Please re-draft in English!

Geoff Sher

Empty Follicle Syndrome” is a misleading term because follicles always contain eggs. However, some eggs may have difficulties detaching and being retrieved. This is more likely to happen when multiple attempts are needed to retrieve an egg from a follicle, indicating the egg may have chromosomal abnormalities.

The hormonal environment created during controlled ovarian stimulation plays a significant role in egg development. In certain cases, follicles may not release their eggs during retrieval, leading to the misconception of “empty” follicles.

This situation is most commonly encountered in older women, those with diminished ovarian reserve (DOR), and women with polycystic ovarian syndrome (PCOS). To address this problem, personalized protocols for controlled ovarian stimulation and careful administration of the hCG trigger shot are important.

The hCG trigger shot is given after optimal ovarian stimulation to initiate the process of reducing the number of chromosomes in the egg. It also helps the egg detach from the follicle’s inner wall. This allows for easier retrieval during the egg retrieval procedure.

Women with increased LH activity, such as older women, those with DOR, and women with PCOS, are more susceptible to the negative effects of LH-induced ovarian testosterone. Excessive LH activity can compromise egg development and increase the chances of chromosomal abnormalities. Medications like clomiphene and Letrozole can stimulate LH release, and certain drugs containing LH or hCG can have negative consequences.

Individualizing the controlled ovarian stimulation protocol, determining the correct dosage and type of hCG trigger, and administering it at the right time are crucial. The recommended dosage of urinary-derived hCG products is 10,000 units, while for recombinant DNA-derived hCG, the optimal dosage is 500 micrograms. A lower dosage of hCG can increase the risk of chromosomal abnormalities in the eggs and negatively impact the outcome of IVF.

Understanding the role of LH activity, the effects of medications on hormone release, and the importance of personalized protocols are vital. By optimizing these factors, the risk of failed egg retrieval and “empty follicle syndrome” can be minimized, improving the chances of successful IVF outcomes.

 _______________________________________________________

PLEASE SHARE THIS WITH OTHERS AND HELP SPREAD THE WORD!!

Herewith are  online links to 2  E-books recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1. From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) ; http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link ;https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

I invite you to visit my very recently launched “Podcast”,  “HAVE A BABY” on RUMBLE;   https://rumble.com/c/c-3304480

If you are interested in having an online consultation with me, please contact my assistant, Patti Converse at 702-533-2691 or email her at concierge@sherivf.com\

Please post in English!

Geoff Sher

A RATIONAL BASIS FOR MANAGEMENT OF IMMUNOLOGIC CAUSES OF EMBRYO IMPLANTATION DYSFUNCTION

Geoffrey Sher MD

In the world of assisted reproduction, when IVF fails repeatedly or without explanation, it’s often assumed that poor embryo quality is the main culprit. However, this view oversimplifies the situation. The process of embryo implantation, which begins about six or seven days after fertilization, involves a complex interaction between embryonic cells and the lining of the uterus. These specialized cells, called trophoblasts, eventually become the placenta. When the trophoblasts meet the uterine lining, they engage in a communication process with immune cells through hormone-like substances called cytokines. This interaction plays a critical role in supporting the successful growth of the embryo. From the earliest stages, the trophoblasts establish the foundation for the exchange of nutrients, hormones, and oxygen between the mother and the baby. The process of implantation not only ensures the survival of early pregnancy but also contributes to the quality of life after birth.

There are numerous uterine factors that can impede embryo implantation potential. However, the vast majority relate to the following three (3) factors:

1. Thin uterine lining (endometrium) . A lining that is <8mm in thickness at the time of ovulation, and/ or the administration of progesterone
2. Irregularity the inner surface of the uterine cavity (caused by protruding sub-mucous fibroids, scar  tissue or polyps )

• Immunologic factors that compromise implantation

Of these 3 factors, the one most commonly overlooked (largely because of the highly complex nature of the problem) is immunologic implantation dysfunction (IID), a common cause of “unexplained (often repeated) IVF failure and recurrent pregnancy loss. This article will focus on the one that most commonly is overlooked ….namely, immunologic implantation dysfunction (IID.

There is a growing recognition that problems with the immune function in the uterus can lead to embryo implantation dysfunction. The failure of proper immunologic interaction during implantation has been implicated as a cause of recurrent miscarriage, late pregnancy fetal loss, IVF failure, and infertility. Some immunologic factors that may contribute to these issues include antiphospholipid antibodies (APA), antithyroid antibodies (ATA) , and activated natural killer cells (NKa).

• Activated natural Killer Cells (NKa):

During ovulation and early pregnancy, the uterine lining is frequented by NK cells and T-cells, which together make up more than 80% of the immune cells in the uterine lining. These cells travel from the bone marrow to the endometrium where they proliferate under hormonal regulation. When exposed to progesterone, they produce TH-1 and TH-2 cytokines. TH-2 cytokines help the trophoblast (embryo’s “root system”) to penetrate the uterine lining, while TH-1 cytokines induce apoptosis (cell suicide), limiting placental development to the inner part of the uterus. The balance between TH1 and TH-2 cytokines is crucial for optimal placental development. NK cells and T-cells contribute to cytokine production. Excessive TH-1 cytokine production is harmful to the trophoblast and endometrial cells, leading to programmed cell death and ultimately to implantation failure.

Functional NK cells reach their highest concentration in the endometrium around 6-7 days after ovulation or exposure to progesterone, which coincides with the time of embryo implantation.

It’s important to note that measuring the concentration of blood NK cells doesn’t reflect NK cell activation (NKa). The activation of NK cells is what matters. In certain conditions like endometriosis, the blood concentration of NK cells may be below normal, but NK cell activation is significantly increased.

There are several laboratory methods to assess NK cell activation (cytotoxicity), including immunohistochemical assessment of uterine NK cells and measuring TH-1 cytokines in the uterus or blood. However, the K-562 target cell blood test remains the gold standard. In this test, NK cells isolated from a woman’s blood are incubated with specific “target cells,” and the percentage of killed target cells is quantified. More than 12% killing indicates a level of NK cell activation that usually requires treatment. Currently, there are only a few Reproductive Immunology Reference Laboratories in the USA capable of reliably performing the K-562 target cell test.

There is a common misconception that adding IL (intralipid) or IVIg to NK cells can immediately downregulate NK cell activity. However, IL and IVIg cannot significantly suppress already activated NK cells. They are believed to work by regulating NK cell progenitors, which then produce downregulated NK cells. To assess the therapeutic effect, IL/IVIg infusion should be done about 14 days before embryos are transferred to the uterus to ensure a sufficient number of normal functional NK cells are present at the implantation site during embryo transfer. Failure to recognize this reality has led to the erroneous demand from IVF doctors for Reproductive Immunology Reference Laboratories to report on NK cell activity before and immediately after exposure to IVIg or IL at different concentrations. However, since already activated NK cells cannot be deactivated in the laboratory, assessing NKa suppression in this way has little clinical benefit. Even if blood is drawn 10-14 days after IL/IVIg treatment, it would take another 10-14 days to receive the results, which would be too late to be practically advantageous.

• Antiphospholipid Antibodies:

Many women who struggle with IVF failure or recurrent pregnancy loss, as well as those with a personal or family history of autoimmune diseases like lupus erythematosus, rheumatoid arthritis, scleroderma, and dermatomyositis, often test positive for antiphospholipid antibodies (APAs). Over 30 years ago, I proposed a treatment for women with positive APA tests. This involved using a low dose of heparin to improve the success of IVF implantation and increase birth rates. Research indicated that heparin could prevent APAs from affecting the embryo’s “root system” ( the trophoblast), thus enhancing implantation. We later discovered that this therapy only benefits women whose APAs target specific phospholipids (phosphatidylethanolamine and phosphatidylserine). Nowadays, longer-acting low molecular weight heparinoids like Lovenox and Clexane have replaced heparin.

• Antithyroid Antibodies ( thyroid peroxidase -TPO and antithyroglobulin antibodies (TGa)

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 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.

Almost 50% of women with antithyroid antibodies do not have activated cytotoxic T lymphocytes (CTL) or natural killer cells (NK cells). This suggests that the antibodies themselves may not be the direct cause of reproductive dysfunction. Instead, the activation of CTL and NK cells, which occurs in about half of the cases with thyroid autoimmunity (TAI), is likely an accompanying phenomenon that damages the early “root system” (trophoblast) of the embryo during implantation.

Treating women who have both antithyroid antibodies and activated NK cells/CTL with intralipid (IL) and steroids improves their chances of successful reproduction. However, women with antithyroid antibodies who do not have activated NK cells/CTL do not require this treatment.

• Treatment Options for Immunologic Implantation Dysfunction (IID):

1. Intralipid (IL) Therapy: IL is a mixture of soybean lipid droplets in water, primarily used for providing nutrition. When administered intravenously, IL supplies essential fatty acids that can activate certain receptors in NK cells, reducing their cytotoxic activity and enhancing implantation. IL, combined with corticosteroids, suppresses the overproduction of pro-inflammatory cytokines by NK cells, improving reproductive outcomes. IL is cost-effective and has fewer side effects compared to other treatments like IVIg.
2. Intravenous immunoglobulin-G (IVIg) Therapy: In the past, IVIg was used to down-regulate activated NK cells. However, concerns about viral infections and the high cost led to a decline in its use. IVIg can be effective, but IL has become a more favorable and affordable alternative.
3. Corticosteroid Therapy: Corticosteroids, such as prednisone and dexamethasone, are commonly used in IVF treatment. They have an immunomodulatory effect and reduce TH-1 cytokine production by CTL. When combined with IL or IVIg, corticosteroids enhance the implantation process. Treatment typically starts 10-14 days before embryo transfer and continues until the 10th week of pregnancy.
4. Heparinoid Therapy: Low molecular weight heparin (Clexane, Lovenox) can improve IVF success rates in women with antiphospholipid antibodies (APAs) and may prevent pregnancy loss in certain thrombophilias when used during treatment. It is administered subcutaneously once daily from the start of ovarian stimulation.
5. TH-1 Cytokine Blockers (Enbrel, Humira): TH-1 cytokine blockers have limited effectiveness in the IVF setting and, in my opinion, no compelling evidence supports their use. They may have a role in treating threatened miscarriage caused by CTL/NK cell activation, but not for IVF treatment. TH-1 cytokines are needed for cellular response, during the early phase of implantation, so completely blocking them could hinder normal implantation.

1. Baby Aspirin and IVF: Baby aspirin doesn’t offer much value in treating implantation dysfunction (IID) and may even reduce the chance of success. This is because aspirin thins the blood and increases the risk of bleeding, which can complicate procedures like egg retrieval or embryo transfer during IVF, potentially compromising its success.
2. Leukocyte Immunization Therapy (LIT): LIT involves injecting the male partner’s lymphocytes into the mother to improve the recognition of the embryo as “self” and prevent rejection. LIT can up-regulate Treg cells and down-regulate NK cell activation, improving the balance of TH-1 and TH-2 cells in the uterus. However, the same benefits can be achieved through IL (Intralipid) therapy combined with corticosteroids. IL is more cost-effective, and the use of LIT is prohibited by law in the USA.

Types of Immunologic Implantation Dysfunction (IID) and NK Cell Activation:

1. Autoimmune Implantation Dysfunction: Women with a personal or family history of autoimmune conditions like Rheumatoid arthritis, Lupus Erythematosus, thyroid autoimmune disease (Hashimoto’s disease and thyrotoxicosis), and endometriosis (in about one-third of cases) may experience autoimmune IID. However, autoimmune IID can also occur without any personal or family history of autoimmune diseases.Treatment for NK cell activation in IVF cases complicated by autoimmune IID involves a combination of daily oral dexamethasone from the start of ovarian stimulation until the 10th week of pregnancy, along with 20% intralipid (IL) infusion 10 days to 2 weeks before embryo transfer. With this treatment, the chance of a viable pregnancy occurring within two completed embryo transfer attempts is approximately 70% for women <40 years old who have  normal ovarian reserve.
2. Alloimmune Implantation Dysfunction: NK cell activation occurs when the uterus is exposed to an embryo that shares certain genotypic (HLA/DQ alpha) similarities with the embryo recipient.
   • Partial DQ alpha/HLA genetic matching: Couples who share only one DQ alpha/HLA gene are considered to have a “partial match.” If NK cell activation is also present, this partial match puts the couple at a disadvantage for IVF success. However, it’s important to note that DQ alpha/HLA matching, whether partial or total, does not cause IID without associated NK cell activation. Treatment for partial DQ alpha/HLA match with NK cell activation involves IL infusion and oral prednisone as adjunct therapy. IL infusion is repeated every 2-4 weeks after pregnancy is confirmed and continued until the 24th week of gestation. In these cases, only one embryo is transferred at a time to minimize the risk of NK cell activation.
   • Total (Complete) Alloimmune Genetic Matching: A total alloimmune match occurs when the husband’s DQ alpha genotype matches both that of the partner. Although rare, this total match along with NK cell activation significantly reduces the chance of a viable pregnancy resulting in a live birth at term. In some cases, the use of a gestational surrogate may be necessary.

It should be emphasized that poor embryo quality is not always the main cause of reproductive dysfunction and that the complex interaction between embryonic cells and the lining of the uterus  plays a critical role in successful implantation. Women with personal or family histories of autoimmune disease or endometriosis and those with unexplained (often repeated) IVF failure or recurrent pregnancy loss, often have immunologic implantation dysfunction (IID as the underlying cause . For such women, it is important to understand how IID leads to reproductive failure and how selective treatment options such as intralipid (IL), corticosteroid and heparinoid therapy, can dramatically  improve reproductive outcomes. Finally, there is real hope that proper identification and management of IID can  significantly improve the chance of successful reproduction and ultimately contribute to better quality of life after birth.

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Call 702-533-2691 and set up an online consultation with me to discuss details!

Geoff Sher

Age should never be a barrier to hope and fulfillment when it comes to IVF. Many women in their early to mid-40s are successfully having IVF babies using their own eggs, especially if they have a good number of eggs left in their ovaries. However, for women with diminished ovarian reserve (DOR) or those over the age of 44, where the chances of success with their own eggs are low, IVF with egg donation can be a highly successful and safe option. Let’s explore why age affects IVF outcomes and discover the possibilities that lie ahead.

The egg plays a crucial role in determining the quality of the embryo, with a “competent” egg having the best chance of developing into a healthy baby. As women age, the chances of having eggs with an irregular number of chromosomes (aneuploid) increase significantly. Fertilizing an aneuploid egg will result in an embryo with an abnormal number of chromosomes, making it unable to develop into a healthy baby.

Chromosomal abnormalities are the main cause of failed implantation, pregnancy losses, and birth defects. As women get older, the risk of chromosomal abnormalities in embryos rises, leading to lower IVF success rates. Additionally, older women may experience hormonal imbalances that further affect egg quality and development. However, personalized stimulation protocols can help protect egg quality and improve IVF outcomes by regulating hormone production and activity.

When it comes to IVF in older women, selecting the right ovarian stimulation protocol is crucial. Various protocols are available, each tailored to meet individual needs. However, certain protocols should be avoided for older women or those with DOR to optimize chances of success.

I selectively use a variety of ovarian stimulation protocols for ovarian stimulation/IVF in older women and those with DOR :

• The conventional long pituitary down-regulation protocol: This involves administering a GnRH agonist like Lupron or Buserelin for a few days prior to initiating ovarian stimulation with gonadotropins. Then, a combination of FSH-dominant gonadotropin and a small dose of Menopur is administered, and ultrasound and blood tests are done to monitor follicle development. The eggs are triggered for maturation with hCG, and the egg retrieval is scheduled for approximately 36 hours later. This protocol is often preferred for older women who have adequate ovarian reserve (AMH=>1.5ng/ml).
• The agonist/antagonist conversion protocol (A/ACP):, This is similar to the conventional long down-regulation protocol. However, instead of using an agonist, a GnRH antagonist is administered from the onset of stimulation with gonadotropins. This protocol is often preferred for older women who have moderately severe DOR (AMH=0.5-1.5ng/ml).
• A/ACP with Estrogen “priming”; For women with very severe, DORI prescribe  estrogen “priming “with skin estradiol (E2) patches or Estradiol injections administered bi-weekly. For some time before commencing gonadotropin stimulation, in an attempt to enhance ovarian response to stimulation. This protocol is sometimes used in older women who have severe DOR ( <0.5-1.5ng/ml).

In my opinion, the following ovarian stimulation protocols all promote over-exposure to LH-induced ovarian testosterone and are best avoided in older women and women with DOR, undergoing ovarian stimulation for IVF:

• Agonist “flare” protocols, which cause a surge of pituitary-LH at the wrong time.
• High dosages , LH-containing fertility drugs (e.g., menotropins such as Menopur).
• Testosterone-based supplements like Androgel.
• DHEA supplementation: DHEA is converted to testosterone in the ovaries.
• Clomiphene citrate & Letrozole, promote exaggerated pituitary LH release that can result in over-production of ovarian testosterone.
• Triggering egg maturation with too low a dosage of hCG (the ideal dosage is 10,000U of urine derived hCG) andf Recombinant DNA-derived hCG ( the ideal dosage is 500mcg of Ovidrel).

In cases where using their own eggs is no longer viable due to age and severe DOR, using donor eggs provides a fulfilling path to parenthood. Although some may initially hesitate due to the lack of genetic relation, it’s important to understand that the person who gives birth is considered the true biological parent in most cultures and legal systems. Becoming a parent through this connection can bring immense joy and fulfillment, as countless successful cases have shown.

Age may reduce the chances, but it does not eliminate the possibility of having a child through IVF. When IVF with own eggs is not an option, embracing the alternative of egg donation opens doors to highly successful and fulfilling paths to parenthood. It’s time to unlock the possibilities and embark on the journey towards creating a loving family.

_________________________________________________________________________________________

PLEASE SHARE THIS WITH OTHERS AND HELP SPREAD THE WORD!!

Herewith are  online links to 2  E-books recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1. From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) ; http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link ;https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

I invite you to visit my very recently launched “Podcast”,  “HAVE A BABY” on RUMBLE;   https://rumble.com/c/c-3304480

If you are interested in having an online consultation with me, please contact my assistant, Patti Converse at 702-533-2691 or email her at concierge@sherivf.com\

• “Empowering Choices: Embryo Banking vs. Egg Banking for Fertility Preservation“

It’s crucial for women to make informed decisions about preserving their fertility. Delaying trying to conceive, relying on egg freezing, or assuming the biological clock can be paused are misconceptions. As women age, egg quality declines, affecting the chance of a successful, healthy pregnancy.

Let’s break down the key points:

1. Age and Egg Quality: As women progress past their mid-thirties, the quality of their eggs declines rapidly. This impacts conception rates, leading to higher miscarriage and chromosomal abnormalities like Down syndrome.
2. Comparing Chances:

1. • At 30, the natural conception rate is around 15-20%, with a 10-15% miscarriage rate and a 1:1000 chance of Down syndrome.
   • At 45, natural conception drops to 1-2%, with a 50-60% miscarriage rate and a 1:40 chance of Down syndrome.

1. IVF and Age:

1. • IVF success rates are better at younger ages, with a 50-60% conception rate for 30-year-olds and a 3-5% chance for 45-year-olds.
   • However, IVF doesn’t eliminate the increased risk of miscarriage or chromosomal abnormalities as women age.

1. IVF Realities:

1. • The success of IVF dramatically decreases with age, making informed decisions crucial.

Preimplantation Genetic Screening (PGS)/Preimplantation Genetic Testing for aneuploidy (PGT-A) is a breakthrough in fertility treatment, aiding the selection of the most viable embryos for a successful pregnancy. By analyzing all chromosomes, it significantly boosts the success rates of IVF. PGS/PGT-A not only increases the chance of a healthy baby per embryo transfer but also reduces the risks of miscarriages and chromosomal birth defects, regardless of the woman’s age.

Who Benefits from PGS/PGT-A?

PGS/PGT-A) has revolutionized embryo evaluation, especially for those facing unexplained IVF failure, infertility, recurrent pregnancy loss (RPL), and older women with diminished ovarian reserve (DOR).

Empowering Older Women: Embryo Banking

PGS/PGT-A is especially beneficial for women over 39 years of age and those with DOR, as it allows the storage (banking) of healthy embryos over multiple cycles, countering the ticking biological clock.. Selective banking of PGS-normal embryos over multiple cycles is a game-changer. It minimizes the impact of age on egg quality, giving these women a chance to make the most of their remaining time to conceive a healthy baby.

Egg Freezing: Factors to Consider

Eggs are vulnerable cells, and freezing a single egg is less effective than freezing a multi-cellular embryo. Additionally, a significant portion of eggs (especially in older women) have chromosomal abnormalities. This makes egg freezing less efficient and  embryo freezing, far more successful, especially when selectively freezing PGS/PGT-A-normal blastocysts.

Choosing the Right Path

Importantly, considering the decline in reproductive potential with age, it’s essential for women and couples to explore their fertility options before the age of 35. An aggressive approach, like moving to assisted reproduction and IVF can significantly improve outcomes. For younger women (<35y) who have normal egg reserves, especially those who are not married,  have not as yet settled on la “permanent” male partner or a do not feel secure with their existing male partner fathering a child with them might preferentially choose egg freezing . Conversely,  women who are comfortable with a designated male partner, older women and those who have DOR might rather select embryo banking.

In the choice between egg and embryo freezing, caution is advised. Current methods for egg selection lack chromosomal analysis. Conversely the performance of PGSGT-A allows for identification of the healthiest embryos for subsequent FET..

Either way, “timing” is a very important consideration.

By understanding these options, you can make an informed decision to maximize your chances of a healthy, happy family. Remember, knowledge is power in the journey to parenthood.

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• ENDOMETRIOSIS AND INFERTILITY: A RATIONAL BASIS FOR TREATMENT.

Women who have endometriosis are much more likely to be infertile. There are several reasons for this:

• First, endometriosis is associated with the presence of toxins in peritoneal secretions. As sperm and egg(s) travel towards the fallopian tubes they are exposed to these toxins which compromise the fertilization process
• Second, in about 25 – 30% of cases, endometriosis is associated with ovulation dysfunction.
• Third, in its most severe form, the condition is associated with scarring and adhesions in the pelvis, resulting in damage to, or blockage of the fallopian tubes, thereby preventing the union of sperm and eggs.
• Fourth, endometriosis is associated with abnormalities of the woman’s immune system which interfere with the ability of the fertilized egg to attach (implant) to the uterine wall.

Until quite recently, we really had no clue as to how reproductive problems associated with endometriosis evolve. Recent medical research has helped shed light on the subject and offers promise with regard to the future treatment of infertility/ reproductive failure associated with this condition. A few examples of recent breakthroughs include the following:

Endometriosis appears to have a genetic (familial) component .In the future, the development of genetic markers might provide an important diagnostic tool.

Patients with endometriosis have immunologic abnormalities. The most significant of these involve the presence of harmful antibodies known as antiphospholipid antibodies (APA) are in the bloodstream of about 66 percent of women with endometriosis. In about half such cases (i.e., about 1/3 of all cases of endometriosis…regardless of severity) the immunologic implantation is profoundly aggravated by the presence of activated (i.e.  “toxic”) natural killer cells (Nka) and activated cytotoxic lymphocytes (CTLa) in the uterine lining (endometrium). These NKa/CTLa attack the invading trophoblast cells (developing “root system” of the embryo/early conceptus) as soon as it tries to gain attachment to the uterine wall. In most cases, this results in death of the embryo even before the pregnancy is diagnosed and sometimes, in a chemical pregnancy or even an early miscarriage. . As such, many women with endometriosis, rather than being infertile, in the strict sense of the word, often actually experience repeated undetected “mini miscarriages”.

Endometriosis often goes unnoticed for many years. Such patients are frequently erroneously labeled as having “unexplained infertility”, until the diagnosis is finally clinched through direct visualization of the lesions at the time of laparoscopy or laparoscopy. Not surprisingly, many patients with so called “unexplained” infertility, if followed for a number of years, will ultimately reveal endometriosis.

Advanced Endometriosis: In its most advanced stage, anatomical disfiguration is causally linked to infertility. In such cases, inspection at laparoscopy or laparoscopy will usually reveal severe pelvic adhesions, scarring and “chocolate cysts”. However, the quality of life of patients with advanced endometriosis is usually so severely compromised by pain and discomfort, that having a baby is often low on the priority list. Accordingly, such patients are usually often more interested in relatively radical medical and surgical treatment options (might preclude a subsequent pregnancy), such as removal of ovaries, fallopian pubis and even the uterus, as a means of alleviating suffering.

Moderately Severe Endometriosis. These patients have a modest amount of scarring/ adhesions and endometriotic deposits which are usually detected on the ovaries, fallopian tubes, bladder surface and low in the pelvis, behind the uterus. In such cases, the fallopian tubes are usually opened and functional.

Mild Endometriosis: These patients who at laparoscopy or laparotomy are found to have a few visible e3ndometrial “implants” but minimal distortion of pelvic anatomy are often erroneously labeled as having “unexplained” infertility. To hold that the there can only infertility can only be attributed to endometriosis if significant anatomical disease can be identified, is to ignore the fact that, biochemical, hormonal and immunological factors profoundly impact fertility. Failure to recognize this salient fact continues to play havoc with the hopes and dreams of many infertile endometriosis patients.

Endometriotic implants produce a toxic “peritoneal factor”

As mentioned above, toxins that impair fertilization are present in the peritoneal secretions of most patients with endometriosis. Impaired fertilization is a feature of endometriosis regardless of its severity. This explains why women with endometriosis three times are less likely to conceive per month of trying and why controlled ovarian stimulation with fertility drugs and/or procedures such as intrauterine insemination probably do not increase the chances of pregnancy over no treatment at all. It also explains why in vitro fertilization (which relies upon removing eggs through aspiration of the ovarian follicles before they can be affected by peritoneal toxins), by bypassing this handicap improves pregnancy rates dramatically and accordingly is the treatment of choice for most endometriosis patients with infertility.

Ovarian Endometriomas

 Advanced endometriosis is often associated with ovarian cysts (endometriomas/chocolate cysts) that are filled with altered blood and can be large and multiple.  When these are sizable (>1cm) they can activate surrounding ovarian connective tissue causing production of excessive male hormones (androgens) such as testosterone and androstenedione. Excessive ovarian androgens can compromise egg development in the affected ovary(ies) resulting in an increased likelihood of numerical chromosomal abnormalities (aneuploidy) and reduced egg/embryo competency”. In my opinion large ovarian endometriomas need to be removed surgically or rough sclerotherapy before embarking on IVF.

The “immunologic connection”

More than two thirds of patients with endometriosis have APA’s in their blood. These antibodies, given certain conditions, are capable of attacking the embryo and preventing implantation. There are at least 21 varieties of APA. Treatment requires prior and specific identification of all 21 sub-types and their gammaglobulin isotypes. Unfortunately, only a handful of Laboratories in the United States are capable of adequately testing for APAs. But it is probably not APAs that cause infertility in endometriosis patients. Rather it is the coexistence activated NK cells (Nka) and (to a lesser extent) activated T-cells (cytotoxic lymphocytes-CTL)that attack the early embryo’s root system as soon as it tries to attach to the uterine wall that causes the problem. The presence of APAs probably represents a marker which identifies those endometriosis patients who have immunologic problems requiring immunotherapy (approximately 30% of women with endometriosis (regardless of its severity) test positive for Nka cells). Optimal treatment is predicated upon an accurate diagnosis (see below).

How endometriosis CAN BE Diagnosed:

Endometriosis should be suspected when symptoms such as painful menstruation (dysmenorrhea), Pain with deep penetration with intercourse (dyspareunia and painful ovulation occur in women during the 2^nd half of their reproductive lives. The diagnosis is even more probable when there is associated infertility or recurrent pregnancy (RPL). Digital pelvic examination tends to be painful because of endometriotic deposits behind the cervix or adjacent to the uterus, which is often in fixed retroversion (tilted backwards and fixed in this position because of adhesions). Sometimes the ovaries are enlarged because of c cysts filled with decomposed blood (endometriotic or “chocolate” cysts).

Ultrasound examination is usually not helpful in diagnosing early endometriosis. However, in more severe cases, ovarian endometriomas have a characteristic appearance by ultrasound examination and can be diagnosed this way.

A new method , known as the BCL-6 (or Receptiva) test done on an endometrial biopsy sample, if positive is highly suggestive (but not absolutely diagnostic) of underlying endometriosis and might be worth doing in cases where the diagnosis is unclear and in cases of “unexplained infertility which is often due to undiagnosed mild to moderately sever endometriosis.

In the final analysis, the diagnosis of endometriosis can only be confirmed through direct visualization of endometrial deposits at the time of pelvic surgery (laparoscopy / laparotomy) or through histopathologic microscopic analysis of affected tissue.

Note: Endometriosis can be the master of disguise. Many women with mild disease are often asymptomatic , presenting with so called “unexplained infertility”. If the endometriosis is at a very early stage, even attempted visualization (at surgery) will often fail to identify the condition. Such women, will often, upon repeat laparoscopy, reveal the condition.

How should infertility associated with endometriosis be managed?

 The following basic concepts apply to management of endometriosis-related infertility:

• Ovulation induction with/without intrauterine insemination: Toxins in the peritoneal secretions of women with endometriosis exert a negative effect on fertilization potential regardless of how sperm reaches the fallopian tubes. It follows that intrauterine insemination will not improve the chances of pregnancy (over no treatment at all) in women with endometriosis.

• Pelvic Surgery aimed at restoring the anatomical integrity of the fallopian tubes does not counter the negative influence of toxic peritoneal factors that inherently reduce the chances of conception in women with endometriosis approximately three-fold. Nor does it address the immunologic dysfunction commonly associated with this condition. Pelvic surgery is relatively contraindicated for the treatment of infertility associated with endometriosis, when the woman is more than 35 years of age. With the pre-menopause approaching, such women do not have the time to waste on such less efficacious alternatives. In contrast, younger women who have time on their side might consider surgery as a viable option. Sizeable ovarian endometriomas should in my opinion, be removed in their entirety. Aspirating the content of such lesions is not adequate as they will return in time.

• In Vitro Fertilization (IVF): Not all women who have endometriosis require IVF! However, this treatment is in my opinion, advisable in the following circumstances:

• women who have advanced endometriosis
• where surgery and prior  treatment with fertility agents and/or IUI has proven to be unsuccessful.
• Women older than 35 years and those with   diminished ovarian reserve-DOR regardless of their age)) and women with endometriosis (regardless of age)
• Women with endometriosis (regardless of its severity who have an  IID (see below)

• The role of selective immunotherapy: In about 33% of cases, endometriosis, (regardless of its severity) is associated with an immunologic implantation dysfunction (IID) linked to activation of uterine natural killer cells (NKa), cytotoxic uterine lymphocytes (CTLa) and to a much lesser extent to APA.  This is diagnosed by testing the woman’s blood for APA and for NKa using the K-562 target cell test. NKa and CTLa activation  can also be determined by endometrial biopsy for cytokine analysis. NKa/CTLa  attack the embryo’s  invading trophoblast cells (developing “root system”) as soon as begins to  attach to the uterine lining. In most cases, this results in death of the embryo even before the pregnancy is diagnosed. Sometimes it presents as a chemical pregnancy or as an early miscarriage. . As such, many women with endometriosis, rather than being infertile, in the strict sense of the word, actually experience repeated undetected “mini miscarriages”.

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

While the exact cause of endometriosis remains an enigma, it is now apparent that immunologic dysfunction is likely to be a significant feature of this disease. Whether immunopathology is causally linked to this condition or whether it occurs in response to endometriosis is unknown. Regardless, the underlying immunologic disorder adversely impacts on implantation of the embryo/early conceptus. It is possible, through thorough and meticulous evaluation, to quantify, typify and thereupon, selectively treat the underlying IID.. In so doing, IVF pregnancy rates can be significantly improved.

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