Ask Our Doctors – Archive
Our Medical Directors are outstanding physicians that you will find to be very personable and compassionate, who take care to ensure that you have the most cutting-edge fertility treatments at your disposal. This is your outlet to ask your questions to the doctors.
Dear Doc , I’m a 42 and a half woman – no children, healthy, sporty willing to have my first baby with my partner. I live in France and believe France is a bit behind when it comes to AMP – this is why I’m contacting you. I have the choice btw doing my first and only ifv with my own egg in May since I’m turning 43 in June : amh 1.25 / fsh : 7.97 / lh : 11.10 / estradiol : 45. I got pregnant at 32 and had a medical aborption since my partner did not want to have the baby- got pregnant on a pill. Would you recommend a long or short protocole?
Thanks
Since this will be your ONLY attempt and you are 43y of age with a an AMH is 1.25ng/ml, you are not likely to propagate many eggs of which (at best) about 1: 10 are likely to be be chromosomally normal, I would strongly suggest IVF wsith egg donation.
Egg donation is the process by which a woman donates eggs for purposes of assisted reproduction or biomedical research. For assisted reproduction purposes, egg donation typically involves in vitro fertilization (IVF) technology, with the eggs being fertilized in the laboratory, unfertilized eggs may be frozen and stored for later use. Egg donation is a third party reproduction as part of assisted reproductive technology (ART).
For many women, disease and/or diminished ovarian reserve precludes achieving a pregnancy with their own eggs. Since the vast majority of such women are otherwise quite healthy and physically capable of bearing a child, egg donation (ED) provides them with a realistic opportunity of going from infertility to parenthood.
Egg donation is associated with definite benefits. Firstly, in many instances, more eggs are retrieved from a young donor than would ordinarily be needed to complete a single IVF cycle. As a result, there are often supernumerary (leftover) embryos for cryopreservation and storage. Secondly, since eggs derived from a young woman are less likely than their older counterparts to produce aneuploid (chromosomally abnormal) embryos, the risk of miscarriage and birth defects such as Down’s syndrome is considerably reduced.
Egg Donation-related, fresh and frozen embryo transfer cycles account for 10%-15% of IVF performed in the United States. The vast majority of egg donation procedures performed in the U.S involve women with declining ovarian reserve. While some of these are done for premature ovarian failure, the majority are undertaken in women over 40 years of age. Recurrent IVF failure due to “poor quality” eggs or embryos is also a relatively common indication for ED in the U.S. A growing indication for ED is in cases of same-sex relationships (predominantly female) where both partners wish to share in the parenting experience by one serving as egg provider and the other, as the recipient.
Ninety percent of egg donation in the U.S is done through the solicitation of anonymous donors who are recruited through a state-licensed egg donor agency. It is less common for recipients to solicit known donors through the services of a donor agency, although this does happen on occasion. It is also not easy to find donors who are willing to enter into such an open arrangement. Accordingly, in the vast majority of cases where the services of a known donor is solicited, it is by virtue of a private arrangement. While the services of non-family members are sometimes sought, it is much more common for recipients to approach close family members to serve as their egg donor.
Some recipients feel the compulsion to know or at least to have met their egg donor, so as to gain first hand familiarity with her physical characteristics, intellect, and character. This having been said, in the U.S. it is much more common to seek the services of anonymous donors. In terms of disclosure to their family, friends and child(ren), recipients using anonymous donors tend to be far more open than those of known donors about the nature of the child’s conception. Most, if not all, egg donor agencies provide a detailed profile, photos, medical and family history of each prospective donor for the benefit and information of the recipient. Agencies generally have a website through which recipients can access donor profiles in the privacy of their own homes in order to select the ideal donor.
Interaction between the recipient and the egg donor program may be conducted in-person, by telephone or online in the initial stages. Once the choice of a donor has been narrowed down to two or three, the recipient is asked to forward all relevant medical records to their chosen IVF physician. Upon receipt of her records, a detailed medical consultation will subsequently held and a physical examination by the treating physician or by a designated alternative qualified counterpart is scheduled. This entire process is usually overseen, facilitated and orchestrated by one of the donor program’s nurse coordinators who, in concert with the treating physician, will address all clinical, financial and logistical issues, as well as answering any questions. At the same time, the final process of donor selection and donor-recipient matching is completed.
Egg donor agencies usually limit the age of egg donors to women under 35 years with normal ovarian reserve in an attempt to minimize the risk of ovarian resistance and negate adverse influence of the “biological clock” (donor age) on egg quality.
No single factor instills more confidence regarding the reproductive potential of a prospective egg donor than a history of her having previously achieved a pregnancy on her own, or that one or more recipients of her eggs having achieved a live birth. Moreover, such a track record makes it far more likely that such an ED will have “good quality eggs”. Furthermore, the fact that an ED readily conceived on her own lessens the likelihood that she herself has tubal or organic infertility. This having been said, the current shortage in the supply of egg donors makes it both impractical and unfeasible, to confine donor recruitment to those women who could fulfill such stringent criteria for qualification.
It is not unheard of for a donor who, at some point after donating eggs, finds herself unable to conceive on her own due to pelvic adhesions or tubal disease, to blame her infertility on complications caused by the prior surgical egg retrieval process. She may even embark upon legal proceedings against the IVF physician and program. It should therefore come as no surprise that it provides a measurable degree of comfort to ED program when a prospective donor is able to provide evidence of having experienced a relatively recent, trouble free spontaneous pregnancy.
Screening of Donors
Genetic Screening: The vast majority of IVF programs in the U.S. follow the recommendations and guidelines of the American Society of Reproductive Medicine (ASRM) for selectively genetic screening of prospective egg donors for conditions such as sickle cell trait or disease, thalassemia, cystic fibrosis and Tay Sachs disease, when medically indicated. Consultation with a geneticist is available through about 90% of programs.
Most recipient couples place a great deal of importance on emotional, physical, ethnic, cultural and religious compatibility with their chosen egg donor. In fact they often will insist that the egg donor be heterosexual.
Psychological Screening: Americans tend to place great emphasis on psychological screening of egg donors. Since most donors are “anonymous,” it is incumbent upon the ED agency or the IVF program to determine the donor’s degree of commitment as well as her motivation for deciding to provide this service. I have on occasions encountered donors who have buckled under the stress and defaulted mid-stream during their cycle of stimulation with gonadotropins. In one case, a donor knowingly stopped administering gonadotropins without informing anyone. She simply awaited cancellation, which was effected when follicles stopped growing and her plasma E2 concentration failed to rise.
Such concerns mandate that assessment of donor motivation and commitment be given appropriate priority. Most recipients in the U.S. tend to be very much influenced by the “character” of the prospective egg donor, believing that a flawed character is likely to be carried over genetically to the offspring. In reality, unlike certain psychoses such as schizophrenia or bipolar disorders, character flaws are usually neuroses and are most likely to be determined by environmental factors associated with upbringing. They are unlikely to be genetically transmitted. Nevertheless, egg donors should be subjected to counseling and screening and should be selectively tested by a qualified psychologists. When in doubt, they should be referred to a psychiatrist for more definitive testing. Selective use of tests such as the MMPI, Meyers-Briggs and NEO-Personality Indicator are used to assess for personality disorders. Significant abnormalities, once detected, should lead to the automatic disqualification of such prospective donors.
When it comes to choosing a known egg donor, it is equally important to make sure that she was not coerced into participating. We try to caution recipients who are considering having a close friend or family member serve as their designated egg donor, that in doing so, the potential always exists that the donor might become a permanent and an unwanted participant in the lives of their new family.
Drug Screening: Because of the prevalence of substance abuse in our society, we selectively call for urine and/or serum drug testing of our egg donors.
Screening for STDs: FDA and ASRM guidelines recommend that all egg donors be tested for sexually transmittable diseases before entering into a cycle of IVF. While it is highly improbable that DNA and RNA viruses could be transmitted to an egg or an embryo through sexual intercourse or IVF, women infected with viruses such as hepatitis B, C, HTLV, HIV etc, must be disqualified from participating in IVF with egg donation due to the (albeit remote) possibility of transmission, as well as the potential legal consequences of the egg donation process being blamed for their occurrence.
In addition, evidence of prior or existing infection with Chlamydia or Gonococcus introduces the possibility that the egg donor might have pelvic adhesions or even irreparably damaged fallopian tubes that might have rendered her infertile. As previously stated, such infertility, subsequently detected might be blamed on infection that occurred during the process of egg retrieval, exposing the caregivers to litigation. Even if an egg donor or a recipient who carries a sexually transmittable viral or bacterial agent is willing to waive all rights of legal recourse, a potential risk still exists that a subsequently affected offspring might in later in life sue for wrongful birth.
Screening of the Recipient
Medical Evaluation: while advancing age, beyond 40 years, is indeed associated with an escalating incidence of pregnancy complications, such risks are largely predicable through careful medical assessment prior to pregnancy. The fundamental question namely: “is the woman capable of safely engaging a pregnancy that would culminate in the safe birth of a healthy baby” must be answered in the affirmative, before any infertility treatment is initiated. For this reason, a thorough cardiovascular, hepatorenal, metabolic and anatomical reproductive evaluation must be done prior to initiating IVF in all cases.
Infectious Screening: the need for careful infectious screening for embryo recipients cannot be overemphasized. Aside from tests for debilitating sexually transmittable diseases, there is the important requirement that cervical mucous and semen be free of infection with ureaplasma urealyticum. This organism which rarely causes symptoms frequents the cervical glands of 15-20% of women in the U.S. The introduction of an embryo transfer catheter via a so infected cervix might transmit the organism into an otherwise sterile uterine cavity leading to early implantation failure and/or first trimester miscarriage.
Immunologic Screening: Certain autoimmune and alloimmune disorders (see elsewhere) can be associated with immunologic implantation dysfunction (IID). In order to prevent otherwise avoidable treatment failure, it is advisable to evaluate the recipient for autoimmune IDD and also to test both the recipient and the sperm provider for alloimmune similarities that could compromise implantation.
Disclosure and Consent
Preparation for egg donation requires full disclosure to all participants regarding what each step of the process involves from start to finish, as well as potential medical and psychological risks. This necessitates that significant time be devoted to this task and that there be a willingness to painstakingly address all questions and concerns posed by all parties involved in the process. An important component of full disclosure involves clear interpretation of the medical and psychological components assessed during the evaluation process. All parties should be advised to seek independent legal counsel so as to avoid conflicts of interest that might arise from legal advice given by the same attorney. Appropriate consent forms are then reviewed and signed independently by the donor and the recipient couple.
Most embryo recipients fully expect their chosen donor to yield a large number of mature, good quality eggs, sufficient to provide enough embryos to afford a good chance of pregnancy as well as several for cryopreservation (freezing) and storage. While such expectations ore often met, this is not always the case. Accordingly, to minimize the trauma of unexpected and usually unavoidable disappointment, it is essential that in the process of counseling and of consummating agreements, the respective parties be fully informed that by making best efforts to provide the highest standards of care, the caregivers can only assure optimal intent and performance in keeping with accepted standards of care. No one can ever promise an optimal outcome. All parties should be made aware that no definitive representation can or will be made as to the number or quality of ova and embryos that will or are likely to become available, the number of supernumerary embryos that will be available for cryopreservation or the subsequent outcome of the IVF donor process.
TYPES OF EGG DONATION
Conventional Egg Donation: This is the basic format used for conducting the process of egg donor IVF. It involves synchronizing the menstrual cycles of both the recipient and the donor by placing the donor and the recipient on a birth control pill so that both parties start stimulation with fertility drugs simultaneously. This ultimately allows for precise timing of the fresh embryo transfer. Using this approach, the anticipated egg donation birth rate is >50% per cycle.
Preimplantation Genetic Sampling (PGS)-Egg Donation: The recent introduction of complete numerical chromosomal assessment (karyotyping) using metaphase Comparative Genomic Hybridization (mCGH) and Next Generation Gene sequencing (NGS) has the potential to change the manner in which egg donation will be performed in the future. CGH/NGS allows full egg/embryo chromosome analysis providing a 70- 80% assurance that the embryo(s) so selected for transfer are highly likely to be “competent” (i.e. capable of producing a healthy baby). Such PGS-egg selection provides about a 50% chance of a baby per transfer of an embryo derived through fertilization of a pre-vitrified euploid egg. This is at least double that reported when conventional egg donation is used. As a result, mCGH/NGS-Egg Donation allows for excellent results when one or two embryos are transferred, virtually eliminating the risk of “high order” multiple pregnancies (triplets or greater). Moreover, since numerical chromosomal irregularities (aneuploidy) are responsible for most miscarriages, the use of CGH also significantly reduces this dreaded complication.
PGS egg selection of necessity mandates the use of Staggered (ST)- IVF. Here the egg donor cycle is divided into two parts. The first involves the egg retrieval, fertilization, embryo biopsy for PGS analysis and embryo cryostorage. The second part involving warming or thawing of the frozen embryo(s) and the subsequent transfer of “competent” embryo(s) to the recipient’s uterus is conducted electively at least several weeks later once the results of PGS testing are available. Since, with St-IVF the egg retrieval and embryo transfer are separated in time, the retrieval can be performed without first having to synchronize the menstrual cycles of the recipient and the egg the donor. In fact, the recipient does not even have to be available when the egg donor is going through cycle. All that is needed is for designated sperm to be available (fresh or frozen) on the day of egg retrieval. This avoids unnecessary travel and inconvenience, and minimizes stress and cost.
Donor Egg Banking: Another imminent advance is the introduction of egg banking. Being able to freeze and bank donor eggs would solve most of these challenges. By using PGS in combination with a egg vitrification (ultra-rapid freezing), we are now capable of improving the birth rate per warmed/thawed egg by a factor of 3-4 fold (from a previous average of <8% per egg to about 27%). Through an electronic catalogue, recipients will be able to select and purchase 1-3 CGH-normal eggs from the comfort of their homes. Thereupon, the selective transfer of 1 or 2 embryos derived from such chromosomally normal eggs could achieve a 50-60% pregnancy rate without the risk of initiating high-order multiple pregnancies in the process. Through this process, the cost, inconvenience and risks associated with “conventional” fresh egg donor cycles would also be reduced significantly.
Financial Considerations
The fee paid to the egg donor agency per cycle usually ranges between $2,000 and $8,000. This does not include the cost associated with psychological and clinical pre-testing, fertility drugs, and donor insurance, which commonly range between $3,000 and $6,000. The medical service costs of the IVF treatment cycle ranges between $8,000 and $14,000. The donor stipend can range from $2,000 too as high $50,000 depending upon the exotic requirements of the recipient couple as well as supply and demand. Thus the total out of pocket expenses for an egg donor cycle in the United States range between $15,000 and $78,000, putting egg donation outside the financial capability of most couples needing this service.
The growing gap between need and affordability has spawned a number of creative ways to try and make IVF with egg donation more affordable. Here are a few examples:
•Egg banking (see above)
•Egg Donor Sharing, where one comprehensive fee is shared between two recipients and the eggs are then divided between them. The downside is that fewer eggs are available embryos for transfer and/or cryopreservation.
•Egg Bartering, where in the course of conventional IVF, a woman undergoing IVF remits some of her eggs to the clinic (who in turn provides it to a recipient patient) in exchange for a deferment of some or all of the IVF fee. In my opinion, such an arrangement can be fraught with problems. For example, in the event that the woman donating some of her eggs fails to conceive while the recipient of her eggs does, it is very possible that she might suffer emotional despair and even go so far as to seek out her genetic offspring. Such action could be very damaging to both her and the recipient, as well as the child.
•Financial Risk Sharing. Certain IVF programs offer financial risk sharing (FRS) which most recipient couples favor greatly. FRS offers qualifying candidates a refund of fees paid if egg donation is unsuccessful. FRS is designed to spread the risk between the providers, and the recipient couple.
Moral, Legal & Ethical Considerations: The “Uniform Parentage Act” which has been adopted by most states in the United States declares that the woman who gives birth to the child will be regarded as the rightful mother. Accordingly, there has to date not been any grounds for legal dispute when it comes to maternal custody of a child born through IVF with egg donation in the majority of states. In a few states such as Mississippi and Arizona the law is less clear but nevertheless, as yet, has not been contested.
The moral-ethical and religious implications of egg donation are diverse and have a profound effect on cultural acceptance of this process. The widely held view that everyone is entitled to their own opinion and has the right to have such opinions respected, governs much of the attitude towards this process in the U.S. The extreme views on each end of the spectrum hold the gentle central swing of the pendulum in place. This attitude is a reflection of the general acceptance in the united states of diverse views and opinions and the willingness to allow free expression of such views and beliefs provided that they don’t infringe on the rights of others.
So where do we go from here? Can and should we, cryopreserve and store eggs or ovarian tissue from a young woman wishing to defer procreation until it becomes convenient? And if we do this, would it be acceptable to eventually have a woman give birth to her own sister or aunt? Can or should we store viable ovarian tissue through generations. Should egg donation simply become a future source of embryos generated for the purpose of providing stem cells, to be used in the treatment of disease states or to “manufacture” fetuses as a source of spare body parts? If the answer to even some of these questions is yes…what about the checks and balances. Who will exercise control and where what form should such control take? Are we willing to engage this slippery slope where the disregard for the dignity of the human embryo leads us to the point where the rights of a human being are more readily ignored? …………………… Personally, I hope not.
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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.
Patients are encouraged to share the information I provide, with their treating Physicians and/or to avail themselves of my personal hands-on services, provided through batched IVF cycles that I conduct every 3 months at Los Angeles IVF (LAIVF) Clinic, Century City, Los Angeles, CA.
If you wish to schedule an online consultation with me, please contact my assistant (Patti Converse) by phone (800-780-7437/702-533-2691), email (concierge@SherIVF.com) or, enroll online on then home-page of my website (www.SherIVF.com).
PLEASE SPREAD THE WORD ABOUT SFS!
Geoff Sher
Let me thank you for your prompt reply : this is highly appreciated and reassuring. I meant an Ivf with my own eggs – I am aware that egg donation would be the best possibility but even if I have 8% of success, I’d like to try with my own egg at least one. 2 doctors are ready to help me but with different protocole – one with long protocole (decaptyl, puregon 225 per day, , ovitrelle 250 & zithromax 250) and a short protocole (gonal 300, menopur 150, ganirellesse & estradiol 550). These are 2 different approaches ; I’d like to have your point on what is according to you the best one. Kind regards
I am 33 years old and was diagnosed with stage 4 endometriosis in 2016. I do not have a regular follicular phase (unpredictable and varied) but my luteal phase is always exactly 14 days.For a year prior to the surgery, I was unable to conceive. After the surgery I got pregnant 4 times, all ending in early loss. Finally, in June 2018, we did IVF, which was successful and I have a 13 month old at home. I will add that I was on heparin injections from day of egg retrieval until 10 weeks pregnant. Hoping to be like some others, I wanted to try naturally for baby number two. I was successful twice, but again, lost both early. After back tracking to all six losses, it looks like I lose them at the exact same time each time. Every single one, I start my period at 18 dpo or 4wk4d. I will note that I am always on progesterone support starting 3 days post ovulation. I’m wondering if there is something I could be doing to stop this or if IVF is just the way I Likely have to conceive? I just don’t want to keep going through heartache and stress if it will never workout naturally.
Are women with a diagnosis of autoimmune infertility more at risk of the coronavirus? I had my miracle baby 13 years ago(was a patient years ago:) Had IVIG, Lovenox, baby asa, steroids d/t elevated NK, APA, ANA(needed all the treatments;). Tested negative for thyroid disease, lupus. Had gestational DM.
Dr. Sher,
I am 40 soon to be 41. I have been ttc unsuccessfully with my partner for two years. One child from previous relationship who is 10, forceps delivery. I have hypothyroidism within good ranges for ttc, no indication of Hashimotos, my sister has Lupus, my mother hypothyroidism. My partner has low 2% semen morphology, everything else appears in good ranges, he is 48. I have had various investigations – hsgs which showed good tubal patency, no fluid in pouch of Douglas, anteverted uterus normal in size and shape, amh 7.7, triple line endometrium, small polyp in cavity or uterus. We are intending to embark on IVF, however I have recently had uterine nk testing in University of Coventry hospital by Dr. Jan Brosens, which showed that a have very low nk cells 0.27% density. My questions, what immunological protocol would you recommend? Is there any hope with such low levels of nk cells? Can you recommend any clinics in the UK who might be able to help us? I have often felt a gut instinct that there might be some immune implantation issues, however all the research I can find it about high nk cells….. please help, and thank you in advance:)
Frankly, I do not think you have an immunologic implantation dysfunction (IID). However, there are very few laboratories in UK/Europe (If any) that can perform immunologic implantation tests adequately.
Unless tests for immunologic implantation dysfunction (IID) are performed correctly and conducted by a one of the few reliable reproductive immunology reference laboratory in the United States, treatment will likely be unsuccessful. . In this regard it is most important that the right tests be ordered and that these be performed by a competent laboratory. There are in my opinion only a handful of reliable Reproductive Immunology Laboratories in the world and most are in the U.S.A. Also, it is my opinion that far too often, testing is inappropriate with the many redundant and incorrect tests being requested from and conducted by suboptimal laboratories. Finally for treatment to have the best chance of being successful, it is vital that the underlying type of IID (autoimmune IID versus alloimmune) be identified correctly and that the type, dosage, concentration and timing of treatments be carefully devised and implemented.
WHO SHOULD UNDERGO IID TESTING?
When it comes to who should be evaluated, the following conditions should in always raise a suspicion of an underlying IID, and trigger prompt testing:
•A diagnosis of endometriosis or the existence of symptoms suggestive of endometriosis (heavy/painful menstruation and pain with ovulation or with deep penetration during intercourse) I would however emphasize that a definitive diagnosis of endometriosis requires visualization of the lesions at laparoscopy or laparotomy)
•A personal or family history of autoimmune disease such as hyper/hypothyroidism (as those with elevated or depressed TSH blood levels, regardless of thyroid hormonal dysfunction), Lupus erythematosus, Rheumatoid arthritis, dermatomyositis, scleroderma etc.)
•“Unexplained” infertility
•Recurrent pregnancy loss (RPL)
•A history of having miscarried a conceptus that, upon testing of products of conception, was found to have a normal numerical chromosomal configuration (euploid).
•Unexplained IVF failure
• “Unexplained” intrauterine growth retardation due to placental insufficiency or late pregnancy loss of a chromosomally normal baby
What Parameters should be tested?
In my opinion, too many Reproductive Immunologists unnecessarily unload a barrage of costly IID tests on unsuspecting patients. In most cases the initial test should be for NK cell activation, and only if this is positive, is it necessary to expand the testing.
The parameters that require measurement include:
oFor Autoimmune Implantation Dysfunction: Autoimmune implantation dysfunction, most commonly presents with presumed “infertility” due to such early pregnancy losses that the woman did not even know she was pregnant in the first place. Sometimes there as an early miscarriage. Tests required are: a) blood levels of all IgA, IgG and IgM-related antiphospholipid antibodies (APA’s) directed against six or seven specific phospholipids, b) both antithyroid antibodies (antithyroid and antimicrosomal antibodies), c) a comprehensive reproductive immunophenotype (RIP) and, c) most importantly, assessment of Natural Killer (NK) cell activity (rather than concentration) by measuring by their killing, using the K-562 target cell test and/or uterine cytokine measurement. As far as the ideal environment for performing such tests, it is important to recognize that currently there are only about 5 or 6, Reproductive Immunology Reference Laboratories in the U.S capable of reliably analyzing the required elements with a sufficient degree of sensitivity and specificity (in my opinion).
oFor Alloimmune implantation Dysfunction: While alloimmune Implantation usually presents with a history of unexplained (usually repeated) miscarriages or secondary infertility (where the woman conceived initially and thereupon was either unable to conceive started having repeated miscarriages it can also present as “presumed” primary infertility. Alloimmune dysfunction is diagnosed by testing the blood of both the male and female partners for matching DQ alpha genes and NK/CTL activation. It is important to note that any DQ alpha match (partial or complete) will only result in IID when there is concomitant NK/CTL activation (see elsewhere on this blog).
How should results be interpreted?
Central to making a diagnosis of an immunologic implantation dysfunction is the appropriate interpretation of natural killer cell activity (NKa) .In this regard, one of the commonest and most serious errors, is to regard the blood concentration of natural killer cells as being significant. Rather it is the activity (toxicity) of NK cells that matters as mentioned. Then there is the interpretation of reported results. The most important consideration is the percentage of target cells “killed” in the “native state”. In most cases a level of >10% killing should be regarded with suspicion and >12% overtly abnormal. In my opinion, trying to interpret the effect of adding IVIG or Intralipid to the sample in order assess whether and to what degree the use of these products would have a therapeutic benefit is seriously flawed and of little benefit. Clinically relevant NK cell deactivation can only be significantly effected in vivo and takes more than a week following infusion to occur. Thus what happens in the laboratory by adding these products to the sample prior to K-562 target cell testing is in my opinion likely irrelevant.
There exists a pervasive but blatant misconception on the part of many, that the addition of Intralipid (IL) /immunoglobulin-G IVIG) can have an immediate down-regulatory effect on NK cell activity. This has established a demand that Reproductive Immunology Reference Laboratories report on NK cell activity before and following exposure to IVIG and/or IL. However, the fact is that activated “functional” NK cells (NKa) cannot be deactivated in the laboratory. Effective down-regulation of activated NK cells can only be adequately accomplished if their activated “progenitor/parental” NK cells are first down-regulated. Thereupon once these down-regulated “precursor” NK cells are exposed to progesterone, they will begin spawning normal and functional NK cells, which takes about 10-14 days. It follows that to assess for a therapeutic response to IVIG/IL therapy would require that the patient first be treated (10-14 days prior to embryo transfer) and thereupon, about 2 weeks later, be retested. While at 1st glance this might seem to be a reasonable approach, in reality it would be of little clinical benefit because even if blood were to be drawn 10 -14 days after IL/IVIG treatment it would require an additional 10 days to receive results from the laboratory, by which time it would be far too late to be of practical advantage.
Neither IVIG nor IL is capable of significantly suppressing already activated “functional NK cells”. For this to happen, the IL/IVIG would have to down-regulate progenitor (parent) NK cell” activity. Thus, it should be infused 10-14 several prior to ovulation or progesterone administration so that the down-regulated “progenitor/precursor” NK cells” can propagate a sufficient number of normally regulated “functional NK cell” to be present at the implantation site 7 days later. In addition, to be effective, IL/IVIG therapy needs to be combined with steroid (dexamethasone/prednisone/prednisolone) therapy to down-regulates (often) concomitantly activated T-cells.
I strongly recommend that you visit http://www.DrGeoffreySherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.
•The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
•Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
•IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation (COS)
•The Fundamental Requirements for Achieving Optimal IVF Success
•Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
•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) Why did my IVF Fail
•Recurrent Pregnancy Loss (RPL): Why do I keep losing my PregnanciesGenetically Testing Embryos for IVF
•Staggered IVF
•Staggered IVF with PGS- Selection of “Competent” Embryos Greatly Enhances the Utility & Efficiency of IVF.
•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?
•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!
•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
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ADDENDUM: PLEASE READ!!
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
Hello Dr Sher,
Thank you for your answer. The laboratory who conducted my unterine biopsy is a leading research institute in the field of reporductive immunology, they have been doing research for over 20 years on recurrent miscarriage and implantation failure becasue of nk cell disfunction. It’s not a private clinic, it is funded by a miscarriage charity here in the UK. They, however cannot recommend anything to treat very low nk cells, although they have recently conducted a study on the use of Sitagliptin to treat women with very low uterine nk cell activity, which they say is promising. However it is not a drug routinely prescribed for this even in private clinics here from what I understand. I’m sorry, maybe my question should’ve been, have you treated women with very low nk cell activity as oppose to high? Is there a treatment? I cannot afford to go to the USA for treatment. I have tested negative for ANA antibodies. Is there any further testing that you recommend which could help me on my journey?
Dear Dr. Sher.
We had one baby from our first IVF, so the result was good even though it looked grim at first
40 follicles
20 eggs retrieved
17 were M2
7 fertilized normally (10 had polyspermic fertilization with up to 6 spermatozoa in one egg)
5 embryos didn’t make it to d3, one didn’t make it to blastocyst.
We transferred a frozen pre-blastocyst embryo which eventually became our healthy baby
Now we want to try another baby, but we think something might have gone wrong with the previous IVF, since there was a lot of polyspermy. I have watched your videos and would like to get your opinion about the tests that we need in order to figure out an optimal protocol for us.
My wife has PCOS based on ultrasound and her AMH was 11,5 µg/l when she was 32. She is not overweight and doesn’t have (at least bad) hirsutism. She does have varying degrees of acne from time to time and her menstrual cycle is long (and with irregular length). She also has hypothyroidism for which she has medication (thyroxine).
I understand from some of your videos that the following tests should be made:
DHEA
17-hydroxyprogesterone
FSH
LH
AMH
insulin
glucose tolerance
E2
testosterone
androstenedione
TSH
Prolactin
SHBG
Questions:
1)We have all those except 17-hydroxyprogesterone which our doctor wouldn’t want to give us. She took that test off from the list even though a previous doctor had prescribed it to us. She says that my wife doesn’t look like someone who would need that based on her looks. Should we still test that one as well, in your opinion, even though my wife doesn’t look on the outside that she would have elevated 17-hydroxyprogesterone?
2)We have a test for DHEA, not DHEAS. Which one should be tested (or both)? I understood from your videos that adrenal PCOS has elevated DHEAS, so do we need DHEAS if we want to check if we have adrenal PCOS or can we infer that from DHEA levels as well?
3)Should we test for antithyroid antibodies and natural killer cells?
Our previous IVF protocol was:
Stimulated with Gonal F (100 units) for 5 days
Then continued with Gonal F (100 units) and added Cetrotide (antagonist) for 6 days
Then one Gonal F and triggered with Gonapeptyl (0,2 units) (agonist) in the evening
Then one day off (Sunday) and egg retrieval on Monday morning.
The clinic is closed on weekends so they had to figure if Friday or Monday would be better for the retrieval. They opted for Monday. Our doctor said that most of the eggs were of decent size (between 14-20mm or 22mm, can’t remember which was the upper limit he said they want them to be), so they thought we didn’t wait too long or anything like that.
We haven’t done those aforementioned tests yet, but our doctor still gave us a new protocol to go by in the next IVF. It includes using metformin, and Menopur with antagonist.
Question:
4)Do I understand correctly that you are of the opinion that metformin only helps if insulin levels or glucose levels are high in hypothalamic-pituitary PCOS, and that it can be even harmful for the egg quality otherwise? We are afraid to start metformin when we don’t have the tests done yet. My wife had a glucose or insulin test done when she was pregnant, and it wasn’t elevated.
5)Do I understand correctly that Menopur contains LH and can be even harmful if the tests show that my wife has elevated levels of androgens to begin with?
A very big thank you in advance, if you can find the time to answer our questions!
1) We have all those except 17-hydroxyprogesterone which our doctor wouldn’t want to give us. She took that test off from the list even though a previous doctor had prescribed it to us. She says that my wife doesn’t look like someone who would need that based on her looks. Should we still test that one as well, in your opinion, even though my wife doesn’t look on the outside that she would have elevated 17-hydroxyprogesterone?
A: Characteristics alone are not important. The test is one of a batch that is needed to formulate a diagnosis because that will influence preliminary treatment as well as selection and implementation of the most ideal protocol for ovarian stimulation. The objective is to protect egg quality..
2) We have a test for DHEA, not DHEAS. Which one should be tested (or both)? I understood from your videos that adrenal PCOS has elevated DHEAS, so do we need DHEAS if we want to check if we have adrenal PCOS or can we infer that from DHEA levels as well?
A: DHEAS not DHEA
3) Should we test for antithyroid antibodies and natural killer cells?
A: That is probably not your problem. WE are talking about egg/embryo “competency here, not implantation issues. This having been said, screening for immunologic implantation issues (including, but not limited to thyroid antibodies), is a wise precaution.
Question:
4) Do I understand correctly that you are of the opinion that metformin only helps if insulin levels or glucose levels are high in hypothalamic-pituitary PCOS, and that it can be even harmful for the egg quality otherwise? We are afraid to start metformin when we don’t have the tests done yet. My wife had a glucose or insulin test done when she was pregnant, and it wasn’t elevated.
A: I do not assert that Metformin will definitely compromise egg development if given in the absence of insulin resistance, but it could. As such In confine the administration of Metformin, to women with demonstarted insulin resistance.
5) Do I understand correctly that Menopur contains LH and can be even harmful if the tests show that my wife has elevated levels of androgens to begin with
A: Menopur contains equal parts of FSH and LH. LH causes production of ovarian androgens (mainly testosterone) which is essential for follicle growth, estrogen production and egg development and without which egg/embryo competency will be compromised. However, overexposure to an excess of androgens will get into the follicular fluid where it can have a significant adverse effect on follicle, egg and embryo development. Since most stimulation protocols make use of an agonist (e.g. Lupron/Superfact) or and antagonist (e.g.Ganirelix/Cetrotide/Orgalutron) which will switch off pituitary LH release, the addition of a small amount of LH in the form of Menopur will augment follicle and egg development.
Its all about striking a balance. This is why I keep stressing the fact that protocols used for ovarian stimulation need to be individualized to the specific patient profile. There is no such thing as a “one size fits all approach. Nowhere is that more true than in women who tend to have increased LH activity (e.g. women with PCOS, older women and those with diminished ovarian reserve.
The importance of the IVF stimulation protocol on egg/embryo quality cannot be overstated. This factor seems often to be overlooked or discounted by t IVF practitioners who use a “one-size-fits-all” approach to ovarian stimulation. My experience is that the use of individualized/customized COS protocols can greatly improve IVF outcome. While no one can influence underlying genetics or turn back the clock on a woman’s age, any competent IVF specialist should be able to tailor the protocol for COS to meet the individual needs of the patient.
Gonadotropins (LH and FSH), whether produced by the pituitary gland or administered by way of fertility drugs, have different “targeted” sites of action in the ovary. FSH targets cells that line the inner wall of the follicle (granulosa cells) and also form the cumulus cells that bind the egg to the inner surface of the follicle. Granulosa cells are responsible for estrogen production.
LH, on the other hand, targets the ovarian connective tissue (stroma/theca) that surrounds ovarian follicles resulting in the production of male hormones such as testosterone (predominantly), androstenedione and DHEA. These androgens are then transported to the granulosa cells of the adjacent follicles in a “bucket brigade fashion”. There FSH converts testosterone to estradiol, causing granulosa cells to multiply (proliferate) and produce estradiol, follicles to grows and eggs to develop (ovogenesis) It follows that ovarian androgens (mainly testosterone) is absolutely indispensable to follicle/ egg growth and development.
However, the emphasis is on a “small” amount of testosterone. Over-exposure of the follicle to testosterone can compromise egg development and lead to an increased likelihood of chromosomal irregularities (aneuploid) following LH/hCG-induced egg maturational division (meiosis) and compromise embryo “competency/quality.
Ovarian androgens can also reach the uterine lining where they sometimes will compromise estrogen receptor -induced endometrial growth and development.
Many older women and those who have diminished ovarian reserve (DOR) have increased LH activity is increased. Such women either over-produce LH and/or the LH produced is far more biologically active. Chronically increased LH activity leads to overgrowth of ovarian connective tissue (stroma/theca). This condition, which is often referred to as Stromal Hyperplasia or hyperthecosis can result in excessive ovarian androgen/testosterone production and poorer egg-embryo quality/competency, Similarly, women with polycystic ovarian syndrome (PCOS), also characteristically have Stromal hyperplasia/hyperthecosis due to chronically increased LH activity. Thus they too often manifest with increased ovarian androgen production. It is therefore not surprising that “poor egg/embryo quality” is often also a feature of PCOS.
In my opinion, the over-administration of LH-containing menotropins such as Menopur, [which is comprised of roughly equal amount of FSH and hCG ,which acts similar to LH)], to older women, women with DOR and those who have PCOS can also lead to reduced egg/embryo competency . Similarly, drugs such as clomiphene or Letrozole that cause the pituitary gland to release excessive amounts of LH, are also potentially harmful to egg development and in my opinion, are best omitted from IVF COS protocols. This is especially the case when it comes to older women and those with DOR, who in my opinion should preferably be stimulated using FSH-dominant products such as Follistim, Puregon, Fostimon and Gonal-F.
Gonadotropin releasing hormone agonists (GnRHa): GnRHa such as Lupron, Buserelin, Superfact, Gonopeptyl etc. are often used to launch ovarian stimulation cycles. They act by causing an initial outpouring followed by a depletion of pituitary gonadotropins. This results in LH levels falling to low concentrations, within 4-7 days, thereby establishing a relatively “LH-free environment”. When GnRHa are administered for about 7 days prior to initiating gonadotropin stimulation (“long” pituitary down-regulation”), the LH depletion that will exist when COS is initiated, will usually be protective of subsequent egg development. In contrast, when the GnRHa administration commences along with the initiation of gonadotropin therapy, there will be a resultant immediate surge in the release of pituitary LH with the potential to increase ovarian testosterone to egg-compromising levels , from the outset of COS. This, in my opinion could be particularly harmful when undertaken in older women and those who have DOR.
GnRH-antagonists such as Ganirelix, Cetrotide and Orgalutron, on the other hand, act very rapidly (within hours) to block pituitary LH release. The purpose in using GnRH antagonists is to prevent the release of LH during COS. In contrast, the LH-lowering effect of GnRH agonists develops over a number of days.
GnRH antagonists are traditionally given, starting after 5th -7th day of gonadotropin stimulation. However, when this is done in older women and those (regardless of age) who have DOR, LH-suppression might be reached too late to prevent the deleterious effect of excessive ovarian androgen production on egg development in the early stage of ovarian stimulation. This is why, it is my preference to administer GnRH-antagonists, starting at the initiation of gonadotropin administration.
My preferred Protocols for Controlled Ovarian Stimulation (COS):
1.“Long” GnRHa (Lupron/Buserelin/Superfact/Gonopeptyl) Pituitary Down-regulation Protocol: The most commonly prescribed protocol for GnRHa/gonadotropin administration is the so-called “long protocol”. Here, GnRHa is given, starting a week or so prior to menstruation. This results in an initial rise in FSH and LH , which is rapidly followed by a precipitous fall to near zero. It is followed by a withdrawal bleed (menstruation), whereupon gonadotropin treatment should commence, while daily Lupron injections continue, to ensure a “low LH” environment. A modification to the “long protocol” which I prefer prescribing for older women and in cases of DOR, is the Agonist/Antagonist Conversion Protocol (A/ACP) where, upon the onset of a GnRHa-induced bleed, the agonist is supplanted by an antagonist (Ganirelix/Cetrotide/Orgalutron) and this is continued until the hCG trigger. In many such cases I often supplement with human growth hormone (HGH) in such cases in an attempt to enhance egg mitochondrial activity and so enhance egg development. This approach is often augmented with preimplantation genetic screening (PGS) of all embryos that reach the expanded blastocyst stage of development by day 5-6 post-fertilization. I also commonly recommend blastocyst banking to many such patients.
2.
3.Short (“Flare”) GnRHa Protocol: Another GnRHa usage for COS is the so called “(micro) flare protocol”. This involves initiating gonadotropin therapy commensurate with initiation of gonadotropin administration. The supposed objective is to deliberately allow Lupron to elicit an initial surge (“flare”) in pituitary FSH release in order to augment FSH administration by increased FSH production. Unfortunately, this “spring board effect” constitutes “a double-edged sword”. While it indeed increases the release of FSH, it at the same time causes a surge in LH release. The latter can evoke excessive ovarian stromal/thecal androgen production which could potentially compromise egg quality, especially when it comes to older women and women with DOR. I am of the opinion that by evoking an exaggerated ovarian androgen response, such “(micro) flare protocols” can harm egg/embryo quality and reduce IVF success rates, especially when it comes to COS in older women, and in women with diminished ovarian reserve. Accordingly, I do not prescribe such protocols to my IVF patients.
4.Estrogen Priming – This is the approach I sometimes prescribe for my patients who have virtually depleted ovarian reserve , as determined by very low blood anti-Mullerian hormone AMH levels ( 40 different countries. All consultations are followed by a detailed written report presenting my personal recommendations for treatment of what often constitute complex Reproductive Issues.
Patients are encouraged to share the information I provide, with their treating Physicians and/or to avail themselves of my personal hands-on services, provided through batched IVF cycles that I conduct every 3 months at Los Angeles IVF (LAIVF) Clinic, Century City, Los Angeles, CA.
If you wish to schedule an online consultation with me, please contact my assistant (Patti Converse) by phone (800-780-7437/702-533-2691), email (concierge@SherIVF.com) or, enroll online on then home-page of my website (www.SherIVF.com).
PLEASE SPREAD THE WORD ABOUT SFS!
Geoff Sher