Es algo serio
Ask Our Doctors
Supporting Your Journey
Our Medical Directors are outstanding physicians that you will find to be very personable and compassionate, who take care to ensure that you have the most cutting-edge fertility treatments at your disposal. This is your outlet to ask your questions to the 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.
Sr
Name: Gabriel Carrillo
Es algo serio
Answer:
Please post in English!
Geoff Sher
IVF Record
Name: Remzi Hobson
Hi,
I was born at your clinic, and I am reaching out to request any records regarding my biological mother. I also have a twin sister.
Please let me know what information you require from me to assist in this matter. I appreciate any help you can provide.
Remzi Mustafa
Son of Timur Mustafa
Born on 17/10/2006
I do not know the date of conception. However, I was two months premature when I was born, which may be helpful.
Best regards.
Author
Answer:
I am no longer at the clinic where you were conceived. If you send me details of where and when you were conceived, I will do my best to provide you with more specific information.
Good luck!
Geoff Sher
Hombre
Name: Lázaro Dibut
Vivo en Kentucky
Author
Answer:
Please re-post in English!
Geoff Sher
Herewith are online links to 2 E-books recently co-authored with my partner at SFS-NY (Drew Tortoriello MD)……. for your reading pleasure:
- 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\
I want to be a donor, but when I access it, it says egg donations, what can I do to donate sperm?
Name: Rodrigo Pereira
I want to be a donor, but when I access it, it says egg donations, what can I do to donate sperm?
Author
Answer:
You would need to research where sperm banks are located in your area and reach out to them!
Good Luck!
Geoff Sher
Article; IVF: FACTORS AFFECTING EGG/EMBRYO “COMPETENCY” DURING CONTROLLED OVARIAN STIMULATION (COS)
Name: Theivanya Udayan
Quick question- sperm and egg cells, don’ t they contain 23 chromosomes only as they are germ cells (Haploid cells) , and not 2x 23 as mentioned in this article?
Author
Answer:
Both sperm and eggs start off with 46 chromosomes. Then during meiosis (reproductive maturational division, the divide their chromosomes in half to 23 (the haploid number). The fusion of the sperm and the egg thereupon reconstitutes the chromosomes in the embryo to 46(the diploid number).
Geoff Sher
Herewith are online links to 2 E-books recently co-authored with my partner at SFS-NY (Drew Tortoriello MD)……. for your reading pleasure:
- 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\
Toxic Uterine Environment
Name: Tamieka Gardner
I have had two failed FET 2nd FET protocol (estradiol, PIO, Aspirin , dexamethasone). I’ve had Hyseroscopy where polyps and scar tissue were removed. Now I’m being told that due to my endometriosis, now Adenomyosis is suspected but I will have a modified natual cycle. MRI scheduled to dx adenoyosis but plan will not change. If another failed FET happened then Lupron will be the next step.. I have not heard anything about an immunological factor or toxins. what are some basic steps I can take to adress possible uterine toxicity. or is it only treatable to specific diagnostics and medications.?
Author
Answer:
Respectfully. Nothing you are telling me add up. Read the article below and then call my assistant Patti and set up an online consultation with ne to discuss your case in detail and to set up a strategic approach.
- IMPLANTATION DYSFUNCTION
Implantation dysfunction is often overlooked as a significant reason for IVF failure. This is especially true when IVF failure is unexplained, or when there are recurring pregnancy losses or underlying issues with the uterus, such as endo-uterine surface lesions, thin uterine lining (endometrium), or immunological factors.
IVF success rates have been improving in the past decade. Currently, in the United States, the average live birth rate per embryo transfer for women under 40 years old using their own eggs is about 2:5 per woman undergoing embryo transfer. However, there is a wide range of success rates among different IVF programs, varying from 20% to almost 50%. Based on these statistics, most women in the United States need to undergo two or more IVF-embryo transfer attempts to have a baby. Many IVF practitioners in the United States attribute the differences in success rates to variations in expertise among embryology laboratories, but this is not entirely accurate. Other factors, such as differences in patient selection, the failure to develop personalized protocols for ovarian stimulation, and the neglect of infectious, anatomical, and immunological factors that affect embryo implantation, are equally important.
Approximately 80% of IVF failures occur due to “embryo incompetency,” mainly caused by ( irregularities in chromosome number (aneuploidy), which is often related to the advancing age of the woman, diminished ovarian reserve ( DOR) but can also be influenced by the ovarian stimulation protocol chosen, and sperm dysfunction (male infertility). However, in around 20% of cases with dysfunction, failure is caused by problems with embryo implantation.
This section will focus on embryo implantation dysfunction and IVF failure which in the vast majority of cases is caused by:
- Anatomical irregularities of the inner uterine surface:
-
- Surface lesions such as polyps/fibroids/ scar tissue
- endometrial thickness
- Immunologic Implantation Dysfunction ( IID)lesions
-
- Autoimmune IID
- 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.
- ENDOMETRIOSIS AND INFERTILITY: A RATIONAL BASIS FOR TREATMENT.
Women who have endometriosis are much more likely to be infertile. There are several reasons for this:
- First, endometriosis is associated with the presence of toxins in peritoneal secretions. As sperm and egg(s) travel towards the fallopian tubes they are exposed to these toxins which compromise the fertilization process
- Second, in about 25 – 30% of cases, endometriosis is associated with ovulation dysfunction.
- Third, in its most severe form, the condition is associated with scarring and adhesions in the pelvis, resulting in damage to, or blockage of the fallopian tubes, thereby preventing the union of sperm and eggs.
- Fourth, endometriosis is associated with abnormalities of the woman’s immune system which interfere with the ability of the fertilized egg to attach (implant) to the uterine wall.
Until quite recently, we really had no clue as to how reproductive problems associated with endometriosis evolve. Recent medical research has helped shed light on the subject and offers promise with regard to the future treatment of infertility/ reproductive failure associated with this condition. A few examples of recent breakthroughs include the following:
Endometriosis appears to have a genetic (familial) component .In the future, the development of genetic markers might provide an important diagnostic tool.
Patients with endometriosis have immunologic abnormalities. The most significant of these involve the presence of harmful antibodies known as antiphospholipid antibodies (APA) 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) and activated cytotoxic lymphocytes (CTLa) in the uterine lining (endometrium). These NKa/CTLa 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”.
Endometriosis often goes unnoticed for many years. Such patients are frequently erroneously labeled as having “unexplained infertility”, until the diagnosis is finally clinched through direct visualization of the lesions at the time of laparoscopy or laparoscopy. Not surprisingly, many patients with so called “unexplained” infertility, if followed for a number of years, will ultimately reveal endometriosis.
Advanced Endometriosis: In its most advanced stage, anatomical disfiguration is causally linked to infertility. In such cases, inspection at laparoscopy or laparoscopy will usually reveal severe pelvic adhesions, scarring and “chocolate cysts”. However, the quality of life of patients with advanced endometriosis is usually so severely compromised by pain and discomfort, that having a baby is often low on the priority list. Accordingly, such patients are usually often more interested in relatively radical medical and surgical treatment options (might preclude a subsequent pregnancy), such as removal of ovaries, fallopian pubis and even the uterus, as a means of alleviating suffering.
Moderately Severe Endometriosis. These patients have a modest amount of scarring/ adhesions and endometriotic deposits which are usually detected on the ovaries, fallopian tubes, bladder surface and low in the pelvis, behind the uterus. In such cases, the fallopian tubes are usually opened and functional.
Mild Endometriosis: These patients who at laparoscopy or laparotomy are found to have a few visible e3ndometrial “implants” but minimal distortion of pelvic anatomy are often erroneously labeled as having “unexplained” infertility. To hold that the there can only infertility can only be attributed to endometriosis if significant anatomical disease can be identified, is to ignore the fact that, biochemical, hormonal and immunological factors profoundly impact fertility. Failure to recognize this salient fact continues to play havoc with the hopes and dreams of many infertile endometriosis patients.
Endometriotic implants produce a toxic “peritoneal factor”
As mentioned above, toxins that impair fertilization are present in the peritoneal secretions of most patients with endometriosis. Impaired fertilization is a feature of endometriosis regardless of its severity. This explains why women with endometriosis three times are less likely to conceive per month of trying and why controlled ovarian stimulation with fertility drugs and/or procedures such as intrauterine insemination probably do not increase the chances of pregnancy over no treatment at all. It also explains why in vitro fertilization (which relies upon removing eggs through aspiration of the ovarian follicles before they can be affected by peritoneal toxins), by bypassing this handicap improves pregnancy rates dramatically and accordingly is the treatment of choice for most endometriosis patients with infertility.
Ovarian Endometriomas
Advanced endometriosis is often associated with ovarian cysts (endometriomas/chocolate cysts) that are filled with altered blood and can be large and multiple. When these are sizable (>1cm) they can activate surrounding ovarian connective tissue causing production of excessive male hormones (androgens) such as testosterone and androstenedione. Excessive ovarian androgens can compromise egg development in the affected ovary(ies) resulting in an increased likelihood of numerical chromosomal abnormalities (aneuploidy) and reduced egg/embryo competency”. In my opinion large ovarian endometriomas need to be removed surgically or rough sclerotherapy before embarking on IVF.
The “immunologic connection”
More than two thirds of patients with endometriosis have APA’s in their blood. These antibodies, given certain conditions, are capable of attacking the embryo and preventing implantation. There are at least 21 varieties of APA. Treatment requires prior and specific identification of all 21 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 is probably not APAs that cause infertility in endometriosis patients. Rather it is the coexistence activated NK cells (Nka) and (to a lesser extent) activated T-cells (cytotoxic lymphocytes-CTL)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 (approximately 30% of women with endometriosis (regardless of its severity) test positive for Nka cells). Optimal treatment is predicated upon an accurate diagnosis (see below).
How endometriosis CAN BE Diagnosed:
Endometriosis should be suspected when symptoms such as painful menstruation (dysmenorrhea), Pain with deep penetration with intercourse (dyspareunia and painful ovulation occur in women during the 2nd half of their reproductive lives. The diagnosis is even more probable when there is associated infertility or recurrent pregnancy (RPL). Digital pelvic examination tends to be painful because of endometriotic deposits behind the cervix or adjacent to the uterus, which is often in fixed retroversion (tilted backwards and fixed in this position because of adhesions). Sometimes the ovaries are enlarged because of c cysts filled with decomposed blood (endometriotic or “chocolate” cysts).
Ultrasound examination is usually not helpful in diagnosing early endometriosis. However, in more severe cases, ovarian endometriomas have a characteristic appearance by ultrasound examination and can be diagnosed this way.
A new method , known as the BCL-6 (or Receptiva) test done on an endometrial biopsy sample, if positive is highly suggestive (but not absolutely diagnostic) of underlying endometriosis and might be worth doing in cases where the diagnosis is unclear and in cases of “unexplained infertility which is often due to undiagnosed mild to moderately sever endometriosis.
In the final analysis, the diagnosis of endometriosis can only be confirmed through direct visualization of endometrial deposits at the time of pelvic surgery (laparoscopy / laparotomy) or through histopathologic microscopic analysis of affected tissue.
Note: Endometriosis can be the master of disguise. Many women with mild disease are often asymptomatic , presenting with so called “unexplained infertility”. If the endometriosis is at a very early stage, even attempted visualization (at surgery) will often fail to identify the condition. Such women, will often, upon repeat laparoscopy, reveal the condition.
How should infertility associated with endometriosis be managed?
The following basic concepts apply to management of endometriosis-related infertility:
- Ovulation induction with/without intrauterine insemination: Toxins in the peritoneal secretions of women with endometriosis exert a negative effect on fertilization potential regardless of how sperm reaches the fallopian tubes. It follows that intrauterine insemination will not improve the chances of pregnancy (over no treatment at all) in women with endometriosis.
- Pelvic Surgery aimed at restoring the anatomical integrity of the fallopian tubes does not counter the negative influence of toxic peritoneal factors that inherently reduce the chances of conception in women with endometriosis approximately three-fold. Nor does it address the immunologic dysfunction commonly associated with this condition. Pelvic surgery is relatively contraindicated for the treatment of infertility associated with endometriosis, when the woman is more than 35 years of age. With the pre-menopause approaching, such women do not have the time to waste on such less efficacious alternatives. In contrast, younger women who have time on their side might consider surgery as a viable option. Sizeable ovarian endometriomas should in my opinion, be removed in their entirety. Aspirating the content of such lesions is not adequate as they will return in time
- In Vitro Fertilization (IVF): Not all women who have endometriosis require IVF! However, this treatment is in my opinion, advisable in the following circumstances:
women who have advanced endometriosis
- where surgery and prior treatment with fertility agents and/or IUI has proven to be unsuccessful.
- Women older than 35 years and those with diminished ovarian reserve-DOR regardless of their age)) and women with endometriosis (regardless of age)
- Women with endometriosis (regardless of its severity who have an IID (see below)
- The role of selective immunotherapy: In about 33% of cases, endometriosis, (regardless of its severity) is associated with an immunologic implantation dysfunction (IID) linked to activation of uterine natural killer cells (NKa), cytotoxic uterine lymphocytes (CTLa) and to a much lesser extent to APA. This is diagnosed by testing the woman’s blood for APA and for NKa using the K-562 target cell test. NKa and CTLa activation can also be determined by endometrial biopsy for cytokine analysis. NKa/CTLa attack the embryo’s invading trophoblast cells (developing “root system”) as soon as begins to attach to the uterine lining. In most cases, this results in death of the embryo even before the pregnancy is diagnosed. Sometimes it presents as a chemical pregnancy or as an early miscarriage. . As such, many women with endometriosis, rather than being infertile, in the strict sense of the word, actually experience repeated undetected “mini miscarriages”.
Women who harbor APA’s often experience improved IVF birth rates when heparinoids (Clexane/Lovenox) are administered from the onset of ovarian stimulation with gonadotropins until the 10th week of pregnancy. NKa is treated with a combination of Intralipid (IL) and steroid therapy: Intralipid (IL) is a solution of small lipid droplets suspended in water. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, alpha-linolenic acid (ALA), an omega-3 fatty acid.IL is made up of 20% soybean oil/fatty acids (comprising linoleic acid, oleic acid, palmitic acid, linolenic acid and stearic acid) , 1.2% egg yolk phospholipids (1.2%), glycerin (2.25%) and water (76.5%).IL exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating NKa.
While the exact cause of endometriosis remains an enigma, it is now apparent that immunologic dysfunction is likely to be a significant feature of this disease. Whether immunopathology is causally linked to this condition or whether it occurs in response to endometriosis is unknown. Regardless, the underlying immunologic disorder adversely impacts on implantation of the embryo/early conceptus. It is possible, through thorough and meticulous evaluation, to quantify, typify and thereupon, selectively treat the underlying IID.. In so doing, IVF pregnancy rates can be significantly improved.
-
- Adenomyosis: A Guide to Symptoms, Diagnosis, and Treatment
What is Adenomyosis?
Adenomyosis is a condition where endometrial glands, which normally line the uterus (endometrium), grow into the muscular wall of the uterus (myometrium). This can cause the uterus to become enlarged, soft, and tender.
Symptoms of Adenomyosis
Women with adenomyosis may experience:
- Pelvic pain (often chronic)
- Heavy and painful periods (menorrhagia and dysmenorrhea)
- Pain during deep penetration during intercourse (dyspareunia)
- Unexplained infertility or difficulty conceiving
- Repeated miscarriages
If a woman presents with these symptoms and has an enlarged, soft, and tender uterus during a pelvic exam, adenomyosis should be suspected.
Diagnosing Adenomyosis
Diagnosing adenomyosis can be challenging because there is no single test that confirms it definitively. However, imaging studies like MRI and ultrasound (sonogram) can provide strong evidence.
Ultrasound Features Suggestive of Adenomyosis
- Generalized enlargement of the uterus
- Asymmetrical thickening of the myometrium (one side thicker than the other)
- Thickened junctional zone (>12mm) with increased blood flow
- Blurred boundary between the endometrium and myometrium
- Cysts in the myometrium
- Non-encapsulated tumors (adenomyomas) in the uterine muscle
Adenomyosis and Infertility
Adenomyosis does not directly affect egg or embryo quality, but it can cause implantation dysfunction due to changes at the endometrial-myometrial junction. Many women with adenomyosis conceive naturally, but for some, the condition can lead to infertility or recurrent pregnancy loss.
Link Between Adenomyosis and Endometriosis
- 30%–70% of women with adenomyosis also have endometriosis, a known cause of infertility.
- Endometriosis can create a toxic pelvic environment that affects egg fertilization and implantation.
- Women with suspected adenomyosis-related infertility should also be evaluated for endometriosis and immunologic implantation dysfunction (IID).
Treatment Options for Adenomyosis
Surgical Treatments
- Conservative surgery: Removing affected portions of the uterus (adenomyomas) can help, but surgery is difficult because adenomyosis does not have clear borders.
- Robot-assisted laparoscopic surgery is becoming more common for focal or nodular adenomyosis, as long as the disease is not widespread.
Medical Treatments
Three main medical treatments are used to manage adenomyosis:
- Hormonal Therapy (GnRH Agonists)
- Medications like Buserelin or Lupron suppress estrogen and shrink adenomyosis lesions.
- Commonly used as a three-month depot injection before embryo transfer in IVF.
- Aromatase Inhibitors (e.g., Letrozole)
- Sometimes used, but with limited success in treating adenomyosis.
- Immunotherapy for Implantation Issues
- If immunologic implantation dysfunction (IID) is suspected, treatment may include:
- Intralipid or IVIG therapy
- Steroids
- Heparin (a blood thinner)
- These treatments are often combined with IVF for women struggling with repeated implantation failure.
Adenomyosis and Pregnancy
- Not all women with adenomyosis are infertile.
- Even with IVF, women with adenomyosis face an increased risk of miscarriage.
- Since the condition does not affect egg or embryo quality, women with severe adenomyosis-related infertility may consider gestational surrogacy as an option.
Conclusion
Adenomyosis can cause pain, heavy periods, infertility, and pregnancy loss, but it does not affect egg or embryo quality. Diagnosis relies on imaging studies like MRI and ultrasound, and treatment options range from hormonal therapy and immunotherapy to surgery. Women struggling with infertility due to adenomyosis should also be evaluated for endometriosis and immune-related implantation dysfunction to determine the best treatment approach.
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\