Ask Our Doctors

Dear Patients,

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

– Geoffrey Sher, MD

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

Name: Maria L

Buenos días Dr,

Soy de Madrid, España. Me acabo de transferir un embrión mosaico de Bajo Grado (30%) para trisomía del cromosoma 6. Me ha implantado, pero por mas que intento buscar información y casos que hayan ido bien, no encuentro nada. Qué probabilidad tengo de que salga bien?
Gracias

Answer:

Please post in English!

 

Geoff Sher

Name: Ana K

Hi Dr. Sher,

I heard you on a recent episode of the Egg Whisperer. I am 35 and I was recently diagnosed with Hashimotos with very high antibodies ( 300 TPO and 900 TgAB). I recently had a failed FET with a genetically normal embryo. Previously I had a miscarriage from natural conception ( blighted ovum). I know that my next step would be to push to get my killer cells tested. For the FET that failed i was on a sterioid ( prednisone) for 7 days. I know you typically you recommend intralipid treatment 10-14 days before transfer as well as on the beta day ( if positive). My question is when should one start a steroid and how long to be on it? thank you!

Answer:

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

Name: Suzaura M

Hi! Ok so I am 42 years old! I have a 17 year old daughter who I had severe pre-eclampsia with at that time. Now doing ivf because I had gotten pregnant naturally 2 times this year and 1st time grew until heartbeat and then stopped and 2nd time more chemical. So now I have 4 fertilized eggs. And a 3 day fresh transfer tomorrow!!! Would u suggest doing 1 or 2 embryos tomorrow during transfer with my history and age? Helpppp . I appreciate

Answer:

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.

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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) ; https://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\

 

Name: Jessica W

I’m almost 40 y/o. I’ve had 4 failed IUIs and two egg retrievals, resulting in only 1 euploid from 47 total eggs retrieved. My fertilization and blast rates are “average” to above average, but my maturity rates are very low. In my first retrieval, only 13 of 20 were mature. In my second retrieval, only 12 of 27 mature. Between my first and second retrievals, on 10/27/23, I had robotic endometriosis surgery with an expert excision surgeon, who found very little endo, but that my left tube was swollen and partially closed. This was a surprise since I had a clear HSG in 9/2022. I also had Ovarian PRP before my second retrieval. What can I do to improve my maturity rate? My RE had me on an antagonist protocol for both cycles and does not think it would help me to change the protocol.

Answer:

  • 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:
    • 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:
    • 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:
    • 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 2nd 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.

 ________________________________________________

Name: Flavia F

Buenas tardes consulto, tengo 39 años y antimulleriana 0,19 muy baja, he intentado 3 ciclos con clomifeno y voy uno con letrozol, leí por aquí que para mi caso no son buenos esos estimulantes??? Gracias

Answer:

Please re-post in english!

 

Geoff Sher

_____________________________________________________________________

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) ; https://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\

 

Name: Gina T

Hi. I have 4 abnormally PGS tested donated embryos. The normally tested ones either didn’t implant or I miscarried. I even did the ERA scratch, and other testing to make sure my uterus was good. Anyway, can abnormal embryos be transferred? I don’t want to discard them if they can. I would donate them but from what I’ve read there’s not a high percentage they would result in a live birth. Thanks so much.

Answer:

Abnormal, non-mosaic embryos (aneuploid should not be transferred.

  • IVF FAILURE WITH “NORMAL” EMBRYOS: EXAMINING AND ADDRESSING  ANATOMICAL AND IMMUNOLOGIC CAUSES.

Implantation dysfunction is often overlooked as a significant reason for IVF failure. This is especially true when IVF failure is unexplained, or when there are recurring pregnancy losses or underlying issues with the uterus, such as endo-uterine surface lesions, thin uterine lining (endometrium), or immunological factors.

IVF success rates have been improving in the past decade. Currently, in the United States, the average live birth rate per embryo transfer for women under 40 years old using their own eggs is about 2:5 per woman undergoing embryo transfer. However, there is a wide range of success rates among different IVF programs, varying from 20% to almost 50%. Based on these statistics, most women in the United States need to undergo two or more IVF-embryo transfer attempts to have a baby. Many IVF practitioners in the United States attribute the differences in success rates to variations in expertise among embryology laboratories, but this is not entirely accurate. Other factors, such as differences in patient selection, the failure to develop personalized protocols for ovarian stimulation, and the neglect of infectious, anatomical, and immunological factors that affect embryo implantation, are equally important.

Approximately 80% of IVF failures occur due to “embryo incompetency,” mainly caused by ( irregularities in chromosome number (aneuploidy), which is often related to the advancing age of the woman, diminished ovarian reserve ( DOR) but can also be influenced by the ovarian stimulation protocol chosen, and sperm dysfunction (male infertility). However, in around 20% of cases with dysfunction, failure is caused by problems with embryo implantation.

This section will focus on embryo implantation dysfunction and IVF failure which in the vast majority of cases is caused by:

  1. 1. Anatomical irregularities of the inner uterine surface:
  2. a) Surface lesions such as polyps/fibroids/ scar tissue
  3. b)endometrial thickness
  4.  
  5. 2. Immunologic Implantation Dysfunction ( IID)lesions
  6. a)Autoimmune IID
  7. b) Alloimmune IID

  1. ANATOMICAL IMPLANTATION DYSFUNCTION
  2. a) Surface lesions such as polyps/fibroids/ scar tissue

When there are problems with the structure of the uterus, it can lead to difficulties in getting pregnant. While uterine fibroids usually don’t cause infertility, they can affect fertility when they distort the uterine cavity or protrude through the lining. Even small fibroids located just beneath the lining and protruding into the cavity can decrease the chances of the embryo attaching. Multiple fibroids within the uterine wall that encroach upon the cavity can disrupt blood flow, impair estrogen delivery, and prevent proper thickening of the lining. These issues can be identified through ultrasound during the menstrual cycle’s proliferative phase. Any lesion on the uterine surface, such as submucous fibroids, adhesions, endometrial polyps, or placental polyps, can interfere with implantation by causing a local inflammatory response similar to the effect of an intrauterine contraceptive device (IUD).

Clearly, even small uterine lesions can have a negative impact on implantation. Considering the high costs and emotional toll associated with in vitro fertilization (IVF) and related procedures, it is reasonable to perform diagnostic tests like hysterosalpingography (HSG), fluid ultrasound examination (hysterosonogram), or hysteroscopy before starting IVF. Uterine lesions that can affect implantation often require surgical intervention. In most cases, procedures like dilatation and curettage (D&C) or hysteroscopic resection are sufficient. Rarely a laparotomy may be needed. Such interventions often lead to an improvement in the response of the uterine lining.

Hysterosonogram( HSN/saline ultrasound) is a procedure where a sterile saline solution is injected into the uterus through the cervix using a catheter. Vaginal ultrasound is then used to examine the fluid-filled cavity for any irregularities that might indicate surface lesions like polyps, fibroid tumors, scarring, or a septum. When performed by an expert, HSN is highly effective in detecting even the smallest lesions and can supplant hysteroscopy in certain cases. HSN is less expensive, less invasive/traumatic, and equally effective as hysteroscopy. The only drawback is that if a lesion is found, hysteroscopy may still be needed for treatment.

Hysteroscopy is a diagnostic procedure performed in an office setting with minimal discomfort to the patient. It involves inserting a thin, lighted instrument called a hysteroscope through the vagina and cervix into the uterus to examine the uterine cavity. Normal saline is used to distend the uterus during the procedure. Like HSN, hysteroscopy allows for direct visualization of the inside of the uterus to identify defects that could interfere with implantation. We have observed that around one in eight IVF candidates have lesions that need attention before undergoing IVF to optimize the chances of success. I strongly recommend that all patients undergo therapeutic surgery, usually hysteroscopy, to correct any identified issues before proceeding with IVF. Depending on the severity and nature of the problem, hysteroscopy may require general anesthesia and should be performed in a surgical facility equipped for laparotomy if necessary.

  1. b) Thickness of the uterine lining (endometrium)

As far back as In 1989, I and my team made an important discovery about using ultrasound to assess the thickness of the endometrium during the late proliferative phase of both “ natural” and hormone-stimulated cycles. The assessment helped predict the chances of conception. We found that an ideal thickness of over 9mm at the time of ovulation , egg retrieval or with the commencement of progesterone therapy in embryo recipient cycles ( e.g., IVF with egg donation, gestational, surrogacy and embryo adoption) was associated with optimal implantation rates, while an endometrial thickness of less than 8 mm was associated with failure to implant or early pregnancy loss in the vast majority of cases. An endometrium measuring <8mm was almost invariably associated with failure to implant or early pregnancy loss in the while an endometrium measuring 8 to 9 mm was regarded as being intermediate, and while pregnancies did occur in this range, the rates were only slightly lower than with an optimal lining of 9 mm

A “poor” uterine lining typically occurs when the innermost layer of the endometrium (basal or germinal endometrium) is unable to respond to estrogen by developing a thick enough outer “functional” layer to support successful embryo implantation and placental development. The “functional” layer, which accounts for two-thirds of the total endometrial thickness, is shed during menstruation if pregnancy does not occur.

The main causes of a poor uterine lining are:

  1. Damage to the basal endometrium due to:
    • Inflammation of the endometrium (endometritis), often resulting from retained products of conception after abortion, miscarriage, or childbirth.
    • Surgical trauma caused by aggressive dilatation and curettage (D&C).
  1. Insensitivity of the basal endometrium to estrogen due to:
    • Prolonged (back to back) use of clomiphene citrate for ovarian stimulation or…
    • Prenatal exposure to diethylstilbestrol (DES), a drug given to prevent miscarriage in the 1960s.
  1. Overexposure of the uterine lining to male hormones produced by the ovaries or administered during ovarian stimulation (primarily testosterone):
    • Older women, women with DOR (poor responders), and women with polycystic ovarian syndrome (PCOS) often have increased biological activity of luteinizing hormone (LH), leading to testosterone overproduction by the ovarian connective tissue (stroma/theca). This effect can be further amplified when certain ovarian stimulation protocols were high doses of menotropins ( e.g., Menopur) are used.
  1. Reduced blood flow to the basal endometrium caused by:
    • Multiple uterine fibroids, especially if they are located beneath the endometrium (submucosal).
    • Uterine adenomyosis, which involves extensive abnormal invasion of endometrial glands into the uterine muscle.

In 1996 I introduced the Vaginal administration of Sildenafil (Viagra) to improve endometrial thickening. The selective administration of Sildenafil has shown great promise in improving uterine blood flow and increasing endometrial thickening in cases of thin endometrial linings. When administered vaginally, it is quickly absorbed and reaches high concentrations in the uterine blood system, diluting as it enters the systemic circulation. This method has been found to have minimal systemic side effects. However, it is important to note that Viagra may not be effective in all cases, as some cases of thin uterine linings may involve permanent damage to the basal endometrium, rendering it unresponsive to estrogen.

Severe endometrial damage leading to poor responsiveness to estrogen can occur in various situations. These include post-pregnancy endometritis (inflammation after childbirth), chronic granulomatous inflammation caused by uterine tuberculosis (rare in the United States), and significant surgical injury to the basal endometrium (which can happen after aggressive D&C procedures).

 

  1. 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 6-7days 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 Intravenous gammaglobulin (IVIg) to NK cells can immediately downregulate NK cell activity. However, neither 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 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.
  6. 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.
  7. 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. Humans have 23 pairs of chromosomes: one set from the sperm and one set from the egg that created us. Our sixth pair of chromosomes each contain DQ alpha genes. Again, one of these genes is from the sperm and one is from the egg that created us.

Like the genes for eye color, DQ alpha/HLA gene combinations differ between people. Thus, the male (whose  sperm created an embryo is likely to have different DQ alpha/HLA gene combinations than the potential mother . However, there are rare situations in which the male and the female partners have  DQ-alpha/HLA gene combinations are the same.

 

The endometrial immune system is programmed to accept embryos with different DQ alpha/HLA gene combinations than its own. This is known as “alloimmune recognition.” So, if the man shares a similar DQ alpha/HLA gene combination with the woman, and his sperm creates an embryo that tries  to implant , her endometrial immune system will see the embryo’s DQ alpha/HLA gene as “too similar” to its own and assume it is a foreign body.

 

Usually, this will lead to NK/T cell activation, the overproduction of TH-1 cytokines, and reproductive failure (i.e., infertility, and pregnancy loss). The severity with which this occurs is an important determinant of whether total implantation failure will occur or whether there would remain enough residual trophoblastic activity that would allow the pregnancy to limp along until the nutritional supply can no longer meet the demands of the pregnancy, at which point pregnancy loss occurs.

 

In cases of paternal-maternal DQ alpha/HLA matching, it will often take several pregnancies for NK cell activation to build to the point that women with alloimmune implantation dysfunction will present with clinical evidence of implantation dysfunction. Sometimes it starts off with one or two live births, whereupon NK/T cell activity starts to build, leading to one or more early miscarriages. Eventually the NK/T cell activation is so high that subsequent pregnancies can be lost before the woman is even aware that she was pregnant at all. At this point, she is often diagnosed with secondary, “unexplained” infertility and/or “unexplained” IVF failure.

 

Alloimmune Implantation Dysfunction is diagnosed by testing the blood of both the male and female partners for matching DQ alpha genes and NK/T cell activation.

 

There are two types of DQ alpha/HLA genetic matching: 

  • 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.

 _____________________________________________________________________

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) ; https://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\

 

Name: Allison B

Hi Dr. Sher,

I heard you on an episode of the Egg Whisperer. I have high testosterone from PCOS and have had one implantation failure and two chemical pregnancies. Could the high testosterone be the cause? My embryos were not genetically tested at that time. Should I be on a steroid prior to my next frozen embryo transfer, and if so, for how long?

Thank you,
Allison

Answer:

  • Navigating Polycystic Ovary Syndrome: Understanding, Hope, and Treatment

 

 

Understanding the intricate interplay of hormones and the impact on egg development empowers us to create personalized protocols, offering hope for improved egg quality and ultimately optimizing the chances of successful IVF for women with PCOS.

 

Polycystic ovary syndrome (PCOS) is a widespread hormonal disorder affecting 5% to 10% of reproductive-age women globally. Women with PCOS often have enlarged ovaries containing multiple small fluid-filled collections (micro-cysts) arranged in a “string of pearls” pattern below the ovarian surface, intertwined with an overgrowth of ovarian connective tissue.

 

PCOS is marked by abnormal ovarian function causing absent, irregular or dysfunctional ovulation and menstruation,  infertility, increased body hair (hirsutism), acne, and higher body weight as indicated by an above normal body mass index (BMI). 

 

Despite substantial research efforts to identify its cause, the origins of PCOS remain elusive, and a definite cure is yet to be found. This disorder is notably diverse and often has a genetic basis within families. 

 

Infertility related to PCOS is attributed to various factors, including irregular gonadotropin (FSH and LH) pituitary secretion, peripheral insulin resistance, elevated levels of adrenal and/or ovarian androgens (male hormones), and dysfunction in growth factors. Individuals with PCOS often battle obesity and insulin resistance. The compensatory surge in insulin levels further stimulates ovarian androgen production, potentially hampering egg maturation. Notably, the degree of insulin resistance is closely linked to anovulation. 

 

PCOS also poses long-term health risks, underscoring the need for vigilant annual health check-ups to monitor potential conditions like non-insulin-dependent diabetes mellitus, hypertension, hypercholesterolemia, cardiovascular disease, and endometrial cancer.

 

Though PCOS-related infertility is typically manageable with fertility drugs, lifestyle modifications involving diet and exercise are fundamental for long-term management. Recent advancements have shown improvements in ovulation rates, androgen levels, pregnancy rates, and even a reduction in first-trimester miscarriage rates through the use of insulin sensitizers like Metformin to address underlying insulin resistance.

 

Most PCOS patients are young and often experience successful pregnancies with oral clomiphene or Letrozole/Femara. However, a subset of PCOS patients with severe ovarian ovulatory dysfunction and those requiring IVF treatment, will usually require injectable gonadotropin medications such as Follistim, Gonal-F, Menopur, etc. These treatments can trigger an exaggerated  response to gonadotropins, potentially leading to complications such as Severe Ovarian Hyperstimulation Syndrome (OHSS) and high-order multiple births ( triplets or greater). For these cases, employing strategies like “prolonged coasting” (see below) and/or delaying embryo transfer for a month or two  in order to allow the ovaries to recover from ovarian stimulation,  and selectively transferring fewer embryos present clear advantages..

PCOS and Egg/Embryo Quality:

 

PCOS and Egg/Embryo “Competency”.


A woman’s potential for successful egg maturation and embryo development is largely determined by genetics. However, this potential can also be significantly influenced by hormonal changes within the ovaries during the pre-ovulatory phase of her menstrual cycle. Achieving the right stimulation of the follicles and precise timing for egg maturation with the LH (Luteinizing Hormone) “surge” or through hCG (human chorionic gonadotropin) administration is crucial for optimal egg quality, fertilization, and subsequent embryo development.

 

Two key hormones, LH and FSH (follicle stimulating hormone), play vital but distinct roles in the development of eggs and follicles. FSH mainly stimulates granulosa cells (lining the follicles) and estrogen production (E2). On the other hand, LH primarily acts on the ovarian stroma (connective tissue around the follicle) to produce androgens ( predominantly testosterone and androstenedione). While a small amount of androgen supports egg and follicle development, excessive exposure can be harmful. Too much androgen can also hinder estrogen-induced growth of the uterine lining.

 

PCOS is commonly associated with elevated LH levels, leading to excess stromal growth, follicle overgrowth (referred to as cysts), and heightened androgen production. Accordingly, suppressing LH secretion using gonadotropin releasing hormone (GnRH) agonists like Lupron/ Buserelin/Superfact and decapeptyl proves beneficial. However, it is important to understand that  some LH is essential for optimal egg and follicle development. Excessive  LH on the other hand results in over-production of LH-induced ovarian androgens, which upon reaching the follicular fluid often  compromises both follicle and egg development.  Consequently, PCOS women who commonly over-produce LH and ovarian androgens  frequently propagate poorly developed follicles and  “dysmature/immature” eggs leading to  poor fertilization and embryo quality as well as an androgen-induced insufficient uterine lining that might prejudice embryo implantation, It is in my opinion, that the compromised egg quality is not necessarily due to an inherent “egg defect “ but  rather due to an adverse ovarian hormonal milieu which can often be avoided by  tailoring stimulation protocols so as to avoid excessive LH-induced androgens, Avoiding .

 

Varieties of PCOS:

 

Polycystic Ovary Syndrome (PCOS) comes in various forms, each requiring tailored treatment. Here, I wish to shed light on the main types and how infertility linked to ovulation dysfunction can be managed.

  • Hypothalamic-Pituitary-PCOS:
    • Most common form with genetic roots.
    • Characterized by high levels of Luteinizing Hormone (LH) and androgen hormones.
    • Often associated with insulin resistance.
  • Adrenal PCOS:
    • Excess male hormones come from overactive adrenal glands.
    • Elevated testosterone and/or androstenedione levels, along with increased dehydroepiandrosterone (DHEAS) levels, confirm diagnosis.
  • Pelvic Adhesive Disease-Related PCOS:
    • Linked to severe endometriosis, pelvic inflammatory disease, or extensive pelvic surgery.
    • Lower response to ovulation induction.
    • Notably, DHEAS levels remain unaffected.

 

Treating Infertility Due to Ovulation Dysfunction:

  • Hypothalamic-Pituitary-/Ovarian PCOS:
    • Successful treatment with fertility drugs like clomiphene citrate, Letrozole, or gonadotropins.
    • In-vitro Fertilization (IVF) is increasingly favored.
    • Oral Metformin can help reduce insulin resistance and androgen levels.
  • Adrenal PCOS:
    • Treated with steroids like prednisone or dexamethasone to suppress adrenal androgen production.
    • Combined with fertility drugs for induced ovulation.
  • PCOS due to Pelvic Adhesive Disease:
    • Often linked to compromised ovarian reserve and higher FSH levels.
    • Requires high doses of gonadotropins and “estrogen priming” for effective ovulation induction or IVF.

 

 

The Risks of Treatment

 

  • High-order multiple pregnancies (triplets, or greater):

PCOS patients undergoing ovulation induction are at greater risk of multiple pregnancies which are especially treacherous both mother and offspring occur with the occurrence of high-order multiple pregnancies. This risk is not preventable when ovulation induction alone is used (with or without IUI) since there is no ability to regulate the number of eggs that are ovulated. Conversely, IVF  allows for the  number of embryos transferred to the uterus to be deliberately regulated. 

 

  • Severe Ovarian Hyperstimulation (OHSS)
    1. OHSS is a significant concern for women with PCOS undergoing fertility treatments , especially where gonadotropins are administered for ovarian stimulation.
    2. Understanding OHSS:
      • Women with PCOS tend to hyper-respond to fertility drugs, often producing excessive ovarian follicles.;
      • his can escalate into OHSS, posing life-threatening risks.

 

Indicators of OHSS:

  • OHSS begins with an abundance of ovarian follicles (often more than 25).
  • Rapid rise in estradiol (E2) levels, sometimes exceeding 3000pg/ml within 7-9 days of stimulation.
  • The risk of OHSS exceeds 80% when the peak blood estradiol level exceeds 6000pg/ml.

 

Symptoms and Signs of OHSS:

 

  • Abdominal swelling due to fluid accumulation (ascites).
  • Sometimes fluid in the chest cavity (hydrothorax) and even around the heart ( pericardial effusion)
  • Rapid weight gain (more than a pound per day) due to fluid retention.
  • Abdominal pain and lower backache.
  • Nausea, diarrhea, and vomiting.
  • Visual disturbances like blurred vision and spots in front of the eyes.
  • Reduced urine output.
  • Cardiovascular complications and bleeding tendencies.

 

Managing OHSS:

 

  • If fluid accumulation compromises breathing, elevating the head of the bed often helps.
  • Drainage of excess fluid through transvaginal sterile needle aspiration (vaginal paracentesis) may be necessary.
  • Symptoms typically subside within 10-12 days of hCG shot if pregnancy doesn’t occur or by the 8th week of pregnancy.
  • Monitor urine output and perform chest X-rays and blood tests regularly to assess the condition.
  • In severe cases, hospitalization and intensive care might be necessary.

 

Avoiding OHSS while protecting egg quality though  “Prolonged Coasting”

 

In the early 1990s, I introduced  a game-changing approach to the prevention of OHSS, called “Prolonged Coasting” (PC) . The method avoids the life-endangering risks associated with this complication while to largely protecting  egg quality . PC  has now become a standard treatment for OHSS prevention. However, the effective success of PC is very largely dependent on meticulous implementation and proper timing.

 

What is “Prolonged Coasting” (PC)?

  • PC involves a strategic pause in administering gonadotropin therapy, while continuing GnRHa (Lupron/Buserelin/Superfact/decapeptyl)
  • This method significantly reduces the risk of OHSS, a life-threatening condition associated with excessive follicle growth.
  • Balancing Act for Egg Quality:
  • While PC is highly effective in averting OHSS, concerns were raised about potential impacts on fertilization rates and embryo implantation.
  • Experience suggests that the perceived egg/embryo quality deficit isn’t directly caused by PC but is more about precise timing.
  • Timing is Crucial: It is initiated when a woman with >25 follicles (total) with an estradiol measurement of >2500pg/ml has at least 50% of her follicles at 14mm diameter. It ends when the rising E2 plateaus and then drops. The key is to wait until the plasma estradiol concentration drops below 2,500 pg/ml before administering hCG. Initiating PC too early or too late can either halt follicle growth abruptly or lead to cystic follicles, both affecting egg quality. The timing allows for a progressive rise in estradiol levels followed by a plateau before a controlled decline, optimizing egg maturation. Even if the estradiol level falls below 1,000 pg/ml by hCG trigger time, resisting the urge to trigger prematurely with hCG is vital. This ensures eggs have adequate time for optimal development, increasing the chances of successful fertilization and embryo quality.

:

Words of caution:

 

  • Pituitary suppression with GnRH antagonists (Ganirelix, Cetrotide, Orgalutron) can falsely suppress E2 levels and in my opinion, is not be suitable, especially in cases like PCOS a decision on timing for PC in large part hinges on the accurate determination of serial blood estradiol levels…Accordingly, I caution against their use in patients with PCOS where “prolonged coasting is contemplated being used.
  • The standard practice of administering hCG (human chorionic gonadotropin) in an attempt to prematurely arrest further follicle growth and so prevent Severe Ovarian Hyperstimulation Syndrome (OHSS) can, by abruptly halting egg development, impact their maturation, prejudice their “competency” and in turn compromise embryo competency”, as well. Mastering the art of “Prolonged Coasting” is a critical step forward in fertility treatments. Precise timing and a patient-centered approach can make a world of difference, providing hope and improved outcomes for women on their journey towards motherhood.

 In summary, when it comes to managing infertility in PCOS women, it is  crucial to tailor stimulation protocols during IVF to minimize exposure to excessive LH-induced ovarian androgens. By limiting the use clomiphene and Letrozole/Femara  as well as LH-containing gonadotropins like Menopur and incorporating “prolonged coasting,” we can provide the necessary time for optimal follicle and egg development before administering hCG. This approach can potentially enhance egg quality and improve outcomes in IVF for women with PCOS.

___________________________________________________________________

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) ; https://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\

 

Name: Sheetal p

My beta hcg on 9 jan is 867 on 16 jan it is 2860 nd on 18 jan it is 3916 is it ok

Answer:

It is probably OK but do an ultrasound to confirm a viable pregnancy!

Geoff Sher

Name: продажа тугоплавких металлов продажа тугоплавких металлов

Приглашаем Ваше предприятие к взаимовыгодному сотрудничеству в направлении производства и поставки никелевого сплава Фольга 1.3911 и изделий из него.

– Поставка карбидов и оксидов
– Поставка изделий производственно-технического назначения (поддоны).
– Любые типоразмеры, изготовление по чертежам и спецификациям заказчика.

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Answer:

___Please re-post in English!

 

Geoff Sher

_______________________________________________________________________

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) ; https://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\

 

Name: Kristin B

Hello. I hope you are well, Dr. Sher. In the rate event that you are reading this, I wanted to see if I might be able to receive your insight. I have just completed my first attempt at egg retrieval today, which did not turn out well. I am wondering if I am a candidate to even pursue another cycle. I am 42 years old, FSH averaging 5/6 (tested multiple times) and normal progesterone. My last AMH test showed an extremely low .003, but just 11 months before it was 0.5, and the year before that 1.25, so it did make me wonder if there was a mistake on the last one. Regardless, I am probably perimenopause but have periods every month (26-28 days). Before my retrieval, I had 8 follicles, two of which were dominant (between 19-22) and two that were only slowing growing, climbing to ten. Sorry for all the details. I was on Gonal f, Menopur and Ganirelex. Trigger of Pregynl 10,000. I was shocked that because the two dominant follicles grew at a nice leg during stims, that no eggs were found. Do you have any insight on if it’s worth it to attempt another cycle with a different protocol?

Answer:

Understanding the impact of age and ovarian reserve on the success of in vitro fertilization (IVF) is crucial when it comes to reproductive health. This article aims to simplify and clarify these concepts, emphasizing their significance in the selection of ovarian stimulation protocols for IVF. By providing you with this information, we hope to shed light on the importance of considering these factors and making informed decisions regarding fertility treatments.

  1. The Role of Eggs in Chromosomal Integrity: In the process of creating a healthy embryo, it is primarily the egg that determines the chromosomal integrity, which is crucial for the embryo’s competency. A competent egg possesses a normal karyotype, increasing the chances of developing into a healthy baby. It’s important to note that not all eggs are competent, and the incidence of irregular chromosome numbers (aneuploidy) increases with age.
  2. Meiosis and Fertilization: Following the initiation of the LH surge or the hCG trigger shot, the egg undergoes a process called meiosis, halving its chromosomes to 23. During this process, a structure called the polar body is expelled from the egg, while the remaining chromosomes are retained. The mature sperm, also undergoing meiosis, contributes 23 chromosomes. Fertilization occurs when these chromosomes combine, resulting in a euploid embryo with 46 chromosomes. Only euploid embryos are competent and capable of developing into healthy babies.
  3. The Significance of Embryo Ploidy: Embryo ploidy, referring to the numerical chromosomal integrity, is a critical factor in determining embryo competency. Aneuploid embryos, which have an irregular number of chromosomes, are often incompetent and unable to propagate healthy pregnancies. Failed nidation, miscarriages, and chromosomal birth defects can be linked to embryo ploidy issues. Both egg and sperm aneuploidy can contribute, but egg aneuploidy is usually the primary cause.
  4. Embryo Development and Competency: Embryos that develop too slowly or too quickly, have abnormal cell counts, contain debris or fragments, or fail to reach the blastocyst stage are often aneuploid and incompetent. Monitoring these developmental aspects can provide valuable insights into embryo competency.
  5. Diminished Ovarian Reserve (DOR): As women advance in their reproductive age, the number of remaining eggs in the ovaries decreases. Diminished ovarian reserve (DOR) occurs when the egg count falls below a certain threshold, making it more challenging to respond to fertility drugs effectively. This condition is often indicated by specific hormone levels, such as elevated FSH and decreased AMH. DOR can affect women over 40, but it can also occur in younger

 

Why IVF should be regarded as treatment of choice for older women an those who have diminished ovarian reserve ( DOR):

Understanding the following factors will go a long way in helping you to make an informed decision and thereby improve the chances of a successful IVF outcome.

  1. Age and Ovarian Reserve: Chronological age plays a vital role in determining the quality of eggs and embryos. As women age, there is an increased risk of aneuploidy (abnormal chromosome numbers) in eggs and embryos, leading to reduced competency. Additionally, women with declining ovarian reserve (DOR), regardless of their age, are more likely to have aneuploid eggs/embryos. Therefore, it is crucial to address age-related factors and ovarian reserve to enhance IVF success.
  2. Excessive Luteinizing Hormone (LH) and Testosterone Effects: In women with DOR, their ovaries and developing eggs are susceptible to the adverse effects of excessive LH, which stimulates the overproduction of male hormones like testosterone. While some testosterone promotes healthy follicle growth and egg development, an excess of testosterone has a negative impact. Therefore, in older women or those with DOR, ovarian stimulation protocols that down-regulate LH activity before starting gonadotropins are necessary to improve egg/embryo quality and IVF outcomes.
  3. Individualized Ovarian Stimulation Protocols: Although age is a significant factor in aneuploidy, it is possible to prevent further decline in egg/embryo competency by tailoring ovarian stimulation protocols. Here are my preferred protocols for women with relatively normal ovarian reserve:
  1. Conventional Long Pituitary Down Regulation Protocol:
  • Begin birth control pills (BCP) early in the cycle for at least 10 days.
  • Three days before stopping BCP, overlap with an agonist like Lupron for three days.
  • Continue daily Lupron until menstruation begins.
  • Conduct ultrasound and blood estradiol measurements to assess ovarian status.
  • Administer FSH-dominant gonadotropin along with Menopur for stimulation.
  • Monitor follicle development through ultrasound and blood estradiol measurements.
  • Trigger egg maturation using hCG injection, followed by egg retrieval.
  1. Agonist/Antagonist Conversion Protocol (A/ACP):
  • Similar to the conventional long down regulation protocol but replace the agonist with a GnRH antagonist from the onset of post-BCP menstruation until the trigger day.
  • Consider adding supplementary human growth hormone (HGH) for women with DOR.
  • Consider using “priming” with estrogen prior to gonadotropin administration
  1. Protocols to Avoid for Older Women or Those with DOR: Certain ovarian stimulation protocols may not be suitable for older women or those with declining ovarian reserve:
  • Microdose agonist “flare” protocols
  • High dosages of LH-containing fertility drugs such as Menopur
  • Testosterone-based supplementation
  • DHEA supplementation
  • Clomiphene citrate or Letrozole
  • Low-dosage hCG triggering or agonist triggering for women with DOR

 

 

Preimplantation Genetic Screening/Testing(PGS/T): PGS/T is a valuable tool for identifying chromosomal abnormalities in eggs and embryos. By selecting the most competent (euploid) embryos, PGS/T significantly improves the success of IVF, especially in older women or those with DOR.

Understanding the impact of advancing age and declining ovarian reserve on IVF outcomes is essential when making decisions about fertility treatments. Age-related factors can affect egg quality and increase the likelihood of aneuploid embryos with resultant IVF failure. Diminished ovarian reserve (DOR) further complicates the process. By considering these factors, you can make informed choices and work closely with fertility specialists to optimize your chances of success. Remember, knowledge is power, and being aware of these aspects empowers you to take control of your reproductive journey.

_____________________________________________________________________

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) ; https://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\

 

 

 

Name: продажа тугоплавких металлов продажа тугоплавких металлов

Приглашаем Ваше предприятие к взаимовыгодному сотрудничеству в сфере производства и поставки никелевого сплава Электрод вольфрамовый Р’Рђ и изделий из него.

– Поставка порошков, и оксидов
– Поставка изделий производственно-технического назначения (втулка).
– Любые типоразмеры, изготовление по чертежам и спецификациям заказчика.

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Answer:

Please Re-post in English!

 

Geoff Sher

______________________________________________________________

 

Name: продажа тугоплавких металлов продажа тугоплавких металлов

Приглашаем Ваше предприятие к взаимовыгодному сотрудничеству в сфере производства и поставки никелевого сплава [url=https://redmetsplav.ru/store/nikel1/rossiyskie_materialy/nikelevye_splavy/43n/ ] 43Рќ [/url] и изделий из него.

– Поставка катализаторов, и оксидов
– Поставка изделий производственно-технического назначения (детали).
– Любые типоразмеры, изготовление по чертежам и спецификациям заказчика.

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Answer:

I apologize but you will need to re-post in English!

Geoff Sher

_____________________________________________________________________

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) ; https://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\

 

 

Name: Javier S

Buenas tardes. Nuestro es el siguiente. Mi mujer presenta hidrosalpx bilateral distal con salida de contraste a la zona pélvica en al menos uno de ellos. ¿Sería efeciva la técnica de la Escleroterapia en este caso para la búsqueda de un embarazo natural?
Muchas gracias por adelantado

Answer:

Please re-post in English!

 

Geoff Sher

Name: Rebecca A

Hola!
Estuve el mes pasado con puregon 75mm pero por una variación de prolactina hemos tenido que dejar el proceso de inseminación.
Desde hace tres semanas he tenido un incremento de flujo vaginal y no puedo estar sin salvaslip. No sé si es normal.

Gracias

Answer:

Please re-post in English!

 

Geoff Sher

Fiv

Name: RJ C

Hola. Tengo 40 años y 0,73 Amh. Me sometí q un ciclo fiv con fostipur 300 y meriofert 150, luego cetrotide, me quedé embarazada pero lo perdí. Me han realizado otro ciclo pero me incluyeron femara y progynova y quitaron centrotide y tenía 14 folículos pero crecían lentos y hubo que cancelar. Os he leído en el foro la importancia de controlar la medicación para no “estropear” la calidad de los óvulos. Cual sería la dosis indicada con mi edad? Y que medicación la adecuada? Gracias. Un saludo

Answer:

Please post in English!

Name: Crystal M

Hi Dr. Sher, I had a hscore of 3.4 on Receptiva dx but had a lap done afterwards that showed 0 endometriosis. Why should I lower estrogen with Lupron if there is no endometriosis?

Answer:

Respectfully, I do not see a reason!

Geoff Sher

Name: Lindsey A

Greetings!
I am a 39yo f, pmhx prolactinoma (dx 1/2023, medically managed now), ulcerative proctitis (on stelara, almost in remission) with 1 natural conception and loss at 8 weeks due to trisomy, now 3 failed IVF stim attempts. My AMH flux is between 1.4-1.8 and FSH around 11. Antral follicle count always 11-15, I’ve done 3 protocols, 1st GnRHa protocol (Gonal-F 300 but i responded so quickly came down to 225u after few days), Meno (150), Ganirelix, HCG) no priming – for 11 eggs, 8 mature, 4 fertilized with ICSI, 2 blast – 1 low mosaic and 1 aneuploid. Had mild OHSS after this.
Second round, Estrogen priming, GnRHa (Gonalf 225u, meno225u) added clomid 5 days, lupron trigger to avoid OHSS, which helped, used ICSI. Got 15 follicles, 12 mature, 11 fertilized only 1 blast aneuploid.
Switched physicians, as prior RE said you just have poor quality eggs not much to do for that, Third wound we did mild dose GnRHa (150u Gonal F, 150u Meno) with priming and letrozole instead of clomid and dual trigger lupron 70u/HCG 1500, 11 follices on last US only 7 collected, 3 mature, we used natural conception, 2 fertilized – 1 blast, again aneuploid.
DNA frag on my husband was moderately positive at my prior RE clinic, but new doc questions validity and doesnt think its the issue. We will see urology just in case.
There is a question if I have undiagnosed endo as I do have some correlating symptoms, positional pain with intercourse, chronic constipation and persistent LLQ aching – which i always attributed to my IBD but now as im close to remission and it persists, i’m rethinking. I also get this excruciating pelvic cramping, around ovulation associated with high intensity excercise, pref saw pelvic pain specialist 3 years ago who did MRI said no endo, no point to lap.
As I am about to be 40, my RE doesn’t feel compelled for me to explore laparoscopy as the healing time would prolong continue IVF and my age is concerning. He is also against growth hormone use, surprising to me.
His next suggestion is lupron down regulation, however I’ve listened to your talk on the egg whisperer on approach for those with challenging egg quality, keeping menopur low to try to avoid excess testosterone affecting quality, utilizing Growth Hormone as well. I tried to bring this up, but its a challenging conversation to have when you’re bring other physicians protocols into the mix.
My questions are, do you think it is worth trying another round without consulting with an endometriosis specialist for lap? If so, do you think lupron down regulation would be beneficial to try in my scenario, or should I be looking for a physician who utilizes GH for poor blast and quality issues? TY for your time, an apologies for the lengthy message. IM a physician assistant, so it’s hard for me to leave details out.

Answer:

In my opinion, we need to have a detailed online consultation to discuss the following issues in detail:

1. Egg/embryo quality issues:  and the influence of the protocol used for ovarian stimulation as well as diminishing ovarian reserve and advancing age..

2. Implantation dysfunction as it might relate to and immunologic implantation dysfunction (possibly linked to underlying endometriosis and/or a personal or family history of autoimmunity).

_________________________________________________________________________

  • UNEXPLAINED” INFERTILITY: A RATIONAL APPROACH TO MANAGEMENT

Infertility affects y 10%-15% of couples who are unable to conceive. In some cases, the cause of infertility cannot be determined using conventional diagnostic methods, leading to a diagnosis of “unexplained infertility.” However, it is important to note that in most cases labeled as “unexplained infertility,” a more thorough evaluation could have revealed an underlying cause. There are two main groups of individuals diagnosed with unexplained infertility: those without any biological problems hindering pregnancy, and those with unidentified reasons due to limited medical information or technology. Fortunately, advancements in testing techniques have made it easier to diagnose and treat infertility in the latter group.

To make a presumptive diagnosis of unexplained infertility, healthcare providers need affirmative answers to several questions. These include whether the woman is ovulating normally, whether the couple engages in regular intercourse during the periovulatory phase of the menstrual cycle, whether the fallopian tubes are normal and open, whether endometriosis can be ruled out, whether the male partner has normal semen parameters (especially sperm count and motility), and whether the presence of high concentrations of antisperm antibodies in the man or woman’s blood is associated with sperm incapacitation.

The diagnosis of unexplained infertility depends on the thoroughness of the healthcare provider in attempting to rule out all potential causes. The fewer tests conducted, the more likely it is that  a presumptive diagnosis of “unexplained” infertility will be made. Below are a few causes of infertility that are often missed leading to the cause of infertility being mischaracterized as being “unexplained: :

  • Subtle abnormalities involving the fallopian tubes without causing them to be “blocked”, often go unnoticed. Examples include subtle peritubal adhesions and/ or developmental or acquired defects involving the tubal fimbria (i.e., the finger-like “petals” at their outer ends), can prevent the collection and transportation of eggs to meet sperm. Detecting these conditions requires direct visualization of lesions through laparoscopy or laparotomy
  • Chromosomal abnormalities in eggs or embryos can also contribute to infertility. Both eggs and embryos must contain the correct number of chromosomes (euploid) for successful fertilization and implantation. Until recently, there was no reliable method to determine their chromosomal status. However, the introduction of preimplantation genetic screening/testing (PGS/T), using genetic tests like next generation gene sequencing (NGS) has enabled the identification of embryo, numerical chromosomal abnormalities (aneuploidy) which when present will prejudice fertility. PGS/T has become an essential tool in diagnosing infertility.
  • Luteinized Unruptured Follicle (LUF) Syndrome is another condition that can contribute to unexplained infertility. In this condition, eggs become trapped in the follicle and are not released, despite routine tests indicating normal ovulation. Hormonal dysfunction related to ovulation can also negatively impact the preparation of the uterine lining, hindering normal implantation.
  • Immunologic implantation dysfunction (IID) can occur when the woman’s or man’s immune system attacks sperm cells, rendering them immobile or causing their destruction. Additionally, immunologic dysfunction involving the uterine lining can lead to early rejection of the implanting embryo, often before the woman realizes she has conceived.
  • Cervical infection, specifically Ureaplasma Urealyticum infection of the cervical glands, can prevent sperm from reaching the eggs in the fallopian tubes. This type of infection is usually undetectable through routine examination or cervical culturing methods.
  • Mild or moderate endometriosis is a condition associated with the production of “pelvic toxins” that reduce the fertilization potential of eggs. Approximately one-third of women with endometriosis also experience IID. Detecting mild or moderately severe endometriosis requires direct visualization of lesions through laparoscopy or laparotomy, and identifying IID requires sophisticated tests performed by specialized Reproductive Immunology Reference Laboratories. In some cases of early endometriosis the lesions are “nonpigmented” and  cannot even be detected through direct vision, yet they can significantly impact fertility through establishing a “toxic” intrapelvic environment that compromises competency of the egg as it traverses the pelvic environment during passage from the ovary to the tube.
  • Psychological factors can also influence fertility. Stress and negativity can interfere with hormonal balance and decrease the ability to conceive.
  • Mild Male Factor infertility that are not readily detected through routine semen analysis.
  • Antisperm antibodies (ASA) in the man or in the woman. This can only be diagnosed using high specialized blood and sperm test.

Management:

When it comes to managing “Unexplained Infertility,” a personalized approach is crucial for success. The first step is to identify any underlying causes whenever possible. For those experiencing ovulation dysfunction due to hormonal imbalances, ovulation induction with oral or injectable fertility drugs is often recommended. In cases where an IID is detected, selective immunotherapy will be required and in cases cervical mucus hostility is caused by a ureaplasma infection, specific and simultaneous antibiotic therapy becomes necessary.

For younger women (under 39 years) facing issues with sperm migration through the cervix, uterus, and fallopian tubes, intrauterine insemination (IUI) with or without controlled ovulation stimulation (COS) is often the recommended course of action. However, if these treatments prove ineffective, or if the woman is over 39 years old, has IID, harbors significant concentrations of antisperm antibodies, or has structural tubal abnormalities, IVF becomes the preferred option. In cases of male infertility that are intractable, moderate, or severe, where natural fertilization seems unlikely, injecting sperm directly into the egg through a procedure called intracytoplasmic sperm injection (ICSI)/IVF  is necessary to achieve fertilization.

It is an undeniable truth that the majority of infertility cases can be diagnosed, which makes it disheartening when the label of “unexplained infertility” is used as an excuse for not conducting a thorough evaluation of the problem. Couples should not simply accept a diagnosis of “unexplained infertility” at face value. Instead, they should actively seek to have their treating physician identify the specific cause of their infertility, as treatment is most likely to be successful when the root cause is fully understood. By taking charge of their reproductive health and exploring all possible avenues, couples can increase their chances of achieving their dream of starting a family.

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  • EGG/ EMBRYO QUALITY IN IVF & HOW SELECTION OF THE IDEAL PROTOCOL FOR OVARIAN STIMULATION INFLUENCES EGG/EMBRYO QUALITY AND 

The journey of in vitro fertilization can be a rollercoaster of emotions for many patients. Often times they have to face the harsh reality that the number and quality of eggs retrieved has fallen short of their expectations. Then, should fertilization of these eggs not propagate  chromosomally normal (euploid), “competent” embryos suitable for transfer to the uterus, many such patients find themselves in a state of emotional distress. They grapple with the inevitable questions of why this happened and how to prevent it from occurring again in the future. This article aims to delve into these queries, providing insights, rational explanations, and therapeutic options. It is an invitation to explore the light at the end of the tunnel. Readers are urged to carefully absorb the entirety of the article in the hope of finding valuable information and renewed hope.

  • The Importance of Chromosomal Integrity: While sperm quality is an important factor, egg quality is by far the most important when it comes to the generation of embryos that are capable of propagating healthy babies (“competent”). In this regard, chromosomal integrity of the egg and embryo, although it is not the only factor , is certainly the main determinant of such competency.
  • The woman’s age: About two thirds of a woman’s eggs in her twenties or early thirties have the correct number of chromosomes, which is necessary for a healthy pregnancy. As a woman gets older, the percentage of eggs with the right number of chromosomes decreases. By age 40, only about one in every 5-6 eggs is likely to be normal, and by the mid-forties, less than one in ten eggs will be normal.
  • Ovarian Reserve (number of available in the ovaries): A woman is born with all the eggs she will ever have. She starts using these eggs when she begins ovulating during puberty. At first, the eggs are used up quickly, but as she gets older, the number of eggs starts to run out. Her brain and pituitary gland try to stimulate the production of more eggs by increasing the output of Follicle Stimulating Hormone (FSH), but unfortunately, this often doesn’t work. When the number of remaining eggs in her ovaries falls below a certain level (which can be different for each woman), her FSH level rises, and production of the ovarian hormone, AMH decreases. This is the start of diminishing ovarian reserve (DOR). Most women experience the onset of DOR in their late 30s or early 40s, but it can happen earlier for some. The lower the ovarian reserve, the lower the AMH level will be, and the fewer eggs will be available for harvesting during IVF-egg retrieval. In such cases, a higher dosage of fertility drugs might be needed to promote better egg production in future attempts. . On the other hand, higher AMH levels mean more eggs are available, and lower doses of fertility drugs are usually needed. DOR is commonly associated with increased bioactivity of pituitary gland-produced LH. This LH activates production of ovarian male hormones (androgens)…predominantly testosterone by ovarian connective tissue (stroma) . While a small amount of  ovarian testosterone is absolutely necessary for optimal follicle and egg development, excessive ovarian testosterone will often access the follicle , and compromise both egg quality and follicle growth and development. In some cases, rapidly increasing  LH-release (“premature LH-surge”) with excessive induced ovarian testosterone can lead to “premature luteinization”  of the follicles with cessation in growth and even to“ premature ovulation”.
  • Importance of Individualized Controlled Ovarian Stimulation (COS) Protocol: It’s not surprising that DOR is more common in older women, but regardless of age, having DOR makes a woman’s eggs more likely to be compromised during controlled ovarian stimulation (COS). The choice of the COS protocol is crucial to preventing unintentional harm to egg and embryo quality. The wrong protocol can disrupt normal egg development and increase the risk of abnormal embryos. That’s why it’s important to tailor the COS protocol to each individual’s needs. This helps optimize follicle growth and the quality of eggs and embryos. The timing of certain treatments is also important for successful outcomes.
  • Embryo Competency and Blastocyst Development: Embryos that don’t develop into blastocysts by day 6 after fertilization are usually chromosomally abnormal or aneuploid (”incompetent”) and not suitable for transfer. However, not all blastocysts are guaranteed to be normal and capable of developing into a healthy baby. As a woman gets older, the chances of a her embryos being chromosomally normal blastocyst decreases. For example, a blastocyst from a 30-year-old woman is more likely to be normal compared to one from a 40-year-old woman.

The IVF stimulation protocol has a big impact on the quality of eggs and embryos especially in women with DOR. Unfortunately, many IVF doctors use the same COS “recipe approach” for everyone without considering individual differences. Using personalized protocols can greatly improve the success of IVF. While we can’t change genetics or reverse a woman’s age, a skilled IVF specialist can customize the COS protocol to meet each patient’s specific needs.

GONADOTROPIN RELEASING HORMONE AGONISTS (GNRHA) AND GNRH-ANTAGONISTS:

  • Gonadotropin releasing hormone agonists (GnRHa). Examples are Lupron, Buserelin, Superfact, and Decapeptyl . These are commonly used to launch  ovarian stimulation cycles. They work by initially causing a release of pituitary gonadotropins, followed by a decrease in LH and FSH levels within 4-7 days. This creates a relatively low LH environment when COS begins, which is generally beneficial for egg development. However, if GnRHa are administered starting concomitant with gonadotropin stimulation (see GnRHa –“flare protocol” -below) it can cause an immediate surge in LH release, potentially leading to high levels of ovarian testosterone that can harm egg quality, especially in older women and those with diminished ovarian reserve (DOR).
  • Gonadotropin releasing hormone antagonists (GnRH-antagonists) : Examples are Ganirelix, Cetrotide, and Orgalutron. GnRH antagonists (take days work quickly (within hours) to block pituitary LH release. Their purpose is to prevent excessive LH release during COS. In contrast, the LH-lowering effect of GnRH agonists takes several days to develop. Traditionally, GnRH antagonists are given starting on the 5th-7th day of gonadotropin stimulation. However, in older women and those with DOR, suppressing LH might happen too late to prevent excessive ovarian androgen production that can negatively impact egg development in the early stages of stimulation. That’s why I prefer to administer GnRH-antagonists right from the beginning of gonadotropin administration.USING BIRTH CONTROL PILLS TO START OVARIAN STIMULATION:

Patients are often told that using birth control pills (BCP) to begin ovarian stimulation will suppress the response of the ovaries. This is true, but only if the BCP is not used correctly. Here’s the explanation:

In natural menstrual cycles and cycles stimulated with fertility drugs, the follicles in the ovaries need to develop receptors that respond to follicle-stimulating hormone (FSH) in order to properly respond to FSH stimulation. Pre-antral follicles (PAFs) do not have these receptors and cannot respond to FSH stimulation. The development of FSH responsivity requires exposure of the pre-antral follicles to FSH for several days, during which they become antral follicles (AFs) and gain the ability to respond to FSH-gonadotropin stimulation. In regular menstrual cycles, the rising FSH levels naturally convert PAFs to AFs. However, the combined BCP suppresses FSH. To counter this suppression, we need to promote increased  FSH production several days before starting COS. This allows the orderly conversion from PAFs to AFs, ensuring proper follicle and egg development.

GnRHa causes an immediate surge in FSH release by the pituitary gland, promoting the conversion from PAF to AF. Therefore, when women take the BCP control pill to launch a cycle of COS, they need to overlap the BCP with a GnRHa for a few days before menstruation. This allows the early recruited PAFs to complete their development and reach the AF stage, so they can respond appropriately to ovarian stimulation. By adjusting the length of time, the woman is on the birth control pill, we can regulate and control the timing of the IVF treatment cycle. Without this step, initiating ovarian stimulation in women coming off birth control pills would be suboptimal.

PROTOCOLS FOR CONTROLLED OVARIAN STIMULATION (COS):

  • GnRH Agonist Ovarian Stimulation Protocols:
    • The long GnRHa protocol: Here, a GnRHa (usually Lupron or Superfact) is given either in a natural cycle, starting 5-7 days before menstruation, overlapping with the BCP for three days. Thereupon, the pill is stopped, while daily  GnRHa injections continue until menstruation occurs (usually 5-7 days later). The GnRHa causes a rapid rise in FSH and LH levels. This is followed about 3-4 days later , by a progressive decline in FSH and LH to near zero levels,  with a concomitant drop in ovarian estradiol and progesterone. This, in turn triggers uterine withdrawal bleeding (menstruation) within 5-7 days of starting the GnRHa administration. Gonadotropin treatment is then initiated while daily GnRHa injections continue to maintain a relatively low LH environment. Gonadotropin administration continues until the hCG “trigger” (see below).
    • Short GnRH-Agonist (“Flare”) Protocol: This protocol involves starting hormone therapy and using GnRH agonist at the same time. The goal is to boost FSH so that with concomitant stimulation with FSH-gonadotropins + the GnRHa-induced surge in pituitary gland FSH release, will augment follicle development. However, this surge also leads to a rise in LH levels, which can cause an excessive production of ovarian male hormones (e.g., testosterone). This could potentially adversely affect the quality of eggs, especially in women over 39 years old, those with low ovarian reserve, and women with PCOS or DOR who already have increased LH sensitivity. In this way, these “flare protocols” can potentially decrease the success rates of IVF. While they are generally safe for younger women with normal ovarian reserve, I personally avoid using this approach on the off chance that even patients with normal ovarian reserve, might experience poor egg quality.
  • GnRH Antagonist-Ovarian Stimulation Protocols:
    • Conventional GnRH Antagonist Protocol: In this approach, daily GnRH antagonist injections are given from the 5th to the 8th day of COS with gonadotropins to the day of the “trigger” (see below). Accordingly, although rapidly acting to lower LH , this effect of GnRH- antagonist only starts suppressing LH from well into the COS cycle which means the ovarian follicles are left exposed and unshielded from pituitary gland -produced, (endogenous) LH during the first several days of stimulation. This can be harmful, especially in the early stage of COS when eggs and follicles are most vulnerable to the effects of over-produced LH-induced excessive ovarian testosterone. Therefore, I believe the Conventional GnRH Antagonist Protocol is not ideal for older women, those with low ovarian reserve, and women with PCOS who already have elevated LH activity. However, this protocol is acceptable for younger women with normal ovarian reserve, although I personally avoid using this approach on the off chance that even patients with normal ovarian reserve, might experience poor egg quality.

It’s important to note that the main reason for using GnRH antagonists is to prevent a premature LH surge, which is associated with poor egg and embryo quality due to follicular exhaustion. However, calling it a “premature LH surge” is misleading because it actually represents the culmination of a progressive increase in LH-induced ovarian testosterone. A better term would be “premature luteinization”. In some such cases, the rise in LH can precipitate “premature ovulation”.

  • Agonist/Antagonist Conversion Protocol (A/ACP): I recommend this protocol for many of my patients, especially for older women and those with DOR or PCOS. The woman starts by taking a BCP for 7-10 days. This overlapped with a GnRHa for 3 days and continued until menstruation ensues about 5-7 days later. At this point  she “converts” from the GnRH-agonist to a GnRH-antagonist (Ganirelix, Orgalutron, or Cetrotide). A few days after this conversion from agonist to antagonist, COS with  gonadotropin stimulation starts. Both the antagonist and the gonadotropins are continued together until the hCG trigger. The purpose is to suppress endogenous LH release throughout the COS process and so  avoid over-exposure of follicles and eggs to LH-induced  excessive ovarian testosterone which as previously stated, can compromise egg and follicle growth and development.   Excessive ovarian testosterone can also adversely affect estrogen-induced growth of the uterine lining (endometrium). Unlike GnRH-agonists, antagonists do not suppress ovarian response to the gonadotropin stimulation. This is why the A/ACP is well-suited for older women and those with diminished ovarian reserve.
  • A/ACP with estrogen priming: This is a modified version of the A/ACP protocol used for women with very low ovarian reserve (AMH=<0.2ng/ml). Estrogen priming is believed to enhance the response of follicles to gonadotropins. Patients start their treatment cycle by taking a combined birth control pill (BCP) for 7-10 days. After that, they overlap daily administration of a GnRH agonist with the BCP for 3 days. The BCP is then stopped, and the daily agonist continues until menstruation ensues (usually 5-7 days later). At this point, the GnRH agonist is supplanted by daily injections of  GnRH antagonist and  Estradiol (E2) “priming” begins using E2 skin patches or intramuscular estradiol valerate injections twice weekly, while continuing the GnRH antagonist. Seven days after starting the estrogen priming COS begins using recombinant FSHr such as Follistim, Gonal-F or Puregon) +menotropin (e.g., Menopur) . The estrogen “priming” continues to the day of the “trigger” (see below).  Egg retrieval is performed 36 hours after the trigger.


Younger women (under 30 years) and women with absent, irregular, or dysfunctional ovulation, as well as those with polycystic ovarian syndrome (PCOS), are at risk of developing a severe condition called Ovarian Hyperstimulation Syndrome (OHSS), which can be life-threatening. To predict this condition, accurate daily blood E2 level monitoring is required.

 

TRIGGERING “EGG MATURATION PRIOR TO EGG RETRIEVAL”

  • The hCG “trigger”: When it comes to helping eggs mature before retrieval, one of the important decisions the doctor needs to make is choosing the “trigger shot” to facilitate the process. Traditionally, hCG (human chorionic gonadotropin) is derived from the urine of pregnant women (hCGu) while a newer recombinant hCG (hCGr), Ovidrel was recently The ideal dosage of hCGu is 10,000U and for Ovidrel, the recommended dosage is 500mcg. Both have the same efficacy. The “trigger” is usually administered by intramuscular injection, 34-36 hours prior to egg retrieval.

Some doctors may choose to lower the dosage of hCG if there is a risk of severe ovarian hyperstimulation syndrome (OHSS). However, I believe that a low dose of hCG (e.g., 5000 units of hCGu or 250 mcg of hCGr ( Ovidrel) might not be enough to optimize egg maturation, especially when there are many follicles. Instead, I suggest using a method called “prolonged coasting” to reduce the risk of OHSS.

  • Using GnRH antagonist alone or combined with hCG as the trigger: Some doctors may prefer to use a GnRH- agonist trigger instead of hCG to reduce the risk of OHSS. The GnRHa “trigger” acts by inducing a “surge of pituitary gland-LH. However, it is difficult to predict the amount of LH that is released in response to a standard agonist trigger. In my opinion, using hCG is a better choice, even in cases of ovarian hyperstimulation, with the condition that “prolonged coasting” is implemented beforehand.
  • Combined use of hCG + GnRH agonist: This approach is better than using a GnRH agonist alone but still not as effective as using the appropriate dosage of hCG.
  • Timing of the trigger: The trigger shot should be given when the majority of ovarian follicles have reached a size of more than 15 mm, with several follicles measuring 18-22 mm. Follicles larger than 22 mm often contain overdeveloped eggs, while follicles smaller than 15 mm usually have underdeveloped and potentially abnormal eggs.

SEVERE OVARIAN HYPERSTIMULATION SYNDROME (OHSS) & “PROLONGED COASTING”

OHSS is a life-threatening condition that can occur during controlled ovarian stimulation (COS) when the blood E2 (estradiol) level rises too high. It is more common in young women with high ovarian reserve, women with polycystic ovarian syndrome (PCOS), and young women who do not ovulate spontaneously. To prevent OHSS, some doctors may trigger egg maturation earlier, use a lower dosage of hCG, or “trigger” using a GnRHa. However, these approaches can compromise egg and embryo quality and reduce the chances of success.

To protect against the risk of OHSS while optimizing egg quality, Physicians can use one of two options. The first is “prolonged coasting,” a procedure I introduced more than three decades ago. It involves stopping gonadotropin therapy while continuing to administer the GnRHa until the risk of OHSS has decreased. The precise timing of “prolonged coasting” is critical. It should be initiated when follicles have reached a specific size accompanied and the  blood estradiol has reached a certain peak.  The second option is to avoid fresh embryo transfer and freeze all “competent” embryos for later frozen embryo transfers (FETs) at a time when the risk of OHSS has subsided. By implementing these strategies, both egg/embryo quality and maternal well-being can be maximized.

In the journey of fertility, a woman is blessed with a limited number of eggs, like precious treasures awaiting their time. As she blossoms into womanhood, these eggs are gradually used, and the reserves start to fade. Yet, the power of hope and science intertwines, as we strive to support the development of these eggs through personalized treatment. We recognize that each woman is unique, and tailoring the protocol to her individual needs can unlock the path to success. We embrace the delicate timing, understanding that not all embryos are destined for greatness. With age, the odds may shift, but our dedication remains steadfast, along with our ultimate objective, which is  to do everything possible to propagate  of a normal pregnancy while optimizing the  quality of that life after birth and all times, minimizing risk to the prospective parents.

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  • ADDRESSING ADVANCING AGE AND DIMINISHING OVARIAN RESERVE (DOR) IN IVF

Understanding the impact of age and ovarian reserve on the success of in vitro fertilization (IVF) is crucial when it comes to reproductive health. This article aims to simplify and clarify these concepts, emphasizing their significance in the selection of ovarian stimulation protocols for IVF. By providing you with this information, we hope to shed light on the importance of considering these factors and making informed decisions regarding fertility treatments.

  1. The Role of Eggs in Chromosomal Integrity: In the process of creating a healthy embryo, it is primarily the egg that determines the chromosomal integrity, which is crucial for the embryo’s competency. A competent egg possesses a normal karyotype, increasing the chances of developing into a healthy baby. It’s important to note that not all eggs are competent, and the incidence of irregular chromosome numbers (aneuploidy) increases with age.
  2. Meiosis and Fertilization: Following the initiation of the LH surge or the hCG trigger shot, the egg undergoes a process called meiosis, halving its chromosomes to 23. During this process, a structure called the polar body is expelled from the egg, while the remaining chromosomes are retained. The mature sperm, also undergoing meiosis, contributes 23 chromosomes. Fertilization occurs when these chromosomes combine, resulting in a euploid embryo with 46 chromosomes. Only euploid embryos are competent and capable of developing into healthy babies.
  3. The Significance of Embryo Ploidy: Embryo ploidy, referring to the numerical chromosomal integrity, is a critical factor in determining embryo competency. Aneuploid embryos, which have an irregular number of chromosomes, are often incompetent and unable to propagate healthy pregnancies. Failed nidation, miscarriages, and chromosomal birth defects can be linked to embryo ploidy issues. Both egg and sperm aneuploidy can contribute, but egg aneuploidy is usually the primary cause.
  4. Embryo Development and Competency: Embryos that develop too slowly or too quickly, have abnormal cell counts, contain debris or fragments, or fail to reach the blastocyst stage are often aneuploid and incompetent. Monitoring these developmental aspects can provide valuable insights into embryo competency.
  5. Diminished Ovarian Reserve (DOR): As women advance in their reproductive age, the number of remaining eggs in the ovaries decreases. Diminished ovarian reserve (DOR) occurs when the egg count falls below a certain threshold, making it more challenging to respond to fertility drugs effectively. This condition is often indicated by specific hormone levels, such as elevated FSH and decreased AMH. DOR can affect women over 40, but it can also occur in younger

 Why IVF should be regarded as treatment of choice for older women an those who have diminished ovarian reserve ( DOR):

Understanding the following factors will go a long way in helping you to make an informed decision and thereby improve the chances of a successful IVF outcome.

  1. Age and Ovarian Reserve: Chronological age plays a vital role in determining the quality of eggs and embryos. As women age, there is an increased risk of aneuploidy (abnormal chromosome numbers) in eggs and embryos, leading to reduced competency. Additionally, women with declining ovarian reserve (DOR), regardless of their age, are more likely to have aneuploid eggs/embryos. Therefore, it is crucial to address age-related factors and ovarian reserve to enhance IVF success.
  2. Excessive Luteinizing Hormone (LH) and Testosterone Effects: In women with DOR, their ovaries and developing eggs are susceptible to the adverse effects of excessive LH, which stimulates the overproduction of male hormones like testosterone. While some testosterone promotes healthy follicle growth and egg development, an excess of testosterone has a negative impact. Therefore, in older women or those with DOR, ovarian stimulation protocols that down-regulate LH activity before starting gonadotropins are necessary to improve egg/embryo quality and IVF outcomes.
  3. Individualized Ovarian Stimulation Protocols: Although age is a significant factor in aneuploidy, it is possible to prevent further decline in egg/embryo competency by tailoring ovarian stimulation protocols. Here are my preferred protocols for women with relatively normal ovarian reserve:
  1. Conventional Long Pituitary Down Regulation Protocol:
  • Begin birth control pills (BCP) early in the cycle for at least 10 days.
  • Three days before stopping BCP, overlap with an agonist like Lupron for three days.
  • Continue daily Lupron until menstruation begins.
  • Conduct ultrasound and blood estradiol measurements to assess ovarian status.
  • Administer FSH-dominant gonadotropin along with Menopur for stimulation.
  • Monitor follicle development through ultrasound and blood estradiol measurements.
  • Trigger egg maturation using hCG injection, followed by egg retrieval.
  1. Agonist/Antagonist Conversion Protocol (A/ACP):
  • Similar to the conventional long down regulation protocol but replace the agonist with a GnRH antagonist from the onset of post-BCP menstruation until the trigger day.
  • Consider adding supplementary human growth hormone (HGH) for women with DOR.
  • Consider using “priming” with estrogen prior to gonadotropin administration
  1. Protocols to Avoid for Older Women or Those with DOR: Certain ovarian stimulation protocols may not be suitable for older women or those with declining ovarian reserve:
  • Microdose agonist “flare” protocols
  • High dosages of LH-containing fertility drugs such as Menopur
  • Testosterone-based supplementation
  • DHEA supplementation
  • Clomiphene citrate or Letrozole
  • Low-dosage hCG triggering or agonist triggering for women with DOR

 Preimplantation Genetic Screening/Testing(PGS/T): PGS/T is a valuable tool for identifying chromosomal abnormalities in eggs and embryos. By selecting the most competent (euploid) embryos, PGS/T significantly improves the success of IVF, especially in older women or those with DOR.

Understanding the impact of advancing age and declining ovarian reserve on IVF outcomes is essential when making decisions about fertility treatments. Age-related factors can affect egg quality and increase the likelihood of aneuploid embryos with resultant IVF failure. Diminished ovarian reserve (DOR) further complicates the process. By considering these factors, you can make informed choices and work closely with fertility specialists to optimize your chances of success. Remember, knowledge is power, and being aware of these aspects empowers you to take control of your reproductive journey.

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  • IMPLANTATION DYSFUNCTION

 

Implantation dysfunction is often overlooked as a significant reason for IVF failure. This is especially true when IVF failure is unexplained, or when there are recurring pregnancy losses or underlying issues with the uterus, such as endo-uterine surface lesions, thin uterine lining (endometrium), or immunological factors.

IVF success rates have been improving in the past decade. Currently, in the United States, the average live birth rate per embryo transfer for women under 40 years old using their own eggs is about 2:5 per woman undergoing embryo transfer. However, there is a wide range of success rates among different IVF programs, varying from 20% to almost 50%. Based on these statistics, most women in the United States need to undergo two or more IVF-embryo transfer attempts to have a baby. Many IVF practitioners in the United States attribute the differences in success rates to variations in expertise among embryology laboratories, but this is not entirely accurate. Other factors, such as differences in patient selection, the failure to develop personalized protocols for ovarian stimulation, and the neglect of infectious, anatomical, and immunological factors that affect embryo implantation, are equally important.

Approximately 80% of IVF failures occur due to “embryo incompetency,” mainly caused by ( irregularities in chromosome number (aneuploidy), which is often related to the advancing age of the woman, diminished ovarian reserve ( DOR) but can also be influenced by the ovarian stimulation protocol chosen, and sperm dysfunction (male infertility). However, in around 20% of cases with dysfunction, failure is caused by problems with embryo implantation.

This section will focus on embryo implantation dysfunction and IVF failure which in the vast majority of cases is caused by:

  1. 1. Anatomical irregularities of the inner uterine surface:
  2. a) Surface lesions such as polyps/fibroids/ scar tissue
  3. b)endometrial thickness
  4.  
  5. 2. Immunologic Implantation Dysfunction ( IID)lesions
  6. a)Autoimmune IID
  7. b) Alloimmune IID

  1. ANATOMICAL IMPLANTATION DYSFUNCTION
  2. a) Surface lesions such as polyps/fibroids/ scar tissue

When there are problems with the structure of the uterus, it can lead to difficulties in getting pregnant. While uterine fibroids usually don’t cause infertility, they can affect fertility when they distort the uterine cavity or protrude through the lining. Even small fibroids located just beneath the lining and protruding into the cavity can decrease the chances of the embryo attaching. Multiple fibroids within the uterine wall that encroach upon the cavity can disrupt blood flow, impair estrogen delivery, and prevent proper thickening of the lining. These issues can be identified through ultrasound during the menstrual cycle’s proliferative phase. Any lesion on the uterine surface, such as submucous fibroids, adhesions, endometrial polyps, or placental polyps, can interfere with implantation by causing a local inflammatory response similar to the effect of an intrauterine contraceptive device (IUD).

Clearly, even small uterine lesions can have a negative impact on implantation. Considering the high costs and emotional toll associated with in vitro fertilization (IVF) and related procedures, it is reasonable to perform diagnostic tests like hysterosalpingography (HSG), fluid ultrasound examination (hysterosonogram), or hysteroscopy before starting IVF. Uterine lesions that can affect implantation often require surgical intervention. In most cases, procedures like dilatation and curettage (D&C) or hysteroscopic resection are sufficient. Rarely a laparotomy may be needed. Such interventions often lead to an improvement in the response of the uterine lining.

Hysterosonogram( HSN/saline ultrasound) is a procedure where a sterile saline solution is injected into the uterus through the cervix using a catheter. Vaginal ultrasound is then used to examine the fluid-filled cavity for any irregularities that might indicate surface lesions like polyps, fibroid tumors, scarring, or a septum. When performed by an expert, HSN is highly effective in detecting even the smallest lesions and can supplant hysteroscopy in certain cases. HSN is less expensive, less invasive/traumatic, and equally effective as hysteroscopy. The only drawback is that if a lesion is found, hysteroscopy may still be needed for treatment.

Hysteroscopy is a diagnostic procedure performed in an office setting with minimal discomfort to the patient. It involves inserting a thin, lighted instrument called a hysteroscope through the vagina and cervix into the uterus to examine the uterine cavity. Normal saline is used to distend the uterus during the procedure. Like HSN, hysteroscopy allows for direct visualization of the inside of the uterus to identify defects that could interfere with implantation. We have observed that around one in eight IVF candidates have lesions that need attention before undergoing IVF to optimize the chances of success. I strongly recommend that all patients undergo therapeutic surgery, usually hysteroscopy, to correct any identified issues before proceeding with IVF. Depending on the severity and nature of the problem, hysteroscopy may require general anesthesia and should be performed in a surgical facility equipped for laparotomy if necessary.

  1. b) Thickness of the uterine lining (endometrium)

As far back as In 1989, I and my team made an important discovery about using ultrasound to assess the thickness of the endometrium during the late proliferative phase of both “ natural” and hormone-stimulated cycles. The assessment helped predict the chances of conception. We found that an ideal thickness of over 9mm at the time of ovulation , egg retrieval or with the commencement of progesterone therapy in embryo recipient cycles ( e.g., IVF with egg donation, gestational, surrogacy and embryo adoption) was associated with optimal implantation rates, while an endometrial thickness of less than 8 mm was associated with failure to implant or early pregnancy loss in the vast majority of cases. An endometrium measuring <8mm was almost invariably associated with failure to implant or early pregnancy loss in the while an endometrium measuring 8 to 9 mm was regarded as being intermediate, and while pregnancies did occur in this range, the rates were only slightly lower than with an optimal lining of 9 mm

A “poor” uterine lining typically occurs when the innermost layer of the endometrium (basal or germinal endometrium) is unable to respond to estrogen by developing a thick enough outer “functional” layer to support successful embryo implantation and placental development. The “functional” layer, which accounts for two-thirds of the total endometrial thickness, is shed during menstruation if pregnancy does not occur.

The main causes of a poor uterine lining are:

  1. Damage to the basal endometrium due to:
    • Inflammation of the endometrium (endometritis), often resulting from retained products of conception after abortion, miscarriage, or childbirth.
    • Surgical trauma caused by aggressive dilatation and curettage (D&C).
  1. Insensitivity of the basal endometrium to estrogen due to:
    • Prolonged (back to back) use of clomiphene citrate for ovarian stimulation or…
    • Prenatal exposure to diethylstilbestrol (DES), a drug given to prevent miscarriage in the 1960s.
  1. Overexposure of the uterine lining to male hormones produced by the ovaries or administered during ovarian stimulation (primarily testosterone):
    • Older women, women with DOR (poor responders), and women with polycystic ovarian syndrome (PCOS) often have increased biological activity of luteinizing hormone (LH), leading to testosterone overproduction by the ovarian connective tissue (stroma/theca). This effect can be further amplified when certain ovarian stimulation protocols were high doses of menotropins ( e.g., Menopur) are used.
  1. Reduced blood flow to the basal endometrium caused by:
    • Multiple uterine fibroids, especially if they are located beneath the endometrium (submucosal).
    • Uterine adenomyosis, which involves extensive abnormal invasion of endometrial glands into the uterine muscle.

In 1996 I introduced the Vaginal administration of Sildenafil (Viagra) to improve endometrial thickening. The selective administration of Sildenafil has shown great promise in improving uterine blood flow and increasing endometrial thickening in cases of thin endometrial linings. When administered vaginally, it is quickly absorbed and reaches high concentrations in the uterine blood system, diluting as it enters the systemic circulation. This method has been found to have minimal systemic side effects. However, it is important to note that Viagra may not be effective in all cases, as some cases of thin uterine linings may involve permanent damage to the basal endometrium, rendering it unresponsive to estrogen.

Severe endometrial damage leading to poor responsiveness to estrogen can occur in various situations. These include post-pregnancy endometritis (inflammation after childbirth), chronic granulomatous inflammation caused by uterine tuberculosis (rare in the United States), and significant surgical injury to the basal endometrium (which can happen after aggressive D&C procedures).

 

  1. 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 6-7days 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 Intravenous gammaglobulin (IVIg) to NK cells can immediately downregulate NK cell activity. However, neither 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 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.
  6. 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.
  7. 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. 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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  • ENDOMETRIOSIS AND IMMUNOLOGIC IMPLANTATION DYSFUNCTION (IID)

More than 50% of patients with endometriosis have antiphospholipid antibodies ( 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.

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 in many cases 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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Name: Isa F

Doctor ayúdeme tengo miedo de haber malogrado mi estimulación ovarica, en mi última inyección que era de ovidrel de 250, no supe ponérmela la inyecte dos veces porque no había puesto la dosis correcta y me di cuenta después de inyectarme y por eso en ese momento, me la volví a inyectar con el resto de la dosis qué faltaba, y siento que no aplique los 250 si no un poquito menos, soy una tonta no supe ponérmela y tengo miedo de haber arruinado todo, qué hago?

Answer:

Please re-post this in English and I will respond promptly!

 

Geoff Sher

Name: Priscilla W

At what age is it unethical to do IVF and do you check ovarian reserves before you make that choice.

Answer:

Over 43y of age, egg donation is advisable because with advancing age, egg quality declines starting at 35 y and really accelerating after 40Y. At a younger age, egg donation should also be seriously contemplated in women who have VERY depleted ovarian reserve (AMH=,0.2ng/ml).

Egg donation is when a woman donates her eggs for assisted reproduction or research purposes. In assisted reproduction, it usually involves using IVF technology, where the eggs are fertilized in a lab. Unfertilized eggs can also be frozen for future use. Egg donation is a form of assisted reproductive technology (ART) involving a third party.

For women who can’t get pregnant with their own eggs due to disease or low ovarian reserve, egg donation offers a realistic chance of becoming parents. It has clear benefits. First, young donors often provide more eggs than needed for a single IVF cycle, resulting in extra embryos that can be frozen for later use. Second, eggs from young donors are much less likely to have chromosomal abnormalities, reducing the risk of miscarriage and birth defects like Down’s syndrome.

Around 10%-15% of IVF procedures in the United States involve egg donation, mostly for older women with diminished ovarian reserve or for menopausal women. A much smaller percentage are performed on younger women who have premature ovarian failure or repeated IVF failures with low-quality eggs or embryos. Another rapidly emerging reason for egg donation is same-sex couples, mainly female, who want to share the experience of parenting, with one partner providing the eggs and the other receiving them. 

Most egg donation in the U.S. is done through licensed egg donor agencies or frozen egg banks, where anonymous donors are recruited. Sometimes recipients seek known donors through an agency, but this is less common and often done through private arrangements. Close family members are often approached as donors. Recipients may want to know or meet their egg donor to become familiar with their physical traits, intellect, and character, but anonymous donors are more common in the U.S. Recipients using anonymous donors are usually more open about the child’s conception when disclosing to family and friends. 

Donor agencies and Egg Banks provide detailed profiles and information about each donor for recipients to choose from. The recipient interacts with the egg donor program or Egg Bank in-person, over the phone, or online. After narrowing down choices, the recipient shares medical records with their IVF physician for consultation and examination. The process is facilitated by nurse coordinators who address all clinical, financial, and logistical aspects. Donor selection and matching are completed during this time. 

Egg donor agencies and egg banks typically prefer donors under 35 years old with normal ovarian reserve to minimize risks. Having a history of successful pregnancies or live births gives confidence in the donor’s reproductive potential. However, due to the shortage of donors, strict criteria like previous successful pregnancies cannot always be met. 

Sometimes donors may blame infertility on complications from the egg retrieval process, leading to legal actions. Evidence of trouble-free pregnancies provides comfort to the egg donor program when selecting a donor.

Screening Egg Donors

Genetic Screening: Many egg donor programs now use genetic screening panels to test for various genetic disorders. They follow the recommendations of the American Society of Reproductive Medicine (ASRM) and screen prospective donors for a host ( a panel) of conditions such as sickle cell trait or disease, thalassemia, cystic fibrosis, and Tay Sachs disease. About 90% of programs offer consultation with a geneticist.

Psychological/Emotional Screening: Recipient couples value compatibility with their chosen egg donor in terms of emotions, physicality, ethnicity, culture, and religion. Psychological screening is important in the United States. Since most donors are anonymous, it’s essential for the donor agency or IVF program to assess the donor’s commitment and motivation for providing this service. Some donors may not cope with the stress and stop their stimulation medication without informing anyone, causing the cycle to be canceled. 

Donor motivation and commitment need to be assessed carefully. Recipients in the U.S. often consider the “character” of the prospective egg donor as significant, believing that flaws in character may be genetically passed on. However, character flaws are usually influenced by environmental factors and unlikely to be genetically transmitted. 

Donors should undergo counseling, screening, and selective testing by a qualified psychologist. If needed, they should be referred to a psychiatrist for further evaluation. Tests like the MMPI, Meyers-Briggs, and NEO-Personality Indicator may be used to assess personality disorders. If significant abnormalities are found, the prospective donor should be automatically disqualified.

When choosing a known egg donor, it’s important to ensure that she is not coerced into participating. Recipients considering a close friend or family member as a donor should be aware that the donor may become a permanent and unwanted participant in their new family’s life.

Drug Screening: Due to the prevalence of substance abuse, we selectively perform urine and/or serum drug testing on our egg donors.

Screening for Sexually Transmitted Diseases (STDs): FDA and ASRM guidelines recommend testing all egg donors for STDs before starting IVF. While it’s highly unlikely for DNA and RNA viruses to be transmitted to an egg or embryo through sexual intercourse or IVF, women infected with viruses like hepatitis B, C, HTLV, HIV, etc., must be disqualified from participating in IVF with egg donation due to the remote possibility of transmission and potential legal consequences. 

Prior or existing infections with Chlamydia or Gonococcus suggest the possibility of pelvic adhesions or irreparably damaged fallopian tubes, which can cause infertility. If such infertility is later attributed to the egg retrieval process, it can lead to litigation. Even if an egg donor or recipient agrees to waive legal rights, there is still a potential risk of the offspring suing for wrongful birth later in life.

 

Screening Embryo Recipients

Medical Evaluation: Before starting infertility treatment, it’s important to assess a woman’s ability to safely carry a pregnancy and give birth to a healthy baby. This involves a thorough evaluation of cardiovascular, hepatorenal, metabolic, and reproductive health.

Infectious Screening: It is crucial to screen embryo recipients for infectious diseases. If the cervix is infected, introducing an embryo transfer catheter can transmit the infection to the sterile uterine cavity, leading to implantation failure or miscarriage in the early stages of pregnancy.

Immunologic Screening: Some autoimmune and alloimmune disorders can affect the success of implantation. To prevent treatment failure, it is advisable to evaluate the recipient for immunologic implantation dysfunction (IID) and in some cases, test both the recipient and sperm provider for alloimmune similarities that could affect implantation.

Disclosure and Consent: Full disclosure about the egg donation process, including medical and psychological risks, is necessary. Sufficient time should be dedicated to addressing questions and concerns from all parties involved. 

It’s important for all parties to seek independent legal advice to avoid conflicts of interest. Consent forms are reviewed and signed by the donor and recipient independently.

Types of Egg Donation

Conventional Egg Donation: This is the standard process for egg donor IVF. The menstrual cycles of the donor and recipient are synchronized using birth control pills. Both parties undergo fertility drug stimulation, allowing for precise timing of fresh embryo transfer. The success rate for pregnancy through this method is over 50% per cycle.

Donor Egg Bank: In this approach, eggs from young donors are frozen and stored for later use in IVF and embryo transfer. Frozen egg banks offer access to non-genetically tested eggs. While it provides convenience, there are minimal financial benefits. 

Through an electronic catalogue, recipients can select and purchase 1-5 frozen eggs. These eggs are fertilized through intracytoplasmic sperm injection (ICSI), and up to 2 embryos are selectively transferred, resulting in a 30-40% pregnancy rate without the risk of multiple pregnancies. This method reduces the cost, inconvenience, and risks associated with conventional fresh egg donor cycles. It is important for the recipient couple to be made aware that frozen eggs are slightly less likely to result in viable embryos as compared to fresh eggs and that the pregnancy rate using frozen eggs is also somewhat lower.

Preimplantation Genetic Screening/Testing for Aneuploidy (PGS/PGT):

The use of PGS/PGT to select embryos for transfer in IVF with egg donation is a topic of debate. Since most egg donors are under 35 years old, about 60-70% of embryos created from their eggs will likely have the correct number of chromosomes (euploid). This means that transferring up to two “untested” embryos from these donors should result in similar pregnancy rates compared to using PGS/PGT for embryo selection. However, it may in the future, become possible and practical to perform PGS/PGT on eggs for selective banking in the future. This could lead to improved success rates using banked eggs that have been tested for chromosomal abnormalities.

Egg Donation with Frozen Embryo Transfer (FET): Advances in embryo cryopreservation technology have made FET cycles a preferred method for many fertility specialists and patients. Whether or not embryos have undergone PGS/PGT testing, they are frozen as blastocysts and transferred in a subsequent FET cycle. This approach is more convenient, less complicated logistically, and can significantly improve the chances of successful pregnancy.

Financial Considerations in the United States:

The cost of an egg donor cycle involves various expenses. The average fee paid to the egg donor agency per cycle is typically between $2,000 – $8,000. Additional costs include psychological and clinical pre-testing, fertility drugs, and donor insurance, which range from $3,000 to $6,000. The medical services for the IVF treatment cycle can cost between $8,000 and $14,000. The donor stipend can vary widely, ranging from $5,000 to as high as $50,000, depending on the specific requirements of the recipient couple and supply-demand factors. Consequently, the total out-of-pocket expenses for an egg donor cycle in the United States ranges from $15,000 to $78,000, making it financially challenging for most couples in need of this service.

To address the growing gap between the need for affordable IVF with egg donation, various creative approaches have emerged. Here are a few examples:

 

  • Egg Banking: As mentioned earlier, egg banking is a method where eggs are preserved and stored for future use.
  • Egg Donor Sharing: This approach involves splitting the cost between two recipients, who then share the eggs for transfer or freezing. However, the downside is that there may be fewer eggs available for each recipient.
  • Egg Bartering: In this scenario, a woman undergoing IVF can exchange some of her eggs with the clinic in return for a reduction in her IVF fee. This arrangement can be problematic because if the woman donating her eggs fails to conceive while the recipient does, it may cause emotional distress and potential complications in the future.
  • Financial Risk Sharing: Some IVF programs offer a refund of fees if the egg donation is unsuccessful. This option is preferred by many recipient couples as it helps to spread the financial risk between the providers and the couple.

Moral, Legal, and Ethical Considerations:

In most States in the USA, the “Uniform Parentage Act” protects the recipient couple from legal disputes relating to parental claims by the donor. This “act” which states that the woman who gives birth to the child is legally recognized as the mother has generally prevented legal disputes over maternal custody in cases of IVF with egg donation. While a few states have less clear laws on this matter, there have been no major legal challenges so far.

The moral, ethical, and religious implications of egg donation vary and greatly influence the cultural acceptance of this process. In the United States, the prevailing attitude is that everyone is entitled to their own opinion and should have their views respected as long as they don’t infringe on the rights of others.

Looking ahead, there are important questions to consider. Should we cryopreserve and store eggs or ovarian tissue from a young woman who wishes to delay having children? Would it be acceptable for a woman to give birth to her own sister or aunt using these stored eggs? Should we store ovarian tissue across generations? Additionally, should egg donation primarily be used for stem cell research or as a source of spare body parts? If we decide to pursue these avenues, how do we ensure proper checks and balances? Are we willing to go down a slippery slope where the dignity of human embryos is disregarded, and the rights of human beings are compromised? Personally, I hope not.

__________________________________________________________________________________

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) ; https://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\

 

 

 

Name: Ridi D

Me and my wife are looking to have an IVF/ICSI cycle. I have a severe non-obstructive azoospermia, I did a micro-tese procedure and they were able to find one good sperm which after that they froze the tissue extracted for further search at the clinic we will choose. The urologist that performed the procedure has instructed me to choose a clinic that has a big embryology lab that can have multiple people spend multiple hours searching through the frozen samples to find more sperm to use for the ICSI.

Therefore my question is how big is the embryology department at your clinic and will there be multiple embryologist that can search for a few hours until they find the sperm from the samples. Thank you!

Answer:

We have the required resources to do this.

 

Geoff Sher

___________________________________________________________________________

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) ; https://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\