for gender selection is fluorescence in-situ-hybridization (FISH). However, this technique does not identify all 23 pairs of chromosomes in the embryo’s cells. At best it can well identify 12. Thus, while FISH provides an excellent method for gender selection and for identification of structural chromosomal aberrations, it is not a reliable method for diagnosing embryo aneuploidy (“competency”).  Conversely, another PGD method, next generation gene sequencing (NGS) which does assess all the embryo’s chromosomes can be used for both detecting all the embryo’s chromosomes and thus can determine embryo “competency” reliably. It also reliably identifies gender. However, while NGS is very bit as reliable as FISH for gender selection, FISH can be done in fresh cycles (i.e. the ET is done in the same cycle as that in which the ER is done), while NGS requires time for testing that requires Staggered IVF (St-IVF) in which the embryos are biopsied on day 3 or day 5-6 (post-fertilization) and  the blastocysts are ultrarapidly frozen (vitrified) and allowed to proceed in culture to blastocysts whereupon they are ultra-rapidly frozen (vitrified) and are then held for transfer in a subsequent cycle. 

Upon completion of FISH, which takes about 24-36 hours, the couple can select which embryo(s) they will transfer to the uterus. If pregnancy results, there is almost a 100% chance it will result in the desired gender. If NGS is used, the degree of accuracy in diagnosing gender, is as reliable as is FISH but in addition, NGS provides information on the entire karyotype (all 23 pairs of chromosomes) which is extremely beneficial because it assesses embryo “competency, while FISH does not.

 

A PERSONAL OPINION:

Sex selection done purely for  family balancing is somewhat  controversial, raising concern that if  widely accessible and freely available, such practice could distort the natural sex ratio, leading to a population gender imbalance. However, for this to happen, there would have to be a significant population preference for sex selection. In reality, the contrary seems to apply, since studies conducted in western societies discount these concerns. In fact, the relatively high cost of IVF with the added cost of gender selection in the United States makes it unlikely that the demand would ever become large enough to impact overall population gender balance. In addition, several studies done in Western countries have shown that the majority of people do not seem to be concerned about the gender of their offspring, and that with a few notable exceptions, gender preference does not appear to be slanted in the direction of either male or female. Thus, from a practical standpoint, such concerns are overstated.

Given that in the United States most couples do not care about the gender of their offspring, and only a minority are interested in selecting the sex of their children there is currently  no risk that IVF sex-selection will impact the population gender balance. Thus, in  my opinion by and large,  freedom of choice should prevail and a service for sex selection should be freely available

 So, in my personal practice, I absolutely do offer gender selection in the following circumstances.

  • Medical Indications for Gender Selection:
    • For cases associated with
      • sex-linked genetic disorders or,
      • serious genetic disorders that are more likely to occur in one gender or the other.
    • Non-Medical Family balancing
      • For couples who have at least one child of the opposite gender to that which they choose for their IVF embryo transfer and,
      • For those women who do not have any children at all but prefer to have a child of one or the other gender.
    • Geoff Sher :
    • Call 702-533-2691 for an online consultation

Name: Kristine S

Hello Dr. Sher, I can only imagine how busy you are so I will try to make this question as brief and concise as possible. I just turned 39. Currently 5wks pregnant (naturally conceived–was told it was an impossibility by RE). I have Graves disease and Hashimotos. History of two miscarriages around 8wks (healthy heartbeats, good HCG, thyroid levels near optimal). I have two living children through fertility (2018 and 2020). My last loss was in May 2022; my first was in 2020 around the time I was diagnosed with Hashimotos. I strongly suspect my losses were due to my immune diseases. I also suspect I will need, at minimum, prednisone (potentially LDN?) to calm my immune response in order to prevent a subsequent loss. I realize I’m working against the clock as my pregnancy advances. I am learning that there are waiting lists everywhere (understandably) and lab results can take weeks. I’m looking for ANY advice here. I live in rural Johnson City TN where there are few specialists or drs who know much about immune diseases and particularly how they influence pregnancy. If you have any referral options, if you have an opening in your schedule, or know of any physicians who have a baseline knowledge of autoimmue responses I would LOVE any help I can get! THANK YOU for you time.

Answer:

I am so happy for you. The fact that you have had 2 children with this underlying autoimmune condition, suggests that you are of the50% of women who have thyroid antibodies but do not have activated uterine natural killer cells. If so, this pregnancy could be safe. Besides, any autoimmune therapy for NKa+ needs to start at least 10 days prior to conception.

Hang in there and keep me in the loop!

Good luck!

 

Geoff Sher

Name: Ola

Dear Dr. Sher,

Do you recommend Sildenafil 4x 25mg/day during the follicular phase or only when the embryo transfer is scheduled?
Do you recommend Sildenafil although there are no previous evidences of lack of thickening of the endometrial walls?

Thank you

Answer:

Yes…only in the follicular phase but not in the absence of an endometrial thickness issue!

Geoff Sher

Name: Vanessa A

I need your advice. I have had two failed embryo transfers. I had my embryos PGT tested and they were normal and very high-quality embryos. I am 37 years old with no underlining health conditions. But maternal history of endometriosis. I have not been diagnosed with this. The second transfer my doctor place me on Lupron for three months. It was ineffective. I have in asking for natural killer cells labs because I watch your videos. I am waiting for the results.

My question is, what if I have elevated NK cells?

My current doctor does not have any solution as to why my second transfer did not work and does not know what she should do for the next protocol.

Dr. Sher, from the research I have done on you, you have so much more knowledge on specialty fertility in cases where women cannot have a successful pregnancy. I would appreciate if you can give me some guidance and advice thank you for your time.

Answer:

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.

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
•Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
•Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF:
•The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 1-Background
•Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 2- Making a Diagnosis
•Immunologic Dysfunction (IID) & Infertility (IID): PART 3-Treatment
•Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
•Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management 🙁 Case Report)
•Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
•Intralipid (IL) Administration in IVF: It’s Composition how it Works Administration Side-effects Reactions and Precautions
•Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
•Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas
•Should IVF Treatment Cycles be provided uninterrupted or be Conducted in 7-12 Pre-scheduled “Batches” per Year
•A personalized, stepwise approach to IVF
•How Many Embryos should be transferred: A Critical Decision in IVF?
•Endometriosis and Immunologic Implantation Dysfunction (IID) and IVF
•Endometriosis and Infertility: Why IVF Rather than IUI or Surgery Should be the Treatment of Choice.
•Endometriosis and Infertility: The Influence of Age and Severity on Treatment Options
•Early -Endometriosis-related Infertility: Ovulation Induction (with or without Intrauterine Insemination-IUI) and Reproductive Surgery Versus IVF
•Treating Ovarian Endometriomas with Sclerotherapy.
•Effect of Advanced Endometriosis with Endometriotic cysts (Endometriomas) on IVF Outcome & Treatment Options.
•Deciding Between Intrauterine Insemination (IUI) and In Vitro Fertilization (IVF).
•Intrauterine Insemination (IUI): Who Needs it & who Does Not: Pro’s &
•Induction of Ovulation with Clomiphene Citrate: Mode of Action, Indications, Benefits, Limitations and Contraindications for its use
•Clomiphene Induction of Ovulation: Its Use and Misuse!

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

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

PLEASE SPREAD THE WORD ABOUT SFS!

Geoff Sher

Name: Ola

Dear Dr. Sher,

I would like to ask you about DUO stim protocol for women with DOR. Is it OK to have double stim within the same menstruation cycle?
I have DOR, endometriosis stage 1, MTHFR, 35 yrs old and 12 chemical pregnancies.
I want to continue with your protocol A/ACP with HGH but just came across this one DUO stim in the clinic where I am thinking of doing IVF NGS.
Thank you very much

Answer:

Respectfully,

I am not a protagonist of Duo-stimulations. In my opinion it can compromise follicle development as well a jeopardize egg/embryo “competency”.

Geoff Sher

Name: Elies E

Dear Doctor,

I saw your video on internet and I noticed that you master very well my case.
I have very low ovarian reserve Amh=0.4
So I live in France and I want to came and have an ivf protocol with you.

Thank you very much

Answer:

Thank you!

If you wish to consult with me online, please contact my assistant, Patti Converse at 702-533-2691.

When it comes to reproductive performance, humans are the least efficient of all mammals. Even in young women under 35y, at best only 1 out of 2 eggs are chromosomally numerically normal (euploid). The remained have an irregular number of chromosomes (aneuploid) and are thus “incompetent”. The incidence of egg aneuploidy increases with age such by age 39 years, 3 in 4 are competent, and by the mid-forties, less 8 to 9 out of 10 are aneuploid. The fertilization of an aneuploid egg will inevitably lead to embryo aneuploid and an aneuploid embryo cannot propagate a normal pregnancy

Within hours of the spontaneous pre-ovulatory luteinizing hormone (LH) surge, and also following administration of the human chorionic gonadotropin (hCG) “trigger” shot (given to induce ovulation after ovarian stimulation with fertility drugs), the egg embarks on a rapid maturational process that involves halving of its 46 chromosomes to 23. During this process, (known as meiosis) 23 chromosomes are retained within the nucleus of the egg while the remaining (now redundant) 23are expelled, enveloped by a thin membrane. This small structure comes to lie immediately below the “shell” of the egg (the zona pellucida) and is known as the 1st polar body or PB-1. The spermatozoon, in the process of its maturation also undergoes meiosis at which time it too reduces its chromosomes by half. Thus in the process of fertilization the sperm divides into two separate functional gametes, each containing 23 chromosomes such that with subsequent fertilization, the 23 chromosomes in the egg, fuse with the 23 chromosomes of the mature sperm resulting in the development of an embryo that has 46 chromosomes (the normal human genome) comprising a combination of the genetic material from both partners.
For the embryo to have exactly 46 chromosomes (the euploid number), both the mature egg and mature spermatozoon must contain exactly 23 chromosomes. Only euploid embryos are “competent” (capable of developing into healthy babies). Those with an irregular number of chromosomes (aneuploid embryos) are “incompetent” and are incapable of developing into healthy babies. While embryo “incompetence” can result from either egg or sperm aneuploidy, it usually stems from egg aneuploidy. However, in cases of moderate or severe male factor infertility, the sperm’s contribution to aneuploidy of the embryo increases significantly.
While embryo ploidy (numerical chromosomal integrity) is not the only determinant of its “competency, it is by far the most important and in fact is rate-limiting factor in human reproduction. It is causal in most cases of “failed implantation” which in turn is responsible for most cases of failed IVF. It causes early miscarriages and is responsible for many chromosomal birth defects such as X-monosomy and Down’s syndrome. . In most cases, embryos that develop too slowly as well as those that grow too fast (i.e. ones that by day 3 post-fertilization comprise fewer than 6 cells or more than 9 cells) and/or embryos that contain a large amount of cell debris or “fragments” are usually aneuploid and are thus “incompetent”. Additionally, embryos that fail to survive in culture to the blastocyst stage are also almost always aneuploid/”incompetent”. At a certain point in the later stage of a woman’s reproductive career, the number of remaining eggs in her ovaries falls below a certain threshold, upon which she is unable to respond optimally to fertility drugs. Often times this is signaled by a rising day 3 blood follicle stimulating hormone (FSH) level. Such women with diminishing ovarian reserve produce fewer eggs in response to ovarian stimulation. While diminished ovarian reserve is most commonly encountered in women over 40 years of age it can and indeed sometimes does occur in much younger women. A few important (but often overlooked concepts should be considered in this regard: 1. Age: It is advancing chronologic age and NOT declining ovarian reserve (as evidenced by abnormal blood AMH or FSH that results in an increased incidence of egg/embryo “incompetence” due to aneuploidy 2. DOR: The ovaries and developing eggs of women with diminished ovarian reserve (regardless of age) are highly susceptible to the adverse effect of excessive Luteinizing Hormone (LH)-induced overproduction of male hormones (mainly testosterone). A little testosterone produced by the ovary promotes normal follicle growth and orderly egg development but too much testosterone has the opposite effect. That is why (especially in women with diminished ovarian reserve who often have high LH and increased ovarian testosterone production , the use of ovarian stimulation protocols that fail to down-regulate LH production prior to initiating stimulation with gonadotropins, often prejudices egg/embryo quality and IVF outcome. Simply stated, while age is certainly the most important factor in determining the incidence of egg/embryo aneuploidy, women with diminished ovarian reserve (regardless of their age), unless they receive customized/individualized protocols of ovarian stimulation are less likely to propagate euploid (competent) eggs/embryos.

Selection of the ideal protocol for controlled ovarian stimulation: While NOTHING can be done to lower the incidence of age-related aneuploidy, it is indeed possible to avoid a further increase in egg/embryo aneuploidy by individualizing the protocols of ovarian stimulation used.

My Preferred Protocols .

a) The conventional long pituitary down regulation protocol: BCP are commenced early in the cycle and continued for at least 10 days. Starting 3 days before the BCP is to be discontinued, it is overlapped with an agonist such as Lupron 10U daily for three (3) days and continued until menstruation begins (which should ensue within 5-7 days of stopping the BCP). At that point an US examination is done along with a baseline measurement of blood estradiol to exclude a functional ovarian cyst. Simultaneously, the Lupron dosage is reduced to 5U daily and an FSH-dominant gonadotropin such as Follistim, Puregon or Gonal-f daily is commenced for 2 days. On the 3rd day the gonadotropin dosage is reduced and a small amount of daily menotropin (Menopur 75U daily) is added. Daily ultrasound and blood estradiol measurements are done starting on the 7th or 8th day of gonadotropin administration and continued until daily ultrasound follicle assessments indicate that most follicles have fully developed. At this point egg maturation is “triggered” using an intramuscular injection of 10,000U hCG. And an egg retrieval is scheduled for 36h later.

b) The agonist/antagonist conversion protocol (A/ACP): This is essentially the same as the conventional long down regulation protocol (as above), except that with the onset of post-BCP menstruation, the agonist is supplanted by daily administration of a GnRH antagonist (e.g. Ganirelix, Cetrotide or Orgalutron) at a dosage of 125mcg daily until the day of the hCG trigger
When it comes to women who have DOR I favor the use of the A/ACP, adding supplementary human growth hormone (HGH). In some cases where the DOR is regarded as severe, I also augment the process with estrogen priming, preferring twice weekly intramuscular administration of estradiol valerate (Delestrogen), starting with the commencement of antagonist injection and continuing for 1 week before commencing gonadotropins and continued until the hCG “trigger. I further recommend that such women be offered access to preimplantation genetic screening (PGS) for4 embryo selection and in some cases, for embryo banking (stockpiling). This is followed in a later hormone replacement cycle with the selective transfer of up to two (2) PGS-normal, euploid blastocysts. In this way we are able to capitalize on whatever residual ovarian reserve and egg quality might still exist and thereby “make hay while the sun still shines” , significantly enhancing the opportunity to achieve a viable pregnancy
The following Ovarian Stimulation Protocols which in my Opinion best Avoided:
a) Microdose agonist (e.g. Lupron) “flare” protocols
b) High doses of LH/hCG-containing fertility drugs (E.G. Menopur).
c) Protocols that incorporate supplementation with male hormones (e.g. testosterone)
d) Supplementation with DHEA
e) Clomiphene citrate or Letrozole which cause an elevation in LH and thus increase ovarian male hormone (testosterone and androstenedione output.
f) “Triggering” egg maturation using too low a dosage of hCG (e.g. 5,000U rather than 10,000U) or Ovidrel e.g. 250mcg of Ovidrel rather than 500mcg)
g) “Triggering” women who have large numbers of follicles using an agonist such as Lupron, Superfact or Buserelin.
Preimplantation Genetic Screening (PGS):
The introduction of preimplantation genetic screening (PGS) for the first time permits identification of all the chromosomes in the egg and embryo such that we can now far better identify “competent” (euploid) embryos for selective transfer to the uterus. This vastly improves the efficiency and success of the IVF process. This additional tool has better equipped us to manage cases with DOR. In my opinion, next generation gene sequencing (NGS), currently represents the most reliable method for performing PGS

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

•IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS) Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
•Egg Banking
•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)
•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): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
• Embryo Banking/Stockpiling: Slows the “Biological Clock” and offers a Selective Alternative to IVF-Egg Donation.
•Preimplantation Genetic Screening (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.
•Embryo Mosaicism”: Are Some Chromosomally Abnormal Embryos Capable of Resulting in Normal Babies and Being Wrongly Discarded?
•How Many Embryos should be transferred: A Critical Decision in IVF.
•Premature Luteinization (“the premature LH surge): Why it happens and how it can be prevented.