Answer:

I can understand your concern/confusion…but respectfully, I think 100-200mg daily is quite adequate.

Sincerely,

Geoff Sher

Answer:

Sadly, this does not look good. Repeat the beta hCG test  in 2 days to see if it doubles.

Going through IVF is a major investment, emotionally, physically, and financially, for every patient or couple. One of the most crucial moments is receiving the result of the blood test for human chorionic gonadotropin (hCG) pregnancy. It’s a big deal! The days after the embryo transfer, waiting for this result, can be extremely stressful. That’s why it’s crucial for the IVF doctor and staff to handle this information with care and professionalism. They should be accessible to the patient/couple and provide results promptly and sensitively.

Testing urine or blood to check for human chorionic gonadotropin (hCG) is the best way to confirm pregnancy. Urine tests are cheaper and more commonly used. They are also more convenient because they can be done anywhere. However, blood tests are more reliable and sensitive than urine tests. They can detect pregnancy earlier and at lower hCG levels. Blood tests are also more accurate and can track changes in hCG levels over time. Urine tests can detect hCG when blood levels are above 20IU, which is about 16-18 days after ovulation or 2-3 days after a missed period. Blood tests can measure any concentration of hCG about 12-13 days after ovulation.

Detecting hCG in the blood early on and tracking its increase is especially useful for women undergoing fertility treatments like controlled ovarian stimulation or in vitro fertilization. The sooner hCG is detected and measured, the more information can be gathered about the success of implantation and the health of the developing embryo.

Typically, two beta hCG blood tests are done, spaced 2-4 days apart. It’s best to wait for the results of the second test before reporting on the pregnancy. This is because an initial result can change, even from equivocal or negative to positive. Sometimes a normal embryo takes longer to implant, and the hCG level can be initially low or undetectable. Regardless of the initial level, the test should be repeated after two days to check for a significant rise in hCG. A significant rise usually indicates that an embryo is implanting, which suggests a possible pregnancy. Waiting for the second test result helps avoid conveying false hope or disappointment.

It’s important to note that beta hCG levels don’t double every two days throughout pregnancy. Once the levels rise above 4,000U, they tend to increase more slowly. Except in specific cases like IVF using an egg donor or transfer of genetically tested embryos, the birth rate following IVF in younger women is around 40% per embryo transfer. Patients need to have realistic expectations and should be informed about how and when they will receive the news, as well as counseling in case of a negative outcome.

When an embryo starts to implant, it releases the pregnancy hormone hCG into the woman’s bloodstream. Around 12 days after egg retrieval, 9 days after a day 3 embryo transfer, or 7 days after a blastocyst transfer, a woman should have a quantitative beta hCG blood pregnancy test performed. By that time, most of the hCG injected to prepare the eggs for retrieval should have cleared from the bloodstream. So, if the test detects more than 10 IU of hCG per ml of blood, it indicates that the embryo has attempted to implant. In third-party IVF (e.g., ovum donation, gestational surrogacy, embryo adoption, or frozen embryo transfers), no hCG trigger is administered, so any amount of hCG detected in the blood is considered significant.

Sometimes, there is a slow initial rise in hCG between the first and second tests (failure to double every 48 hours). In such cases, a third and sometimes a fourth hCG test should be done at two-day intervals. A failure to double on the third and/or fourth test is a poor sign and could indicate a failed or dysfunctional implantation. In some cases, a progressively slow rising hCG level might indicate an ectopic pregnancy, which requires additional testing and follow-up.

In certain situations, the first beta hCG level starts high, drops with the second test, and then starts doubling again. This could suggest that initially, multiple embryos started to implant but only one survived to continue a healthy implantation.

It’s customary for the IVF clinic staff to inform the patient/couple and the referring physician about the hCG pregnancy test results. Often, the IVF physician or nurse-coordinator coordinates with the referring physician to arrange all necessary pregnancy tests. If the patient/couple prefer to make their own arrangements, the program should provide detailed instructions.

In some cases, when the two blood pregnancy tests show that one or more embryos are implanting, certain programs recommend daily injections of progesterone or the use of vaginal hormone suppositories for several weeks to support the implantation process. Others give hCG injections three times a week until the pregnancy can be confirmed by ultrasound examination. Some IVF programs don’t prescribe any hormones after the embryo transfer.

Patients with appropriate doubling of hCG levels within two days after frozen embryo transfer (FET) or third-party IVF procedures such as surrogacy or egg donation may receive estradiol and progesterone injections, often along with vaginal hormone suppositories, for 10 weeks after the implantation is diagnosed by blood pregnancy testing.

A positive Beta hCG blood pregnancy test indicates the possibility of conception, but ultrasound confirmation is needed to confirm the pregnancy. Until then, it is referred to as a “chemical pregnancy.” Only when ultrasound examination confirms the presence of a gestational sac, clinical examination establishes a viable pregnancy, or after abortion when products of conception are detected, is it called a clinical intrauterine pregnancy.

A significantly elevated  hCG blood level without concomitant detection of an gestational sac inside the uterus by ultrasound after 5 weeks gestation raises the suspicion of an ectopic (tubal) pregnancy.

The risk of miscarriage gradually decreases once a viable clinical pregnancy is diagnosed (a conceptus with a regular heartbeat of 110-180 beats per minute). From this point onward, the risk of miscarriage is usually 10- 15% for women under 40 years old and around 35% for women in their early forties.

Dealing with successful IVF cases is relatively easy as everyone feels happy and validated. The real challenge lies in handling unsuccessful cases. Setting rational expectations from the beginning is crucial. In some cases (fortunately rare), emotional pressure may overwhelm the patient/couple, leading to a need for counseling or psychiatric therapy. I always advise my patients that receiving optimal care doesn’t always guarantee the desired outcome. There are many variables beyond our control, especially the unpredictable nature of fate. With around 36 years of experience in this field, I strongly believe that when it comes to IVF, the saying “man proposes while God disposes” always holds.

There are a few important things to consider when interpreting blood hCG levels. Levels can vary widely, ranging from 5mIU/ml to over 400mIU/ml, 10 days after ovulation or egg retrieval. The levels double every 48-72 hours until the 6th week of pregnancy, after which the doubling rate slows down to about 96 hours. By the end of the 1st trimester, hCG levels reach 13,000-290,000 IU and then slowly decline to around 26,000-300,000 IU at full term. Here are the average hCG levels during the first trimester:

• 3 weeks after the last menstrual period (LMP): 5-50 IU
• 4 weeks LMP: 5-426 IU
• 5 weeks LMP: 18-7,340 IU
• 6 weeks LMP: 1,080-56,500 IU
• 7-8 weeks LMP: 7,650-229,000 IU
• 9-12 weeks LMP: 25,700-288,000 IU

Most doctors wait until around the 7th week to perform an ultrasound to confirm pregnancy. By that time, the heartbeat should be clearly visible, providing a more reliable assessment of the pregnancy’s viability.

In some cases, blood hCG levels can be unusually high or increase faster than normal. This could indicate multiple pregnancies or a molar pregnancy. Rarely, conditions unrelated to pregnancy, such as certain ovarian tumors or cancers, can cause detectable hCG levels in both blood and urine.

To summarize, testing urine or blood for hCG is the most reliable way to confirm pregnancy. Urine tests are more common and convenient, while blood tests are more accurate and can detect pregnancy earlier. Tracking hCG levels in the blood is especially important for women undergoing fertility treatments. It’s essential to wait for the results of a second blood test before confirming pregnancy to avoid false hope or disappointment. Interpreting hCG levels requires considering various factors, and doctors usually perform an ultrasound around the 7th week for a more accurate assessment. Unusually high hCG levels may indicate multiple pregnancies or other conditions unrelated to pregnancy. Providing sensitive and timely communication of results is crucial for IVF clinics to support patients through the emotional journey.

________________________________________________________________________________

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\

Answer:

This is highly suggestive of an 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:

1. • 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:

1. • 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):

1. • 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:

1. • 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.

_________________________________________________________________________________

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\

Answer:

Sadly, this does not look good!

Sorry

Geoff Sher

Answer:

Please redraft your question in English!

Geoff Sher

Answer:

In my opinion, you are still likely to be on a “safe track”. I suggest you wait 10 days and do an US for confirmation.

Going through IVF is a major investment, emotionally, physically, and financially, for every patient or couple. One of the most crucial moments is receiving the result of the blood test for human chorionic gonadotropin (hCG) pregnancy. It’s a big deal! The days after the embryo transfer, waiting for this result, can be extremely stressful. That’s why it’s crucial for the IVF doctor and staff to handle this information with care and professionalism. They should be accessible to the patient/couple and provide results promptly and sensitively.

Testing urine or blood to check for human chorionic gonadotropin (hCG) is the best way to confirm pregnancy. Urine tests are cheaper and more commonly used. They are also more convenient because they can be done anywhere. However, blood tests are more reliable and sensitive than urine tests. They can detect pregnancy earlier and at lower hCG levels. Blood tests are also more accurate and can track changes in hCG levels over time. Urine tests can detect hCG when blood levels are above 20IU, which is about 16-18 days after ovulation or 2-3 days after a missed period. Blood tests can measure any concentration of hCG about 12-13 days after ovulation.

Detecting hCG in the blood early on and tracking its increase is especially useful for women undergoing fertility treatments like controlled ovarian stimulation or in vitro fertilization. The sooner hCG is detected and measured, the more information can be gathered about the success of implantation and the health of the developing embryo.

Typically, two beta hCG blood tests are done, spaced 2-4 days apart. It’s best to wait for the results of the second test before reporting on the pregnancy. This is because an initial result can change, even from equivocal or negative to positive. Sometimes a normal embryo takes longer to implant, and the hCG level can be initially low or undetectable. Regardless of the initial level, the test should be repeated after two days to check for a significant rise in hCG. A significant rise usually indicates that an embryo is implanting, which suggests a possible pregnancy. Waiting for the second test result helps avoid conveying false hope or disappointment.

It’s important to note that beta hCG levels don’t double every two days throughout pregnancy. Once the levels rise above 4,000U, they tend to increase more slowly. Except in specific cases like IVF using an egg donor or transfer of genetically tested embryos, the birth rate following IVF in younger women is around 40% per embryo transfer. Patients need to have realistic expectations and should be informed about how and when they will receive the news, as well as counseling in case of a negative outcome.

When an embryo starts to implant, it releases the pregnancy hormone hCG into the woman’s bloodstream. Around 12 days after egg retrieval, 9 days after a day 3 embryo transfer, or 7 days after a blastocyst transfer, a woman should have a quantitative beta hCG blood pregnancy test performed. By that time, most of the hCG injected to prepare the eggs for retrieval should have cleared from the bloodstream. So, if the test detects more than 10 IU of hCG per ml of blood, it indicates that the embryo has attempted to implant. In third-party IVF (e.g., ovum donation, gestational surrogacy, embryo adoption, or frozen embryo transfers), no hCG trigger is administered, so any amount of hCG detected in the blood is considered significant.

Sometimes, there is a slow initial rise in hCG between the first and second tests (failure to double every 48 hours). In such cases, a third and sometimes a fourth hCG test should be done at two-day intervals. A failure to double on the third and/or fourth test is a poor sign and could indicate a failed or dysfunctional implantation. In some cases, a progressively slow rising hCG level might indicate an ectopic pregnancy, which requires additional testing and follow-up.

In certain situations, the first beta hCG level starts high, drops with the second test, and then starts doubling again. This could suggest that initially, multiple embryos started to implant but only one survived to continue a healthy implantation.

It’s customary for the IVF clinic staff to inform the patient/couple and the referring physician about the hCG pregnancy test results. Often, the IVF physician or nurse-coordinator coordinates with the referring physician to arrange all necessary pregnancy tests. If the patient/couple prefer to make their own arrangements, the program should provide detailed instructions.

In some cases, when the two blood pregnancy tests show that one or more embryos are implanting, certain programs recommend daily injections of progesterone or the use of vaginal hormone suppositories for several weeks to support the implantation process. Others give hCG injections three times a week until the pregnancy can be confirmed by ultrasound examination. Some IVF programs don’t prescribe any hormones after the embryo transfer.

Patients with appropriate doubling of hCG levels within two days after frozen embryo transfer (FET) or third-party IVF procedures such as surrogacy or egg donation may receive estradiol and progesterone injections, often along with vaginal hormone suppositories, for 10 weeks after the implantation is diagnosed by blood pregnancy testing.

A positive Beta hCG blood pregnancy test indicates the possibility of conception, but ultrasound confirmation is needed to confirm the pregnancy. Until then, it is referred to as a “chemical pregnancy.” Only when ultrasound examination confirms the presence of a gestational sac, clinical examination establishes a viable pregnancy, or after abortion when products of conception are detected, is it called a clinical intrauterine pregnancy.

A significantly elevated  hCG blood level without concomitant detection of an gestational sac inside the uterus by ultrasound after 5 weeks gestation raises the suspicion of an ectopic (tubal) pregnancy.

The risk of miscarriage gradually decreases once a viable clinical pregnancy is diagnosed (a conceptus with a regular heartbeat of 110-180 beats per minute). From this point onward, the risk of miscarriage is usually 10- 15% for women under 40 years old and around 35% for women in their early forties.

Dealing with successful IVF cases is relatively easy as everyone feels happy and validated. The real challenge lies in handling unsuccessful cases. Setting rational expectations from the beginning is crucial. In some cases (fortunately rare), emotional pressure may overwhelm the patient/couple, leading to a need for counseling or psychiatric therapy. I always advise my patients that receiving optimal care doesn’t always guarantee the desired outcome. There are many variables beyond our control, especially the unpredictable nature of fate. With around 36 years of experience in this field, I strongly believe that when it comes to IVF, the saying “man proposes while God disposes” always holds.

There are a few important things to consider when interpreting blood hCG levels. Levels can vary widely, ranging from 5mIU/ml to over 400mIU/ml, 10 days after ovulation or egg retrieval. The levels double every 48-72 hours until the 6th week of pregnancy, after which the doubling rate slows down to about 96 hours. By the end of the 1st trimester, hCG levels reach 13,000-290,000 IU and then slowly decline to around 26,000-300,000 IU at full term. Here are the average hCG levels during the first trimester:

• 3 weeks after the last menstrual period (LMP): 5-50 IU
• 4 weeks LMP: 5-426 IU
• 5 weeks LMP: 18-7,340 IU
• 6 weeks LMP: 1,080-56,500 IU
• 7-8 weeks LMP: 7,650-229,000 IU
• 9-12 weeks LMP: 25,700-288,000 IU

Most doctors wait until around the 7th week to perform an ultrasound to confirm pregnancy. By that time, the heartbeat should be clearly visible, providing a more reliable assessment of the pregnancy’s viability.

In some cases, blood hCG levels can be unusually high or increase faster than normal. This could indicate multiple pregnancies or a molar pregnancy. Rarely, conditions unrelated to pregnancy, such as certain ovarian tumors or cancers, can cause detectable hCG levels in both blood and urine.

To summarize, testing urine or blood for hCG is the most reliable way to confirm pregnancy. Urine tests are more common and convenient, while blood tests are more accurate and can detect pregnancy earlier. Tracking hCG levels in the blood is especially important for women undergoing fertility treatments. It’s essential to wait for the results of a second blood test before confirming pregnancy to avoid false hope or disappointment. Interpreting hCG levels requires considering various factors, and doctors usually perform an ultrasound around the 7th week for a more accurate assessment. Unusually high hCG levels may indicate multiple pregnancies or other conditions unrelated to pregnancy. Providing sensitive and timely communication of results is crucial for IVF clinics to support patients through the emotional journey.

______________________________________________________________________________________

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\

Answer:

I really do not believe this will be an issue. A P4 of 16ng/ml at this stage is still adequate.

Good luck!

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\

Answer:

Measuring and interpreting Blood hCG to Assess Pregnancy Viability Following ART Treatments.

Geoffrey Sher MD

I know of no medical announcement associated with the degree of emotional anticipation and anguish as that associated with a pending diagnosis/confirmation of pregnancy following infertility treatment. In fact, hardly a day goes by where I am not confronted by a patient anxiously seeking interpretation of a pregnancy test result.

Testing urine or blood for the presence of human chorionic gonadotropin (hCG) is the most effective and reliable way to confirm conception. The former, is far less expensive than the latter and is the most common method used. It is also more convenient because it can be performed in the convenience of the home setting. However, urine hCG testing for pregnancy is not nearly as reliable or as sensitive e as is blood hCG testing. Blood testing can detect implantation several days earlier than can a urine test. Modern pregnancy urine test kits can detect hCG about 16-18 days following ovulation (or 2-3 days after having missed a menstrual period), while blood tests can detect hCG, 12-13 days post-ovulation (i.e. even prior to menstruation).

The ability to detect hCG in the blood as early as possible and thereupon to track its increase, is particularly valuable in women undergoing controlled ovarian stimulation (COS) with or without intrauterine insemination (IUI) or after IVF. The earlier hCG can be detected in the blood and its concentration measured, the sooner levels can be tracked serially over time and so provide valuable information about the effectiveness of implantation, and the potential viability of the developing conceptus.

There are a few important points that should be considered when it comes to measuring interpreting blood hCG levels. These include the following:

• All modern day blood (and urine) hCG tests are highly specific in that they measure exclusively for hCG. There is in fact no cross-reactivity with other hormones such as estrogen, progesterone or LH.
• Post conception hCG levels, measured 10 days post ovulation or egg retrieval can vary widely (ranging from 5mIU/ml to above 400mIU/ml. The level will double every 48–72 hours up to the 6th week of gestation whereupon the doubling rate starts to slow down to about 96 hours. An hCG level of 13,000-290, 0000 mIU/ml is reached by the end of the 1st trimester (12 weeks) whereupon it slowly declines to approximately 26,000– 300,000 mIU/ml by full term. Below are the average hCG levels during the first trimester:

• • 3 weeks LMP: 5 – 50 mIU/ml
  • 4 weeks LMP: 5 – 426 mIU/ml
  • 5 weeks LMP: 18 – 7,340 mIU/ml
  • 6 weeks LMP: 1,080 – 56,500 mIU/ml
  • 7 – 8 weeks LMP: 7, 650 – 229,000 mIU/ml
  • 9 – 12 weeks LMP: 25,700 – 288,000 mIU/ml

• A single hCG blood level is not sufficient to assess the viability of an implanting embryo. Caution should be used in making too much of an initial hCG level. This is because a normal pregnancy can start with relatively low hCG blood levels. It is the rate of the rise of the blood hCG level that is relevant.
• In some cases the initially hCG level is within the normal range, but then fails to double in the ensuing 48-72hours. In some cases it might even plateau or decline, only to start doubling appropriately thereafter. When this happens, it could be due to:
  • A recovering implantation, destined to develop into a clinical gestation
  • A failing implantation (a chemical pregnancy)
  • A multiple pregnancy which is spontaneously reducing (i.e., one or more of the concepti is being lost) or,
  • An ectopic pregnancy which will either absorb spontaneously (a chemical-tubal gestation), or evolve into a full blown tubal pregnancy continue and declare itself through characteristic symptoms and signs of an intraperitoneal bleed.
• The blood hCG test needs to be repeated at least once after 48h and in some cases it will need to be repeated one or more times (at 48h intervals) thereafter, to confirm that implantation is progressing normally.
• Ultimately the diagnosis of a viable pregnancy requires confirmation of the presence of an intrauterine gestational sac by ultrasound examination. The earliest that this can be achieved is when the beta hCG level exceeds 1,000mIU/ml (i.e., around 5-6 weeks).
• Most physicians prefer to defer the performance of a routine US diagnosis of pregnancy until closer to the 7th week. This is because by that time, cardiac activity should be clearly detectable, allowing for more reliable assessment of pregnancy viability.
• There are cases where the blood beta hCG level is extraordinarily high or the rate of rise is well above the normal doubling rate. The commonest explanation is that more than one pregnancy has implanted. However in some cases it can point to a molar pregnancy
• Finally, there on rare occasions, conditions unrelated to pregnancy can result in detectable hCG levels in blood and urine. They include ovarian tumors that produce hCG, such as certain types of cystic teratomas (dermoid cysts) and some ovarian cancers such as dysgerminomas.

______________________________________________________________________________________________________

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\

Answer:

Congratulations Cassidy,

The needle size (although unnecessarily large) will in no way adversely effect delivery of the medication or outcome.

Good luck!

Geoff Sher

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\

Answer:

In my opinion, this sounds very much like an implantation dysfunction.

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

 Geoffrey Sher MD

 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:

1. • 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:

1. • 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):

1. • 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:

1. • 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.

____________________________________________________________________________________

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\

Answer:

I do not think the surge or the  “trigger” with Ovidrel will change the timing of the FET. But to be quite honest, I personally prevent FET’s in hormone replacement cycles to better pinpoint the ideal window of implantation.

Prior to  2 decades ago, most women undergoing IVF would have embryos transferred to the uterus in the same cycle that the egg retrieval was performed (“Fresh” Embryo Transfer). This was because embryo cryopreservation (freezing) was a hazardous undertaking.  In fact, it resulted in about 30% not surviving the freezing process and those that did, having about one half the potential of “fresh embryos to implant and propagate a viable pregnancy. The main reason for the high attrition rate associated with embryo cryopreservation is that the “conventional” freezing” process that was done slowly and this resulted in ice forming within the embryo’s cells, damaging or destroying them. The introduction of an ultra-rapid cryopreservation process (vitrification) freezes the embryos so rapidly as to avoid ice crystals from developing. As a result, >90% survive the freeze/thaw process in as good a condition as they were prior to being frozen and thus without being compromised in their ability to propagate a viable pregnancy.

Recently, there have been several articles that have appeared in the literature suggest that an altered hormonal environment may be the reason for this effect.  There have also been reports showing that when singletons (pregnancy with one baby) conceived naturally are compared to singletons conceived through a “fresh” embryo transfers they tend to have a greater chance of low birth weight/prematurity. This difference was not observed in babies born following FET.  Hence, there is a suspicion that the altered hormonal environment during the fresh cycle may be the causative factor.

Available evidence suggests that FET (of pre-vitrified blastocysts) is at least as successful as is the transfer of “fresh” embryos and might even have the edge. The reason for this is certainly unlikely to have anything to do with the freezing process itself. It more than likely  has to do with two factors:

1. An ever increasing percentage of FET’s involve the transfer of PGS-tested, fully karyotyped, euploid blastocysts that have a greater potential to propagate viable pregnancies, than is the case with “fresh” ET’s where the embryos have rarely undergone prior PGS selection for “competency”…and,
2. With targeted hormone replacement therapy for FET, one is far better able to better to optimally prepare the endometrium for healthy implantation than is the case where embryos are transferre3d following ovarian stimulation with fertility drugs.

There are additional factors other than method used for embryo cryopreservation that influence outcome following FET. These include

• An emerging trend towards selective transferring only advanced (day 5-6) embryos (blastocysts).
•  (PGS) to allow for the selective transfer of genetic competent (euploid) embryos
• Addressing underlying causes of implantation dysfunction (anatomical and immunologic uterine factors) and
•  Exclusive use of ultrasound guidance for delivery of embryos transferred to the uterus.

Against this background, the use of FET has several decided advantages:

• The ability to cryostore surplus embryos left over after fresh embryo transfer
• The ability to safely hold embryos over for subsequent transfer in a later frozen embryo transfer (FET) cycle (i.e. Staggered IVF) in cases where:

• 1. Additional time is needed to perform preimplantation Genetic testing for embryo competency.
  2. In cases where ovarian hyperstimulation increases the risk of life-endangering complications associated with critically severe ovarian hyperstimulation syndrome (OHSS).
  3. To bank (stockpile) embryos for selective transfer of karyotypically normal embryos in older women or those who are diminished ovarian reserve
  4. The ability to store embryos in cases of IVF with third party parenting (Egg Donation; Gestational Surrogacy and Embryo donation) and so improve convenience for those couples seeking such services.

Preimplantation Genetic Sampling with FET:

The introduction of preimplantation genetic sampling (PGS) to karyotyping of embryos for selective transfer of the most “competent” embryos, requires in most cases that the tested blastocysts be vitribanked while awaiting test results and then transferred to the uterus at a later date. Many IVF programs have advocated the routine use of PGS in IVF purported to improve IVF outcome. But PGS should in my opinion should only be used selectively. I do not believe that it is needed for all women undergoing IVF. First there is the significant additional cost involved and second it will not benefit everyone undergoing IVF, in my opinion.

While PGS is a good approach for older women and those with diminished ovarian reserve (DOR) and also for woman who experience recurrent pregnancy loss (RPL) or “unexplained” recurrent IVF failure recent data suggests that it will not improve IVF success rates in  women under 36Y  who have normal ovarian reserve, who represent the majority of women seeking IVF treatment. Nor is it needed in women (regardless of their age) undergoing IVF with eggs donated by a younger donor.  This is because in such women about 1:2/3 of their eggs/embryos are usually chromosomally normal, and in most cases will upon fertilization produce multiple blastocysts per IVF attempt, anyway. Thus in such cases the transfer of 2 blastocysts will likely yield the same outcome regardless of whether the embryos had been subjected to PGS or not. The routine use of

It is another matter when it comes to women who have diminished ovarian reserve and/or DOR contemplating embryo banking and for women with unexplained recurrent IVF failure, recurrent pregnancy loss and women with alloimmune implantation dysfunction who regardless of their age or ovarian reserve require PGS for diagnostic reasons.

Embryo Banking: Some IVF centers are doing embryo banking cycles with Preimplantation Genetic Screening (PGS).  With Embryo Banking” several IVF cycles are performed sequentially (usually about 2 months apart), up to the egg retrieval stage. The eggs are fertilized and the resulting advanced embryos are biopsied. The biopsy specimens are held over until enough 4-8 blastocysts have been vitribanked, thus providing a reasonable likelihood that one or more will turn out to be PGS-normal. At this point the biopsy specimens (derived all banking cycles) are sent for PGS testing at one time (a significant cost-saver), the chromosomally normal blastocysts are identified and the women are scheduled for timed FET procedures….. with a good prospect of  a markedly improved chance of success as well as a reduced risk of miscarriage.

Standard (proposed) Regimen for preparing the uterus for frozen embryo transfer FET) is as follows:

 The recipient’s cycle is initiated with an oral contraceptive-OC (e.g. Marvelon/Lo-Estrin; Lo-Ovral etc) for at least 10 days. This is later overlapped with 0.5 mg. (10 units) Lupron/Lucrin (or Superfact/Buserelin) daily for 3 days. Thereupon the OC is withdrawn and daily 0.25 mg (5 units) of Lupron/Lucrin/Superfact injections are continued. Menstruation will usually ensue within 1 week. At this point, an ultrasound examination is performed to exclude ovarian cyst(s) and a blood estradiol measurement is taken (it needs to be <70pg/ml) until daily progesterone administration is initiated some time later. The daily Lupron/Lucrin/Superfact is continued until the initiation of progesterone therapy (see below).

Four milligram (4mg) Estradiol valerate (Delestrogen) IM is injected SC, twice weekly (on Tuesday and Friday), commencing within a few days of Lupron/Lucrin/Superfact-induced menstruation. Blood is drawn on Monday and Thursday for measurement of blood [E2].  This allows for planned adjustment of the E2V dosage scheduled for the next day. The objective is to achieve a plasma E2 concentration of 500-1,000pg/ml and an endometrial lining of >8mm, as assessed by ultrasound examination done after 10 days of estrogen exposure i.e. a day after the 3^rd dosage of Delestrogen..  The twice weekly, final (adjusted) dosage of E2V is continued until pregnancy is discounted by blood testing or an ultrasound examination. Dexamethasone 0.75 mg is taken orally, daily with the start of the Lupron/Lucrin/Superfact. Oral folic acid (1 mg) is taken daily commencing with the first E2V injection and is continued throughout gestation. Patients also receive Ciprofloxin 500mg BID orally starting with the initiation of Progesterone therapy and continuing for 10 days.

Luteal support commences 6 days prior to the ET, with intramuscular progesterone in oil (PIO) at an initial dose of 50 mg (P4-Day 1).  Starting on progesterone administration-Day 2, PIO is increased to 100 mg daily continuing until the 10^th week of pregnancy, or until a blood pregnancy test/negative ultrasound (after the 6-7^th gestational week), discounts a viable pregnancy.

Also, commencing on the day following the ET, the patient inserts one (1) vaginal progesterone suppository (100 mg) in the morning + 2mg E2V vaginal suppository (in the evening) and this is continued until the 10^th week of pregnancy or until pregnancy is discounted by blood testing or by an ultrasound examination after the 6-7^th gestational week. Dexamethasone o.75mg is continued to the 10^th week of pregnancy (tailed off from the 8^th to 10^th week) or as soon as pregnancy is ruled out. With the obvious exception of the fact that embryo recipients do not receive an hCG injections, luteal phase and early pregnancy hormonal support and immuno-suppression is otherwise the same as for conventional IVF patients.  Blood pregnancy tests are performed 13 days and 15 days after the first P4 injection was given.

Note: One (1) vaginal application of Crinone 8% is administered on the 1^st day (referred to as luteal phase day 0 – LPO). On LP Day 1, they will commence the administration of Crinone 8% twice daily (AM and PM) until the day of embryo transfer.  Withhold Crinone on the morning of the embryo transfer and resume Crinone administration in the PM.   Crinone twice daily is resumed from the day after embryo transfer. Contingent upon positive blood pregnancy tests, and subsequently upon the ultrasound confirmation of a viable pregnancy, administration of Crinone twice daily are continued until the 10^th week of pregnancy.

Regime for Thawing and Transferring Cryopreserved Embryos/Morulae/Blastocysts:

Patients undergoing ET with cryopreserved embryos/morulas/blastocysts will have their embryos thawed and transferred by the following regimen.

_______________________________________________________________________________________________

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\

Answer:

Given your age and history, I would not be at all surprised if this were an implantation dysfunction (possibly immunologic). See the urticles below . In my opinion, you should delay doing another FET until there is a diagnosis.

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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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:

1. • 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:

1. • 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):

1. • 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:

1. • 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.

 ______________________________________________________________________________________________________________________________

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\

Answer:

It is most unusual but it can happen due to an egg issue or due to a laboratory dysfunction. In my opinion the most important remedy is to use an individualized protocol for ovarian stimulation to try and protect egg development during stimulation.

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.

_________________________________________________________________________

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\

Answer:

Very possibly Yes!

Endometriosis is a condition where the lining of the uterus grows in other places besides its usual spot inside the uterus. It can affect the Fallopian tubes, ovaries, and bowel and on rare occasions can even disseminate beyond the pelvis and abdominal cavity. While it may seem like a physical barrier to fertility is the main cause of infertility in endometriosis, this is an oversimplified view.

The truth is that even mild cases of endometriosis can make it harder to get pregnant. However, it doesn’t mean that women with this condition are completely unable to have children. Compared to women without endometriosis who ovulate normally and are the same age, women with mild to moderate endometriosis are about four to six times less likely to have a successful pregnancy.

Unfortunately, endometriosis commonly goes undiagnosed for many years. Women with this condition are often mistakenly labeled as having “unexplained infertility” until the lesions are seen during an abdominal-pelvic surgical procedure. It’s not surprising that many patients with “unexplained” infertility eventually discover they have endometriosis if they are followed over a period spanning several years.

The journey of women with endometriosis can be challenging, particularly when it comes to fertility. However, it’s important to remember that there is hope and numerous ways to overcome these obstacles.

Reasons behind the impact of endometriosis on fertility.

• Toxic Pelvic Environment: Endometriosis creates a toxic pelvic environment that can compromise the fertilization process. Even women with mild to moderate endometriosis, whose fallopian tubes are usually healthy, face difficulties in conceiving due to exposure to peritoneal toxins. Unlike what some may believe, surgical intervention or medication alone cannot eradicate this toxic influence. Visible endometriotic deposits are just the tip of the iceberg, as numerous translucent deposits produce toxins that impact fertility. Consequently, surgical removal of visible deposits or other treatments such as controlled ovarian stimulation (COS) with or without intrauterine insemination may not improve the chances of pregnancy. In such cases, IVF is the most effective method to enhance pregnancy potential by protecting the eggs from exposure to the toxic pelvic environment.
• Ovulation Dysfunction: Approximately 25-30% of endometriosis cases are associated with ovulation dysfunction. This often requires COS in an attempt to increase the chances of pregnancy. Unfortunately, the toxic pelvic environment often diminishes the effectiveness of anything other than in vitro fertilization (IVF) in enhancing pregnancy potential. Although this may seem disheartening, IVF offers great hope for women facing this challenge.
• Pelvic Adhesions and Tubal damage: Advanced endometriosis can lead to pelvic adhesions and scarring, which damage, immobilize or obstruct the fallopian tubes, preventing the union of sperm and eggs. This can present a significant obstacle to fertility.
• Endometriomas (chocolate cysts): Advanced endometriosis often involves the development of ovarian cysts called endometriomas or chocolate cysts. These cysts contain altered blood and can be large and multiple. When these endometriomas grow larger than 1cm, they can activate surrounding ovarian tissue leading to the local production of excessive male hormones such as testosterone. This hormonal imbalance can compromise egg development and increase the likelihood of chromosomal abnormalities, reducing the competency of eggs and embryos. Therefore, eliminating such cysts surgically or by sclerotherapy ( see below) before pursuing IVF is strongly recommended.
• Immunologic implantation dysfunction (IID). Endometriosis, regardless of its severity, is associated with immunologic implantation dysfunction (IID) in more than 30% of cases. This dysfunction ( among other effects) involves the activation of uterine natural killer cells (NKa) and cytotoxic lymphocytes (CTL). These immune cells attack the developing embryo’s “root system” ( trophoblast) as it tries to attach to the uterine wall, often resulting in undetected early losses , chemical pregnancies and miscarriages. Understanding this aspect of endometriosis-related infertility is crucial to provide appropriate care and support.

While advanced endometriosis can cause significant anatomical damage and infertility, it’s important to note that the quality of life for these patients is often severely compromised by pain and discomfort. In such cases, the priority may shift towards finding relief from symptoms through medical and surgical treatment options, thereby deferring or (sometimes) even precluding future pregnancies.

For patients with moderately severe endometriosis, there is a moderate amount of scarring, adhesions, and endometriotic deposits. However, the fallopian tubes are usually open and functional, offering a chance ( albeit markedly reduced) of natural conception.

Diagnosis:

The  identification of endometriosis as the cause of Infertility, starts with having a high index of suspicion. Symptoms such as heavy/prolonged and  painful menstruation with painful deep vaginal penetration and ovulation pain along with difficulty in conceiving are strong suggestions of underlying endometriosis. A definitive diagnosis requires surgical  visualization of endometriotic lesions and/or pelvic adhesive disease , and/or ultrasound /MRI detection of ovarian endometriotic cysts. However, the exception of cases that require removal of endometriomas or urgent relief of incapacitating symptoms, successful treatment of the underlying infertility in most cases will not require such confirmation. 

It is also important to recognize that early endometriosis can be free of the symptoms and signs referred to above while still having a profoundly deleterious impact on fertility. A newer endometrial biopsy test ( Receptiva/BCL-6) can help identify  such women thereby avoiding the need for invasive trans-abdominal surgery( e.g., laparoscopy) to detect and diagnose the condition. 

Dismissing “unexplained infertility” solely on the basis of viable anatomical disease overlooks these crucial aspects and can hinder the hopes and dreams of many women facing endometriosis-related infertility.

Management of endometriosis-related Infertility: :When it comes to managing endometriosis-related infertility, there are several important considerations. Let’s explore these concepts to understand the available treatments and their potential for success.

1. Controlled Ovulation Stimulation (COS) with/without Intrauterine Insemination (IUI): The toxins present in the peritoneal secretions of women with endometriosis have a negative impact on fertilization potential, regardless of how sperm reach the fallopian tubes. This explains why COS with or without IUI does not significantly improve the chances of pregnancy compared to no treatment at all. In these cases, in vitro fertilization (IVF) is the most effective option to bypass these challenges and increase the chances of conception.

1. Pelvic Surgery: While laparoscopy or laparotomy surgery can aim to restore the anatomical integrity of the fallopian tubes, it does not address the negative influence of toxic peritoneal factors or the IID, often associated with endometriosis. Pelvic surgery is generally not recommended as a primary treatment for infertility related to endometriosis, especially for women over 35 years of age, as time is of the essence. However, for younger women who have more time on their side, surgery can be a viable option, with approximately 30% of women conceiving within a few years following corrective pelvic surgery.
2.  

Sclerotherapy for Ovarian Endometriomas: Sclerotherapy ( often not a readily available medical service) offers a non-invasive, safe, and effective method to permanently eliminate ovarian endometriomas, without the need for invasive surgery. The procedure which involves draining the cysts and injecting a solution( e.g., tetracycline hydrochloride 5%) into the emptied cyst cavity, results in the disappearance of the lesions in over 75% of cases. This outpatient procedure is cost-effective, minimizes post-procedural pain and complications, and eliminates the need for laparoscopy or laparotomy.

1. Selective Immunotherapy: More than half of women with endometriosis have antiphospholipid antibodies (APA) that can hinder the development of the embryo’s “root system” ( trophoblast). Additionally, about one-third of cases involve the activation of uterine natural killer cells (NKa) and cytotoxic lymphocytes (CTL), which can significantly impede implantation. Diagnostic tests which cannot be adequately performed by most laboratories snd must be directed to a handful of Reproductive Immunology Reference laboratories in the United States, can identify such immunologic implantation dysfunctions (IID). Treatment options include heparinoids, such as Clexane/Lovenox, to improve IVF success rates in women with APA, and a combination of Intralipid (IL) and steroid therapy to down-regulate NKa/cytotoxic T-cells. IL therapy is a cost-effective alternative to Intravenous Gamma globulin (IVIg) with comparable efficacy and fewer side effects.

1. The Role of IVF: The toxic pelvic environment caused by endometriosis reduces natural fertilization potential. Consequently, women who are ovulating normally, have patent fallopian tubes, and suffer from endometriosis are much less likely to conceive naturally or with fertility agents alone, including IUI. In such cases, IVF is the most effective approach to overcome the adverse pelvic environment and increase the chances of pregnancy. It is important to note that not all women with endometriosis require IVF, but for those > 35y for whom time is a serious consideration and for women with endometriosis ( regardless of their age) where there are additional factors such male factor infertility, IID or diminished or DOR, IVF is often is the treatment of choice.

In summary, while endometriosis can present challenges on the path to fertility, there is hope, IVF offers promising solutions to enhance pregnancy potential. With the right medical care, support, and understanding, women with endometriosis can embark on a journey towards fulfilling their dreams of starting a family.  

In Summary:

For young women under 35 years of age with endometriosis and have adequate ovarian reserve , expectant treatment may be preferable if they have normal reproductive anatomy and fertile male partners. However, for older women or those with additional factors, such as pelvic adhesions, ovarian endometriomas, male infertility, IID, or DOR, IVF should be considered as the primary treatment option. 

While endometriosis can present challenges on the path to fertility, there is hope. Medical advances such as IVF, offer promising solutions to enhance pregnancy potential. With the right medical care, support, and understanding, women with endometriosis can embark on a journey towards fulfilling their dreams of starting a family.

 _____________________________________________________

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

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

1. From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) ; 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\

Answer:

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If you’ve undergone in vitro fertilization (IVF) and didn’t achieve a successful pregnancy, you may be wondering why. It’s important to know that IVF outcomes can be unpredictable, but there are factors that can affect your chances. Let’s explore some common reasons for IVF failure in simpler terms.

1. Age: A woman’s age is a significant factor in IVF success. Generally, women under 35 have a higher chance of getting pregnant through IVF, around 35-40% per embryo transfer. However, this success rate decreases as women get older. For women in their mid-forties, the success rate drops to under 5%. This decline is mainly because the quality of eggs decreases as women age, affecting their ability to develop normally.

1. Egg/Embryo Competency: Apart from age, the quality and competency of embryos also affect IVF success. The quality of eggs and embryos is influenced by a woman’s age. However, for older women or those with fewer eggs, the specific IVF protocol used to stimulate the ovaries becomes crucial. A more aggressive approach may be needed to maximize the chances of success. Previously, it was thought that the uterus was better for embryo development than the lab environment. So, early-stage embryos were transferred to the uterus based on their appearance. However, we now know that embryos that have progressed further in development are more likely to be successful. Embryos that don’t reach the blastocyst stage within 5-6 days after fertilization are considered less competent and not suitable for transfer. Additionally, Preimplantation Genetic Sampling / Testing (PGS/T) allows us to check the chromosomes of embryos. This technique helps select the most competent embryos for transfer, especially for older women, those with fewer eggs, repeated IVF failures, and recurrent pregnancy loss.

1. Number of Embryos Transferred: Some people believe that transferring more embryos increases the chances of success. While this may have some truth, it’s essential to know that if the problem lies with the ovarian stimulation protocol, transferring more embryos won’t solve it. Also, transferring more embryos doesn’t fix issues related to embryo implantation dysfunction, such as anatomical or immunologic problems. Moreover, multiple embryos can lead to higher-order multiple pregnancies, which pose risks. To minimize these risks, it’s generally recommended to transfer a maximum of two embryos, or even just one, especially when using eggs from young women.

1. Implantation Dysfunction (ID): Implantation dysfunction is often overlooked as a cause of unexplained IVF failure, especially in young women with normal ovarian reserve and fertile partners. Failure to identify and address these issues can result in repeated IVF failures. If transferring competent embryos repeatedly fails to result in a viable pregnancy, implantation dysfunction should be considered. The most common causes include:

1. 1. Thin Uterine Lining: When the lining of the uterus is too thin, it can affect the embryo’s ability to implant and grow.
   2. Surface Lesions in the Uterus: Polyps, fibroids, or scar tissue in the uterus can interfere with embryo implantation.
   3. Immunologic Implantation Dysfunction (IID): Sometimes, the immune system can mistakenly attack the embryo, preventing successful implantation.
   4. Endocrine/Molecular Endometrial Receptivity Issues: Hormonal or molecular issues in the uterine lining can impact the embryo’s ability to attach and develop.
   5. Ureaplasma Urealyticum (UU) Infection: This infection in the cervical mucous and uterine lining can lead to unexplained early pregnancy loss or IVF failure. Both partners should be tested and treated if positive to prevent transmission.

Certain causes of infertility are difficult or impossible  to reverse, e.g.; advanced age of the woman, severe male infertility, and immunologic implantation dysfunction associated with certain specific genetic factors.

Understanding the common factors contributing to IVF failure can help you have informed discussions with your doctor and make decisions for future attempts. Factors like the number of embryos transferred and implantation dysfunction play significant roles. While success cannot be guaranteed, knowing these factors can guide you in maximizing your chances and addressing potential issues.

   _________________________________________________________________________________________________________________________________________

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\

Answer:

Dear Dr Dorr,

We do not manage patients during pregnancy.We only address reproductive dysfunction.

Might I I suggest that you reach out to an obstetrician to look after your wife while you are in NY. If you need help in finding one., please let me know and I will try to assist!

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\

Answer:

Your TSH is modestly elevated. In my opinion this is an indication to evaluate for antithyroid antibodies, which if present, could suggest an underlying autoimmune, immunologic implantation dysfunction linked to activation of uterine natural killer cells (NKa). This should be addressed in advance of undergoing FET in my opinion..

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

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

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

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

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

 _________________________________________________________________________________________________

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\

Answer:

Pleased post your question/comment 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\

Answer:

I sincerely do not believe that this would impact embryo implantation one way or another.

Geoff Sher