Thank you for reaching out. I will do my best to help:

1. Given your diminished ovarian reserve; IUI is definitely not for you. The success rate is far too low and you do not have the time to spare. You do need IVF but unless an individualized protocol for ovarian stimulation that wont likely work either. Please read the article I wrote below and then consider calling Patti (702-533-2691) or emailing her at concierge@sherivf.com to set up an online consultation with me.

Geoffrey Sher MD

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• ADDRESSING DIMINISHING OVARIAN RESERVE (DOR) IN IVF

Understanding the impact of 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 women 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. Ovarian Reserve: While chronological age plays a vital role in determining the quality of eggs and embryos [there is an increased risk of egg aneuploidy (irregular chromosome number) in eggs,  leading to reduced embryo 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 both older women or those who (regardless of their age) have DOR, ovarian stimulation protocols that down-regulate LH activity before starting gonadotropins are necessary to improve egg/embryo quality and IVF outcomes.
3. It is possible to regulate the  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 in Women with DOR: Certain ovarian stimulation protocols may not be suitable for women 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 for aneuploidy (PGS/PGTA): PGS/PGTA is a valuable tool for identifying chromosomal abnormalities in eggs and embryos. By selecting the most competent (euploid) embryos, PGS/PGTA significantly improves the success of IVF, in women with DOR.

Understanding the impact of declining ovarian reserve on IVF outcomes is essential when making decisions about fertility treatments. Diminished ovarian reserve (DOR) can affect egg quality and increase the likelihood of aneuploid embryos with resultant IVF failure. By considering this factor, 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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• INTRAUTERINE INSEMINATION : THE PRO’S AND CON’S

Intrauterine insemination (IUI), the injection of sperm into the uterus by means of a catheter directed through the cervix, has been practiced for many years. The premise of this procedure is that sperm can reach and fertilize the egg more easily if placed directly into the uterine cavity. In the early ‘60s, physicians were injecting small quantities of raw, untreated semen (sperm plus seminal plasma) directly into the uterus at the time of expected ovulation. However, when more than 0.2 ml of semen was injected into the uterus, serious and sometimes life endangering shock-like reactions often occurred. It was subsequently identified that the reason for such reactions related to the presence of prostaglandins within the seminal plasma. This led to the practice of injecting small amounts (less than 0.2 ml) of raw semen. However, the pregnancy rates were dismal and side effects, such as severe cramping and infection were rampant.

As early as 1982, I began to recognize the potential advantage of washing and centrifuging raw semen to separate sperm from the seminal fluid, and thereby remove prostaglandins that cause most of the problems. I subsequently introduced and reported on IUJ in the journal, Fertility and Sterility (April 1984).

Reasons for IUI:

• Using frozen donor sperm: To prevent the transmission of HIV and other sexually transmitted diseases, donated semen is frozen and stored for at least six months. After retesting for HIV, the thawed semen is used for insemination. Since freezing sperm can reduce its effectiveness, the semen is processed for IUI. Fertility drugs may not be needed if the recipient is ovulating normally.
• Using the husband’s sperm: If a husband has difficulty with sexual function or timing, his sperm may be collected and processed for IUI.
• Insufficient cervical mucus: Sometimes, the cervical mucus can create a barrier that prevents sperm from passing through. This can be due to physical problems with the mucus, cervical infection, or anti-sperm antibodies. In most cases, IUI can be done during natural cycles, unless the woman has problems with ovulation. However, if infertility is caused by anti-sperm antibodies in the cervical mucus, IUI will not be effective, and in vitro fertilization (IVF) should be considered.
• Abnormal ovulation: In some cases, when a woman needs fertility drugs to induce ovulation, combining IUI with the medication can improve pregnancy rates.

SELECTING THE OPTIMAL CONTROLLED OVARIAN STIMULATION (COS) PROTOCOL FOR IUI

Oral Fertility Drugs:

Oral fertility drugs like clomiphene citrate (Serophene) and Letrozole (Femara)are gentle ovarian stimulants that are typically recommended for younger women with normal egg reserves but who face issues with ovulation, mild sperm problems, or unexplained infertility. In cases of unexplained infertility, the American Society for Reproductive Medicine (ASRM) suggests starting with 3-4 cycles of ovarian stimulation and intrauterine insemination (IUI) using clomiphene or letrozole. Using clomiphene or letrozole alone, timed intercourse alone, or IUI alone does not significantly improve the monthly chance of conceiving with unexplained infertility. It is the combination of these oral stimulants with IUI that can increase the pregnancy rate.

1. Clomiphene citrate (Serophene/Clomid) is the most commonly prescribed agent for inducing ovulation in women who do not ovulate regularly, those with dysfunctional ovulation, and women with unexplained infertility. When used in young women with these issues and sufficient ovarian reserve, the viable pregnancy rate is reported to be between 6% and 10% per cycle of treatment. Clomiphene is also used to prepare women for intrauterine insemination and in vitro fertilization (IVF). Clomiphene’s popularity stems from its low cost, ease of use, and low risk of severe complications such as ovarian hyperstimulation syndrome (OHSS). The treatment usually starts with a daily oral dose of 50 mg for 5 days, but it can be increased to as much as 200 mg per day, starting on cycle day 2, 3, 4, or 5. Typically, a spontaneous LH surge occurs about 8-9 days after the last 50 mg dosage. In some cases, a trigger of 10,000 IU of hCG can be given when there is at least one ovarian follicle measuring 18-20 mm in size. Clomiphene works by inducing ovulation through its “antiestrogen effect.” By blocking estrogen receptors in the hypothalamus (a part of the brain), it tricks the brain into perceiving low estrogen levels. In response, the hypothalamus stimulates the pituitary gland to release an increased amount of follicle-stimulating hormone (FSH), which then stimulates the growth and development of ovarian follicles. This ultimately leads to a surge in pituitary LH release, followed by ovulation from one or more of the larger follicles. As the follicles grow, they release more estrogen into the bloodstream, completing the feedback loop initiated by the hypothalamus in response to the anti-estrogen effects of clomiphene. Before prescribing clomiphene to a woman, several factors should be considered carefully: Clomiphene is less effective than gonadotropin therapy and its effectiveness decreases with age. It is best suited for younger women (under 35 years) with normal ovarian reserve, as they are more likely to respond by producing multiple follicles. At least two sizeable follicles should develop during clomiphene treatment to ensure proper cervical mucus production and the development of a receptive uterine lining.

• Clomiphene should not be used for more than three consecutive cycles in a row. Using it for more cycles can be ineffective and even work as a contraceptive. The anti-estrogenic effects of clomiphene can affect cervical mucus and thin the uterine lining over time. After three consecutive cycles, it is recommended to have a resting cycle before considering another clomiphene cycle.
• Clomiphene is not suitable for older women or those with diminished ovarian reserve (DOR). The release of LH caused by clomiphene can lead to excessive testosterone production in the ovaries, which can hinder egg development. Women with DOR are particularly vulnerable due to overgrowth of ovarian connective tissue, where testosterone is produced.
• About 20% of clomiphene cycles may result in “trapped” ovulation, where the egg remains stuck in the follicle despite hormone changes suggesting ovulation. This can affect the chances of a successful pregnancy.
• Women with long gaps between their periods (over 45 days) may not respond well to clomiphene and may benefit more from injectable gonadotropins

2. Letrozole (Femara) is a medication used for inducing ovulation as part of the IVF process. It works by blocking a certain enzyme called aromatase, which leads to a decrease in estrogen levels and an increase in follicle-stimulating hormone (FSH) secretion. This helps in the growth of ovarian follicles and the production of estrogen. Unlike clomiphene, another medication used for ovulation induction, letrozole does not have anti-estrogen effects on the body, so it does not dry up cervical mucus or make the uterine lining less responsive to estrogen. However, letrozole, like clomiphene, can increase the production of luteinizing hormone (LH) from the pituitary gland, which can result in higher levels of testosterone in the ovaries. While some testosterone is necessary for follicle and egg development, too much of it can hinder their growth and increase the risk of abnormal eggs. Therefore, it might not be advisable to use letrozole or clomiphene in IVF cycles, especially for older women or those with diminished ovarian reserve (DOR) who tend to have higher LH activity. Letrozole can still be used in women who have absent or dysfunctional ovulation not related to DOR, and it can be an alternative to clomiphene in some cases to avoid issues with the uterine lining. The usual starting dose of letrozole is 2.5 mg taken orally daily for 5 days, starting on day 2, 3, 4, or 5 of the menstrual cycle. The dosage can be increased to 5 or 7.5 mg if necessary. Some studies suggest that letrozole may be more effective than clomiphene for treating infertility in women with polycystic ovary syndrome (PCOS), resulting in higher rates of ovulation without significant differences in birth defects.

Common side effects of both clomiphene and letrozole: include hot flashes, sweating, nausea, tiredness, diarrhea, and joint pain.

Injectable Fertility Drugs: .

While the cost and  risk of side effects such as severe ovarian hyperstimulation syndrome (OHSS)  using injectable fertility drugs such as gonadotropins to prepare for IUI are definitely far greater than when oral agents re used for controlled ovarian stimulation (COS),  they are in my opinion nevertheless preferred for IUI. The success rate using such drugs is probably 20-30% higher than when clomiphene or letrozole are used. Therefore, in the hands of Physicians well-schooled in the use of gonadotropins therapy, this is by far a better approach than using oral agents.

The Risks of Multiple Births with COS in women undergoing IUI.  in IUI:

When women ovulate normally, they usually develop multiple follicles in their ovaries, which contain eggs and supporting cells. However, only one or two of these follicles will actually mature and release an egg, while the others do not reach this stage. This natural process is called “selection.” In women who ovulate normally, the selected follicles will be larger than the others. Once these selected follicles release eggs, the remaining follicles cannot ovulate. As a result, women who ovulate normally do not have a significantly higher chance of having multiple pregnancies with three or more babies. On the other hand, women who do not ovulate at all or have dysfunctional ovulation may develop multiple follicles at the same rate, resulting in the release of several eggs at once. This increases the chances of pregnancy but also raises the risk of multiple pregnancies. Interestingly, almost all cases of high order multiple pregnancies (more than twins) associated with fertility drug use have occurred in women who do not ovulate normally. Therefore, the risk of having high order multiple pregnancies only applies to women with absent or dysfunctional ovulation. These women should receive counseling about the potential complications of premature birth and the option of selective reduction of pregnancies during the third month. Another option to avoid this risk altogether is to choose in vitro fertilization (IVF), where the number of embryos transferred to the uterus can be controlled to limit the number of potential babies.

Intrauterine insemination (IUI) can be a valuable fertility treatment if used appropriately and selectively for the right reasons. The use of fertility drugs should not be seen as necessary for all IUI cases, and IUI itself should not be considered a mandatory step before opting for IVF.

Intrauterine insemination (IUI) can be a valuable fertility treatment if used appropriately and selectively for the right reasons. The use of fertility drugs should not be seen as necessary for all IUI cases, and IUI itself should not be considered a mandatory step before opting for IVF.

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ADDITIONAL INFORMATION:

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

For more than 50 years, scientists have been working to perfect the art of freezing and storing a woman’s eggs, also known as “egg banking”. Although there have been challenges, the progress has been both amazing and is promising. 

Since the birth of the first “frozen egg baby” in the mid-1980s, we’ve celebrated than 6,000 -7000 births worldwide from thawed eggs. However, this is a relatively a small number when compared to the 5-6 million IVF babies and 1.5- to 2 million babies born from transferred frozen embryos during the same time.

Recently, there have been significant improvements in using frozen eggs to create embryos. Presently,  success rates are comparable to that  using frozen embryos especially when the latter have been screened for competency, using preimplantation genetic testing (PGT/ preimplantation genetic testing for aneuploidy ( PGT-A). Interestingly, currently, eggs are not screened using these techniques before they are frozen.

Let’s talk about who can benefit from this incredible advancement:

• Fertility Preservation (FP) for Women: FP is like a beacon of hope for women looking to preserve their fertility for the future. The potential demand for FP using frozen eggs is estimated to be 4-6 times higher than traditional IVF. This can be a lifeline for:
  • Women facing the possibility of losing their ovarian function due to approaching menopause, planned ovary removal, or medical treatments like radiation or chemotherapy.
  • Women planning to delay childbearing due to career aspirations, not being ready for a permanent relationship, or concerns about their biological clock.
  • Couples Opposed to Embryo Freezing: For couples who have ethical or religious concerns about freezing embryos, the option of freezing eggs brings hope and aligns with their beliefs.

As technology continues to evolve, we are moving towards a future where egg freezing is both safe, reliable, and accessible to all. It allows individuals to make informed decisions about their future and family planning. However, a word of advice: Women should consider freezing their eggs at a younger age (below 35 years) when their eggs are at their healthiest. Older women, especially those over 39, should approach this with caution as the “competency” of their eggs declines with age.

Imagine having the chance to fulfill the dream of having a family through a wonderful solution called egg banking. This amazing process involves storing healthy eggs that are later used to help women struggling with infertility to have a baby through IVF and embryo transfer.

In the United States, around 20,000 IVF procedures using donated eggs happen each year, making up about 15% of all IVF cycles. People are seeking affordable options for IVF, with many traveling abroad \for lower-cost treatments.

• Donor Egg Banks: Recently, frozen egg banks have emerged, offering access to eggs that haven’t been genetically tested. While using fresh donor eggs is a bit more successful than using frozen ones (around 40-50% versus 30-35% success rate per embryo transfer), the difference is very small . However, many frozen eggs may not survive the thawing process to become embryos, which affects the success rate. To improve success rates, most egg banks suggest buying at least six eggs at a time, each costing about $3,000.

In the United States, the cost of IVF using frozen donor eggs is high, prompting many to seek treatment in other countries ( “Medical tourism”). A significant part of this cost is associated with donor stipends and agency fees. This is why there’s a real need for a better way to access healthy donated eggs for IVF.

Conclusion:

The in vitro fertilization (IVF) market in the United States is rapidly growing and is approaching a value of $25 billion. The demand for egg banking, especially for Fertility Preservation (FP), is expected to be two to three times greater than conventional IVF. If even 10% of this potential FP market is tapped within the next five years, it could result in an annual industry worth over $3.5 billion. This shows the incredible potential of egg banking in making family dreams come true.

This amazing  journey of advancements is paving the way for new hopes and dreams. It’s about giving people choices and the power to decide when and how to shape their families. Egg banking is not just about preserving eggs; it’s about preserving dreams and the possibility of a beautiful tomorrow.

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ADDITIONAL INFORMATION:

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

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\

I would never presume tom tell your doctor what to do with regard to your stimulation.

I can tell you that regardless of protocol, the chance of propagating euploid (“competent”) eggs at 45y is very slim (!:2o eggs or so will end up being viable). Obviously if in addition you have diminished ovarian reserve (A low AMH) the number of extractable eggs will be reduced. This reduces that chance at a successful outcome further. I am not a believer in ovarian PRP.

If you insist upon using your own eggs in spite of the realization that you ideally need donated eggs, then the protocol used for ovarian stimulation becomes your prime challenge.

I am unable te recommend  a specific protocol without having access to much more information.

I suggest yo call my assistant, Patti at 702-533-2691 and set up an online consultation with me to discuss

Geoff Sher.

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ADDITIONAL INFORMATION:

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

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\

If they were frozen on day-3…indeed you could do that. But if they were frozen as blastocysts, the thaw-biopsy-refreeze can damage the embryos.

Good luck

Geoff Sher

ADDITIONAL INFORMATION:

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 ;http

1. s://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

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\

The two are by and large interchangeable. The steroid administration should start at the beginning of the cycle and continue to the 10th week. It should then be tailed off over 2 weeks.

Geoff Sher

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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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ADDITIONAL INFORMATION:

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 ;http

1. s://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

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\

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• UNDERSTANDING RECURRENT PREGNANCY LOSS ( RPL): CAUSES AND SOLUTIONS.

When it comes to reproduction, humans face challenges compared to other mammals. A significant number of fertilized eggs in humans do not result in live births, with up to 75% failing to develop, and around 30% of pregnancies ending within the first 10 weeks  (first trimester). Recurrent pregnancy loss (RPL) refers to two or more consecutive failed pregnancies, which is relatively rare, affecting less than 5% of women for two losses and only 1% for three or more losses. Understanding the causes of pregnancy loss and finding solutions is crucial for those affected. This article aims to explain the different types of pregnancy loss and shed light on potential causes.

Types of Pregnancy Loss: Pregnancy loss can occur at various stages, leading to different classifications:

1. Early Pregnancy Loss: Also known as a miscarriage, this typically happens in the first trimester. Early pregnancy losses are usually sporadic, not recurring. In over 70% of cases, these losses are due to chromosomal abnormalities in the embryo, where there are more or fewer than the normal 46 chromosomes. Therefore, they are not likely to be repetitive.
2. Late Pregnancy Loss: Late pregnancy losses occur after the first trimester (12th week) and are less common (1% of pregnancies). They often result from anatomical abnormalities in the uterus or cervix. Weakness in the cervix, known as cervical incompetence, is a frequent cause. Other factors include developmental abnormalities of the uterus, uterine fibroid tumors, intrauterine growth retardation, placental abruption, premature rupture of membranes, and premature labor.

Causes of Recurrent Pregnancy Loss (RPL): Recurrent pregnancy loss refers to multiple consecutive miscarriages. While chromosomal abnormalities are a leading cause of sporadic early pregnancy losses, RPL cases are mostly attributed to non-chromosomal factors. Some possible causes include:

1. Uterine Environment Problems: Issues with the uterine environment can prevent a normal embryo from properly implanting and developing. These problems may include inadequate thickening of the uterine lining, irregularities in the uterine cavity (such as polyps, fibroid tumors, scarring, or adenomyosis), hormonal imbalances (progesterone deficiency or luteal phase defects), and deficient blood flow to the uterine lining.
2. Immunologic Implantation Dysfunction (IID): IID is a significant cause of RPL, contributing to 75% of cases where chromosomally normal embryos fail to implant. It involves the immune system’s response to pregnancy, which can interfere with successful implantation.
3. Blood Clotting Disorders: Thrombophilia, a hereditary clotting disorder, can disrupt the blood supply to the developing fetus, leading to pregnancy loss.
4. Genetic and Structural Abnormalities: Genetic abnormalities are rare causes of RPL, while structural chromosomal abnormalities occur infrequently (1%). Unbalanced translocation, where part of one chromosome detaches and fuses with another, can lead to pregnancy loss. Studies also suggest that damaged sperm DNA can negatively impact fetal development and result in miscarriage.

IMMUNOLOGIC IMPLANTATION DYSFUNCTION AND RPL:

Autoimmune IID: Here an immunologic reaction is produced by the individual to his/her body’s own cellular components. The most common antibodies that form in such situations are APA and antithyroid antibodies (ATA). But it is only when specialized immune cells in the uterine lining, known as cytotoxic lymphocytes (CTL) and natural killer (NK) cells, become activated and start to release an excessive/disproportionate amount of TH-1 cytokines that attack the root system of the embryo, that implantation potential is jeopardized. Diagnosis of such activation requires highly specialized blood test for cytokine activity that can only be performed by a handful of reproductive immunology reference laboratories in the United States. Alloimmune IID, (i.e., where antibodies are formed against antigens derived from another member of the same species), is believed to be a common immunologic cause of recurrent pregnancy loss. Autoimmune IID is often genetically transmitted. Thus, it should not be surprising to learn that it is more likely to exist in women who have a family (or personal) history of primary autoimmune diseases such as lupus erythematosus (LE), scleroderma or autoimmune hypothyroidism (Hashimoto’s disease), autoimmune hyperthyroidism (Grave’s disease), rheumatoid arthritis, etc. Reactionary (secondary) autoimmunity can occur in conjunction with any medical condition associated with widespread tissue damage. One such gynecologic condition is endometriosis. Since autoimmune IID is usually associated with activated NK and T-cells from the outset, it usually results in such very early destruction of the embryo’s root system that the patient does not even recognize that she is pregnant. Accordingly, the condition usually presents as “unexplained infertility” or “unexplained IVF failure” rather than as a miscarriage. Alloimmune IID, on the other hand, usually starts off presenting as unexplained miscarriages (often manifesting as RPL). Over time as NK/T cell activation builds and eventually becomes permanently established the patient often goes from RPL to “infertility” due to failed implantation. RPL is more commonly the consequence of alloimmune rather than autoimmune implantation dysfunction. However, regardless, of whether miscarriage is due to autoimmune or alloimmune implantation dysfunction the final blow to the pregnancy is the result of activated natural killer cells (NKa) and cytotoxic lymphocytes (CTL B) in the uterine lining that damage the developing embryo’s “root system” (trophoblast) so that it can no longer sustain the growing conceptus. This having been said, it is important to note that autoimmune IID is readily amenable to reversal through timely, appropriately administered, selective immunotherapy, and alloimmune IID is not. It is much more difficult to treat successfully, even with the use of immunotherapy. In fact, in some cases the only solution will be to revert to selective immunotherapy plus using donor sperm (provided there is no “match” between the donor’s DQa profile and that of the female recipient) or alternatively to resort to gestational surrogacy.

DIAGNOSING THE CAUSE OF RPL.

In the past, women who miscarried were not evaluated thoroughly until they had lost several pregnancies in a row. This was because sporadic miscarriages are most commonly the result of embryo numerical chromosomal irregularities (aneuploidy) and thus not treatable. However, a consecutive series of miscarriages points to a repetitive cause that is non-chromosomal and is potentially remediable. Since RPL is most commonly due to a uterine pathology or immunologic causes that are potentially treatable, it follows that early chromosomal evaluation of products of conception could point to a potentially treatable situation. Thus, I strongly recommend that such testing be done in most cases of miscarriage. Doing so will avoid a great deal of unnecessary heartache for many patients. Establishing the correct diagnosis is the first step toward determining effective treatment for couples with RPL. It results from a problem within the pregnancy itself or within the uterine environment where the pregnancy implants and grows. Diagnostic tests useful in identifying individuals at greater risk for a problem within the pregnancy itself include Karyotyping (chromosome analysis) both prospective parents Assessment of the karyotype of products of conception derived from previous miscarriage specimens Ultrasound examination of the uterine cavity after sterile water is injected or sonohysterogram, fluid ultrasound, etc.) Hysterosalpingogram (dye X-ray test) Hysteroscopic evaluation of the uterine cavity Full hormonal evaluation (estrogen, progesterone, adrenal steroid hormones, thyroid hormones, FSH/LH, etc.) Immunologic testing to include Antiphospholipid antibody (APA) panel Antinuclear antibody (ANA) panel Antithyroid antibody panel (i.e., antithyroglobulin and antimicrosomal antibodies) Reproductive immunophenotype Natural killer cell activity (NKa) assay (i.e., K562 target cell test) Alloimmune testing of both the male and female partners

TREATMENT OF RPL

• Treatment for Anatomic Abnormalities of the Uterus: 

This involves restoration through removal of local lesions such as fibroids, scar tissue, and endometrial polyps or timely insertion of a cervical cerclage (a stitch placed around the neck of the weakened cervix) or the excision of a uterine septum when indicated. Treatment of Thin Uterine Lining: A thin uterine lining has been shown to correlate with compromised pregnancy outcome. Often this will be associated with reduced blood flow to the endometrium. Such decreased blood flow to the uterus can be improved through treatment with sildenafil and possibly aspirin. sildenafil (Viagra) Therapy. Viagra has been used successfully to increase uterine blood flow. However, to be effective it must be administered starting as soon as the period stops up until the day of ovulation and it must be administered vaginally (not orally). Viagra in the form of vaginal suppositories given in the dosage of 25 mg four times a day has been shown to increase uterine blood flow as well as thickness of the uterine lining. To date, we have seen significant improvement of the thickness of the uterine lining in about 70% of women treated. Successful pregnancy resulted in 42% of women who responded to the Viagra. It should be remembered that most of these women had previously experienced repeated IVF failures. Use of Aspirin: This is an anti-prostaglandin that improves blood flow to the endometrium. It is administered at a dosage of 81 mg orally, daily from the beginning of the cycle until ovulation.

Treating Immunologic Implantation Dysfunction with Selective Immunotherapy: 

Modalities such as intralipid (IL), intravenous immunoglobulin-G (IVIG),  heparinoids (Lovenox/Clexane), and corticosteroids (dexamethasone, prednisone, prednisolone) can be used in select cases depending on autoimmune or alloimmune dysfunction. The Use of IVF in the Treatment of RPL In the following circumstances, IVF is the preferred option: When in addition to a history of RPL, another standard indication for IVF (e.g., tubal factor, endometriosis, and male factor infertility) is superimposed and in cases where selective immunotherapy is needed to treat an immunologic implantation dysfunction.  The reason for IVF being a preferred approach when immunotherapy is indicated is that in order to be effective, immunotherapy needs to be initiated well before spontaneous or induced ovulation. Given the fact that the anticipated birthrate per cycle of COS with or without IUI is at best about 15%, it follows that short of IVF, to have even a reasonable chance of a live birth, most women with immunologic causes of RPL would need to undergo immunotherapy repeatedly, over consecutive cycles. Conversely, with IVF, the chance of a successful outcome in a single cycle of treatment is several times greater and, because of the attenuated and concentrated time period required for treatment, IVF is far safer and thus represents a more practicable alternative Since embryo aneuploidy is a common cause of miscarriage, the use of preimplantation genetic screening/ testing (PGS/T), with tests such as next generation gene sequencing (NGS), can provide a valuable diagnostic and therapeutic advantage in cases of RPL. PGS/T requires IVF to provide access to embryos for testing. There are a few cases of intractable alloimmune dysfunction due to absolute DQ alpha gene matching ( where there is a complete genotyping match between the male and female partners) where Gestational Surrogacy or use of donor sperm could represent the only viable recourse, other than abandoning treatment altogether and/or resorting to adoption. Other non-immunologic factors such as an intractably thin uterine lining or severe uterine pathology might also warrant that last resort consideration be given to gestational surrogacy. Conclusion:

Understanding the causes of pregnancy loss is crucial for individuals experiencing recurrent miscarriages. While chromosomal abnormalities are a common cause of sporadic early pregnancy losses, other factors such as uterine environment problems, immunologic implantation dysfunction, blood clotting disorders, and genetic or structural abnormalities can contribute to recurrent losses. By identifying the underlying cause, healthcare professionals can provide appropriate interventions and support to improve the chances of a successful pregnancy. The good news is that if a couple with RPL is open to all of the diagnostic and treatment options referred to above, a live birthrate of 70%–80% is ultimately achievable.

ADDITIONAL INFORMATION:

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

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\