Ask Our Doctors

Dear Patients,

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

– Geoffrey Sher, MD

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

Follicular cyst and FSH stimulation

Name: Anne C

Dear Dr. Sher,

I am 43 years old and am trying for the last time, after five unsuccessful attempts (I have reached the euploid stage before).

This time I have 9 antral follicles, but I also have a follicular cyst. It is regressing: four days ago it was 15mm and today it’s 12mm. My period started yesterday, and I have been taking estradiol for 10 days. I haven’t started FSH, and my doctor wants to reassess in another 4 days.

My question is: if the cyst is still there, for example at 10mm, should I proceed with this cycle? What is the risk to my ovary? Will the cyst hinder the growth of the other oocytes? Should I go ahead or postpone to the next cycle, despite my age?

Thanks again for being so kind and sharing your wisdom with us all.

Anne

Answer:

I see no reason not to proceed with the cycle!

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:

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

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\

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Donar ovulos

Name: Yoannys v

Quisiera saber cómo puedo hacer para donar mis óvulos
Y si califico para ello

Answer:

Please re-post in English!

Geoff Sher

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Thin endometrium luteal phase

Name: Alina D

Dear Dr. Sher,

Thanks for creating this forum, I really appreciate.

My periods are lighter since I gave birth to my daughter 8 months ago (no breastfeeding).

My endometrium measured 9.3 mm the day before ovulation, 8.6 mm 2 days post ovulation and 7.8mm 9 days post ovulation.
Shouldn’t it be growing instead of getting thinner? We are TTC our second baby and I am worried.
I am on progesterone supplementation during luteal phase.

Thank you a lot

Answer:

It is the thickness of the endometrium pre-ovulation that matters.

Good luck!

Geoff Sher

___________________________________________________

Back in 1989, I conducted a study that examined how the thickness of a woman’s uterine lining, known as the endometrium, affected the successful implantation of embryos in IVF patients. The study revealed that when the uterine lining measured less than 8mm in thickness by the day of the “hCG trigger” in fresh IVF cycles, or at the start of progesterone therapy in embryo recipient cycles (such as frozen embryo transfers or egg donation IVF), the chances of pregnancy and birth were significantly improved. In my opinion, an ideal estrogen-promoted endometrial lining should measure at least 9mm in thickness, while a lining of 8-9mm is considered “intermediate.” In most cases, an estrogenic lining of less than 8mm is unlikely to result in a viable pregnancy.

A “poor” uterine lining typically occurs when the innermost layer of the endometrium, called the basal or germinal endometrium, fails to respond to estrogen and cannot develop a thick enough outer “functional” layer to support optimal embryo implantation and placenta development. The “functional” layer makes up two-thirds of the total endometrial thickness and is the layer that sheds during menstruation if no pregnancy occurs.

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

Damage to the basal endometrium due to:

- Inflammation of the endometrium (endometritis) often resulting from retained products of conception after abortion, miscarriage, or birth.
- Surgical trauma caused by aggressive uterine scraping during procedures like D&C.

Insensitivity of the basal endometrium to estrogen due to:

- Prolonged or excessive use of clomiphene citrate.
- Prenatal exposure to diethylstilbestrol (DES), a drug given to pregnant women in the 1960s to prevent miscarriage.

Overexposure of the uterine lining to ovarian male hormones, mainly testosterone, which can occur in older women, women with diminished ovarian reserve, and women with polycystic ovarian syndrome (PCOS) who have increased LH biological activity. This hormonal imbalance leads to the overproduction of testosterone in the ovary’s connective tissue, further exacerbated by certain ovarian stimulation methods used in IVF.
Reduced blood flow to the basal endometrium, often caused by:

- Multiple uterine fibroids, especially those located beneath the endometrium (submucosal).
- Uterine adenomyosis, an abnormal invasion of endometrial glands into the uterine muscle.

“The Viagra Connection”

Eighteen years ago, I reported on the successful use of vaginal Sildenafil (Viagra) in treating women with implantation dysfunction caused by thin endometrial linings. This breakthrough led to the birth of the world’s first “Viagra baby.” Since then, thousands of women with thin uterine linings have been treated with Viagra, and many have gone on to have babies after multiple unsuccessful IVF attempts.

Viagra gained popularity in the 1990s as an oral treatment for erectile dysfunction. Inspired by its mechanism of action, which increases penile blood flow through enhanced nitric oxide activity, I investigated whether vaginal administration of Viagra could improve uterine blood flow, deliver more estrogen to the basal endometrium, and promote endometrial thickening. Our findings confirmed that vaginal Viagra achieved these effects, while oral administration did not provide significant benefits. To facilitate treatment, we collaborated with a compound pharmacy to produce vaginal Viagra suppositories.

In our initial trial, four women with a history of poor endometrial development and failed conception underwent IVF treatment combined with vaginal Viagra therapy. The Viagra suppositories were administered four times daily for 8-11 days and stopped 5-7 days before embryo transfer. This treatment resulted in a rapid and significant improvement in uterine blood flow, leading to enhanced endometrial development in all four cases. Three of these women subsequently conceived. In 2002, I expanded the trial to include 105 women with repeated IVF failure due to persistently thin endometrial linings. About 70% of these women responded positively to Viagra therapy, with a notable increase in endometrial thickness. Forty-five percent achieved live births after a single cycle of IVF with Viagra treatment, and the miscarriage rate was only 9%. Women who did not show improvement in endometrial thickness following Viagra treatment did not achieve viable pregnancies.

When administered vaginally, Viagra is quickly absorbed and reaches the uterine blood system in high concentrations. It then dilutes as it enters the systemic circulation, explaining why treatment is virtually free from systemic side effects.

It is important to note that Viagra may not improve endometrial thickness in all cases. Approximately 30-40% of women treated may not experience any improvement. In severe cases of thin uterine linings where the basal endometrium has been permanently damaged and becomes unresponsive to estrogen, Viagra treatment is unlikely to be effective. This can occur due to conditions such as post-pregnancy endometritis, chronic inflammation resulting from uterine tuberculosis (rare in the United States), or extensive surgical damage to the basal endometrium.

In my practice, I sometimes recommend combining vaginal Viagra administration with oral Terbutaline (5mg). Viagra relaxes the muscle walls of uterine spiral arteries, while terbutaline relaxes the uterine muscle itself. The combination of these medications synergistically enhances blood flow through the uterus, improving estrogen delivery to the endometrial lining. However, it’s important to monitor potential side effects of Terbutaline such as agitation, tremors, and palpitations. Women with cardiac disease or irregular heartbeat should not use Terbutaline.

Approximately 75% of women with thin uterine linings respond positively to treatment within 2-3 days. Those who do not respond well often have severe inner ( (basal) endometrial lining damage, where improved uterine blood flow cannot stimulate a positive response. Such cases are commonly associated with previous pregnancy-related endometrial inflammation, occurring after abortions, infected vaginal deliveries, or cesarean sections.

Viagra therapy has been a game-changer for thousands of women with thin uterine linings, allowing them to successfully overcome infertility and build their families.

___________________________________________________

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:

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

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

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

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Hernandez

Name: Yohanna E

Yo estoy esterilizada pero qué será saber si puedo salir embarazada Se si hay alguna oportunidad para poderlo hacer

Answer:

Please Repost in English!

Geoff Sher

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Irresponsive endometrium after Lupron

Name: Carolina G

Hi Dr Geoffrey,
I’ve been dealing with fertility issues for years (endometriosis, fibroids) and last year, after two unsuccessful embryo transfers (of genetically normal embryos), I decided to have a laparoscopy surgery to treat the endometriosis and remove the intramural 8cm fibroid. After the surgery I was prescribed Lupron for 4 months coupled with Norethindrone. Approximately 5 months after the surgery I had a hysteroscopy to get prepared for a new transfer cycle and the doctor found adhesions and a septum. They cleaned everything and scheduled a follow up hysteroscopy in which they also found some minor adhesions that were removed. I started preparing for transfer and my endometrium didn’t respond to estrogen and produced fluid (I had had fluid before but my lining had been able to grow). During estrogen stimulation I progressively used 1 patch, 2 patches, 4 patches, 8mg of oral estrogen (all of this for about 6-7 weeks) with no improvement to the growth or fluid. I stopped the estrogen for two weeks and had another hysteroscopy in which they removed scar tissue (from the same places as before) and I’m now in 4mg estrogen therapy for a month. Do you have any ideas of what else could I do if my lining remains irresponsive after this? Could I be doing something else now while on the estrogen therapy to help with the endometrium growth?
Really appreciate your thoughts.
Thanks,
Carolina.

Answer:

Asherman Syndrome is a medical condition characterized by severe intrauterine adhesions, also known as synechiae. These adhesions can cause significant damage to the basal layer of the endometrium, the part of the uterus responsible for developing the uterine lining (endometrium) under the influence of hormones like estrogen and progesterone. When the basal endometrium is severely affected, it can lead to a reduction in menstrual flow (hypomenorrhea) or complete cessation of menstruation (amenorrhea), and infertility.
Causes of Asherman Syndrome

The most common cause of Asherman Syndrome is inflammation of the uterine lining, a condition called endometritis. This inflammation often occurs after childbirth (post-partum) , after an incomplete miscarriage or post-abortal. However, it can also result from uterine surgeries, such as the removal of fibroid tumors (myomectomy) that encroach upon or penetrate the uterine cavity.

Treatment for Asherman Syndrome

The primary treatment for Asherman Syndrome involves a procedure called hysteroscopic resection. During this procedure, a telescope-like instrument is introduced through the vagina and cervix into the uterine cavity. This allows surgeons to directly remove as much scar tissue as possible and free any adhesions that have fused the walls of the uterine cavity together. The goal is to uncover viable basal endometrium and promote its growth to cover the surface of the uterine cavity. In some cases, a small balloon may be placed in the uterine cavity for a short period to prevent adhesion recurrence. Women undergoing this treatment typically receive supplemental estrogen to encourage endometrial growth.

Fertility Complications

Asherman Syndrome can lead to scarring and blockage of the uterine entrance to the fallopian tubes. This blockage often affects the ability of the uterus to support embryo implantation. In rare cases, pregnancy can occur in the fallopian tubes, leading to an ectopic pregnancy. Ectopic pregnancies are dangerous and require early diagnosis and treatment to prevent severe intra-abdominal bleeding.

A Glimmer of Hope: Viagra Suppositories

Recent research has explored the use of Viagra vaginal suppositories to improve blood flow and enhance the delivery of estrogen to the endometrium. This innovative approach has shown promise in improving endometrial development, especially in cases where traditional treatments have failed. Approximately 75% of women who struggled with poor endometrial development, often after multiple failed IVF attempts, experienced positive results with this treatment. Some of these women successfully conceived and went on to deliver healthy babies, providing renewed hope for those facing infertility challenges.

Challenges and Considerations

However, for women with extensive damage to the basal endometrium due to Asherman Syndrome, improving blood flow with Viagra may not be sufficient in achieving the necessary endometrial development. In such cases, it’s essential for women to consider alternative options, including adoption or gestational surrogacy, to fulfill their dreams of parenthood.

In conclusion, Asherman Syndrome is a complex condition that can have a profound impact on a woman’s reproductive health. While treatments like hysteroscopic resection and innovative approaches with Viagra offer some hope, the severity of the condition may necessitate exploring alternative paths to parenthood. It’s crucial for individuals facing this challenge to consult with their healthcare providers to determine the best course of action for their unique circumstances.
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:

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

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

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

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Failed donor embryo FET

Name: private

Hi there, I hope you are well. I had failed pgs tested 3AA embryo donation. Era receptive microbiom recently tested lactobacillus <90% clexane prednisone 2 tabs 600mg progesterone IM daily. Esdridol 2 x4mg a day. Folic acid etc transfer day 19. Had 2 successful natural pregnancies 10 and 7 year ago. Age 43 now.
One folicle grew slightly and LH was high week before transfer. After transfer 4 days white blood cells 10.9 had intralipid infusion. Interleukin iL6 <2 couolenweeks before transfer.
I had taken probiotics week before and crispatus maybe disrupted microbiom or high LH effect implantation. I have no ovaries removed due to hydrosalpinx. I would have pre menopausal symptoms before treatment, night sweat, some insomnia. Any thoughts greatly appreciated I don’t have much money left to continue blindly again. Thank you

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.

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.
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.
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.
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.
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.

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.
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.
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:

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.

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

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:

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

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

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

Geoff Sher

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Ovó donación

Name: Aracely O

Ovó donación tengo 51 años y pérdidas recurrente incluso con ovó donación

Answer:

Please re-post this question in English!

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

Geoff Sher

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Next Steps

Name: Christy L

aI am a 36 y.o. female with PCOS. I have had 2 miscarriages at 6 weeks (1 from an IVF transfer recently and 1 from letrozole round several years ago) , and 2 failed IVF transfers that failed to implant. (along with multiple failed letrozole rounds and 2 failed IUI’s prior to IVF). For each of my transfers my lining has always looked great (usually between 10-11 mm thickness with a trilaminar pattern prior to starting progesterone). I have 5 untested embryos left (age: 35 at embryo transfer). Next steps are ERA/EMMA/ALICE and recurrent pregnancy loss blood panel. Are there any additional tests you would suggest or any specific protocols/medications you would suggest trying for the next FET? (previous protocols were standard protocols involving estrogen and progesterone)

Answer:

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

ANATOMICAL IMPLANTATION DYSFUNCTION
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.

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:

Damage to the basal endometrium due to:

- Inflammation of the endometrium (endometritis), often resulting from retained products of conception after abortion, miscarriage, or childbirth.
- Surgical trauma caused by aggressive dilatation and curettage (D&C).

Insensitivity of the basal endometrium to estrogen due to:

- Prolonged (back to back) use of clomiphene citrate for ovarian stimulation or…
- Prenatal exposure to diethylstilbestrol (DES), a drug given to prevent miscarriage in the 1960s.

Overexposure of the uterine lining to male hormones produced by the ovaries or administered during ovarian stimulation (primarily testosterone):

- Older women, women with DOR (poor responders), and women with polycystic ovarian syndrome (PCOS) often have increased biological activity of luteinizing hormone (LH), leading to testosterone overproduction by the ovarian connective tissue (stroma/theca). This effect can be further amplified when certain ovarian stimulation protocols were high doses of menotropins ( e.g., Menopur) are used.

Reduced blood flow to the basal endometrium caused by:

- Multiple uterine fibroids, especially if they are located beneath the endometrium (submucosal).
- Uterine adenomyosis, which involves extensive abnormal invasion of endometrial glands into the uterine muscle.

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

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

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:

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.
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.
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.
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.
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.
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.
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:

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.
Alloimmune Implantation Dysfunction:NK cell activation occurs when the uterus is exposed to an embryo that shares certain genotypic (HLA/DQ alpha) similarities with the embryo recipient. Humans have 23 pairs of chromosomes: one set from the sperm and one set from the egg that created us. Our sixth pair of chromosomes each contain DQ alpha genes. Again, one of these genes is from the sperm and one is from the egg that created us.

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

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

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

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

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

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

Partial DQ alpha/HLA genetic matching: Couples who share only one DQ alpha/HLA gene are considered to have a “partial match.” If NK cell activation is also present, this partial match puts the couple at a disadvantage for IVF success. However, it’s important to note that DQ alpha/HLA matching, whether partial or total, does not cause IID without associated NK cell activation. Treatment for partial DQ alpha/HLA match with NK cell activation involves IL infusion and oral prednisone as adjunct therapy. IL infusion is repeated every 2-4 weeks after pregnancy is confirmed and continued until the 24th week of gestation. In these cases, only one embryo is transferred at a time to minimize the risk of NK cell activation.
Total (Complete) Alloimmune Genetic Matching:A total alloimmune match occurs when the husband’s DQ alpha genotype matches both that of the partner. Although rare, this total match along with NK cell activation significantly reduces the chance of a viable pregnancy resulting in a live birth at term. In some cases, the use of a gestational surrogate may be necessary.

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

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

Geoff Sher

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Recurrent Implantation Failure

Name: Delaney D

Hello!

I am a 24 y.o. female, Gravida 0, AMH 0.2-0.8, four failed IUI’s, and now 4 failed transfers with 5 embryos never implanting. I’ve done two ERA’s (both postreceptive at 96 and 72 hours) but we’ve ignored these results due to their abnormality. We’ve tried medicated and natural cycles. Embryos not PGT tested d/t age. Next steps include a 3rd egg retrieval, PGT testing, laparoscopic surgery, hysteroscopy, and a full immune protocol with a reproductive immunologist. Is there anything else that plays into implantation failure that you think is worth trying? The rather abnormal ERA results make me question if I truly have a displaced receptive window. Gestational carrier is not a route I want to go down at this time. I appreciate your input!

Answer:

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

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

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

b) Thickness of the uterine lining (endometrium)

The main causes of a poor uterine lining are:

Damage to the basal endometrium due to:

- Inflammation of the endometrium (endometritis), often resulting from retained products of conception after abortion, miscarriage, or childbirth.
- Surgical trauma caused by aggressive dilatation and curettage (D&C).

Insensitivity of the basal endometrium to estrogen due to:

- Prolonged (back to back) use of clomiphene citrate for ovarian stimulation or…
- Prenatal exposure to diethylstilbestrol (DES), a drug given to prevent miscarriage in the 1960s.

Overexposure of the uterine lining to male hormones produced by the ovaries or administered during ovarian stimulation (primarily testosterone):

- Older women, women with DOR (poor responders), and women with polycystic ovarian syndrome (PCOS) often have increased biological activity of luteinizing hormone (LH), leading to testosterone overproduction by the ovarian connective tissue (stroma/theca). This effect can be further amplified when certain ovarian stimulation protocols were high doses of menotropins ( e.g., Menopur) are used.

Reduced blood flow to the basal endometrium caused by:

- Multiple uterine fibroids, especially if they are located beneath the endometrium (submucosal).
- Uterine adenomyosis, which involves extensive abnormal invasion of endometrial glands into the uterine muscle.

IMMUNOLOGIC IMPLANTATION DYSFUNCTION (IID)

Activated natural Killer Cells (NKa):

Antiphospholipid Antibodies:

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

Treatment Options for IID:

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.
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.
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.
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.
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.
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.
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:

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.
Alloimmune Implantation Dysfunction:NK cell activation occurs when the uterus is exposed to an embryo that shares certain genotypic (HLA/DQ alpha) similarities with the embryo recipient. Humans have 23 pairs of chromosomes: one set from the sperm and one set from the egg that created us. Our sixth pair of chromosomes each contain DQ alpha genes. Again, one of these genes is from the sperm and one is from the egg that created us.

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

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

Partial DQ alpha/HLA genetic matching: Couples who share only one DQ alpha/HLA gene are considered to have a “partial match.” If NK cell activation is also present, this partial match puts the couple at a disadvantage for IVF success. However, it’s important to note that DQ alpha/HLA matching, whether partial or total, does not cause IID without associated NK cell activation. Treatment for partial DQ alpha/HLA match with NK cell activation involves IL infusion and oral prednisone as adjunct therapy. IL infusion is repeated every 2-4 weeks after pregnancy is confirmed and continued until the 24th week of gestation. In these cases, only one embryo is transferred at a time to minimize the risk of NK cell activation.
Total (Complete) Alloimmune Genetic Matching:A total alloimmune match occurs when the husband’s DQ alpha genotype matches both that of the partner. Although rare, this total match along with NK cell activation significantly reduces the chance of a viable pregnancy resulting in a live birth at term. In some cases, the use of a gestational surrogate may be necessary.

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:

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

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\

Show Complete Answer

Egg Retrieval with Immature Eggs

Name: Stephanie T

I got 29 eggs during my egg retrieval but was told that only 5 were mature. I am trying to understand why my maturity rate was so low. I triggered when 10+ follicles were at 20mm, and many at 18mm. 15 GV, 9 M1, 5, M2. My E2 was above 8000 at trigger.

Answer:

Embarking on the journey of IVF often raises questions about the likelihood of success and the quality of embryos. While it’s challenging to predict outcomes due to various factors, there’s hope and information to guide you.

Firstly, the key to fertilization potential lies in the chromosomal integrity of the egg. Women in their twenties or early thirties have a higher chance of having eggs with the required number of chromosomes for a healthy pregnancy. However, as age advances, this percentage decreases, emphasizing the importance of timely decisions.

Secondly, embryos that don’t develop into blastocysts are usually chromosomally abnormal and are not suitable for transfer, as they may lead to implantation issues or miscarriages. Not all blastocysts are guaranteed to be chromosomally normal, and this likelihood decreases with the age of the woman. Understanding this helps set realistic expectations.

While species and genetic factors play a role in egg quality, our choice of a controlled ovarian stimulation (COS) protocol also matters. Selecting the right COS protocol is crucial, especially for older women, those with diminished ovarian reserve (DOR), and those with polycystic ovarian syndrome. An individualized approach to optimize follicle growth and egg quality can significantly impact IVF outcomes.

In a natural ovulation cycle, hormonal changes are finely tuned to support healthy follicle development and egg maturation. When undergoing IVF, it’s essential to avoid disrupting this delicate balance. The Human Chorionic Gonadotropin (hCG) “trigger shot” should be carefully timed to enhance the chances of success.

In summary, understanding the influence of age, genetics, and COS protocols on egg quality is crucial for a successful IVF journey. The decision-making process becomes even more critical for older women or those facing specific fertility challenges. By embracing personalized approaches and staying informed, you can navigate the path of IVF with hope and optimism.

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:

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

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\

Show Complete Answer

Re: progesterone level before FET transfer

Name: Eliana G

Good afternoon Dr. Tortoriello,

I’m doing a fifth stimulated frozen embryo transfer due to thin lining issues and now have the best lining I’ve ever had of 8.7 mm, trilaminar. I expect to do my trigger injection tonight and start taking estrogen 2 mg daily with progesterone daily. My doctor said I have a choice of using progesterone suppository or PIO 50 mg injections daily but as the injection is best absorbed by the body she recommends the PIO injection to have a successful pregnancy.

My question is do you think that I could have too much progesterone in my body prior to transfer with PIO injections as I’m already producing my own progesterone? I want to do what’s best, and I’m reading some studies online that indicate too high levels of progesterone can reduce live birth rates. Thank you, Eliana G.

Answer:

Here is my suggested/personal approach to FET:

Two decades ago, when women went through IVF (in vitro fertilization), they usually had their embryos put in the uterus right after the eggs were collected in the same cycle (known as “Fresh” Embryo Transfer). Freezing embryos at that time was risky, with about 30% not surviving the process, and those that did had lower chances of successfully implanting and growing a healthy pregnancy compared to fresh embryos. This was because the slow freezing process led to ice forming within the embryo’s cells, harming them.

But things changed with a new, faster freezing method called vitrification. With vitrification, embryos are frozen so quickly that ice crystals don’t have a chance to form. More than 90% of embryos survive this process in excellent condition, just like they were before freezing, giving them a better chance to develop into healthy pregnancies.

Modern advancements in frozen embryo transfers (FET) have shown great promise, possibly even surpassing the success rates of transferring “fresh” embryos. This improvement likely isn’t because of the freezing process itself, but rather due to two key factors:

a) FET often involves transferring blastocysts that have been carefully tested and selected through preimplantation genetic screening (PGS)/preimplantation genetic testing for aneuploidy ( PGT-A) , increasing the chances of a successful pregnancy compared to “fresh” transfers where such selection is not done.
b) The hormone replacement therapy (HRT) used for FET helps prepare the uterus optimally for implantation, improving the overall conditions for a healthy pregnancy compared to the ovarian stimulation with fertility drugs used in Fresh IVF cycles.

Considering these factors, FET offers several clear advantages:

Safe storage of extra embryos for future transfers.
Flexibility to delay transfers for additional testing or to avoid complications.
Preserving embryos for selective transfer in cases of advanced maternal age or diminished ovarian reserve (DOR).
Convenience in assisted reproductive services involving third-party parenting, like egg donation or gestational surrogacy.

These advancements provide hope and options for couples seeking successful IVF journeys and healthy outcomes for growing families.

The advent of PGS/PGT heralded a major advance in IVF as it enables us to choose the healthiest embryos for transfer to the uterus, thereby significantly boosting the chances of a successful pregnancy. The performance of PGS/PGTA virtually mandates that advanced embryos ( blastocysts) be biopsied 5-6 days after fertilization and that an additional period of 10 days be allowed for genetic testing to be performed. It follows that such blastocysts be vitrified and stored for FET to be performed in a later cycle.

For women who are older or have a lower number of eggs (diminished ovarian reserve-DOR ), as well as those who have faced repeated pregnancy loss or IVF failure, PGS/ PGT-A can be a game-changer. It helps identify the best embryos for successful transfer. However, for younger women who tend to have normal egg reserves, and because of their youth produce a larger number of quality eggs/ embryos the benefits of PGS might not be necessary.

When it comes to creating a reserve of embryos through “Embryo Banking,” FET is mandatory and ground-breaking. Here, multiple IVF cycles are conducted over an extended period of time allowing for the collection and banking of a good number of advanced ( usually PGS/PGT-A tested) embryos ( blastocysts) for future dispensation. Once we’ve gathered a promising group of such embryos, well-timed FETs can be undertaken, significantly improving the chances of a successful pregnancy and reducing the risk of miscarriage.

Through these advancements, we are able to offer greater hope and possibilities to those on their journey to parenthood, making IVF an even more effective and accessible option.

Let’s break down the process to prepare the uterus for a frozen embryo transfer (FET) in simpler terms:

Cycle Start: To begin, the recipient takes birth control pills (like Marvelon, Desogen ,Lo-Estrin etc.,)for about 10 days. The patient commences 0.75mg Dexamethasone daily OR 10mg prednisone BID at cycle start. This 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
Hormone Kickstart: After 10 days, they start another medication called Lupron/Lucrin/decapeptyl/ Superfact/ Buserelin through a shot.
Monitoring Progress: The doctors keep an eye on the progress by doing ultrasounds and blood tests to make sure things are on track.
Boosting Hormones: Delestrogen 4mg IM is injected, twice weekly (on Tuesday and Friday), commencing within a few days of Lupron/Lucrin/Superfact, Decapeptyl-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 the 10^th week of pregnancy or until pregnancy is discounted by blood testing or by an ultrasound examination. Dexamethasone/Prednisone is 0.75 mg is taken (as above) and oral folic acid (1 mg) is taken daily commencing with the first E2V injection and is continued throughout gestation.
Antibiotic prophylaxis: Patients also receive Ciprofloxin 500mg BID orally starting with the initiation of Progesterone therapy and continuing for 10 days.
Luteal support: commences on day-1 , 6 days prior to the FET, with intramuscular progesterone in oil (PIO) at an initial dose of 75-100 mg (-Day 1). Daily administration- is continued until late in the evening of Day 5 ( I suggest 10.00PM-11.00PM) . Daily PIO (75mg-100mg) is continued 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 FET, 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.

Timing the FET: This is performed as early as possible on the morning of Day-6
Blood pregnancy Testing: Blood pregnancy tests are performed 13 days and 15 days after the first PIO injection was given

*Note: In cases where intramuscular progesterone administration is not well tolerated, we tend to use a vaginal gel known as Crinone8%. This gel is used twice a day (morning and evening) until the day of the embryo transfer.

Preparing for Transfer: On the morning of the embryo transfer, we pause using the gel but resume it in the evening. The day after the transfer, we continue using the gel twice a day. . If the blood pregnancy tests show a positive result and 2-3 weeks later an ultrasound examination confirms a viable pregnancy, the Crinone 8% gel is continued twice daily up to the 10th week of pregnancy

Regime for Thawing and Transferring Cryopreserved Embryos/Blastocysts:

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

	Day 2 (P4)	Day 6 (P4)
PN	Thaw	ET
Day 3 Embryo	Thaw	ET
Blastocysts frozen on day 5 post-ER		Thaw-FET
Blastocysts frozen on day 6, post-ER		Thaw-FET

Monitoring Pregnancy: Regular check-ups and tests are done to confirm if the pregnancy is successful.

Geoff Sher

Show Complete Answer

Ivf

Name: Vera E

Dr am 44 had a miscarriage in October naturally without ivf thinking of starting ivf last period was January 21 until date no flow and am not pregnant your advice pls and thxs

Answer:

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

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

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

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

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

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

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

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

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

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

_________________________________________________________________________

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:

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

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\

Show Complete Answer

Low Amh

Name: A C

Hello doctor ,
I’m 33yrs old ….AMH came back .56 and progesterone on day 3 was 16.6 and I had chemical pregnancy in 2020….i don’t have kids and I’m not going to have any kids naturally …so even ivf is not for me because of my low amh? What should I do please help me is the amh is too low to have a baby ..thank you

Answer:

The AMH is NOT too low for IVF. In fact IVF is indicated but the protocol used for ovarian stimulation must be tailored.

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

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.
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.
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.
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.
Diminished Ovarian Reserve (DOR): As women advance in their reproductive age, the number of remaining eggs in the ovaries decreases. Diminished ovarian reserve (DOR) occurs when the egg count falls below a certain threshold, making it more challenging to respond to fertility drugs effectively. This condition is often indicated by specific hormone levels, such as elevated FSH and decreased AMH. DOR can affect women over 40, but it can also occur in younger

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

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

Ovarian Reserve: While chronological age plays a vital role in determining the quality of eggs and embryos [there is an increased risk of egg aneuploidy (irregular chromosome number) in eggs, leading to reduced embryo competency. Additionally, women with declining ovarian reserve (DOR), regardless of their age, are more likely to have aneuploid eggs/embryos. Therefore, it is crucial to address age-related factors and ovarian reserve to enhance IVF success.
Excessive Luteinizing Hormone (LH) and Testosterone Effects: In women with DOR, their ovaries and developing eggs are susceptible to the adverse effects of excessive LH, which stimulates the overproduction of male hormones like testosterone. While some testosterone promotes healthy follicle growth and egg development, an excess of testosterone has a negative impact. Therefore, in both older women or those who (regardless of their age) have DOR, ovarian stimulation protocols that down-regulate LH activity before starting gonadotropins are necessary to improve egg/embryo quality and IVF outcomes.
It is possible to regulate the decline in egg/embryo competency by tailoring ovarian stimulation protocols. Here are my preferred protocols for women with relatively normal ovarian reserve:

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.

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

Protocols to Avoid in Women with DOR: Certain ovarian stimulation protocols may not be suitable for women with declining ovarian reserve:

Microdose agonist “flare” protocols
High dosages of LH-containing fertility drugs such as Menopur
Testosterone-based supplementation
DHEA supplementation
Clomiphene citrate or Letrozole
Low-dosage hCG triggering or agonist triggering for women with DOR

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

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

__________________________________________________________________

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:

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

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\

Show Complete Answer

What is the likelihood of my pregnancy succeeding

Name: Shelby N

I had my first blood test done my levels are around 57 and they couldnt see anything on an ultrasound they had me wait 4 days to do repeat testing and my numbers are only at 71

Answer:

This is a slow rise and the likelihood is that the pregnancy will not survive! However, repeat th hCG test in 2 days to see if it doubles as it should.

So sorry!

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.

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:

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

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\

Show Complete Answer

IVF consultation

Name: Vessie V

1.3, 2.1cm Trigger was 10000 IU Gonasi HP (hCG) and on day 11. Only 1 mature egg was retrieved, and fertilised using ICSI. My day 3 update is a slow growing embryo of 3 cells with some fragmentation. I don’t know whether I should be proceeding with the second stimulation…. Can you please help me with advice on the correct protocol in my situation. PAST IVF HISTORY December 2022/January 2023: Dual Stimulation Protocol 3-4 follicles in each ovary at start of priming Priming: Androgel 1% (started on Day 3 of cycle and stopped on Day 2 of next cycle just before stimulation) At start of First stimulation (Day 3): 5 antral follicles in Right ovary and 3 antral follicles in Left ovary Medications: Pergoveris: 350 IU Clomiphene: 100mg Cetrotide: 0.25mg Day 8 (First stimulation cycle): 3 follicles developing First stimulation cycle: 2 eggs retrieved and 2 eggs fertilized with 1 embryo to blastocyst (biopsied and frozen); PGT-A indicates aneuploidy At start of Second Stimulation: 2 follicles in Right ovary and 2 follicles in Left ovary Day 8 (Second stimulation cycle): possibly 3 follicles developing Second stimulation cycle: 2 eggs retrieved and 2 eggs fertilized with 1 embryo to blastocyst (biopsied and frozen); PGT-A indicates aneuploidy June 2023: Dual stimulation protocol Found out that my partner has a high degree of DNA fragmentation in his sperm just after starting ovarian stimulation. Priming: Androgel 1% (started on Day 3 of cycle and stopped on Day 2 of next cycle just before stimulation) Estrace (twice per day, started 7 days after positive ovulation test) At start of First stimulation (Day 2): 4 follicles in the Right ovary and 3 follicles in the Left ovary Medications: Gonal-F: 300IU Menopur: 150 IU Clomiphene: 100mg Cetrotide: 0.25mg Day 9: 5 follicles in Right ovary and 5 follicles in Left ovary, possibly 2-3 developing First stimulation cycle: 1 egg retrieved and abnormally fertilized At start of Second stimulation: 2-3 follicles in Right ovary and 1 follicle in Left ovary Day 8: 1 follicle developing No eggs retrieved.

Answer:

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

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

Let’s break down the key points:

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

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

IVF and Age:

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

IVF Realities:

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

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

Who Benefits from PGS/PGT-A?

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

Empowering Older Women: Embryo Banking

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

Egg Freezing: Factors to Consider

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

Choosing the Right Path

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

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

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

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

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:

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

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\

Show Complete Answer

Stimulation Protocol for Severe DOR

Name: private

I’m 40 about to turn 41 with what’s been described as severe DOR, amh is dropping fast. 2 years ago it was .22, last april .08 and this past test (after my stimulation complications) it’s now .03. Last year I completed 7 retrievals back to back using mild IVF. Retrieved around 1-4 per round, but only 1 made it to blast and then was abnormal. I switched doctors and they insisted on traditional IVF. I completed 2 rounds with the same outcome and by the 3rd, first I had break through follicles for 3 cycles and then finally started stimulation and my estrogen dropped, follicles disappeared and I didn’t get my period for 2 months. Then tried an IUI with clomid and it was unsuccessful, but I had 2 follicles with the stim. Tried a second IUI and same thing happened. She pushed 3 rounds of clomid, before canceling bc Estrogen dropped and follicles disappeared again and now a month and a half later waiting for my period. My dr said I cannot be stimulated and her hands are tied. My question is this. Before I move onto a donor egg, I feel like with a different mild stim protocol like before, I must be able to get something and/or finally do a fresh transfer. I found a new dr and they want to do natural IVF, although I’m nervous about having the same stim reaction, I’m equally nervous about no stim at all and the cost and time of these cycles for only 1 potential follicle in the end. Please advise on what type of protocol you would suggest (I know a lot of drs would say stop) if I was insisting on 1 or 2 more rounds of IVF before giving up. Thank you!

Answer:

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.
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.
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.
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.
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.

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.
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.
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:

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.

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

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

_________________________________________________________________________________________________

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:

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

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\

Show Complete Answer

High TNF alpha

Name: private

What is the recommended transfer protocol for someone with high TNF Alpha. I was given prednisone but it did not work. Prior to transfer it was 45.0 and I was prescribed 25mg prednisone for a month but it increased to 51.7 instead and that was only found out after transferring a genetically tested embryo that failed to implant.

Answer:

Elevated TNF alpha indicates activated natural killer cell activity.

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

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

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

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

Immunologic factors that compromise implantation

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

Activated natural Killer Cells (NKa):

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

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

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

Antiphospholipid Antibodies:

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

Treatment Options for Immunologic Implantation Dysfunction (IID):

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.
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.
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.
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.
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.

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.
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:

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.
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.

_____________________________________________________________

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:

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

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\

Show Complete Answer

Suggested ivf protocol

Name: Irit B

Dear doctor Sher

I am a 44.5 femal, suffering from secondary repeated miscarriages due to alloiimunity (dq-alpha gene match + extremly elevated nk cells).

Right now I am going through the 7th miscarriage. I had the 6th miscarriage on October 23. Failed on immune protocols.
Cannot use steroids as i had adison crises and ovarian damage due to steroids overload. Took me a lot of time to recover (with a lot of hard work on my side).

I would like to use the service of a gestational carrier with my own eggs.
I get pregnant naturally but barely respond to hormons (if at all).

What kind of medications and stimulation protocol would you offer me to use?
You write about a trigger with 2 ovidral injections, is it in use alongside with 2 decapeptile or just 2 ovidrals?

I am overseas therefore I cannot do the ivf at your clinic.

Your advice is deeply appreciated,
Irit

Answer:

Clearly you are a candidate for gestational surrogacy, provided that you have competent, euploid embryos available to transfer. Using a gestational surrogate for transfer of such a blastocyst, is pretty straight forward. Most IVF programs that do FET can advise appropriately. However, be sure that the blastocyst transferred is euploid and competent!

Good luck!

Geoff Sher

___________________________________________________________________________

Show Complete Answer

Failed ivf cycle

Name: Nino K

Hello doctor; i am 32 yo female, amh 1.59 ng/ml.

Partner 32 years old with varicocele, 0 morphology and very low count. (Impossible to check for dna fragmentation)

I am Insulin resistant, on metformin 750 for 5 months now with no results. No pcos, BMI 22.

Had 1 failed icsi (we did picsi and used calcium). 8 eggs retrieved, 4 fertilized, 2 reached day 3 compact stage; both arrested by day 5.
Did estrogen priming. Afc 7.
My protocol started on day 2 from menstrual cycle:
Day1: Cetrotide 0.25 morning ; gonal f 250 evening
Day2: Same
Day 3: Same
Day 4: same
Day 5: same (estradiol 2380 pg/ml)
Day 6: Cetrotide 0.25 morning; gonal f 75 evening; decapeptyle 0.1 (2 injections) at 24:00.
Day 7: nothing
Day 8: egg retrieval.

Please kindly write me what do you think about this protocol. Could it have contributed to failed cycle?

I thank you in advance and look forward to your response.
Best regards,
Nina

Answer:

There clearly is both male factor infertility and diminished ovarian reserve (DOR). Both issues need to be thoroughly evaluated and addressed. The cause of the male factor will need further testing and the DOR requires a very individualized approach to ovarian stimulation…(see below).

I strongly suggest that you contact my assistant, Patti Converse (702-533-2691) and set up an online consultation with me to discuss,

ADDRESSING DIMINISHING OVARIAN RESERVE (DOR) IN IVF

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.
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.
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.
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.
Diminished Ovarian Reserve (DOR): As women advance in their reproductive age, the number of remaining eggs in the ovaries decreases. Diminished ovarian reserve (DOR) occurs when the egg count falls below a certain threshold, making it more challenging to respond to fertility drugs effectively. This condition is often indicated by specific hormone levels, such as elevated FSH and decreased AMH. DOR can affect women over 40, but it can also occur in younger

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

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

Ovarian Reserve: While chronological age plays a vital role in determining the quality of eggs and embryos [there is an increased risk of egg aneuploidy (irregular chromosome number) in eggs, leading to reduced embryo competency. Additionally, women with declining ovarian reserve (DOR), regardless of their age, are more likely to have aneuploid eggs/embryos. Therefore, it is crucial to address age-related factors and ovarian reserve to enhance IVF success.
Excessive Luteinizing Hormone (LH) and Testosterone Effects: In women with DOR, their ovaries and developing eggs are susceptible to the adverse effects of excessive LH, which stimulates the overproduction of male hormones like testosterone. While some testosterone promotes healthy follicle growth and egg development, an excess of testosterone has a negative impact. Therefore, in both older women or those who (regardless of their age) have DOR, ovarian stimulation protocols that down-regulate LH activity before starting gonadotropins are necessary to improve egg/embryo quality and IVF outcomes.
It is possible to regulate the decline in egg/embryo competency by tailoring ovarian stimulation protocols. Here are my preferred protocols for women with relatively normal ovarian reserve:

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.

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

Protocols to Avoid in Women with DOR: Certain ovarian stimulation protocols may not be suitable for women with declining ovarian reserve:

Microdose agonist “flare” protocols
High dosages of LH-containing fertility drugs such as Menopur
Testosterone-based supplementation
DHEA supplementation
Clomiphene citrate or Letrozole
Low-dosage hCG triggering or agonist triggering for women with DOR

__________________________________________________________________________

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:

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

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\

Show Complete Answer

Natural Conception with NKa and DQa Partial Match

Name: Jessica B

Hello Dr. Sher,

I’m hoping you can provide me some insight and comfort. Quick history – I have had 6 early losses prior to 7 weeks over 4 years. After a lot of testing and trials with my RE, we went towards IVF. 3 cycles – one failed, one miscarriage, and one live birth. After the second transfer, we reached out to another doctor who was able to get some immune testing done for us. We learned I had elevated NK cells and my husband and I were a partial DQa match. I was prescribed intralipids prior to transfer and up until 24 weeks. We now have a healthy 2 year old!

Fast forward to now – we were looking into trying for a second child, likely through IVF, when we fell pregnant naturally! I am currently 9 weeks, when I had never gotten past 7 weeks prior to my son. When learning I was pregnant, I contacted my RE since she had been through everything with us before, and she allowed me to go on Prednisone starting at 10mg and increased to 15mg. Her hands are tied by her practice in that she cannot prescribe intralipids. She also informed me that it has gotten more difficult to get infusions for some reason in Pennsylvania (I confirmed this with the infusion company I had used previously).

My question is, what is the likelihood that I can carry this pregnancy full term without intralipids and only on prednisone (am I taking enough and when would I wean)? I also take baby aspirin, Claritin, Pepcid, and Benadryl (antihistamine protocol). I’m grateful for this pregnancy, but am so afraid of a late term loss.

Thank you for your time!

Answer:

Anything is possible, and I hope it works out. However, it would be of no value in my opinion, to start with immunotherapy now. Intralipid therapy should be initiated 10-14 days before conception to be of significant help!

Good luck and G-d bless!

Geoff Sher

Show Complete Answer

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