The euploid embryo!

Please have her reach out to my Office Manager, Patti Converse (conciege@sherivf.com and set up a consultation online, with me.

Geoff Sher

• ENDOMETRIOSIS: A RATIONAL BASIS FOR IVF

Endometriosis is a condition where the uterine lining (endometrium) grows on pelvic structures outside the uterine cavity. In early stage- endometriosis there is usually little, if any, visible evidence of anatomical distortion sufficient to compromise the release of an egg (ovulation) or its transportation from the ovary to the fallopian tube. In contrast, more advanced endometriosis, is characterized by the presence of pelvic adhesions sufficient to distort normal pelvic anatomy and interfere with fertilization as well as egg/embryo transportation mechanisms.

While it is tempting to conclude that normally ovulating women with mild to moderate endometriosis would have no difficulty in conceiving if their anatomical disease is addressed surgically or that endometriosis-related infertility is confined to cases with more severe anatomical disease…nothing could be further from the truth.

The natural conception rate for healthy ovulating women in their early 30’s (who are free of endometriosis) is about 15% per month of trying and 70% per year of actively attempting to conceive. Conversely, the conception rate for women of a comparable age who have mild or moderate pelvic endometriosis (absent or limited anatomical disease) is about 5-6% per month and 40% after 3 years of trying. The reduced conception rate in women with endometriosis can, in large part be explained by:

• Toxins in the peritoneal fluid: It is very common for women with mild endometriosis to do exactly this…have 1 pregnancy and then battle to conceive again. This is referred to 2ndary infertility and Endometriosis is the commonest cause I know of. The explanation is that all women with endometriosis (regardless of its severity) have” toxic factors” in their pelvic peritoneal fluid. Eggs, as they pass from the ovary (ies) to the Fallopian tube(s) to reach the awaiting sperm, become exposed to these “toxins” which renders the egg envelopment (zona pellucida) resistant to sperm penetration. This reduces fertilization potential by a factor of at least 3 or 4. This means that if, in the absence of endometriosis, an egg has a 15% chance of being fertilized and thereupon resulting in a baby, that same egg, in a woman with endometriosis would have no more than a 5% chance. Thus if the overall chance of a having a baby per year of actively trying is about 12% then the chance in a woman with mild endometriosis (of the same age) would probably be no more than 3-4%. Only IVF or ICSI which by their very nature involve extracting eggs before they are released (ovulated) in to the “toxic peritoneal environment” can bypass this effect. This explains why a women with endometriosis who is lucky enough to become pregnant on her own or following the use of fertility drugs (with or without intrauterine insemination), often experiences secondary infertility later in her reproductive career. It also helps  explain why normally ovulating women with endometriosis and patent Fallopian tubes do not benefit significantly from intrauterine insemination, with or without the use of fertility drugs, or from surgery to remove endometriotic lesions (since many endometriotic deposits are non-pigmented, thus  invisible to the naked eye and cannot be removed surgically). In such cases only IVF improves the chance of a baby per month of trying.  Simply put…. if a normally ovulating woman who has mild to moderate endometriosis conceives following IUI, surgery or the use of fertility drugs, it is probably in spite of (rather than due) to such treatments.
• Immunologic Implantation failure: We have previously reported that >50%% of women with endometriosis (regardless of severity) have antiphospholipid antibodies (APA) in their blood. Also, and perhaps much more significant, is the fact that, approximately one third of women who have endometriosis (regardless of severity) show evidence of increased NK cell activity. In such cases there is a high likelihood of early or later IID. In the case of early IID, rejection occurs prior to embryo attachment to the uterine wall, usually even before the pregnancy hormone, hCG can be detected in the woman’s blood. Strictly speaking, rather than suffering from “true infertility” such women are experiencing are having “mini miscarriages “which occur so early on that the women does not even realize that she conceived in the first place. In the case of the latter (later implantation failure), poor implantation might manifest as a miscarriage. It is not certain whether APA’s themselves cause implantation failure. We believe that they could be “markers”, pointing to those women who are at increased risk of immunologic implantation failure. Selective immunomodulation with heparin (for the APA) and/or Intralipid/steroid therapy can often effectively counter immunologic implantation failure and lead to successful AR-induced pregnancies in women who have APA and/or increased NK cell/CTL activation.
• Endometriomas: These are cystic lesions within the ovary that result from the accumulation of “menstrual blood” which is produced by the endometrial lining that lines these “cysts”. Decomposition of this blood causes the blood to become like molten chocolate in color and consistency. Hence the name “chocolate cysts’. Endometriomas can activate the surrounding ovarian connective tissue (stroma) leading to the excess production of male hormones (androgens)such as This can compromise egg production and quality in the affected ovary. In our opinion, any ovarian endometrioma that is more than 1cm in size should be removed. The traditional way of doing this is surgically. A few years ago, we introduced “sclerotherapy”. This is, a relatively non-invasive, safe and effective outpatient method to permanently eliminate endometriomas without surgery being required.Sclerotherapy for ovarian endometriomas involves needle aspiration of the liquid content of the endometriotic cyst, followed by the injection of 95% ethanol into the cyst cavity. Treatment results in disappearance of the lesion within 6-8 weeks, in more than 75% of cases so treated. Ovarian sclerotherapy can be performed under local anesthesia or under general anesthesia. It has the advantage of being an ambulatory office- based procedure, at low cost, with a low incidence of significant post-procedural pain or complications and the avoidance of the need for laparoscopy or laparotomy

Adhesions and Scar tissue: Endometriosis and/or its surgical treatment can result in adhesions and/or scarring. This can compromise tubal function and can as a very late manifestation of endometriosis block the tubes. Scarring can also compromise blood flow to the ovaries and result in reduced ovarian reserve and resistance to ovarian stimulation with fertility drugs.

• SCLEROTHERAPY OF ENDOMETRIOMAS

The precise mechanism by which ovarian endometrioma causes infertility is unknown. In women with ovarian endometriomas, infertility is potentially associated with a decreased oocyte retrieval rate, reduced oocyte quality and reduced embryo quality. I personally believe that it is local irritation caused by the cystic space occupying lesion within the ovary that irritates surrounding connective tissue increasing ovarian testosterone production which in turn permeates ovarian follicles resulting in compromised follicle and egg development in the affected ovary (ies)

Traditional surgical treatment of endometriomas involves gaining access to the ovary (ies) through an abdominal incision, or via laparoscopy, for drainage of the cyst contents and subsequent removal or ablation of the cyst wall. Unfortunately, in many cases, normal ovarian tissue is inadvertently removed along with the cyst wall, which may decrease the number of available oocytes for subsequent fertility treatment. A large percentage of such women have advanced stage disease and have had multiple previous surgeries. In the presence of pelvic adhesions, visualization of anatomic structures may be inadequate, leading to a higher incidence of cyst recurrence. This may further diminish the potential response to ovarian stimulation with gonadotropins. Additionally, women with advanced endometriosis are more likely to develop pelvic adhesions as well as an increased risk of surgical complications.

About 15 years ago I introduced sclerotherapy to treat women who had endometriomas and were preparing for IVF treatment. Sclerotherapy is an effective non-surgical treatment for endometriosis of the ovary. Ovarian sclerotherapy involves ultrasound-guided aspiration of endometrioma content followed by the introduction into the cyst cavity of a sclerosing agent such as 5% tetracycline hydrochloride (my preference), 95% ethanol or methotrexate either under local anesthesia or with the patient receiving conscious sedation. The sclerosing agent destroys the endometrium lining the inside of the endometrioma and prevents cyst recurrence. Sclerotherapy is much less invasive than laparoscopic surgery and takes approximately 20–30 min to perform. Unlike other treatment options, it will not damage healthy surrounding ovarian tissue and is thus also less likely to reduce ovarian reserve. Risks of sclerotherapy treatment are uncommon but they include infection, pain (due to leaking of the sclerosing agent into the pelvic cavity, internal bleeding, and recurrence in about 10% of cases. To prevent this, I infuse about 250cc of sterile normal saline solution into the pelvic cavity before performing sclerotherapy so that any leakage of the sclerosing agent into the pelvis will be diluted. Thereupon at the conclusion of the procedure, I aspirate the solution from the pelvis and with it , most of the potentially irritating sclerosing agent. In more than 70% of cases, treatment will result in disappearance of the lesion within 6 to 8 weeks. In 20% of cases, residual seroma develops within 6 weeks. Simple transvaginal drainage of the residual cyst will in most cases lead to permanent dissolution.

Ovarian sclerotherapy can be performed under local anesthesia or under general anesthesia. It has the advantage of being an ambulatory office-based procedure at a low cost, with a low incidence of significant post-procedural pain or complications, and the avoidance of the need for surgery.

Sclerotherapy is a safe and effective alternative to surgery. It is a definitive treatment, even for recurrent ovarian endometriomas, in properly selected patients planning to undergo IVF. Since the procedure is associated with a small, but realistic possibility of adhesion formation, it should only be used in cases where IVF is the only fertility treatment appropriate for a patient. Women who intend to try and conceive through natural conception or intrauterine insemination will be better off undergoing standard laparotomy or laparoscopy to treat their endometriomas.

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.