I suggest you email Patti Converse (concierge@sherivf.com and set up an online consultation with me.

Geoff Sher

i PERSONALLY AM NOT A BIG BELIEVER IN THE VALUE OF ERA TESTING.

GEOFF SHER

• UNEXPLAINED” INFERTILITY: A RATIONAL APPROACH TO MANAGEMENT

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

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

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

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

Management:

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

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

It is an undeniable truth that the majority of infertility cases can be diagnosed, which makes it disheartening when the label of “unexplained infertility” is used as an excuse for not conducting a thorough evaluation of the problem. Couples should not simply accept a diagnosis

Geoffrey Sher MD  (Contact concierge@sherIVF.com if you wish to talk with me)

Yes you can go ahead. However, please be aware that 30% of women with endometriosis (regardless of severity, havd an immunologic implantation dysfunction (see below) which needs treatment.

Geoff Sher

Contact my Office manager..for appointment:    Concierge@sherivf.com

• ENDOMETRIOSIS AND IMMUNOLOGIC IMPLANTATION FAILURE.

Patients with endometriosis have immunologic abnormalities. The most significant of these involve the presence of harmful antibodies known as antiphospholipid antibodies (APA) which are in the bloodstream of about 66 percent of women with endometriosis. In about half such cases (i.e. about 1/3 of all cases of endometriosis…regardless of severity) the immunologic implantation is profoundly aggravated by the presence of  activated (i.e  “toxic”) Natural Killer cells (Nka)  in the uterine lining (endometrium). These NKa attack the invading  trophoblast cells (developing “root system” of the embryo/early conceptus) as soon as it tries to gain attachment to the uterine wall. In most  cases, this results in death of the embryo even before the pregnancy is diagnosed and sometimes, in a chemical pregnancy or even an early miscarriage. . As such, many women with endometriosis, rather than being infertile, in the strict sense of the word, often actually experience repeated undetected “mini-miscarriages”. Treatment requires prior and specific identification of all 18 sub-types and their gammaglobulin isotypes. Unfortunately, only a handful of Laboratories in the United States are capable of adequately testing for APAs. But it probably not APAs that cause infertility in endometriosis patients. Rather it is the co-existence of toxic or activated NK cells (Nka) that attack the early embryo’s root system as soon as it tries to attach to the uterine wall that causes the problem. The presence of APAs probably represents a marker which identifies those endometriosis patients who have immunologic problems requiring immunotherapy Women with APA’s experience improved IVF birth rates when mini-dose heparin is administered from the onset of ovarian stimulation with gonadotropins until the 8^th week of pregnancy.

Heparin therapy alone, only benefits APA+ women who do not have positive blood tests for Nka while women who test positive for Nka require intralipid/steroid therapy.

Embarking on the journey of in vitro fertilization (IVF) can be a daunting experience especially for women with sub-normal AMH levels (diminished ovarian reserve -DOR). Here is a novel and highly effective protocol known as the Agonist/Antagonist Conversion Protocol (A/ACP), designed to optimize the chances of success for women facing this challenge.

Let’s dive into the details of this innovative ovarian stimulation protocol :

The A/ACP – An Overview

The A/ACP is a carefully structured treatment plan that combines the use of monophasic birth control pills (BCP) with advanced hormonal therapies to enhance follicular development in women with DOR. Here’s a step-by-step breakdown of how it works:

• BCP Initiation: The treatment begins on days 1 to 5 of a selected menstrual cycle with monophasic birth control pills such as Orthonovum 1/35, Desogen, Marvelon, Lo-Estrin, or Lo-Ovral. The duration of BCP use should be at least 8 days. To mitigate the slightly increased risk of thromboembolism associated with BCP, patients are advised to take a daily baby aspirin (81mg) daily while taking the BCP.
• Human Growth Hormone(HGH: After at least 8 days of BCP, patients start receiving daily subcutaneous injections of human growth hormone (Omnitrope 20U). This hormone likely augments follicular growth and egg development.
• GnRH-Agonist Phase: The next phase involves the addition of daily subcutaneous injections of a gonadotropin-releasing hormone agonist -GnRHa (10U Lupron). This phase continues until menstruation begins, typically within 5-7 days after discontinuing BCP. At the point that menstruation ensues, a vaginal ultrasound and blood estradiol (E2) measurement is done to to make sure that there are no ovarian cysts and that the blood E2 concentration is < 70pg/ ml ( <200pmol/L) so that ovarian stimulation can commence.
• Baseline ultrasound and blood E2 measurement: If a functional ovarian cyst is detected, the Lupron can be continued for as long as it takes to resolve or ( alternatively/preferably) the cyst can be drained under local anesthesia through transvaginal needle aspiration. This usually ensures that E2 levels rapidly drop to below baseline ( 70pg/ml) and menstruation occurs promptly.
• Transition to GnRH-Antagonist and Gonadotropins: At the onset of menstruation, the protocol transitions to a critical phase:

1. Switch to GnRH-Antagonist ( e.g., Ganirelix, Cetrotide, or Orgalutron): Leuprolide is replaced with daily subcutaneous injections of 250mcg GnRH antagonist.
2. Continued Hormonal Support: Daily administration of human growth hormone continues and gonadotropin injections are initiated.

3          Day 1: FSHr (e.g., Follistim, Gonal-F, Puregon, Fostimon (____) + Menopur 75u are administered daily for 2 days.

4          Day 3: FSHr dosage is decreased to ___u while Menopur 75u daily continues. . This regimen continues until the hCG “trigger.”

5          Daily Ultrasound and blood E2 monitoring commences 6-7 days after initiating gonadotropin injections through daily daily ultrasound and plasma estradiol (E2) assessments which are crucial during this phase to gauge follicle growth and development.

6          Timing the hCG “Trigger”: The  A/ACP can result in falsely understated blood E2 levels. Therefore, this protocol prioritizes follicular size to determine when the hCG “trigger” should be administered.

• Who Benefits from the A/ACP? The A/ACP is specifically tailored for women with diminished ovarian reserve (DOR). It aims to counteract the suppressive effects of conventional long pituitary agonist down-regulation protocols, which can be less effective for this group. However, it’s essential to note that the A/ACP may not be suitable for individuals who have severe DOR ( i.e.,  have reduced  basal AMH levels, irregular ovulation, PCOS, or those prone to severe ovarian hyperstimulation syndrome (OHSS), as accurate E2 measurements are crucial in all such 
• The hCG “Trigger” and Beyond: The final stage involves the hCG “trigger,” which is a single intramuscular injection of 10,000u Pregnyl, Profasi, Novarel, or 500mcg Ovidrel. Simultaneously, human growth hormone, gonadotropin administration, and GnRH antagonist administration cease on the day of the hCG “trigger.” Prophylactic oral antibiotics ( e.g., 500mg Ciprofloxin twice daily) are initiated to prevent infection-related complications.
• Moving to egg retrieval (ER): Roughly 36h following the “trigger” , an ER is conducted ( usually under conscious sedation) under the supervision of a qualified anesthesiologist.
• Preimplantation Genetic Screening/ Testing for embryo aneuploidy(PGS/PGTa):For patients opting for PGS/PGTa, blastocyst biopsy is performed on day 5-6 blastocysts, and the specimens are sent for next-generation gene sequencing (NGS) chromosomal karyotype f. Depending on chromosomal integrity, normal ( euploid) and “ mosaic” embryos can be transferred in subsequent cycles.
• Hormonal Support and Embryo Transfer (ET):Hormonal support with intramuscular progesterone in oil (PIO), or vaginal progesterone suppositories ( e.g.,Crinone 8% ——for those that cannot tolerate PIO, can be used. Also. estrogen supplementation can be administered to try and optimize the chance of a successful ET.

In conclusion, the A/ACP is a novel and highly effective approach to ovarian stimulation for IVF, designed to optimize IVF outcomes for women with DOR. While it requires meticulous monitoring and may not be suitable for all patients, it is a potentially beneficial addition to the therapeutic armamentarium.

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:

1. 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.
2. 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.

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

 I hope this helps!

Geoff Sher

Please contact my assistant, Patti at concierge@sherivf.com if you would like to have an online consultation with me to discuss in depth.

The cause of your trisomy pregnancy was likely age-related egg aneuploidy. The chance of an embryo having the right chromosomal configuration declines with  with advancing age. Since you already have several children, you might want to stop. However, since you et pregnant quite easily on your own, and  seem intent on having another baby ,  perhaps you should keep trying on your own and if you do conceive, get tested in the 1st trimester using chorionic villus sampling (CVS) or in the 2nd trimester by amniocentesis to establish the fetal chromosomal integrity..

IVF with PGTA (to test the chromosomal integrity of the embryo) is the only way to minimize the risk of having another aneuploid pregnancy.

Good luck!

Geoff Sher

PS: If interested, email my assistant, Patti Converse at concierge@sherivf.vom and she will set you up with an online consultation so we can discuss your situation in depth.