There are several possible factors :Diminished ovarian reserve: Protocol selection for ovarian stimulation; Male factor; egg quality; implantation dysfunction (possibly related to an autoimmune, immunologic implantation dysfunction.(IID) such as Thyroid autoimmune disease and underlying ndometriosis. Obviously I cannot address all these here. I suggest we talk….SO, I invite you to contact my assistant, Patti Converse (702-533-2691) and set up an online consultation with me to talk..

Whenever a patient fails to achieve a viable pregnancy following embryo transfer (ET), the first question asked is why! Was it simply due to, bad luck?, How likely is the failure to recur in future attempts and what can be done differently, to avoid it happening next time?.

It is an indisputable fact that any IVF procedure is at least as likely to fail as it is to succeed. Thus when it comes to outcome, luck is an undeniable factor. Notwithstanding, it is incumbent upon the treating physician to carefully consider and address the causes of IVF failure before proceeding to another attempt:

1. Age: The chance of a woman under 35Y of age having a baby per embryo transfer is about 35-40%. From there it declines progressively to under 5% by the time she reaches her mid-forties. This is largely due to declining chromosomal integrity of the eggs with advancing age…”a wear and tear effect” on eggs that are in the ovaries from birth.
2. Embryo Quality/”competency (capable of propagating a viable pregnancy)”. As stated, the woman’s age plays a big role in determining egg/embryo quality/”competency”. This having been said, aside from age the protocol used for controlled ovarian stimulation (COS) is the next most important factor. It is especially important when it comes to older women, and women with diminished ovarian reserve (DOR) where it becomes essential to be aggressive, and to customize and individualize the ovarian stimulation protocol.

 We used to believe that the uterine environment is more beneficial to embryo development than is the incubator/petri dish and that accordingly, the earlier on in development that embryos are transferred to the uterus, the better. To achieve this goal, we used to select embryos for transfer based upon their day two or microscopic appearance (“grade”).  But we have since learned that the further an embryo has advanced in its development, the more likely it is to be “competent” and that embryos failing to reach the expanded blastocyst stage within 5-6 days of being fertilized are almost invariably “incompetent” and are unworthy of being transferred. Moreover, the introduction into clinical practice about 15y ago, (by Levent Keskintepe PhD and myself) of Preimplantation Genetic Sampling (PGS), which assesses for the presence of all the embryos chromosomes (complete chromosomal karyotyping), provides another tool by which to select the most “competent” embryos for transfer. This methodology has selective benefit when it comes to older women, women with DOR, cases of unexplained repeated IVF failure and women who experience recurrent pregnancy loss (RPL).

1. The number of the embryos transferred: Most patients believe that the more embryos transferred the greater the chance of success. To some extent this might be true, but if the problem lies with the use of a suboptimal COS protocol, transferring more embryos at a time won’t improve the chance of success. Nor will the transfer of a greater number of embryos solve an underlying embryo implantation dysfunction (anatomical molecular or immunologic).Moreover, the transfer of multiple embryos, should they implant, can and all too often does result in triplets or greater (high order multiples) which increases the incidence of maternal pregnancy-induced complications and of premature delivery with its serious risks to the newborn. It is for this reason that I rarely recommend the transfer of more than 2 embryos at a time and am moving in the direction of advising single embryo transfers …especially when it comes to transferring embryos derived through the fertilization of eggs from young women.

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

1. A“ thin uterine lining”
2. A uterus with surface lesions in the cavity (polyps, fibroids, scar tissue)
3. Immunologic implantation dysfunction (IID)
4. Endocrine/molecular endometrial receptivity issues
5. Ureaplasma Urealyticum (UU) Infection of cervical mucous and the endometrial lining of the uterus, can sometimes present as unexplained early pregnancy loss or unexplained failure following intrauterine insemination or IVF. The infection can also occur in the man, (prostatitis) and thus can go back and forth between partners, with sexual intercourse. This is the reason why both partners must be tested and if positive, should be treated contemporaneously.

Certain causes of infertility are repetitive and thus cannot readily be reversed. Examples include advanced age of the woman; severe male infertility; immunologic infertility associated with alloimmune implantation dysfunction (especially if it is a “complete DQ alpha genetic match between partners plus uterine natural killer cell activation (NKa).

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.
• Ovarian Stimulation in Women Who have Diminished Ovarian Reserve (DOR): Introducing the Agonist/Antagonist Conversion protocol
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
• Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
• The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
• Blastocyst Embryo Transfers should be the Standard of Care in IVF
• IVF: How Many Attempts should be considered before Stopping?
• “Unexplained” Infertility: Often a matter of the Diagnosis Being Overlooked!
• IVF Failure and Implantation Dysfunction:
• The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 1-Background
• Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 2- Making a Diagnosis
• Immunologic Dysfunction (IID) & Infertility (IID): PART 3-Treatment
• Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
• Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management 🙁 Case Report)
• Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
• Intralipid (IL) Administration in IVF: It’s Composition; how it Works; Administration; Side-effects; Reactions and Precautions
• Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
• Endometrial Thickness, Uterine Pathology and Immunologic Factors
• Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
• Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
• A personalized, stepwise approach to IVF
• How Many Embryos should be transferred: A Critical Decision in IVF?

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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

WE really should talk! To me it seams that there is an underlying implantation dysfunction that is likely immunologic in origin. If I am correct then respectfully, in my opinion,  the  treatment to address the immunologic implantation dysfunction (IID) was not optimal/adequate.I invite you to contact my assistant, Patti converse (702-533-2691) and set up an online consultation with me.

Implantation dysfunction is unfortunately often overlooked as an important cause of IVF failure. This is especially relevant in cases of unexplained IVF failure, recurrent pregnancy loss (RPL), and in women with underlying endo-uterine surface lesions, thickness of the uterine lining (endometrium) and /or immunologic factors.

IVF success rates have been improving over the last decade. The average live birth rate per embryo transfer in the U.S.A for women under 40y using their own eggs is currently better than 1:3 women. However, there is still a wide variation from program to program for IVF live birth rates, ranging from 20% to near 50%. Based upon these statistics, most women undergoing IVF in the United States require two or more attempts to have a baby. IVF practitioners in the United States commonly attribute the wide dichotomy in IVF success rates to variability in expertise of the various embryology laboratories. This is far from accurate. In fact, other factors such as wide variations in patient selection and the failure to develop individualized protocols for ovarian stimulation or to address those infectious, anatomical, and immunologic factors that influence embryo implantation are at least equally important.

About 80% of IVF failures are due to “embryo incompetency” that is largely due to aneuploidy      usually related to advancing age of the woman and is further influenced by other factors such as the protocol selected for ovarian stimulation, diminished ovarian reserve (DOR), and severe male factor infertility. However, in about 20% of dysfunctional cases embryo implantation is the cause of failure.

This section will focus on implantation dysfunction and IVF failure due to:

ANATOMICAL ENDO-UTERINE SURFACE LESIONS

            It has long been suspected that anatomical defects of the uterus might result in infertility. While the presence of uterine fibroids, in general, are unlikely to cause infertility, an association between their presence and infertility has been observed in cases where the myomas distort the uterine cavity or protrude through the endometrial lining.  Even small fibroids that lie immediately under the endometrium (submucous fibroids) and protrude into the uterine cavity have the potential to lower embryo implantation.  Multiple fibroids in the uterine wall (intramural fibroids) that encroach upon the uterine cavity can sometimes so compromise blood flow that estrogen delivery is impaired, and the endometrium is unable to thicken properly. This can usually be diagnosed by ultrasound examination during the proliferative phase of the menstrual cycle.  It is likely that any surface lesion in the uterine cavity, whether submucous fibroids, intrauterine adhesions a small endometrial or a placental polyp, has the potential to interfere with implantation by producing a local inflammatory response, not too dissimilar in nature from that which is caused by an intrauterine contraceptive device (IUD).       

            Clearly, since even small uterine lesions have the potential to adversely affect implantation, the high cost (financial, physical, and emotional) associated with IVF and related procedures, justifies the routine performance of diagnostic procedures such as an HSG, hysterosonogram (fluid ultrasound examination), or hysteroscopy prior to initiating IVF.  Identifiable uterine lesions that have the potential of impairing implantation usually require surgical intervention.  In most cases, dilatation and curettage (D & C) or hysteroscopic resection will suffice. Some cases might require the performance of a laparotomy.  Such intervention will often result in subsequent improvement of the endometrial response.      

Sonohysterography [Fluid ultrasonography (FUS)]: Fluid ultrasonography is a procedure whereby a sterile solution of saline is injected via a catheter through the cervix and into the uterine cavity. The fluid-distended cavity is examined by vaginal ultrasound for any irregularities that might point to surface lesions such as polyps, fibroid tumors, scarring, or a uterine septum. If performed by an expert, a FUS is highly effective in recognizing even the smallest lesion and can replace hysteroscopy under such circumstances. FUS is less expensive, less traumatic, and equally as effective as hysteroscopy. The only disadvantage lies in the fact that if a lesion is detected, it may require the subsequent performance of hysteroscopy to treat the problem anyway.

Hysteroscopy: Diagnostic hysteroscopy is an office procedure that is performed under intravenous sedation, general anesthesia, or paracervical block with minimal discomfort to the patient. This procedure involves the insertion of a thin, lighted, telescope like instrument known as a hysteroscope through the vagina and cervix into the uterus to fully examine the uterine cavity. The uterus is first distended with normal saline, which is passed through a sleeve adjacent to the hysteroscope. As is the case with FUS, diagnostic hysteroscopy facilitates examination of the inside of the uterus under direct vision for defects that might interfere with implantation. We have observed that approximately one in eight candidates for IVF have lesions that require attention prior to undergoing IVF in order to optimize the chances of a successful outcome. We strongly recommend that all patients undergo therapeutic surgery (usually by hysteroscopy) to correct the pathology prior to IVF.  Depending on the severity and nature of the pathology, therapeutic hysteroscopy may require general anesthesia and, in such cases, should be performed in an outpatient surgical facility or conventional operating room where facilities are available for laparotomy, a procedure in which an incision is made in the abdomen to expose the abdominal contents for diagnosis, or for surgery should this be required.       

THICKNESS OF THE UTERINE LINING (ENDOMETRIUM):

As far back as in 1989 we first reported on the finding that ultrasound assessment of the late proliferative phase endometrium can identify those candidates who are least likely to conceive. We noted that the ideal thickness of the endometrium at the time of ovulation or egg retrieval is >8 mm and that thinner linings are associated with decreased implantation rates.

More than 30 years ago we first showed that in normal and “stimulated” cycles, pre-ovulatory endometrial thickness and ultrasound appearance is predictive of embryo implantation (pregnancy) potential following ET. With conventional IVF and with FET, endometrial lining at the time of the “trigger shot” or with the initiation of progesterone needs to preferably be at least 8 mm in sagittal thickness with a triple line (trilaminar) appearance. Anything less than an 8mm endometrial thickness       is associated with a reduction in live birth rate per ET. An 8-9mm thickness represents a transitional measurement…a “gray zone”.  Hitherto, attempts to augment endometrial growth in women with poor endometrial linings by bolstering circulating estrogen blood levels (through the administration of increased doses of fertility drugs, aspirin administration and by supplementary estrogen therapy) yielded disappointing results.

            A “poor” uterine lining is usually the result of the innermost layer of endometrium (the basal or germinal endometrium from which endometrium grows) not being able to respond to estrogen by propagating an outer, “functional” layer thick enough to support optimal embryo implantation and development of a healthy placenta (placentation). The “functional” layer ultimately comprises 2/3 of the full endometrial thickness and is the layer that sheds with menstruation if no pregnancy occurs.

The main causes of a “poor” uterine lining are:

• Damage to the basal endometrium because of:
• Inflammation of the endometrium (endometritis) most commonly resulting from infected products left over following abortion, miscarriage, or birth
• Surgical trauma due to traumatic uterine scraping, (i.e. due to an over-aggressive D & C)
• Insensitivity of the basal endometrium to estrogen due to:
• Prolonged, over-use/misuse of clomiphene citrate
• Prenatal exposure to diethylstilbestrol (DES). This is a drug that was given to pregnant women in the 1960’s to help prevent miscarriage
• Over-exposure of the uterine lining to ovarian male hormones (mainly testosterone): Older women, women with diminished ovarian reserve (poor responders) and women with polycystic ovarian syndrome -PCOS tend to have raised LH biological activity. This causes the connective tissue in the ovary (stroma/theca) to overproduce testosterone. The effect may be further exaggerated when certain methods for ovarian stimulation such as “flare” protocols and high dosages of Menopur are used in such cases.
• Reduced blood flow to the basal endometrium: Examples include.
• Multiple uterine fibroids – especially when these are present under the endometrium (submucosal)
• Uterine adenomyosis (excessive, abnormal invasion of the uterine muscle by endometrial glands).

Vaginal Viagra: About 35 years ago, after reporting on the benefit of administering vaginal Sildenafil (Viagra) to women who had implantation dysfunction due to thin endometrial linings we announced the birth of the world’s first “Viagra baby.”  Viagra administered vaginally, but not orally, in affected women improves uterine blood flow causing more estrogen to be delivered to the basal endometrium and increasing the endometrial thickening.  Following vaginal administration, Viagra is rapidly absorbed and quickly reaches the uterine blood system in high concentrations. Thereupon it dilutes out as it is absorbed into the systemic circulation. This probably explains why treatment is virtually devoid of systemic side effects.  It is important to recognize that Viagra will NOT be effective in improving endometrial thickness in all cases. In fact, about one third of women treated fail to show any improvement. This is because in certain cases of thin uterine linings, the basal endometrium will have been permanently damaged and left unresponsive to estrogen. This happens in cases of severe endometrial damage due mainly to post-pregnancy endometritis (inflammation), chronic granulomatous inflammation due to uterine tuberculosis (hardly ever seen in the United States) and following extensive surgical injury to the basal endometrium (as sometimes occurs following over-zealous D&C’s).

• Immunologic factors: These also play a role in IVF failure (see “Immunologic factors and Implantation” …see below.

IMMUNOLOGIC IMPLANTATION DYSFUNCTION (IID)

            Currently, with few exceptions, practitioners of assisted reproduction tend to attribute “unexplained and/or repeated” IVF failure(s), almost exclusively to poor embryo quality, advocating adjusted protocols for ovarian stimulation and/or gamete and embryo preparation as a potential remedy. The idea, having failed IVF, that all it takes to ultimately succeed is to keep trying the same recipe is over-simplistic.

            The implantation process begins six or seven days after fertilization of the egg. At this time, specialized embryonic cells (i.e., trophoblasts), that later become the placenta begin growing into the uterine lining. When the trophoblast and the uterine lining meet, they, along with immune cells in the lining, become involved in a “cross talk” through mutual exchange of hormone-like substances called cytokines. Because of this complex immunologic interplay, the uterus can foster the embryo’s successful growth. Thus, from the earliest stage, the trophoblast establishes the very foundation for the nutritional, hormonal and respiratory interchange between mother and baby.  In this manner, the interactive process of implantation is not only central to survival in early pregnancy but also to the quality of life after birth.

There is an ever growing realization, recognition, and acceptance of the fact that uterine immunologic dysfunction can lead to immunologic implantation dysfunction (IID) with “unexplained” infertility, IVF failure, and recurrent pregnancy loss (RPL).

DIAGNOSIS 

Because immunologic problems may lead to implantation failure, it is important to properly evaluate women with risk factors such as:

• Unexplained or recurrent IVF failures
• Unexplained infertility or a family history of autoimmune diseases (e.g., rheumatoid arthritis, lupus erythematosus and hypothyroidism).
• Recurrent Pregnancy Loss (RPL)
• Endometriosis
• A personal or family history of autoimmune conditions, e.g., Rheumatoid Arthritis, Lupus erythematosus, autoimmune hypothyroidism (Hashimoto’s disease) etc.

            Considering its importance, it is not surprising that the failure of a properly functioning immunologic interaction during implantation has been implicated as a cause of recurrent miscarriage, late pregnancy fetal loss, IVF failure and infertility. A partial list of immunologic factors that may be involved in these situations includes:

• Antiphospholipid antibodies (APA)
• Antithyroid antibodies (ATA/AMA)
• Activated natural killer cells (NKa)

ACTIVATED NATURAL KILLER CELLS (NKa):

Following ovulation and during early pregnancy, NK cells and T-cells comprise more than 80% of the lymphocyte-immune cells that frequent the uterine lining. These lymphocytes (white blood cells) journey from the bone marrow to the uterus and under hormonal regulation, proliferate there. After exposure to progesterone (due to induced /spontaneous exogenous administration), they begin to produce TH-1 and TH-2 cytokines. TH-2 cytokines are humoral in nature and induce the trophoblast (“root system of the embryo”) to permeate the uterine lining while TH-I cytokines induce a process referred to as apoptosis (cell suicide) thereby confining placental development to the inner part of the uterus. Optimal placental development (placentation) mandates that there be a balance between TH1 and TH-2 cytokines. Most of the cytokine production originates from NK cells (rather than from cytotoxic T-cells/Lymphocytes (CTL)). Excessive production/release of TH-1 cytokines, is toxic to the trophoblast and to endometrial cells, leading to programmed death/suicide (apoptosis) and subsequently to IID.

Functional NK cells reach a maximal concentration in the endometrium by about t day 6-7 days after exposure to progesterone …. This timing corresponds with when the embryo implants into the uterine lining (endometrium).

It is important to bear in mind that measurement of the concentration of blood NK cells has little or no relevance when it comes to assessing NK cell activation (NKa). Rather, it is the NK cell activation that matters. In fact, there are certain conditions (such as with endometriosis) where the NK cell blood concentration is below normal, but NK cell activation is markedly increased.

There are several methods by which NK cell activation (cytotoxicity) can be assessed in the laboratory. Methods such as immunohistochemical assessment of uterine NK cells and/or through measurement of uterine or blood TH-1 cytokines. However, the K-562 target cell blood test still remains the gold standard. With this test, NK cells, isolated from the woman’s blood using Flow Cytometry are incubated in the presence of specific “target cells”. The percentage (%) of “target cells” killed is then quantified. More than 12% killing suggests a level of NK cell activation that usually requires treatment.

Currently, there are less than a half dozen Reproductive Immunology Reference Laboratories in the U.S.A that are capable of performing the K-562 target cell test reliably.

There exists a pervasive but blatant misconception on the part of many, that the addition of IL or IVIg to a concentration of NK cells could have an immediate down-regulatory effect on NK cell activity. Neither IVIg nor IL is capable of significantly suppressing already activated “functional NK cells”. They are believed to work through “regulating” NK cell progenitors which only thereupon will start to propagate down-regulated NK cells. Thus, testing for a therapeutic effect would require that the IL/IVIg infusion be done about 14 days prior to ovulation or progesterone administration…  in order to allow for a sufficient number of normal (non-activated) “functional” NK cell” to be present at the implantation site when the embryos are transferred.

Failure to recognize this reality has, in our opinion, established an erroneous demand by practicing IVF doctors, that Reproductive Immunology Reference Laboratories report on NK cell activity before and again, immediately following laboratory exposure to IVIg and/or IL in different concentrations. Allegedly, this is to allow the treating physician to report back to their patient(s) on whether an IL or IVIG infusion will be effective in downregulating their Nka.  But, since already activated NK cells (NKa) cannot be deactivated in the laboratory, effective NKa down-regulation can only be adequately accomplished through deactivation of NK cell “progenitors /parental” NK cells in order to allow them thereupon, to s propagate normal “functional” NK cells and his takes about 10-14 days, such practice would be of little clinical benefit. This is because even if blood were to be drawn 10 -14 days after IL/IVIg treatment it would require at least an additional 10 -14days to receive results from the laboratory, by which time it would be far too late to be of practical advantage.

ANTIPHOSPHOLIPID ANTIBODIES:

 Many women who experience “unexplained” IVF failure, women with RPL, those with a personal or family history of autoimmune diseases such as lupus erythematosus, rheumatoid arthritis, scleroderma, and dermatomyositis (etc.)  as well as women who have endometriosis (“silent” or overt) test positive for APAs. More than 30 years ago, we were the first to propose that women who test positive for APA’s be treated with a mini-dose heparin to improve IVF implantation and thus birth rates. This approach was based upon research that suggested that heparin repels APAs from the surface of the trophoblast (the embryo’s “root system) thereby reducing its ant-implantation effects.  We subsequently demonstrated that such therapy only improved IVF outcome in women whose APAs were directed against two specific IgG and/or IgM phospholipids [i.e., phosphatidylethanolamine (PE) and phosphatidylserine (PS)].  More recently low dosage heparin therapy has been supplanted using longer acting low molecular weight heparinoids such as Lovenox and Clexane.   It is very possible that APAs alone do not cause IID but that their presence might help to identify a population at risk due to concomitant activation of uterine natural killer cells (Nka) which through excessive TH-1 cytokine production causes in IID: This is supported by the following observations:

• The presence of female APAs in cases of male factor cases appears to bear no relationship to IID.
• Only APA positive women who also test positive for abnormal NK activity appear to benefit from selective immunotherapy with intralipid/IVIg/ steroids.
• Most APA positive women who have increased NK cell activity also harbor IgG or IgM phosphatidylethanolamine (PE) and phosphatidylserine (PS) antibodies.

ANTITHYROID ANTIBODIES: (ATA).

 A clear relationship has been established between ATA and reproductive failure (especially recurrent miscarriage and infertility).

Between 2% and 5% of women of the childbearing age have reduced thyroid hormone activity (hypothyroidism). Women with hypothyroidism often manifest with reproductive failure i.e., infertility, unexplained (often repeated) IVF failure, or recurrent pregnancy loss (RPL). The condition is 5-10 times more common in women than in men. In most cases hypothyroidism is caused by damage to the thyroid gland resulting from of thyroid autoimmunity (Hashimoto’s disease) caused by damage done to the thyroid gland by antithyroglobulin and antimicrosomal auto-antibodies. 

The increased prevalence of hypothyroidism and thyroid autoimmunity (TAI) in women is likely the result of a combination of genetic factors, estrogen-related effects, and chromosome X abnormalities.  This having been said, there is significantly increased incidence of thyroid antibodies in non-pregnant women with a history of infertility and recurrent pregnancy loss and thyroid antibodies ^can be present asymptomatically in women without them manifesting with overt clinical or endocrinologic evidence of thyroid disease. In addition, these antibodies may persist in women who have suffered from hyper- or hypothyroidism even after normalization of their thyroid function by appropriate pharmacological treatment. The manifestations of reproductive dysfunction thus seem to be linked more to the presence of thyroid autoimmunity (TAI) than to clinical existence of hypothyroidism and treatment of the latter does not routinely result in a subsequent improvement in reproductive performance.

It follows, that if antithyroid autoantibodies are associated with reproductive dysfunction they may serve as useful markers for predicting poor outcome in patients undergoing assisted reproductive technologies.

Some years back, I reported on the fact that 47% of women who harbor thyroid autoantibodies, regardless of the absence or presence of clinical hypothyroidism, have activated uterine natural killer cells (NKa) cells and cytotoxic lymphocytes (CTL) and that such women often present with reproductive dysfunction. We demonstrated that appropriate immunotherapy with IVIG or intralipid (IL) and steroids, subsequently often results in a significant improvement in reproductive performance in such cases.

The fact that almost 50% of women who harbor antithyroid antibodies do not have activated CTL/NK cells suggests that it is NOT the antithyroid antibodies themselves that cause reproductive dysfunction. The activation of CTL and NK cells that occurs in half of the cases with TAI is probably an epiphenomenon with the associated reproductive dysfunction being due to CTL/NK cell activation that damages the early “root system” (trophoblast) of the implanting embryo. We have shown that treatment of those women who have thyroid antibodies + NKa/CTL using IL/steroids, improves subsequent reproductive performance while women with thyroid antibodies who do not harbor NKa/CTL do not require or benefit from such treatment

TEATMENT OF IID:

The mainstay of treatment involves the selective use of:

• Intralipid (IL) infusion
• IVIg therapy
• Corticosteroids (Prednisone/dexamethasone)
• Heparinoids (Lovenox/Clexane)

Intralipid (IL) Therapy:  IL is a suspension of soybean lipid droplets in water and is primarily used as source of parenteral nutrition. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, and alpha-linolenic acid (ALA), an omega-3 fatty acid.     

It is thought that fatty acids within the emulsion serve as ligands that activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cell cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent.

            Whatever the exact mechanism of action might be, Intralipid acts primarily to suppress NK cell over-production of TH-I cytokines. It exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating cytotoxic /activated natural killer cells (NKa). This effect is enhanced through the concomitant administration of corticosteroids such as dexamethasone, prednisolone and prednisone which augment immune modulation of T cells. The combined effect of IL + steroid therapy suppresses pro-inflammatory cellular TH1 cytokines such as interferon gamma and TNF-alpha that are produced in excess by activated NK cells and cytotoxic lymphocytes/T-cells (CTL).   IL will, in about 80% of cases, successfully down-regulate activated natural killer cells (NKa) over a period of 2-3 weeks. It is likely to be just as effective as IVIg in this respect but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for ~ 4-6 weeks when administered in early pregnancy.

Intralipid is a suspension of soybean lipid droplets in water and is primarily used as source of parenteral nutrition. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, and alpha-linolenic acid (ALA), an omega-3 fatty acid.     

It is thought that fatty acids within the emulsion serve as ligands that activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cell cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent.

            Whatever the exact mechanism of action might be, Intralipid acts primarily to suppress NK cell over-production of TH-I cytokines. It exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating cytotoxic /activated natural killer cells (NKa). This effect is enhanced through the concomitant administration of corticosteroids such as dexamethasone, prednisolone and prednisone which augment immune modulation of T cells. The combined effect of IL + steroid therapy suppresses pro-inflammatory cellular TH1 cytokines such as interferon gamma and TNF-alpha that are produced in excess by activated NK cells and cytotoxic lymphocytes/T-cells (CTL).   IL will, in about 80% of cases, successfully down-regulate activated natural killer cells (NKa) over a period of 2-3 weeks. It is likely to be just as effective as IVIg in this respect but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for ~ 4-6 weeks when administered in early pregnancy.

            Can laboratory testing be used to assess for an immediate effect of IL on Nka suppression?  Since the downregulation of NKa through IL (or IVIg) therapy can take several weeks to become measurable, it follows that there is really no benefit in trying to assess the potential efficacy of such treatment by retesting NKa in the laboratory after adding IL (or IVIg) to the cells being tested.

IVIg Therapy:  Until about a decade ago, the only effective and available way (in the US) to down-regulate activated NK cells was through the intravenous administration of a blood product known as immunoglobulin-G (IVIg). The fear (albeit unfounded) that the administration of this product might lead to the transmission of viral infections such as HIV and hepatitis C, plus the high cost of IVIG along with the fact that significant side effects occurred about 20% of the time, led to bad press and bad publicity for the entire field of reproductive immunology. It was easier for RE’s to simply say “I don’t believe IVIg works” and thereby avoid risk and bad publicity. But the thousands of women who had babies because of NK cell activity being downregulated through its use, attests to IVIg’s efficacy. But those of us who felt morally obligated to many desperate patients who would not conceive without receiving IVIg were facing an uphill battle. The bad press caused by fear mongering took its toll and spawned a malicious controversy. It was only through the introduction of IL less (about 15-20 years ago ), that the tide began to turn in favor of those patients who required low cost, safe and effective immunotherapy to resolve their IID.

 Corticosteroid Therapy (e.g., Prednisone, and Dexamethasone): Corticosteroid therapy has become a mainstay in the treatment of most women undergoing IVF. It is believed by most to enhance implantation due to an overall immunomodulatory effect. Corticosteroids reduce TH-1 cytokine production by CTL. When given in combination with IL or IVIG they augment the implantation process. The prednisone or dexamethasone therapy must commence (along with IL/IVIg) 10-14 days prior to egg retrieval and continue until pregnancy is discounted or until the 10th week of pregnancy.

 Heparinoid Therapy: There is compelling evidence that the subcutaneous administration of low molecular heparin (Clexane, Lovenox) once daily, (starting with the onset of ovarian stimulation) can improve IVF birthrate in women who test positive for APAs and might prevent later pregnancy loss when used to treat certain thrombophilias (e.g., homozygous MTHFR mutation)

What About Baby Aspirin? In our opinion, aspirin has little (if any) value when it comes to IID, and besides, it could even reduce the chance of success. The reason for this is that aspirin thins the blood and increases the potential to bleed. This effect can last for up to a week and could complicate an egg retrieval procedure or result in “concealed” intrauterine bleeding at the time of embryo transfer, thereby potentially compromising IVF success.

TH-1 Cytokine Blockers (Enbrel, Humira): TH-1 cytokine blockers, (Enbrel and Humira) are in our opinion relatively ineffective in the IVF setting. There has to date been no convincing data to support their use. However, these blockers could have a role in the treatment of a threatened miscarriage thought to be due to CTL/NK activation, but not for IVF. The reason is that the very initial phase of implantation requires a cellular response involving TH-1 cytokines. To block them completely (rather than simply restore a TH-1:TH-2 balance as occurs with IL therapy) so very early on could compromise rather than benefit implantation.

Leukocyte Immunization Therapy (LIT): The subcutaneous injection of the male partner’s lymphocytes to the mother is thought to enhance the ability for the mother’s decidua (uterus) to recognize the DQ alpha matching embryo as “self” or “friend” and thereby avert its rejection. LIT has been shown to up-regulate Treg cells and thus down-regulate NK cell activation thereby improving decidual TH-1:TH-2 balance. Thus, there could be a therapeutic benefit from such therapy. However, the same benefit can be achieved through the use of IL plus corticosteroids. Besides, IL is much less expensive, and the use of LIT is prohibited by law in the U.S.A.

There are two categories of immunologic implantation dysfunction (IID) linked to NK cell activation (NKa).

Autoimmune Implantation Dysfunction: Here, the woman will often have a personal or family history of autoimmune conditions such as Rheumatoid arthritis, Lupus Erythematosus, and thyroid autoimmune activity (e.g., Hashimoto’s disease) etc. Autoimmune as well as in about one third of cases of endometriosis, regardless of severity.  Autoimmune sometimes also occurs in the absence of a personal or family history of autoimmune disease.

When it comes to treating  NKa in  IVF cases complicated by autoimmune implantation dysfunction,  the combination of daily oral dexamethasone commencing with the onset of ovarian stimulation and continuing until the 10th week of pregnancy, combined with an initial infusion of IL (100ml, 20% Il dissolved in 500cc of saline solution, 10-14  days prior to PGT-normal embryo transfer and repeated once more (only), as  soon as the blood pregnancy test is positive), the anticipated chance of a viable pregnancy occurring within 2 completed IVF attempts (including fresh + frozen ET’s)  in women under 39Y (who have normal ovarian reserve)  is approximately  65%.

Alloimmune Implantation Dysfunction: Here, NK cell activation results from uterine exposure to an embryo derived through fertilization by a spermatozoon that shares certain genotypic (HLA/DQ alpha) similarities with that of the embryo recipient.

Partial DQ alpha/HLA match:  Couples who upon genotyping are shown to share only one DQ alpha/HLA gene are labeled as having a “partial match”. The detection of a “partial match” in association with NKa puts the couple at a considerable disadvantage with regard to IVF outcome. It should be emphasized however, that in the absence of associated Nka, DQ alpha/HLA matching whether “partial” or “total (see below) will NOT cause an IID. Since we presently have no way of determining which embryo carries a matching paternal DQ alpha gene, it follows that each embryo transferred will have about half the chance of propagating a viable pregnancy. Treatment of a partial DQ alpha/HLA match (+ Nka) involves the same IL, infusion as for autoimmune-Nka with one important caveat, namely that here we prescribe oral prednisone as adjunct therapy (rather than dexamethasone) and the IL infusion is repeated every 2-4 weeks following the diagnosis of pregnancy and continued until the 24th week of gestation. Additionally, (as alluded to elsewhere) in such cases we transfer a single (1) embryo at a time. This is because, the likelihood is that one out of two embryos will “match” and we are fearful that if we transfer >1 embryo, and one transferred embryos “matches” it could cause further activation of uterine NK cells and so prejudice the implantation of all transferred embryos. Here it should be emphasized that if associated with Nka, a matching embryo will still be at risk of rejection even in the presence of Intralipid (or IVIg) therapy.

Total (complete) DQ alpha Match:   Here the husband’s DQ alpha genotype matches both of that of his partner’s. While this occurs very infrequently, a total alloimmune (DQ alpha) match with accompanying Nka, means that the chance of a viable pregnancy resulting in a live birth at term, is unfortunately greatly diminished.  Several instances in our experience have required the use of a gestational surrogate.

It is indeed unfortunate that so many patients are being denied the ability to go from “infertility to family” simply because (for whatever reason) so many reproductive specialists refuse to embrace the role of immunologic factors in the genesis of intractable reproductive dysfunction. Hopefully this will change, and the sooner the better.

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

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

I think we should talk!

You clearly have an implantation dysfunction which needs to be identified, quantified and addressed.

I invite you to contact my assistant, Patti Converse at 702-533-2691 and set up an online consultation with me.

Implantation dysfunction is unfortunately often overlooked as an important cause of IVF failure. This is especially relevant in cases of unexplained IVF failure, recurrent pregnancy loss (RPL), and in women with underlying endo-uterine surface lesions, thickness of the uterine lining (endometrium) and /or immunologic factors.

IVF success rates have been improving over the last decade. The average live birth rate per embryo transfer in the U.S.A for women under 40y using their own eggs is currently better than 1:3 women. However, there is still a wide variation from program to program for IVF live birth rates, ranging from 20% to near 50%. Based upon these statistics, most women undergoing IVF in the United States require two or more attempts to have a baby. IVF practitioners in the United States commonly attribute the wide dichotomy in IVF success rates to variability in expertise of the various embryology laboratories. This is far from accurate. In fact, other factors such as wide variations in patient selection and the failure to develop individualized protocols for ovarian stimulation or to address those infectious, anatomical, and immunologic factors that influence embryo implantation are at least equally important.

About 80% of IVF failures are due to “embryo incompetency” that is largely due to aneuploidy      usually related to advancing age of the woman and is further influenced by other factors such as the protocol selected for ovarian stimulation, diminished ovarian reserve (DOR), and severe male factor infertility. However, in about 20% of dysfunctional cases embryo implantation is the cause of failure.

This section will focus on implantation dysfunction and IVF failure due to:

ANATOMICAL ENDO-UTERINE SURFACE LESIONS

            It has long been suspected that anatomical defects of the uterus might result in infertility. While the presence of uterine fibroids, in general, are unlikely to cause infertility, an association between their presence and infertility has been observed in cases where the myomas distort the uterine cavity or protrude through the endometrial lining.  Even small fibroids that lie immediately under the endometrium (submucous fibroids) and protrude into the uterine cavity have the potential to lower embryo implantation.  Multiple fibroids in the uterine wall (intramural fibroids) that encroach upon the uterine cavity can sometimes so compromise blood flow that estrogen delivery is impaired, and the endometrium is unable to thicken properly. This can usually be diagnosed by ultrasound examination during the proliferative phase of the menstrual cycle.  It is likely that any surface lesion in the uterine cavity, whether submucous fibroids, intrauterine adhesions a small endometrial or a placental polyp, has the potential to interfere with implantation by producing a local inflammatory response, not too dissimilar in nature from that which is caused by an intrauterine contraceptive device (IUD).       

            Clearly, since even small uterine lesions have the potential to adversely affect implantation, the high cost (financial, physical, and emotional) associated with IVF and related procedures, justifies the routine performance of diagnostic procedures such as an HSG, hysterosonogram (fluid ultrasound examination), or hysteroscopy prior to initiating IVF.  Identifiable uterine lesions that have the potential of impairing implantation usually require surgical intervention.  In most cases, dilatation and curettage (D & C) or hysteroscopic resection will suffice. Some cases might require the performance of a laparotomy.  Such intervention will often result in subsequent improvement of the endometrial response.      

Sonohysterography [Fluid ultrasonography (FUS)]: Fluid ultrasonography is a procedure whereby a sterile solution of saline is injected via a catheter through the cervix and into the uterine cavity. The fluid-distended cavity is examined by vaginal ultrasound for any irregularities that might point to surface lesions such as polyps, fibroid tumors, scarring, or a uterine septum. If performed by an expert, a FUS is highly effective in recognizing even the smallest lesion and can replace hysteroscopy under such circumstances. FUS is less expensive, less traumatic, and equally as effective as hysteroscopy. The only disadvantage lies in the fact that if a lesion is detected, it may require the subsequent performance of hysteroscopy to treat the problem anyway.

Hysteroscopy: Diagnostic hysteroscopy is an office procedure that is performed under intravenous sedation, general anesthesia, or paracervical block with minimal discomfort to the patient. This procedure involves the insertion of a thin, lighted, telescope like instrument known as a hysteroscope through the vagina and cervix into the uterus to fully examine the uterine cavity. The uterus is first distended with normal saline, which is passed through a sleeve adjacent to the hysteroscope. As is the case with FUS, diagnostic hysteroscopy facilitates examination of the inside of the uterus under direct vision for defects that might interfere with implantation. We have observed that approximately one in eight candidates for IVF have lesions that require attention prior to undergoing IVF in order to optimize the chances of a successful outcome. We strongly recommend that all patients undergo therapeutic surgery (usually by hysteroscopy) to correct the pathology prior to IVF.  Depending on the severity and nature of the pathology, therapeutic hysteroscopy may require general anesthesia and, in such cases, should be performed in an outpatient surgical facility or conventional operating room where facilities are available for laparotomy, a procedure in which an incision is made in the abdomen to expose the abdominal contents for diagnosis, or for surgery should this be required.       

THICKNESS OF THE UTERINE LINING (ENDOMETRIUM):

As far back as in 1989 we first reported on the finding that ultrasound assessment of the late proliferative phase endometrium can identify those candidates who are least likely to conceive. We noted that the ideal thickness of the endometrium at the time of ovulation or egg retrieval is >8 mm and that thinner linings are associated with decreased implantation rates.

More than 30 years ago we first showed that in normal and “stimulated” cycles, pre-ovulatory endometrial thickness and ultrasound appearance is predictive of embryo implantation (pregnancy) potential following ET. With conventional IVF and with FET, endometrial lining at the time of the “trigger shot” or with the initiation of progesterone needs to preferably be at least 8 mm in sagittal thickness with a triple line (trilaminar) appearance. Anything less than an 8mm endometrial thickness       is associated with a reduction in live birth rate per ET. An 8-9mm thickness represents a transitional measurement…a “gray zone”.  Hitherto, attempts to augment endometrial growth in women with poor endometrial linings by bolstering circulating estrogen blood levels (through the administration of increased doses of fertility drugs, aspirin administration and by supplementary estrogen therapy) yielded disappointing results.

            A “poor” uterine lining is usually the result of the innermost layer of endometrium (the basal or germinal endometrium from which endometrium grows) not being able to respond to estrogen by propagating an outer, “functional” layer thick enough to support optimal embryo implantation and development of a healthy placenta (placentation). The “functional” layer ultimately comprises 2/3 of the full endometrial thickness and is the layer that sheds with menstruation if no pregnancy occurs.

The main causes of a “poor” uterine lining are:

• Damage to the basal endometrium because of:
• Inflammation of the endometrium (endometritis) most commonly resulting from infected products left over following abortion, miscarriage, or birth
• Surgical trauma due to traumatic uterine scraping, (i.e. due to an over-aggressive D & C)
• Insensitivity of the basal endometrium to estrogen due to:
• Prolonged, over-use/misuse of clomiphene citrate
• Prenatal exposure to diethylstilbestrol (DES). This is a drug that was given to pregnant women in the 1960’s to help prevent miscarriage
• Over-exposure of the uterine lining to ovarian male hormones (mainly testosterone): Older women, women with diminished ovarian reserve (poor responders) and women with polycystic ovarian syndrome -PCOS tend to have raised LH biological activity. This causes the connective tissue in the ovary (stroma/theca) to overproduce testosterone. The effect may be further exaggerated when certain methods for ovarian stimulation such as “flare” protocols and high dosages of Menopur are used in such cases.
• Reduced blood flow to the basal endometrium: Examples include.
• Multiple uterine fibroids – especially when these are present under the endometrium (submucosal)
• Uterine adenomyosis (excessive, abnormal invasion of the uterine muscle by endometrial glands).

Vaginal Viagra: About 35 years ago, after reporting on the benefit of administering vaginal Sildenafil (Viagra) to women who had implantation dysfunction due to thin endometrial linings we announced the birth of the world’s first “Viagra baby.”  Viagra administered vaginally, but not orally, in affected women improves uterine blood flow causing more estrogen to be delivered to the basal endometrium and increasing the endometrial thickening.  Following vaginal administration, Viagra is rapidly absorbed and quickly reaches the uterine blood system in high concentrations. Thereupon it dilutes out as it is absorbed into the systemic circulation. This probably explains why treatment is virtually devoid of systemic side effects.  It is important to recognize that Viagra will NOT be effective in improving endometrial thickness in all cases. In fact, about one third of women treated fail to show any improvement. This is because in certain cases of thin uterine linings, the basal endometrium will have been permanently damaged and left unresponsive to estrogen. This happens in cases of severe endometrial damage due mainly to post-pregnancy endometritis (inflammation), chronic granulomatous inflammation due to uterine tuberculosis (hardly ever seen in the United States) and following extensive surgical injury to the basal endometrium (as sometimes occurs following over-zealous D&C’s).

• Immunologic factors: These also play a role in IVF failure (see “Immunologic factors and Implantation” …see below.

IMMUNOLOGIC IMPLANTATION DYSFUNCTION (IID)

            Currently, with few exceptions, practitioners of assisted reproduction tend to attribute “unexplained and/or repeated” IVF failure(s), almost exclusively to poor embryo quality, advocating adjusted protocols for ovarian stimulation and/or gamete and embryo preparation as a potential remedy. The idea, having failed IVF, that all it takes to ultimately succeed is to keep trying the same recipe is over-simplistic.

            The implantation process begins six or seven days after fertilization of the egg. At this time, specialized embryonic cells (i.e., trophoblasts), that later become the placenta begin growing into the uterine lining. When the trophoblast and the uterine lining meet, they, along with immune cells in the lining, become involved in a “cross talk” through mutual exchange of hormone-like substances called cytokines. Because of this complex immunologic interplay, the uterus can foster the embryo’s successful growth. Thus, from the earliest stage, the trophoblast establishes the very foundation for the nutritional, hormonal and respiratory interchange between mother and baby.  In this manner, the interactive process of implantation is not only central to survival in early pregnancy but also to the quality of life after birth.

There is an ever growing realization, recognition, and acceptance of the fact that uterine immunologic dysfunction can lead to immunologic implantation dysfunction (IID) with “unexplained” infertility, IVF failure, and recurrent pregnancy loss (RPL).

DIAGNOSIS 

Because immunologic problems may lead to implantation failure, it is important to properly evaluate women with risk factors such as:

• Unexplained or recurrent IVF failures
• Unexplained infertility or a family history of autoimmune diseases (e.g., rheumatoid arthritis, lupus erythematosus and hypothyroidism).
• Recurrent Pregnancy Loss (RPL)
• Endometriosis
• A personal or family history of autoimmune conditions, e.g., Rheumatoid Arthritis, Lupus erythematosus, autoimmune hypothyroidism (Hashimoto’s disease) etc.

            Considering its importance, it is not surprising that the failure of a properly functioning immunologic interaction during implantation has been implicated as a cause of recurrent miscarriage, late pregnancy fetal loss, IVF failure and infertility. A partial list of immunologic factors that may be involved in these situations includes:

• Antiphospholipid antibodies (APA)
• Antithyroid antibodies (ATA/AMA)
• Activated natural killer cells (NKa)

ACTIVATED NATURAL KILLER CELLS (NKa):

Following ovulation and during early pregnancy, NK cells and T-cells comprise more than 80% of the lymphocyte-immune cells that frequent the uterine lining. These lymphocytes (white blood cells) journey from the bone marrow to the uterus and under hormonal regulation, proliferate there. After exposure to progesterone (due to induced /spontaneous exogenous administration), they begin to produce TH-1 and TH-2 cytokines. TH-2 cytokines are humoral in nature and induce the trophoblast (“root system of the embryo”) to permeate the uterine lining while TH-I cytokines induce a process referred to as apoptosis (cell suicide) thereby confining placental development to the inner part of the uterus. Optimal placental development (placentation) mandates that there be a balance between TH1 and TH-2 cytokines. Most of the cytokine production originates from NK cells (rather than from cytotoxic T-cells/Lymphocytes (CTL)). Excessive production/release of TH-1 cytokines, is toxic to the trophoblast and to endometrial cells, leading to programmed death/suicide (apoptosis) and subsequently to IID.

Functional NK cells reach a maximal concentration in the endometrium by about t day 6-7 days after exposure to progesterone …. This timing corresponds with when the embryo implants into the uterine lining (endometrium).

It is important to bear in mind that measurement of the concentration of blood NK cells has little or no relevance when it comes to assessing NK cell activation (NKa). Rather, it is the NK cell activation that matters. In fact, there are certain conditions (such as with endometriosis) where the NK cell blood concentration is below normal, but NK cell activation is markedly increased.

There are several methods by which NK cell activation (cytotoxicity) can be assessed in the laboratory. Methods such as immunohistochemical assessment of uterine NK cells and/or through measurement of uterine or blood TH-1 cytokines. However, the K-562 target cell blood test still remains the gold standard. With this test, NK cells, isolated from the woman’s blood using Flow Cytometry are incubated in the presence of specific “target cells”. The percentage (%) of “target cells” killed is then quantified. More than 12% killing suggests a level of NK cell activation that usually requires treatment.

Currently, there are less than a half dozen Reproductive Immunology Reference Laboratories in the U.S.A that are capable of performing the K-562 target cell test reliably.

There exists a pervasive but blatant misconception on the part of many, that the addition of IL or IVIg to a concentration of NK cells could have an immediate down-regulatory effect on NK cell activity. Neither IVIg nor IL is capable of significantly suppressing already activated “functional NK cells”. They are believed to work through “regulating” NK cell progenitors which only thereupon will start to propagate down-regulated NK cells. Thus, testing for a therapeutic effect would require that the IL/IVIg infusion be done about 14 days prior to ovulation or progesterone administration…  in order to allow for a sufficient number of normal (non-activated) “functional” NK cell” to be present at the implantation site when the embryos are transferred.

Failure to recognize this reality has, in our opinion, established an erroneous demand by practicing IVF doctors, that Reproductive Immunology Reference Laboratories report on NK cell activity before and again, immediately following laboratory exposure to IVIg and/or IL in different concentrations. Allegedly, this is to allow the treating physician to report back to their patient(s) on whether an IL or IVIG infusion will be effective in downregulating their Nka.  But, since already activated NK cells (NKa) cannot be deactivated in the laboratory, effective NKa down-regulation can only be adequately accomplished through deactivation of NK cell “progenitors /parental” NK cells in order to allow them thereupon, to s propagate normal “functional” NK cells and his takes about 10-14 days, such practice would be of little clinical benefit. This is because even if blood were to be drawn 10 -14 days after IL/IVIg treatment it would require at least an additional 10 -14days to receive results from the laboratory, by which time it would be far too late to be of practical advantage.

ANTIPHOSPHOLIPID ANTIBODIES:

 Many women who experience “unexplained” IVF failure, women with RPL, those with a personal or family history of autoimmune diseases such as lupus erythematosus, rheumatoid arthritis, scleroderma, and dermatomyositis (etc.)  as well as women who have endometriosis (“silent” or overt) test positive for APAs. More than 30 years ago, we were the first to propose that women who test positive for APA’s be treated with a mini-dose heparin to improve IVF implantation and thus birth rates. This approach was based upon research that suggested that heparin repels APAs from the surface of the trophoblast (the embryo’s “root system) thereby reducing its ant-implantation effects.  We subsequently demonstrated that such therapy only improved IVF outcome in women whose APAs were directed against two specific IgG and/or IgM phospholipids [i.e., phosphatidylethanolamine (PE) and phosphatidylserine (PS)].  More recently low dosage heparin therapy has been supplanted using longer acting low molecular weight heparinoids such as Lovenox and Clexane.   It is very possible that APAs alone do not cause IID but that their presence might help to identify a population at risk due to concomitant activation of uterine natural killer cells (Nka) which through excessive TH-1 cytokine production causes in IID: This is supported by the following observations:

• The presence of female APAs in cases of male factor cases appears to bear no relationship to IID.
• Only APA positive women who also test positive for abnormal NK activity appear to benefit from selective immunotherapy with intralipid/IVIg/ steroids.
• Most APA positive women who have increased NK cell activity also harbor IgG or IgM phosphatidylethanolamine (PE) and phosphatidylserine (PS) antibodies.

ANTITHYROID ANTIBODIES: (ATA).

 A clear relationship has been established between ATA and reproductive failure (especially recurrent miscarriage and infertility).

Between 2% and 5% of women of the childbearing age have reduced thyroid hormone activity (hypothyroidism). Women with hypothyroidism often manifest with reproductive failure i.e., infertility, unexplained (often repeated) IVF failure, or recurrent pregnancy loss (RPL). The condition is 5-10 times more common in women than in men. In most cases hypothyroidism is caused by damage to the thyroid gland resulting from of thyroid autoimmunity (Hashimoto’s disease) caused by damage done to the thyroid gland by antithyroglobulin and antimicrosomal auto-antibodies. 

The increased prevalence of hypothyroidism and thyroid autoimmunity (TAI) in women is likely the result of a combination of genetic factors, estrogen-related effects, and chromosome X abnormalities.  This having been said, there is significantly increased incidence of thyroid antibodies in non-pregnant women with a history of infertility and recurrent pregnancy loss and thyroid antibodies ^can be present asymptomatically in women without them manifesting with overt clinical or endocrinologic evidence of thyroid disease. In addition, these antibodies may persist in women who have suffered from hyper- or hypothyroidism even after normalization of their thyroid function by appropriate pharmacological treatment. The manifestations of reproductive dysfunction thus seem to be linked more to the presence of thyroid autoimmunity (TAI) than to clinical existence of hypothyroidism and treatment of the latter does not routinely result in a subsequent improvement in reproductive performance.

It follows, that if antithyroid autoantibodies are associated with reproductive dysfunction they may serve as useful markers for predicting poor outcome in patients undergoing assisted reproductive technologies.

Some years back, I reported on the fact that 47% of women who harbor thyroid autoantibodies, regardless of the absence or presence of clinical hypothyroidism, have activated uterine natural killer cells (NKa) cells and cytotoxic lymphocytes (CTL) and that such women often present with reproductive dysfunction. We demonstrated that appropriate immunotherapy with IVIG or intralipid (IL) and steroids, subsequently often results in a significant improvement in reproductive performance in such cases.

The fact that almost 50% of women who harbor antithyroid antibodies do not have activated CTL/NK cells suggests that it is NOT the antithyroid antibodies themselves that cause reproductive dysfunction. The activation of CTL and NK cells that occurs in half of the cases with TAI is probably an epiphenomenon with the associated reproductive dysfunction being due to CTL/NK cell activation that damages the early “root system” (trophoblast) of the implanting embryo. We have shown that treatment of those women who have thyroid antibodies + NKa/CTL using IL/steroids, improves subsequent reproductive performance while women with thyroid antibodies who do not harbor NKa/CTL do not require or benefit from such treatment

TEATMENT OF IID:

The mainstay of treatment involves the selective use of:

• Intralipid (IL) infusion
• IVIg therapy
• Corticosteroids (Prednisone/dexamethasone)
• Heparinoids (Lovenox/Clexane)

Intralipid (IL) Therapy:  IL is a suspension of soybean lipid droplets in water and is primarily used as source of parenteral nutrition. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, and alpha-linolenic acid (ALA), an omega-3 fatty acid.     

It is thought that fatty acids within the emulsion serve as ligands that activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cell cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent.

            Whatever the exact mechanism of action might be, Intralipid acts primarily to suppress NK cell over-production of TH-I cytokines. It exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating cytotoxic /activated natural killer cells (NKa). This effect is enhanced through the concomitant administration of corticosteroids such as dexamethasone, prednisolone and prednisone which augment immune modulation of T cells. The combined effect of IL + steroid therapy suppresses pro-inflammatory cellular TH1 cytokines such as interferon gamma and TNF-alpha that are produced in excess by activated NK cells and cytotoxic lymphocytes/T-cells (CTL).   IL will, in about 80% of cases, successfully down-regulate activated natural killer cells (NKa) over a period of 2-3 weeks. It is likely to be just as effective as IVIg in this respect but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for ~ 4-6 weeks when administered in early pregnancy.

Intralipid is a suspension of soybean lipid droplets in water and is primarily used as source of parenteral nutrition. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, and alpha-linolenic acid (ALA), an omega-3 fatty acid.     

It is thought that fatty acids within the emulsion serve as ligands that activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cell cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent.

            Whatever the exact mechanism of action might be, Intralipid acts primarily to suppress NK cell over-production of TH-I cytokines. It exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating cytotoxic /activated natural killer cells (NKa). This effect is enhanced through the concomitant administration of corticosteroids such as dexamethasone, prednisolone and prednisone which augment immune modulation of T cells. The combined effect of IL + steroid therapy suppresses pro-inflammatory cellular TH1 cytokines such as interferon gamma and TNF-alpha that are produced in excess by activated NK cells and cytotoxic lymphocytes/T-cells (CTL).   IL will, in about 80% of cases, successfully down-regulate activated natural killer cells (NKa) over a period of 2-3 weeks. It is likely to be just as effective as IVIg in this respect but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for ~ 4-6 weeks when administered in early pregnancy.

            Can laboratory testing be used to assess for an immediate effect of IL on Nka suppression?  Since the downregulation of NKa through IL (or IVIg) therapy can take several weeks to become measurable, it follows that there is really no benefit in trying to assess the potential efficacy of such treatment by retesting NKa in the laboratory after adding IL (or IVIg) to the cells being tested.

IVIg Therapy:  Until about a decade ago, the only effective and available way (in the US) to down-regulate activated NK cells was through the intravenous administration of a blood product known as immunoglobulin-G (IVIg). The fear (albeit unfounded) that the administration of this product might lead to the transmission of viral infections such as HIV and hepatitis C, plus the high cost of IVIG along with the fact that significant side effects occurred about 20% of the time, led to bad press and bad publicity for the entire field of reproductive immunology. It was easier for RE’s to simply say “I don’t believe IVIg works” and thereby avoid risk and bad publicity. But the thousands of women who had babies because of NK cell activity being downregulated through its use, attests to IVIg’s efficacy. But those of us who felt morally obligated to many desperate patients who would not conceive without receiving IVIg were facing an uphill battle. The bad press caused by fear mongering took its toll and spawned a malicious controversy. It was only through the introduction of IL less (about 15-20 years ago ), that the tide began to turn in favor of those patients who required low cost, safe and effective immunotherapy to resolve their IID.

 Corticosteroid Therapy (e.g., Prednisone, and Dexamethasone): Corticosteroid therapy has become a mainstay in the treatment of most women undergoing IVF. It is believed by most to enhance implantation due to an overall immunomodulatory effect. Corticosteroids reduce TH-1 cytokine production by CTL. When given in combination with IL or IVIG they augment the implantation process. The prednisone or dexamethasone therapy must commence (along with IL/IVIg) 10-14 days prior to egg retrieval and continue until pregnancy is discounted or until the 10th week of pregnancy.

 Heparinoid Therapy: There is compelling evidence that the subcutaneous administration of low molecular heparin (Clexane, Lovenox) once daily, (starting with the onset of ovarian stimulation) can improve IVF birthrate in women who test positive for APAs and might prevent later pregnancy loss when used to treat certain thrombophilias (e.g., homozygous MTHFR mutation)

What About Baby Aspirin? In our opinion, aspirin has little (if any) value when it comes to IID, and besides, it could even reduce the chance of success. The reason for this is that aspirin thins the blood and increases the potential to bleed. This effect can last for up to a week and could complicate an egg retrieval procedure or result in “concealed” intrauterine bleeding at the time of embryo transfer, thereby potentially compromising IVF success.

TH-1 Cytokine Blockers (Enbrel, Humira): TH-1 cytokine blockers, (Enbrel and Humira) are in our opinion relatively ineffective in the IVF setting. There has to date been no convincing data to support their use. However, these blockers could have a role in the treatment of a threatened miscarriage thought to be due to CTL/NK activation, but not for IVF. The reason is that the very initial phase of implantation requires a cellular response involving TH-1 cytokines. To block them completely (rather than simply restore a TH-1:TH-2 balance as occurs with IL therapy) so very early on could compromise rather than benefit implantation.

Leukocyte Immunization Therapy (LIT): The subcutaneous injection of the male partner’s lymphocytes to the mother is thought to enhance the ability for the mother’s decidua (uterus) to recognize the DQ alpha matching embryo as “self” or “friend” and thereby avert its rejection. LIT has been shown to up-regulate Treg cells and thus down-regulate NK cell activation thereby improving decidual TH-1:TH-2 balance. Thus, there could be a therapeutic benefit from such therapy. However, the same benefit can be achieved through the use of IL plus corticosteroids. Besides, IL is much less expensive, and the use of LIT is prohibited by law in the U.S.A.

There are two categories of immunologic implantation dysfunction (IID) linked to NK cell activation (NKa).

Autoimmune Implantation Dysfunction: Here, the woman will often have a personal or family history of autoimmune conditions such as Rheumatoid arthritis, Lupus Erythematosus, and thyroid autoimmune activity (e.g., Hashimoto’s disease) etc. Autoimmune as well as in about one third of cases of endometriosis, regardless of severity.  Autoimmune sometimes also occurs in the absence of a personal or family history of autoimmune disease.

When it comes to treating  NKa in  IVF cases complicated by autoimmune implantation dysfunction,  the combination of daily oral dexamethasone commencing with the onset of ovarian stimulation and continuing until the 10th week of pregnancy, combined with an initial infusion of IL (100ml, 20% Il dissolved in 500cc of saline solution, 10-14  days prior to PGT-normal embryo transfer and repeated once more (only), as  soon as the blood pregnancy test is positive), the anticipated chance of a viable pregnancy occurring within 2 completed IVF attempts (including fresh + frozen ET’s)  in women under 39Y (who have normal ovarian reserve)  is approximately  65%.

Alloimmune Implantation Dysfunction: Here, NK cell activation results from uterine exposure to an embryo derived through fertilization by a spermatozoon that shares certain genotypic (HLA/DQ alpha) similarities with that of the embryo recipient.

Partial DQ alpha/HLA match:  Couples who upon genotyping are shown to share only one DQ alpha/HLA gene are labeled as having a “partial match”. The detection of a “partial match” in association with NKa puts the couple at a considerable disadvantage with regard to IVF outcome. It should be emphasized however, that in the absence of associated Nka, DQ alpha/HLA matching whether “partial” or “total (see below) will NOT cause an IID. Since we presently have no way of determining which embryo carries a matching paternal DQ alpha gene, it follows that each embryo transferred will have about half the chance of propagating a viable pregnancy. Treatment of a partial DQ alpha/HLA match (+ Nka) involves the same IL, infusion as for autoimmune-Nka with one important caveat, namely that here we prescribe oral prednisone as adjunct therapy (rather than dexamethasone) and the IL infusion is repeated every 2-4 weeks following the diagnosis of pregnancy and continued until the 24th week of gestation. Additionally, (as alluded to elsewhere) in such cases we transfer a single (1) embryo at a time. This is because, the likelihood is that one out of two embryos will “match” and we are fearful that if we transfer >1 embryo, and one transferred embryos “matches” it could cause further activation of uterine NK cells and so prejudice the implantation of all transferred embryos. Here it should be emphasized that if associated with Nka, a matching embryo will still be at risk of rejection even in the presence of Intralipid (or IVIg) therapy.

Total (complete) DQ alpha Match:   Here the husband’s DQ alpha genotype matches both of that of his partner’s. While this occurs very infrequently, a total alloimmune (DQ alpha) match with accompanying Nka, means that the chance of a viable pregnancy resulting in a live birth at term, is unfortunately greatly diminished.  Several instances in our experience have required the use of a gestational surrogate.

It is indeed unfortunate that so many patients are being denied the ability to go from “infertility to family” simply because (for whatever reason) so many reproductive specialists refuse to embrace the role of immunologic factors in the genesis of intractable reproductive dysfunction. Hopefully this will change, and the sooner the better.

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

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

I suggest we talk. Please consider calling Patti Converse (my assistant) at 702-533-2691 and set up an online consultation with me to discuss.

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

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

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

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

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

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

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

I strongly recommend that you visit 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!

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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

I really think I can help you. I invite you to contact my assistant, Patti Converse at 702-533-2691 and set up an online consultation with me.

Currently, with few exceptions, practitioners of assisted reproduction tend to attribute “unexplained and/or repeated” IVF failure(s), almost exclusively to poor embryo quality, advocating adjusted protocols for ovarian stimulation and/or gamete and embryo preparation as a potential remedy. The idea, having failed IVF, that all it takes to ultimately succeed is to keep trying the same recipe is over-simplistic.

The implantation process begins six or seven days after fertilization of the egg. At this time, specialized embryonic cells (i.e., trophoblasts), that later become the placenta begin growing into the uterine lining. When the trophoblast and the uterine lining meet, they, along with immune cells in the lining, become involved in a “cross talk” through mutual exchange of hormone-like substances called cytokines. Because of this complex immunologic interplay, the uterus can foster the embryo’s successful growth. Thus, from the earliest stage, the trophoblast establishes the very foundation for the nutritional, hormonal and respiratory interchange between mother and baby.  In this manner, the interactive process of implantation is not only central to survival in early pregnancy but also to the quality of life after birth.

There is an ever growing realization, recognition, and acceptance of the fact that uterine immunologic dysfunction can lead to immunologic implantation dysfunction (IID) with “unexplained” infertility, IVF failure, and recurrent pregnancy loss (RPL).

DIAGNOSIS 

Because immunologic problems may lead to implantation failure, it is important to properly evaluate women with risk factors such as:

• Unexplained or recurrent IVF failures
• Unexplained infertility or a family history of autoimmune diseases (e.g., rheumatoid arthritis, lupus erythematosus and hypothyroidism).
• Recurrent Pregnancy Loss (RPL)
• Endometriosis
• A personal or family history of autoimmune conditions, e.g., Rheumatoid Arthritis, Lupus erythematosus, autoimmune hypothyroidism (Hashimoto’s disease) etc.

Considering its importance, it is not surprising that the failure of a properly functioning immunologic interaction during implantation has been implicated as a cause of recurrent miscarriage, late pregnancy fetal loss, IVF failure and infertility. A partial list of immunologic factors that may be involved in these situations includes:

• Antiphospholipid antibodies (APA)
• Antithyroid antibodies (ATA/AMA)
• Activated natural killer cells (NKa)

ACTIVATED NATURAL KILLER CELLS (NKa):

Following ovulation and during early pregnancy, NK cells and T-cells comprise more than 80% of the lymphocyte-immune cells that frequent the uterine lining. These lymphocytes (white blood cells) journey from the bone marrow to the uterus and under hormonal regulation, proliferate there. After exposure to progesterone (due to induced /spontaneous exogenous administration), they begin to produce TH-1 and TH-2 cytokines. TH-2 cytokines are humoral in nature and induce the trophoblast (“root system of the embryo”) to permeate the uterine lining while TH-I cytokines induce a process referred to as apoptosis (cell suicide) thereby confining placental development to the inner part of the uterus. Optimal placental development (placentation) mandates that there be a balance between TH1 and TH-2 cytokines. Most of the cytokine production originates from NK cells (rather than from cytotoxic T-cells/Lymphocytes (CTL)). Excessive production/release of TH-1 cytokines, is toxic to the trophoblast and to endometrial cells, leading to programmed death/suicide (apoptosis) and subsequently to IID.

Functional NK cells reach a maximal concentration in the endometrium by about t day 6-7 days after exposure to progesterone …. This timing corresponds with when the embryo implants into the uterine lining (endometrium).

It is important to bear in mind that measurement of the concentration of blood NK cells has little or no relevance when it comes to assessing NK cell activation (NKa). Rather, it is the NK cell activation that matters. In fact, there are certain conditions (such as with endometriosis) where the NK cell blood concentration is below normal, but NK cell activation is markedly increased.

There are several methods by which NK cell activation (cytotoxicity) can be assessed in the laboratory. Methods such as immunohistochemical assessment of uterine NK cells and/or through measurement of uterine or blood TH-1 cytokines. However, the K-562 target cell blood test still remains the gold standard. With this test, NK cells, isolated from the woman’s blood using Flow Cytometry are incubated in the presence of specific “target cells”. The percentage (%) of “target cells” killed is then quantified. More than 12% killing suggests a level of NK cell activation that usually requires treatment.

Currently, there are less than a half dozen Reproductive Immunology Reference Laboratories in the U.S.A that are capable of performing the K-562 target cell test reliably.

There exists a pervasive but blatant misconception on the part of many, that the addition of IL or IVIg to a concentration of NK cells could have an immediate down-regulatory effect on NK cell activity. Neither IVIg nor IL is capable of significantly suppressing already activated “functional NK cells”. They are believed to work through “regulating” NK cell progenitors which only thereupon will start to propagate down-regulated NK cells. Thus, testing for a therapeutic effect would require that the IL/IVIg infusion be done about 14 days prior to ovulation or progesterone administration…  in order to allow for a sufficient number of normal (non-activated) “functional” NK cell” to be present at the implantation site when the embryos are transferred.

Failure to recognize this reality has, in our opinion, established an erroneous demand by practicing IVF doctors, that Reproductive Immunology Reference Laboratories report on NK cell activity before and again, immediately following laboratory exposure to IVIg and/or IL in different concentrations. Allegedly, this is to allow the treating physician to report back to their patient(s) on whether an  IL or IVIG infusion will be effective in down-regulating their Nka.  But, since already activated NK cells (NKa) cannot be deactivated in the laboratory, effective NKa down-regulation can only be adequately accomplished through deactivation of NK cell “progenitors /parental” NK cells in order too allow them thereupon, to s propagate normal “functional” NK cells and his takes about 10-14 days, such practice  would be of little clinical benefit. This is because even if blood were to be drawn 10 -14 days after IL/IVIg treatment it would require at least  an additional 10 -14days to receive results from the laboratory, by which time it would be far too late to be of practical advantage.

ANTIPHOSPHOLIPID ANTIBODIES:

 Many women who experience “unexplained” IVF failure, women with RPL, those with a personal or family history of autoimmune diseases such as lupus erythematosus, rheumatoid arthritis, scleroderma, and dermatomyositis (etc.)  as well as women who have endometriosis (“silent” or overt) test positive for APAs. More than 30 years ago, we were the first to propose that women who test positive for APA’s be treated with a mini-dose heparin to improve IVF implantation and thus birth rates. This approach was based upon research that suggested that heparin repels APAs from the surface of the trophoblast (the embryo’s “root system) thereby reducing its ant-implantation effects.  We subsequently demonstrated that such therapy only improved IVF outcome in women whose APAs were directed against two specific IgG and/or IgM phospholipids [i.e., phosphatidylethanolamine (PE) and phosphatidylserine (PS)].  More recently low dosage heparin therapy has been supplanted using longer acting low molecular weight heparinoids such as Lovenox and Clexane.   It is very possible that APAs alone do not cause IID but that their presence might help to identify a population at risk due to concomitant activation of uterine natural killer cells (Nka) which through excessive TH-1 cytokine production causes in IID: This is supported by the following observations:

• The presence of female APAs in cases of male factor cases appears to bear no relationship to IID.
• Only APA positive women who also test positive for abnormal NK activity appear to benefit from selective immunotherapy with intralipid/IVIg/ steroids.
• Most APA positive women who have increased NK cell activity also harbor IgG or IgM phosphatidylethanolamine (PE) and phosphatidylserine (PS) antibodies.

ANTITHYROID ANTIBODIES: (ATA).

 A clear relationship has been established between ATA and reproductive failure (especially recurrent miscarriage and infertility).

Between 2% and 5% of women of the childbearing age have reduced thyroid hormone activity (hypothyroidism). Women with hypothyroidism often manifest with reproductive failure i.e., infertility, unexplained (often repeated) IVF failure, or recurrent pregnancy loss (RPL). The condition is 5-10 times more common in women than in men. In most cases hypothyroidism is caused by damage to the thyroid gland resulting from of thyroid autoimmunity (Hashimoto’s disease) caused by damage done to the thyroid gland by antithyroglobulin and antimicrosomal auto-antibodies. 

The increased prevalence of hypothyroidism and thyroid autoimmunity (TAI) in women is likely the result of a combination of genetic factors, estrogen-related effects, and chromosome X abnormalities.  This having been said, there is significantly increased incidence of thyroid antibodies in non-pregnant women with a history of infertility and recurrent pregnancy loss and thyroid antibodies ^can be present asymptomatically in women without them manifesting with overt clinical or endocrinologic evidence of thyroid disease. In addition, these antibodies may persist in women who have suffered from hyper- or hypothyroidism even after normalization of their thyroid function by appropriate pharmacological treatment. The manifestations of reproductive dysfunction thus seem to be linked more to the presence of thyroid autoimmunity (TAI) than to clinical existence of hypothyroidism and treatment of the latter does not routinely result in a subsequent improvement in reproductive performance.

It follows, that if antithyroid autoantibodies are associated with reproductive dysfunction they may serve as useful markers for predicting poor outcome in patients undergoing assisted reproductive technologies.

Some years back, I reported on the fact that 47% of women who harbor thyroid autoantibodies, regardless of the absence or presence of clinical hypothyroidism, have activated uterine natural killer cells (NKa) cells and cytotoxic lymphocytes (CTL) and that such women often present with reproductive dysfunction. We demonstrated that appropriate immunotherapy with IVIG or intralipid (IL) and steroids, subsequently often results in a significant improvement in reproductive performance in such cases.

The fact that almost 50% of women who harbor antithyroid antibodies do not have activated CTL/NK cells suggests that it is NOT the antithyroid antibodies themselves that cause reproductive dysfunction. The activation of CTL and NK cells that occurs in half of the cases with TAI is probably an epiphenomenon with the associated reproductive dysfunction being due to CTL/NK cell activation that damages the early “root system” (trophoblast) of the implanting embryo. We have shown that treatment of those women who have thyroid antibodies + NKa/CTL using IL/steroids, improves subsequent reproductive performance while women with thyroid antibodies who do not harbor NKa/CTL do not require or benefit from such treatment

TEATMENT OF IID:

The mainstay of treatment involves the selective use of :

• Intralipid (IL) infusion
• IVIg therapy
• Corticosteroids (Prednisone/dexamethasone)
• Heparinoids (Lovenox/Clexane)

Intralipid (IL) Therapy:  IL is a suspension of soybean lipid droplets in water and is primarily used as source of parenteral nutrition. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, and alpha-linolenic acid (ALA), an omega-3 fatty acid.     

It is thought that fatty acids within the emulsion serve as ligands that activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cell cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent.

            Whatever the exact mechanism of action might be, Intralipid acts primarily to suppress NK cell over-production of TH-I cytokines. It exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating cytotoxic /activated natural killer cells (NKa). This effect is enhanced through the concomitant administration of corticosteroids such as dexamethasone, prednisolone and prednisone which augment immune modulation of T cells. The combined effect of IL + steroid therapy suppresses pro-inflammatory cellular TH1 cytokines such as interferon gamma and TNF-alpha that are produced in excess by activated NK cells and cytotoxic lymphocytes/T-cells (CTL).   IL will, in about 80% of cases, successfully down-regulate activated natural killer cells (NKa) over a period of 2-3 weeks. It is likely to be just as effective as IVIg in this respect but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for ~ 4-6 weeks when administered in early pregnancy.

Intralipid is a suspension of soybean lipid droplets in water and is primarily used as source of parenteral nutrition. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, and alpha-linolenic acid (ALA), an omega-3 fatty acid.     

It is thought that fatty acids within the emulsion serve as ligands that activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cell cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent.

            Whatever the exact mechanism of action might be, Intralipid acts primarily to suppress NK cell over-production of TH-I cytokines. It exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating cytotoxic /activated natural killer cells (NKa). This effect is enhanced through the concomitant administration of corticosteroids such as dexamethasone, prednisolone and prednisone which augment immune modulation of T cells. The combined effect of IL + steroid therapy suppresses pro-inflammatory cellular TH1 cytokines such as interferon gamma and TNF-alpha that are produced in excess by activated NK cells and cytotoxic lymphocytes/T-cells (CTL).   IL will, in about 80% of cases, successfully down-regulate activated natural killer cells (NKa) over a period of 2-3 weeks. It is likely to be just as effective as IVIg in this respect but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for ~ 4-6 weeks when administered in early pregnancy.

            Can laboratory testing be used to assess for an immediate effect of IL on Nka suppression?  Since the downregulation of NKa through IL (or IVIg) therapy can take several weeks to become measurable, it follows that there is really no benefit in trying to assess the potential efficacy of such treatment by retesting NKa in the laboratory after adding IL (or IVIg) to the cells being tested.

IVIg Therapy:  Until about a decade ago, the only effective and available way (in the US) to down-regulate activated NK cells was through the intravenous administration of a blood product known as immunoglobulin-G (IVIg). The fear (albeit unfounded) that the administration of this product might lead to the transmission of viral infections such as HIV and hepatitis C, plus the high cost of IVIG along with the fact that significant side effects occurred about 20% of the time, led to bad press and bad publicity for the entire field of reproductive immunology. It was easier for RE’s to simply say “I don’t believe IVIg works” and thereby avoid risk and bad publicity. But the thousands of women who had babies because of NK cell activity being downregulated through its use, attests to IVIg’s efficacy. But those of us who felt morally obligated to many desperate patients who would not conceive without receiving IVIg were facing an uphill battle. The bad press caused by fear mongering took its toll and spawned a malicious controversy. It was only through the introduction of IL less (about 15-20 years ago ), that the tide began to turn in favor of those patients who required low cost, safe and effective immunotherapy to resolve their IID.

 Corticosteroid Therapy (e.g., Prednisone, and Dexamethasone): Corticosteroid therapy has become a mainstay in the treatment of most women undergoing IVF. It is believed by most to enhance implantation due to an overall immunomodulatory effect. Corticosteroids reduce TH-1 cytokine production by CTL. When given in combination with IL or IVIG they augment the implantation process. The prednisone or dexamethasone therapy must commence (along with IL/IVIg)  10-14 days prior to egg retrieval and continue until pregnancy is discounted or until the 10th week of pregnancy.

 Heparinoid Therapy: There is compelling evidence that the subcutaneous administration of low molecular heparin (Clexane, Lovenox) once daily, (starting with the onset of ovarian stimulation) can improve IVF birthrate in women who test positive for APAs and might prevent later pregnancy loss when used to treat certain thrombophilias (e.g. homozygous MTHFR mutation)

What About Baby Aspirin? In our opinion, aspirin has little (if any) value when it comes to IID, and besides, it could even reduce the chance of success. The reason for this is that aspirin thins the blood and increases the potential to bleed. This effect can last for up to a week and could complicate an egg retrieval procedure or result in “concealed” intrauterine bleeding at the time of embryo transfer, thereby potentially compromising IVF success.

TH-1 Cytokine Blockers (Enbrel, Humira): TH-1 cytokine blockers, (Enbrel and Humira) are in our opinion relatively ineffective in the IVF setting. There has to date been no convincing data to support their use. However, these blockers could have a role in the treatment of a threatened miscarriage thought to be due to CTL/NK activation, but not for IVF. The reason is that the very initial phase of implantation requires a cellular response involving TH-1 cytokines. To block them completely (rather than simply restore a TH-1:TH-2 balance as occurs with IL therapy) so very early on could compromise rather than benefit implantation.

Leukocyte Immunization Therapy (LIT): The subcutaneous injection of the male partner’s lymphocytes to the mother is thought to enhance the ability for the mother’s decidua (uterus) to recognize the DQ alpha matching embryo as “self” or “friend” and thereby avert its rejection. LIT has been shown to up-regulate Treg cells and thus down-regulate NK cell activation thereby improving decidual TH-1:TH-2 balance. Thus, there could be a therapeutic benefit from such therapy. However, the same benefit can be achieved through the use of IL plus corticosteroids. Besides, IL is much less expensive, and the use of LIT is prohibited by law in the U.S.A.

There are two categories of immunologic implantation dysfunction (IID) linked to NK cell activation (NKa).

Autoimmune Implantation Dysfunction:

Here, the woman will often have a personal or family history of autoimmune conditions such as Rheumatoid arthritis, Lupus Erythematosus, and thyroid autoimmune activity (e.g., Hashimoto’s disease) etc. Autoimmune as well as in about one third of cases of endometriosis, regardless of severity.  Autoimmune sometimes also occurs in the absence of a personal or family history of autoimmune disease.

When it comes to treating  NKa in  IVF cases complicated by autoimmune implantation dysfunction,  the combination of daily oral dexamethasone commencing with the onset of ovarian stimulation and continuing until the 10th week of pregnancy, combined with an initial infusion of IL (100ml, 20% Il dissolved in 500cc of saline solution, 10-14  days prior to PGT-normal embryo transfer and repeated once more (only), as  soon as the blood pregnancy test is positive), the anticipated chance of a viable pregnancy occurring within 2 completed IVF attempts (including fresh + frozen ET’s)  in women under 39Y (who have normal ovarian reserve)  is approximately  65%.

Alloimmune Implantation Dysfunction:

 Here, NK cell activation results from uterine exposure to an embryo derived through fertilization by a spermatozoon that shares certain genotypic (HLA/DQ alpha) similarities  with that of the embryo recipient.

Partial DQ alpha/HLA match:  Couples who upon genotyping are shown to share only one DQ alpha/HLA gene are labeled as having a “partial match”. The detection of a “partial match” in association with NKa puts the couple at a considerable disadvantage with regard to IVF outcome. It should be emphasized however, that in the absence of associated Nka, DQ alpha/HLA matching whether “partial” or “total (see below) will NOT cause an IID. Since we presently have no way of determining which embryo carries a matching paternal DQ alpha gene, it follows that each embryo transferred will have about half the chance of propagating a viable pregnancy. Treatment of a partial DQ alpha/HLA match (+ Nka) involves the same IL, infusion as for autoimmune-Nka with one important caveat, namely that here we prescribe oral prednisone as adjunct therapy (rather than dexamethasone) and the IL infusion is repeated every 2-4 weeks following the diagnosis of pregnancy and continued until the 24th week of gestation. Additionally, (as alluded to elsewhere) in such cases we transfer a single (1) embryo at a time. This is because, the likelihood is that one out of two embryos will “match” and we are fearful that if we transfer >1 embryo, and one transferred embryos “matches” it could cause further activation of uterine NK cells and so prejudice the implantation of all transferred embryos. Here it should be emphasized that if associated with Nka, a matching embryo will still be at risk of rejection even in the presence of Intralipid (or IVIg) therapy.

Total (complete) DQ alpha Match:   Here the husband’s DQ alpha genotype matches both of that of his partner’s. While this occurs very infrequently, a total alloimmune (DQ alpha) match with accompanying Nka, means that the chance of a viable pregnancy resulting in a live birth at term, is unfortunately greatly diminished.  Several instances in our experience have required the use of a gestational surrogate.

It is indeed unfortunate that so many patients are being denied the ability to go from “infertility to family” simply because (for whatever reason) so many reproductive specialists refuse to embrace the role of immunologic factors in the genesis of intractable reproductive dysfunction. Hopefully this will change, and the sooner the better.

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.
• 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

I really suspect an underlying implantation dysfunction…probably an immunologic implantation dysfunction. If I am correct, you were not (in my opinion)  adequately treated. WE should talk!!

Might I suggest that you contact my assistant, Patti Converse at 702-533-2691 and set up an online consultation with me. I believe it would be well worthwhile .

Implantation dysfunction is unfortunately often overlooked as an important cause of IVF failure. This is especially relevant in cases of unexplained IVF failure, recurrent pregnancy loss (RPL), and in women with underlying endo-uterine surface lesions, thickness of the uterine lining (endometrium) and /or immunologic factors.

IVF success rates have been improving over the last decade. The average live birth rate per embryo transfer in the U.S.A for women under 40y using their own eggs is currently better than 1:3 women. However, there is still a wide variation from program to program for IVF live birth rates, ranging from 20% to near 50%. Based upon these statistics, most women undergoing IVF in the United States require two or more attempts to have a baby. IVF practitioners in the United States commonly attribute the wide dichotomy in IVF success rates to variability in expertise of the various embryology laboratories. This is far from accurate. In fact, other factors such as wide variations in patient selection and the failure to develop individualized protocols for ovarian stimulation or to address those infectious, anatomical, and immunologic factors that influence embryo implantation are at least equally important.

About 80% of IVF failures are due to “embryo incompetency” that is largely due to aneuploidy      usually related to advancing age of the woman and is further influenced by other factors such as the protocol selected for ovarian stimulation, diminished ovarian reserve (DOR), and severe male factor infertility. However, in about 20% of dysfunctional cases embryo implantation is the cause of failure.

This section will focus on implantation dysfunction and IVF failure due to:

ANATOMICAL ENDO-UTERINE SURFACE LESIONS

            It has long been suspected that anatomical defects of the uterus might result in infertility. While the presence of uterine fibroids, in general, are unlikely to cause infertility, an association between their presence and infertility has been observed in cases where the myomas distort the uterine cavity or protrude through the endometrial lining.  Even small fibroids that lie immediately under the endometrium (submucous fibroids) and protrude into the uterine cavity have the potential to lower embryo implantation.  Multiple fibroids in the uterine wall (intramural fibroids) that encroach upon the uterine cavity can sometimes so compromise blood flow that estrogen delivery is impaired, and the endometrium is unable to thicken properly. This can usually be diagnosed by ultrasound examination during the proliferative phase of the menstrual cycle.  It is likely that any surface lesion in the uterine cavity, whether submucous fibroids, intrauterine adhesions a small endometrial or a placental polyp, has the potential to interfere with implantation by producing a local inflammatory response, not too dissimilar in nature from that which is caused by an intrauterine contraceptive device (IUD).       

            Clearly, since even small uterine lesions have the potential to adversely affect implantation, the high cost (financial, physical, and emotional) associated with IVF and related procedures, justifies the routine performance of diagnostic procedures such as an HSG, hysterosonogram (fluid ultrasound examination), or hysteroscopy prior to initiating IVF.  Identifiable uterine lesions that have the potential of impairing implantation usually require surgical intervention.  In most cases, dilatation and curettage (D & C) or hysteroscopic resection will suffice. Some cases might require the performance of a laparotomy.  Such intervention will often result in subsequent improvement of the endometrial response.      

Sonohysterography [Fluid ultrasonography (FUS)]: Fluid ultrasonography is a procedure whereby a sterile solution of saline is injected via a catheter through the cervix and into the uterine cavity. The fluid-distended cavity is examined by vaginal ultrasound for any irregularities that might point to surface lesions such as polyps, fibroid tumors, scarring, or a uterine septum. If performed by an expert, a FUS is highly effective in recognizing even the smallest lesion and can replace hysteroscopy under such circumstances. FUS is less expensive, less traumatic, and equally as effective as hysteroscopy. The only disadvantage lies in the fact that if a lesion is detected, it may require the subsequent performance of hysteroscopy to treat the problem anyway.

Hysteroscopy: Diagnostic hysteroscopy is an office procedure that is performed under intravenous sedation, general anesthesia, or paracervical block with minimal discomfort to the patient. This procedure involves the insertion of a thin, lighted, telescope like instrument known as a hysteroscope through the vagina and cervix into the uterus to fully examine the uterine cavity. The uterus is first distended with normal saline, which is passed through a sleeve adjacent to the hysteroscope. As is the case with FUS, diagnostic hysteroscopy facilitates examination of the inside of the uterus under direct vision for defects that might interfere with implantation. We have observed that approximately one in eight candidates for IVF have lesions that require attention prior to undergoing IVF in order to optimize the chances of a successful outcome. We strongly recommend that all patients undergo therapeutic surgery (usually by hysteroscopy) to correct the pathology prior to IVF.  Depending on the severity and nature of the pathology, therapeutic hysteroscopy may require general anesthesia and, in such cases, should be performed in an outpatient surgical facility or conventional operating room where facilities are available for laparotomy, a procedure in which an incision is made in the abdomen to expose the abdominal contents for diagnosis, or for surgery should this be required.       

THICKNESS OF THE UTERINE LINING (ENDOMETRIUM):

As far back as in 1989 we first reported on the finding that ultrasound assessment of the late proliferative phase endometrium can identify those candidates who are least likely to conceive. We noted that the ideal thickness of the endometrium at the time of ovulation or egg retrieval is >8 mm and that thinner linings are associated with decreased implantation rates.

More than 30 years ago we first showed that in normal and “stimulated” cycles, pre-ovulatory endometrial thickness and ultrasound appearance is predictive of embryo implantation (pregnancy) potential following ET. With conventional IVF and with FET, endometrial lining at the time of the “trigger shot” or with the initiation of progesterone needs to preferably be at least 8 mm in sagittal thickness with a triple line (trilaminar) appearance. Anything less than an 8mm endometrial thickness       is associated with a reduction in live birth rate per ET. An 8-9mm thickness represents a transitional measurement…a “gray zone”.  Hitherto, attempts to augment endometrial growth in women with poor endometrial linings by bolstering circulating estrogen blood levels (through the administration of increased doses of fertility drugs, aspirin administration and by supplementary estrogen therapy) yielded disappointing results.

            A “poor” uterine lining is usually the result of the innermost layer of endometrium (the basal or germinal endometrium from which endometrium grows) not being able to respond to estrogen by propagating an outer, “functional” layer thick enough to support optimal embryo implantation and development of a healthy placenta (placentation). The “functional” layer ultimately comprises 2/3 of the full endometrial thickness and is the layer that sheds with menstruation if no pregnancy occurs.

The main causes of a “poor” uterine lining are:

• Damage to the basal endometrium because of:
• Inflammation of the endometrium (endometritis) most commonly resulting from infected products left over following abortion, miscarriage, or birth
• Surgical trauma due to traumatic uterine scraping, (i.e. due to an over-aggressive D & C)
• Insensitivity of the basal endometrium to estrogen due to:
• Prolonged, over-use/misuse of clomiphene citrate
• Prenatal exposure to diethylstilbestrol (DES). This is a drug that was given to pregnant women in the 1960’s to help prevent miscarriage
• Over-exposure of the uterine lining to ovarian male hormones (mainly testosterone): Older women, women with diminished ovarian reserve (poor responders) and women with polycystic ovarian syndrome -PCOS tend to have raised LH biological activity. This causes the connective tissue in the ovary (stroma/theca) to overproduce testosterone. The effect may be further exaggerated when certain methods for ovarian stimulation such as “flare” protocols and high dosages of Menopur are used in such cases.
• Reduced blood flow to the basal endometrium: Examples include.
• Multiple uterine fibroids – especially when these are present under the endometrium (submucosal)
• Uterine adenomyosis (excessive, abnormal invasion of the uterine muscle by endometrial glands).

Vaginal Viagra: About 35 years ago, after reporting on the benefit of administering vaginal Sildenafil (Viagra) to women who had implantation dysfunction due to thin endometrial linings we announced the birth of the world’s first “Viagra baby.”  Viagra administered vaginally, but not orally, in affected women improves uterine blood flow causing more estrogen to be delivered to the basal endometrium and increasing the endometrial thickening.  Following vaginal administration, Viagra is rapidly absorbed and quickly reaches the uterine blood system in high concentrations. Thereupon it dilutes out as it is absorbed into the systemic circulation. This probably explains why treatment is virtually devoid of systemic side effects.  It is important to recognize that Viagra will NOT be effective in improving endometrial thickness in all cases. In fact, about one third of women treated fail to show any improvement. This is because in certain cases of thin uterine linings, the basal endometrium will have been permanently damaged and left unresponsive to estrogen. This happens in cases of severe endometrial damage due mainly to post-pregnancy endometritis (inflammation), chronic granulomatous inflammation due to uterine tuberculosis (hardly ever seen in the United States) and following extensive surgical injury to the basal endometrium (as sometimes occurs following over-zealous D&C’s).

• Immunologic factors: These also play a role in IVF failure (see “Immunologic factors and Implantation” …see below.

IMMUNOLOGIC IMPLANTATION DYSFUNCTION (IID)

            Currently, with few exceptions, practitioners of assisted reproduction tend to attribute “unexplained and/or repeated” IVF failure(s), almost exclusively to poor embryo quality, advocating adjusted protocols for ovarian stimulation and/or gamete and embryo preparation as a potential remedy. The idea, having failed IVF, that all it takes to ultimately succeed is to keep trying the same recipe is over-simplistic.

            The implantation process begins six or seven days after fertilization of the egg. At this time, specialized embryonic cells (i.e., trophoblasts), that later become the placenta begin growing into the uterine lining. When the trophoblast and the uterine lining meet, they, along with immune cells in the lining, become involved in a “cross talk” through mutual exchange of hormone-like substances called cytokines. Because of this complex immunologic interplay, the uterus can foster the embryo’s successful growth. Thus, from the earliest stage, the trophoblast establishes the very foundation for the nutritional, hormonal and respiratory interchange between mother and baby.  In this manner, the interactive process of implantation is not only central to survival in early pregnancy but also to the quality of life after birth.

There is an ever growing realization, recognition, and acceptance of the fact that uterine immunologic dysfunction can lead to immunologic implantation dysfunction (IID) with “unexplained” infertility, IVF failure, and recurrent pregnancy loss (RPL).

DIAGNOSIS 

Because immunologic problems may lead to implantation failure, it is important to properly evaluate women with risk factors such as:

• Unexplained or recurrent IVF failures
• Unexplained infertility or a family history of autoimmune diseases (e.g., rheumatoid arthritis, lupus erythematosus and hypothyroidism).
• Recurrent Pregnancy Loss (RPL)
• Endometriosis
• A personal or family history of autoimmune conditions, e.g., Rheumatoid Arthritis, Lupus erythematosus, autoimmune hypothyroidism (Hashimoto’s disease) etc.

            Considering its importance, it is not surprising that the failure of a properly functioning immunologic interaction during implantation has been implicated as a cause of recurrent miscarriage, late pregnancy fetal loss, IVF failure and infertility. A partial list of immunologic factors that may be involved in these situations includes:

• Antiphospholipid antibodies (APA)
• Antithyroid antibodies (ATA/AMA)
• Activated natural killer cells (NKa)

ACTIVATED NATURAL KILLER CELLS (NKa):

Following ovulation and during early pregnancy, NK cells and T-cells comprise more than 80% of the lymphocyte-immune cells that frequent the uterine lining. These lymphocytes (white blood cells) journey from the bone marrow to the uterus and under hormonal regulation, proliferate there. After exposure to progesterone (due to induced /spontaneous exogenous administration), they begin to produce TH-1 and TH-2 cytokines. TH-2 cytokines are humoral in nature and induce the trophoblast (“root system of the embryo”) to permeate the uterine lining while TH-I cytokines induce a process referred to as apoptosis (cell suicide) thereby confining placental development to the inner part of the uterus. Optimal placental development (placentation) mandates that there be a balance between TH1 and TH-2 cytokines. Most of the cytokine production originates from NK cells (rather than from cytotoxic T-cells/Lymphocytes (CTL)). Excessive production/release of TH-1 cytokines, is toxic to the trophoblast and to endometrial cells, leading to programmed death/suicide (apoptosis) and subsequently to IID.

Functional NK cells reach a maximal concentration in the endometrium by about t day 6-7 days after exposure to progesterone …. This timing corresponds with when the embryo implants into the uterine lining (endometrium).

It is important to bear in mind that measurement of the concentration of blood NK cells has little or no relevance when it comes to assessing NK cell activation (NKa). Rather, it is the NK cell activation that matters. In fact, there are certain conditions (such as with endometriosis) where the NK cell blood concentration is below normal, but NK cell activation is markedly increased.

There are several methods by which NK cell activation (cytotoxicity) can be assessed in the laboratory. Methods such as immunohistochemical assessment of uterine NK cells and/or through measurement of uterine or blood TH-1 cytokines. However, the K-562 target cell blood test still remains the gold standard. With this test, NK cells, isolated from the woman’s blood using Flow Cytometry are incubated in the presence of specific “target cells”. The percentage (%) of “target cells” killed is then quantified. More than 12% killing suggests a level of NK cell activation that usually requires treatment.

Currently, there are less than a half dozen Reproductive Immunology Reference Laboratories in the U.S.A that are capable of performing the K-562 target cell test reliably.

There exists a pervasive but blatant misconception on the part of many, that the addition of IL or IVIg to a concentration of NK cells could have an immediate down-regulatory effect on NK cell activity. Neither IVIg nor IL is capable of significantly suppressing already activated “functional NK cells”. They are believed to work through “regulating” NK cell progenitors which only thereupon will start to propagate down-regulated NK cells. Thus, testing for a therapeutic effect would require that the IL/IVIg infusion be done about 14 days prior to ovulation or progesterone administration…  in order to allow for a sufficient number of normal (non-activated) “functional” NK cell” to be present at the implantation site when the embryos are transferred.

Failure to recognize this reality has, in our opinion, established an erroneous demand by practicing IVF doctors, that Reproductive Immunology Reference Laboratories report on NK cell activity before and again, immediately following laboratory exposure to IVIg and/or IL in different concentrations. Allegedly, this is to allow the treating physician to report back to their patient(s) on whether an IL or IVIG infusion will be effective in downregulating their Nka.  But, since already activated NK cells (NKa) cannot be deactivated in the laboratory, effective NKa down-regulation can only be adequately accomplished through deactivation of NK cell “progenitors /parental” NK cells in order to allow them thereupon, to s propagate normal “functional” NK cells and his takes about 10-14 days, such practice would be of little clinical benefit. This is because even if blood were to be drawn 10 -14 days after IL/IVIg treatment it would require at least an additional 10 -14days to receive results from the laboratory, by which time it would be far too late to be of practical advantage.

ANTIPHOSPHOLIPID ANTIBODIES:

 Many women who experience “unexplained” IVF failure, women with RPL, those with a personal or family history of autoimmune diseases such as lupus erythematosus, rheumatoid arthritis, scleroderma, and dermatomyositis (etc.)  as well as women who have endometriosis (“silent” or overt) test positive for APAs. More than 30 years ago, we were the first to propose that women who test positive for APA’s be treated with a mini-dose heparin to improve IVF implantation and thus birth rates. This approach was based upon research that suggested that heparin repels APAs from the surface of the trophoblast (the embryo’s “root system) thereby reducing its ant-implantation effects.  We subsequently demonstrated that such therapy only improved IVF outcome in women whose APAs were directed against two specific IgG and/or IgM phospholipids [i.e., phosphatidylethanolamine (PE) and phosphatidylserine (PS)].  More recently low dosage heparin therapy has been supplanted using longer acting low molecular weight heparinoids such as Lovenox and Clexane.   It is very possible that APAs alone do not cause IID but that their presence might help to identify a population at risk due to concomitant activation of uterine natural killer cells (Nka) which through excessive TH-1 cytokine production causes in IID: This is supported by the following observations:

• The presence of female APAs in cases of male factor cases appears to bear no relationship to IID.
• Only APA positive women who also test positive for abnormal NK activity appear to benefit from selective immunotherapy with intralipid/IVIg/ steroids.
• Most APA positive women who have increased NK cell activity also harbor IgG or IgM phosphatidylethanolamine (PE) and phosphatidylserine (PS) antibodies.

ANTITHYROID ANTIBODIES: (ATA).

 A clear relationship has been established between ATA and reproductive failure (especially recurrent miscarriage and infertility).

Between 2% and 5% of women of the childbearing age have reduced thyroid hormone activity (hypothyroidism). Women with hypothyroidism often manifest with reproductive failure i.e., infertility, unexplained (often repeated) IVF failure, or recurrent pregnancy loss (RPL). The condition is 5-10 times more common in women than in men. In most cases hypothyroidism is caused by damage to the thyroid gland resulting from of thyroid autoimmunity (Hashimoto’s disease) caused by damage done to the thyroid gland by antithyroglobulin and antimicrosomal auto-antibodies. 

The increased prevalence of hypothyroidism and thyroid autoimmunity (TAI) in women is likely the result of a combination of genetic factors, estrogen-related effects, and chromosome X abnormalities.  This having been said, there is significantly increased incidence of thyroid antibodies in non-pregnant women with a history of infertility and recurrent pregnancy loss and thyroid antibodies ^can be present asymptomatically in women without them manifesting with overt clinical or endocrinologic evidence of thyroid disease. In addition, these antibodies may persist in women who have suffered from hyper- or hypothyroidism even after normalization of their thyroid function by appropriate pharmacological treatment. The manifestations of reproductive dysfunction thus seem to be linked more to the presence of thyroid autoimmunity (TAI) than to clinical existence of hypothyroidism and treatment of the latter does not routinely result in a subsequent improvement in reproductive performance.

It follows, that if antithyroid autoantibodies are associated with reproductive dysfunction they may serve as useful markers for predicting poor outcome in patients undergoing assisted reproductive technologies.

Some years back, I reported on the fact that 47% of women who harbor thyroid autoantibodies, regardless of the absence or presence of clinical hypothyroidism, have activated uterine natural killer cells (NKa) cells and cytotoxic lymphocytes (CTL) and that such women often present with reproductive dysfunction. We demonstrated that appropriate immunotherapy with IVIG or intralipid (IL) and steroids, subsequently often results in a significant improvement in reproductive performance in such cases.

The fact that almost 50% of women who harbor antithyroid antibodies do not have activated CTL/NK cells suggests that it is NOT the antithyroid antibodies themselves that cause reproductive dysfunction. The activation of CTL and NK cells that occurs in half of the cases with TAI is probably an epiphenomenon with the associated reproductive dysfunction being due to CTL/NK cell activation that damages the early “root system” (trophoblast) of the implanting embryo. We have shown that treatment of those women who have thyroid antibodies + NKa/CTL using IL/steroids, improves subsequent reproductive performance while women with thyroid antibodies who do not harbor NKa/CTL do not require or benefit from such treatment

TEATMENT OF IID:

The mainstay of treatment involves the selective use of:

• Intralipid (IL) infusion
• IVIg therapy
• Corticosteroids (Prednisone/dexamethasone)
• Heparinoids (Lovenox/Clexane)

Intralipid (IL) Therapy:  IL is a suspension of soybean lipid droplets in water and is primarily used as source of parenteral nutrition. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, and alpha-linolenic acid (ALA), an omega-3 fatty acid.     

It is thought that fatty acids within the emulsion serve as ligands that activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cell cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent.

            Whatever the exact mechanism of action might be, Intralipid acts primarily to suppress NK cell over-production of TH-I cytokines. It exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating cytotoxic /activated natural killer cells (NKa). This effect is enhanced through the concomitant administration of corticosteroids such as dexamethasone, prednisolone and prednisone which augment immune modulation of T cells. The combined effect of IL + steroid therapy suppresses pro-inflammatory cellular TH1 cytokines such as interferon gamma and TNF-alpha that are produced in excess by activated NK cells and cytotoxic lymphocytes/T-cells (CTL).   IL will, in about 80% of cases, successfully down-regulate activated natural killer cells (NKa) over a period of 2-3 weeks. It is likely to be just as effective as IVIg in this respect but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for ~ 4-6 weeks when administered in early pregnancy.

Intralipid is a suspension of soybean lipid droplets in water and is primarily used as source of parenteral nutrition. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, and alpha-linolenic acid (ALA), an omega-3 fatty acid.     

It is thought that fatty acids within the emulsion serve as ligands that activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cell cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent.

            Whatever the exact mechanism of action might be, Intralipid acts primarily to suppress NK cell over-production of TH-I cytokines. It exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating cytotoxic /activated natural killer cells (NKa). This effect is enhanced through the concomitant administration of corticosteroids such as dexamethasone, prednisolone and prednisone which augment immune modulation of T cells. The combined effect of IL + steroid therapy suppresses pro-inflammatory cellular TH1 cytokines such as interferon gamma and TNF-alpha that are produced in excess by activated NK cells and cytotoxic lymphocytes/T-cells (CTL).   IL will, in about 80% of cases, successfully down-regulate activated natural killer cells (NKa) over a period of 2-3 weeks. It is likely to be just as effective as IVIg in this respect but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for ~ 4-6 weeks when administered in early pregnancy.

            Can laboratory testing be used to assess for an immediate effect of IL on Nka suppression?  Since the downregulation of NKa through IL (or IVIg) therapy can take several weeks to become measurable, it follows that there is really no benefit in trying to assess the potential efficacy of such treatment by retesting NKa in the laboratory after adding IL (or IVIg) to the cells being tested.

IVIg Therapy:  Until about a decade ago, the only effective and available way (in the US) to down-regulate activated NK cells was through the intravenous administration of a blood product known as immunoglobulin-G (IVIg). The fear (albeit unfounded) that the administration of this product might lead to the transmission of viral infections such as HIV and hepatitis C, plus the high cost of IVIG along with the fact that significant side effects occurred about 20% of the time, led to bad press and bad publicity for the entire field of reproductive immunology. It was easier for RE’s to simply say “I don’t believe IVIg works” and thereby avoid risk and bad publicity. But the thousands of women who had babies because of NK cell activity being downregulated through its use, attests to IVIg’s efficacy. But those of us who felt morally obligated to many desperate patients who would not conceive without receiving IVIg were facing an uphill battle. The bad press caused by fear mongering took its toll and spawned a malicious controversy. It was only through the introduction of IL less (about 15-20 years ago ), that the tide began to turn in favor of those patients who required low cost, safe and effective immunotherapy to resolve their IID.

 Corticosteroid Therapy (e.g., Prednisone, and Dexamethasone): Corticosteroid therapy has become a mainstay in the treatment of most women undergoing IVF. It is believed by most to enhance implantation due to an overall immunomodulatory effect. Corticosteroids reduce TH-1 cytokine production by CTL. When given in combination with IL or IVIG they augment the implantation process. The prednisone or dexamethasone therapy must commence (along with IL/IVIg) 10-14 days prior to egg retrieval and continue until pregnancy is discounted or until the 10th week of pregnancy.

 Heparinoid Therapy: There is compelling evidence that the subcutaneous administration of low molecular heparin (Clexane, Lovenox) once daily, (starting with the onset of ovarian stimulation) can improve IVF birthrate in women who test positive for APAs and might prevent later pregnancy loss when used to treat certain thrombophilias (e.g., homozygous MTHFR mutation)

What About Baby Aspirin? In our opinion, aspirin has little (if any) value when it comes to IID, and besides, it could even reduce the chance of success. The reason for this is that aspirin thins the blood and increases the potential to bleed. This effect can last for up to a week and could complicate an egg retrieval procedure or result in “concealed” intrauterine bleeding at the time of embryo transfer, thereby potentially compromising IVF success.

TH-1 Cytokine Blockers (Enbrel, Humira): TH-1 cytokine blockers, (Enbrel and Humira) are in our opinion relatively ineffective in the IVF setting. There has to date been no convincing data to support their use. However, these blockers could have a role in the treatment of a threatened miscarriage thought to be due to CTL/NK activation, but not for IVF. The reason is that the very initial phase of implantation requires a cellular response involving TH-1 cytokines. To block them completely (rather than simply restore a TH-1:TH-2 balance as occurs with IL therapy) so very early on could compromise rather than benefit implantation.

Leukocyte Immunization Therapy (LIT): The subcutaneous injection of the male partner’s lymphocytes to the mother is thought to enhance the ability for the mother’s decidua (uterus) to recognize the DQ alpha matching embryo as “self” or “friend” and thereby avert its rejection. LIT has been shown to up-regulate Treg cells and thus down-regulate NK cell activation thereby improving decidual TH-1:TH-2 balance. Thus, there could be a therapeutic benefit from such therapy. However, the same benefit can be achieved through the use of IL plus corticosteroids. Besides, IL is much less expensive, and the use of LIT is prohibited by law in the U.S.A.

There are two categories of immunologic implantation dysfunction (IID) linked to NK cell activation (NKa).

Autoimmune Implantation Dysfunction: Here, the woman will often have a personal or family history of autoimmune conditions such as Rheumatoid arthritis, Lupus Erythematosus, and thyroid autoimmune activity (e.g., Hashimoto’s disease) etc. Autoimmune as well as in about one third of cases of endometriosis, regardless of severity.  Autoimmune sometimes also occurs in the absence of a personal or family history of autoimmune disease.

When it comes to treating  NKa in  IVF cases complicated by autoimmune implantation dysfunction,  the combination of daily oral dexamethasone commencing with the onset of ovarian stimulation and continuing until the 10th week of pregnancy, combined with an initial infusion of IL (100ml, 20% Il dissolved in 500cc of saline solution, 10-14  days prior to PGT-normal embryo transfer and repeated once more (only), as  soon as the blood pregnancy test is positive), the anticipated chance of a viable pregnancy occurring within 2 completed IVF attempts (including fresh + frozen ET’s)  in women under 39Y (who have normal ovarian reserve)  is approximately  65%.

Alloimmune Implantation Dysfunction: Here, NK cell activation results from uterine exposure to an embryo derived through fertilization by a spermatozoon that shares certain genotypic (HLA/DQ alpha) similarities with that of the embryo recipient.

Partial DQ alpha/HLA match:  Couples who upon genotyping are shown to share only one DQ alpha/HLA gene are labeled as having a “partial match”. The detection of a “partial match” in association with NKa puts the couple at a considerable disadvantage with regard to IVF outcome. It should be emphasized however, that in the absence of associated Nka, DQ alpha/HLA matching whether “partial” or “total (see below) will NOT cause an IID. Since we presently have no way of determining which embryo carries a matching paternal DQ alpha gene, it follows that each embryo transferred will have about half the chance of propagating a viable pregnancy. Treatment of a partial DQ alpha/HLA match (+ Nka) involves the same IL, infusion as for autoimmune-Nka with one important caveat, namely that here we prescribe oral prednisone as adjunct therapy (rather than dexamethasone) and the IL infusion is repeated every 2-4 weeks following the diagnosis of pregnancy and continued until the 24th week of gestation. Additionally, (as alluded to elsewhere) in such cases we transfer a single (1) embryo at a time. This is because, the likelihood is that one out of two embryos will “match” and we are fearful that if we transfer >1 embryo, and one transferred embryos “matches” it could cause further activation of uterine NK cells and so prejudice the implantation of all transferred embryos. Here it should be emphasized that if associated with Nka, a matching embryo will still be at risk of rejection even in the presence of Intralipid (or IVIg) therapy.

Total (complete) DQ alpha Match:   Here the husband’s DQ alpha genotype matches both of that of his partner’s. While this occurs very infrequently, a total alloimmune (DQ alpha) match with accompanying Nka, means that the chance of a viable pregnancy resulting in a live birth at term, is unfortunately greatly diminished.  Several instances in our experience have required the use of a gestational surrogate.

It is indeed unfortunate that so many patients are being denied the ability to go from “infertility to family” simply because (for whatever reason) so many reproductive specialists refuse to embrace the role of immunologic factors in the genesis of intractable reproductive dysfunction. Hopefully this will change, and the sooner the better.

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

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