Ask Our Doctors

Clomiphene (syn; Clomid , Serophene) is by far the most widely prescribed agent for the induction of human ovulation for women who do not ovulate, those with dysfunctional ovulation and women with ”unexplained” infertility. When used in young women (who have adequate ovarian reserve) with these problems the viable pregnancy rate is reported as being between 6% and 10% per cycle of treatment. Aside from conventional ovulation induction, clomiphene has been used in preparing women for intrauterine insemination and even for IVF. I personally rarely prescribe clomiphene because across the board, success rates are significantly lower than when gonadotropin therapy is used. The main reasons for clomiphene’s popularity is its low cost, simplicity of use and the low risk of dangerous complications such as severe ovarian hyperstimulation syndrome (OHSS).

Clomiphene treatment can be initiated at a dose of 50 mg (orally) daily for 5 days but it can be increased to as much as 200mg per day, starting on cycle 2, 3, 4, or 5. A spontaneous LH surge will usually follow within about 8-9 days of the last 50mg dosage. In some cases, 10,000U of hCG can be given as a trigger when there is at least one ovarian follicle of 18-20 mm in size. Routinely using the hCG trigger does tend to decrease pregnancy potential.

Clomiphene works by inducing ovulation through its “antiestrogen effect” which, by blocking estrogen receptors in an area of the brain known as the hypothalamus, tricks the brain into “thinking” that estrogen levels are low. In response, the hypothalamus prompts the pituitary gland to release an exaggerated amount of follicle-stimulating hormone (FSH), which in turn stimulates the growth and development of ovarian follicles, ultimately resulting in a surge in the release of pituitary LH. About 38-42 hours later, ovulation occurs from one or more of the larger follicles. As the follicles grow, they release more and more estrogen into the bloodstream, thus closing the feedback circle that the hypothalamus initiated in response to the anti-estrogen properties of Clomiphene.

There are several factors that need to be considered carefully before deciding to prescribe clomiphene to any woman:

• Clomiphene citrate therapy is less effective than gonadotropin therapy and its efficacy declines with advancing age: Many infertile couples undergoing ovulation induction believe that the success rate using clomiphene citrate is equivalent to what we see in fertile couples trying to get pregnant on their own and to what is encountered when gonadotropins (Menopur/Follistim/Gonal-F and Puregon) are used. This is not the case. The truth is that the rate of conception with clomiphene therapy is actually about 30% lower than the natural fertility rate for normally ovulating women, and about 25% lower than when gonadotropin stimulation is used for ovarian stimulation in similar patients. Moreover, the discrepancy is further magnified with advancing maternal age, where in women under 35 years, the pregnancy rate with clomiphene treatment is about 10% per cycle, about 5% between 35 and 40 years and <2% for women in their early to mid-forties.
• Clomiphene use should ideally be confined to younger women: Ideally the use of clomiphene should in my opinion be restricted to younger women (under 35 years) who have normal “ovarian reserve” (as assessed by basal blood FSH, and antimullerian hormone (AMH) levels). These are the women who are most likely to respond by producing multiple follicles. It is necessary that at least 3 sizeable follicles (>15mm) develop on clomiphene treatment, in order to override the “anti-estrogenic” effects of this drug and so insure adequate cervical mucus production as well as the development of a receptive endometrium.
• Clomiphene should usually not be administered for more than 3 consecutive (back-to- back) cycles: If used back-to-back for more than 3 consecutive cycles, clomiphene is not only ineffective, but actually starts to function as a “relative” contraceptive! This is often is a shocking revelation to many women. Clomiphene’s anti-estrogenic effect is not confined to the hypothalamus. Any cells that have a high concentration of estrogen receptors will also be so affected. Needless to say, the cervical glands (that produce estrogenic mucus to facilitate sperm transport and the endometrial lining (endometrium) that thickens under the effect of estrogen are also highly vulnerable to a buildup of antiestrogen effects over successive back-to back cycles of clomiphene therapy. This why with >3 consecutive back-to back clomiphene cycles cervical mucus tends to thicken and dry up and the endometrium will thin, seriously reducing the likelihood of success. These anti-estrogenic manifestations require that following 3 back-to back clomiphene cycles of stimulation there be at  least 1 resting (non-clomiphene treated) cycle, before doing a 4^th cycle.
• Clomiphene should not be used in older women or in women who have diminished ovarian reserve (DOR): With clomiphene stimulation, the  release of pituitary FSH is always accompanied by the concomitant release of Luteinizing Hormone (LH). LH causes the ovary to produce male hormone (androgens) and testosterone. The production by the ovaries of a modest amount of testosterone would not present a problem. However, an excessive production of ovarian testosterone prejudices egg development and thus ultimately compromises embryo competency. Older women and women with DOR are the most vulnerable because they tend to have overgrowth of ovarian connective tissue (stroma/theca) which is the site where androgens are produced. The concentration of androgens is always much higher at the site of production (the ovaries) than in the peripheral blood (a dilution effect). Thus in older women and those with DOR, there will be excessive ovarian androgens that can compromise egg quality and thus ultimately reduce the chance of having a baby. The older the woman and/or the more severe the DOR, the greater this adverse effect is likely to be.
• “Trapped” ovulation (LUF-Syndrome): About 20% of clomiphene cycles are associated with “trapped” ovulation (Luteinized Unruptured Follicle (LUF) Syndrome). This means that in spite of hormone changes suggesting that ovulation has occurred, the egg remains trapped in the ovary. Obviously this is not condusive to the establishment of a successful pregnancy.
• Endometriosis is a “relative contraindication” to the use of clomiphene: Women with endometriosis (regardless of its severity) have” toxic factors” in their pelvic peritoneal fluid. Eggs, as they pass from the ovaries to the Fallopian tubes 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%. This serves to 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). 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 treatment.
• Women with long gaps between menstruation are often not ideal candidates for clomiphene: Women who consistently have  >45 days between their periods will not respond well to clomiphene induction of ovulation and are better off going directly to injectable gonadotropins.
• Multiple pregnancy: The incidence of multiple pregnancies with clomiphene induction of ovulation is about 5%. This is much lower than the 25% rate encountered when gonadotropins are given to women with absent or dysfunctional ovulation.

Clomiphene therapy is often used as a first line approach to inducing ovulation in women with irregular or absent ovulation such as in women with polycystic ovarian syndrome (PCOS). Its use in my opinion is best confined to women who menstruate/ovulate irregularly (but who bleed at least every 45 days), younger women, women who do not have tubal disease or endometriosis, women under 40 years of age (preferably <35Y), and women who do not have DOR . It should also be avoided when there is co-existing male factor infertility.  If pregnancy fails to occur after 3 consecutive cycles of clomiphene therapy, then in my opinion, it is time to move on to gonadotropin therapy, combined with IUI or IVF/ICSI depending on the underlying cause of the infertility.

 Geoff Sher

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

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

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

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

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

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Respectfully!

I personally would not perform a SNH during a cycle of FET!

Geoff Sher

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

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

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

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With sperm antibodies, IUI is really not a tangible option. You need IVF/ICSI.

Antisperm antibodies (ASA) are immunoglobulins that attach to sperm. They are most commonly encountered in semen, blood, cervical mucous and follicular fluid. Not all ASA bind to sperm. However, those that do so can inhibiting fertilization. Methods used to detect for the presence of SAs in blood, in the seminal plasma of the ejaculate or in the cervical mucus only measure those immunoglobulins that bind to sperm components.

ASAs are related to the stimulation of sperm antigen. Detection of ASA requires access to standard sperm antigens that are associated with fertilization. An ideal sperm antigen should be sperm specific, accessible to the antibody and play a key role in fertilization..

In about 1-4% of infertility cases the presence of antisperm antibodies (ASA) in the male or female appear to be the cause. While the presence of ASA reduces both male and fertility significantly, it does not necessarily always prevent conception altogether.  Rather, the effects are graduated; i.e., the larger the immunologic response (concentration of antibodies), the less likely it is that a pregnancy will occur and when the blood level rises above 40%, natural conception is highly unlikely to occur.

Like any other kind of antibody manufactured by the body, sperm antibodies are formed in response to antigens.  These antigens are proteins, which appear on the outer sperm membranes as the young sperm cells, develop within the male testes. In the man’s own body, his sperm are regarded as foreign invading proteins and as such would normally be targeted for attack However, under normal conditions, direct contact between the man’s blood and sperm is prevented by a cellular structure in the testes called the blood/testis barrier.  This barrier is formed by so-called, Sertoli cells, which abut very closely against each other, forming tight junctions that separate the developing sperm cells from the blood and prevent immunologic stimulation.  However, the blood/ testis barrier can be broken by physical or chemical injury or by infection.  When this barrier is breached, sperm antigens escape from their immunologically protected environment and come in direct contact with blood elements that launch an immunologic attack.

Once sperm and blood come in contact, whether in the male or female, specific antibodies are produced against them by specialized blood cells call T- and B-lymphocytes.  The three main types of sperm antibodies produced are Immunoglobulin G (IgG), Immunoglobulin A (IgA) and Immunoglobulin M (IgM).  These antibodies bind to the proteins (antigens) on the sperm head, midpiece or tail.  The antibodies formed may be of the circulatory type (in the blood serum) or secretory type (in the tissue).  This is important because high levels of antibodies in the blood serum do not invariably mean that the antibodies will find their way to the semen where they can affect the sperm.  For example, the concentration of IgG is much lower in secretions of the reproductive tract that it is in the blood.  Conversely, the local level of IgA is higher in the reproductive secretions than in the blood.  This is an important point, which we will return to later.

Once sperm antibodies have formed, they can affect sperm in several different ways.  Some antibodies will cause sperm to stick together or agglutinate.  Agglutinated sperm clump together in dense masses and thus are unable to migrate through the cervix into the uterus.  Other antibodies mark the sperm for attack by Natural killer (NK) cells of the body’s immune system (ie; opsonizing antibodies).  Some antibodies cause reactions between the sperm membrane and the cervical mucus preventing the sperm from swimming through the cervix (ie; immobilizing antibodies).  Antibodies can also block the sperm’s ability to bind to the zona pellucida of the egg, a prerequisite for fertilization (ie; blocking antibodies).  Finally, there is recent evidence that the fertilized egg shares some of the same antigens that are found on the sperm.  It is possible that sperm antibodies present in the mother can react with the early embryo, resulting in its destruction by phagocytic (ie; phagocytic antibodies) cells.

In my opinion, ASA tests are best performed on blood. There are a number of diagnostic tests available to detect the presence of sperm antibodies.  There are several methods for the diagnosis These tests are performed by flow cytometry and the ELISA (enzyme-linked immunoabsorbent assay), the Franklin-Dukes sperm agglutination assay or the Immunobead Binding Test (IBT).the  indirect immunofluorescence (IIF) assay, to name a few. My preference is the IBT.

In the male, IgA and IgG are found in the semen although there is controversy as to whether they originate locally (secreted by testicular cells) or cross over from the circulation.  Antibodies of the IgM class are not found in semen.

Like the source of some antibodies, the question of the critical levels of sperm antibodies is also hotly debated among clinicians.  There seems to be general agreement that blood levels above 30% by the IBT are associated with significant fertility problems.

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

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

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

Studiers have shown that pregnancy is highly unlikely following natural intercourse or intrauterine insemination when either the woman or the man harbors significant antisperm antibodies.

Attempts have to try and remove antibodies from sperm by allowing the sperm to swim through a column of beads are by and large unsuccessful. And, while there have been isolated reports that administration of corticosteroids (eg; prednisone) will temporarily suppress antibody production pregnancy rates are poor. Besides, corticosteroid therapy carries with it the risk of significant side, some of which (although infrequent) can be serious. As an example, in the man spontaneous fractures (especially of the neck of the femur) have been reported in 2 % of cases. I do not recommend this treatment.

In Vitro Fertilization (IVF) with intracytoplasmic Sperm injection (ICSI) is the best option. Here each egg is injected with a single sperm and whether there are antibodies attached to the outer surface of the sperm becomes irrelevant.. In fact, pregnancy and birth rates are the same as in cases where IVF is performed for reasons other than male factor infertility. IVF/ICSI success rates are also .not unaffected by the concentration of antisperm antibodies.

Frequently, when following vigorous and often repeated flushing of follicles at egg retrieval they fail to yield eggs, it is ascribed to “Empty Follicle Syndrome.” This is a gross misnomer, because all follicles contain eggs. So why were no eggs retrieved from the follicles? Most likely it was because they would/could not yield the eggs they harbored.

This situation is most commonly seen in older women, women who have severely diminished ovarian reserve, and in women with polycystic ovarian syndrome (PCOS). In my opinion it is often preventable when an optimal, individualized and strategic protocol for controlled ovarian stimulation (COS) is employed and the correct timing and dosage is applied to the “hCG trigger shot.”

Normally, following optimal ovarian stimulation, the hCG “trigger shot” is given for the purpose of it triggering meiosis (reproductive division) that is intended to halve the number of chromosomes from 46 to 23 within 32-36 hours. The hCG trigger also enables the egg to signal the “cumulus cells” that bind it firmly to the inner wall of the follicle (through enzymatic activity), to loosen or disperse, so that the egg can detach and readily be captured at egg retrieval (ER).

Ordinarily, normal eggs (and even those with only one or two chromosomal irregularities) will readily detach and be captured with the very first attempt to empty a follicle. Eggs that have several chromosomal numerical abnormalities (i.e., are “complex aneuploid”) are often unable to facilitate this process. This explains why when the egg is complex aneuploid, its follicle will not yield an egg…and why, when it requires repeated flushing of a follicle to harvest an egg, it is highly suggestive of it being aneuploid and thus “incompetent” (i.e., incapable of subsequently propagating a normal embryo).

Older women, women with diminished ovarian reserve, and those with polycystic ovarian syndrome, tend to have more biologically active LH in circulation. LH causes production of male hormone (androgens, predominantly testosterone), by ovarian connective tissue (stroma/theca). A little testosterone is needed for optimal follicle development and for FSH-induced ovogenesis (egg development). Too much LH activity compromises the latter, and eggs so affected are far more likely to be aneuploid following meiosis.

Women with the above conditions have increased LH activity and are thus more likely to produce excessive ovarian testosterone. It follows that sustained, premature elevations in LH or premature luteinization (often referred to as a “premature LH surge”) will prejudice egg development. Such compromised eggs are much more likely to end up being complex aneuploid following the administration of the hCG trigger, leading to fruitless attempts at retrieval and the so called “empty follicle syndrome.”

The developing eggs of women who have increased LH activity (older women, women with diminished ovarian reserve, and those with PCOS) are inordinately vulnerable to the effects of protracted exposure to LH-induced ovarian testosterone. Because of this, the administration of medications that provoke further pituitary LH release (e.g., clomiphene and Letrozole), drugs that contain LH or hCG (e.g., Menopur), or protocols of ovarian stimulation that provoke increased exposure to the woman’s own pituitary LH (e.g., “flare-agonist protocols”) and the use of “late pituitary blockade” (antagonist) protocols can be prejudicial.

The importance of individualizing COS protocol selection, precision with regard to the dosage and type of hCG trigger used, and the timing of its administration in such cases cannot be overstated. The ideal dosage of urinary-derived hCG (hCG-u) such as Novarel, Pregnyl and Profasi is 10,000U. When recombinant DNA-derived hCG (hCG-r) such as Ovidrel is used, the optimal dosage is 500mcg. A lower dosage of hCG can, by compromising meiosis, increase the risk of egg aneuploidy, and thus of IVF outcome.

There is in my opinion no such condition as “Empty Follicle Syndrome.” All follicles contain eggs. Failure to access those eggs at ER can often be a result of the protocol used for controlled ovarian stimulation.

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ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

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

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

Ever since January 1993 when a study was reported by researchers at Stanford University suggesting that the use of fertility agents increased the risk of ovarian cancer, there has been tremendous concern and anxiety among women who use fertility drugs. At first the findings seemed well founded because intuitively it made biological sense that fertility drugs might promote cancer because they increase the number of ovulations a woman has. And so the studies received wide public attention. It subsequently turned out that this study which was based on, data compiled from 12 retrospective studies on ovarian cancer patients done in the late seventies and early eighties was seriously flawed for the following reasons:

• While, retrospective (trohoc) studies have value in identifying an area of relevance for subsequent evaluation they are inadequate for reaching definitive conclusions. The only valid way to conclusively determine whether there is a link between prior use of fertility drugs and ovarian cancer would be through prospectively controlled statistical studies that compare the risk of ovarian cancer in infertile women who undergo ovarian stimulation with infertile women who do not.
• Infertile women who spend more than five years trying to conceive have about a 3 times higher risk for ovarian cancer than do fertile women. This is especially true when the infertility is due to absent or dysfunctional ovulation. Prior to the 90’s when the era of ovulation induction for intrauterine insemination (IUI) and IVF began to take off , the commonest indication for the use of fertility drugs was to induce  ovulation in women who were not ovulating at all or normally. That all changed as more and more normally ovulating women started having IUI and IVF. Today, in 1st world countries, the number of normally ovulating women who receive fertility drugs exceeds those who receive such treatment because of absent or abnormal ovulation.  Thus the emphasis has changed dramatically and with it, the risk of ovarian cancer has declined commensurately.
• Animal studies suggest that in contrast to gonadotropins, clomiphene citrate might after long and sustained usage, be carcinogenic. Since the 1993 Stanford University study data was derived at a time when most women undergoing COH were receiving clomiphene citrate (rather than gonadotropins), the possibility exists that the higher incidence of ovarian cancer  might at least in part be due to this factor.
• The 1993 report did not take into account that pregnancy itself has a protective effect against the development of ovarian cancer. This means that those women who in fact conceived following the use of fertility drugs might through the occurrence of pregnancy have reduced their risk of subsequently getting ovarian cancer.

Most important is the fact that several large prospective studies have now refuted the existence of a link between the use of gonadotropins and ovarian cancer. On the other hand, there does appear to be an association between ovarian cancer and certain causes of infertility itself, such as endometriosis.

While the case is still out with regard to whether or not in humans the prolonged and repeated use of clomiphene citrate increases the risk of ovarian cancer, when it comes to the use of gonadotropins for controlled ovarian stimulation (COS) women can in my opinion, breathe easy.

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

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

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

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Not really!

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

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

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

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No!  By and large, I do not!

Geoff Sher

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ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

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

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

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I do not think that starting the BCP on Day-6will have any adverse effects on your treatment.

One often hears the expressed opinion that the BCP suppresses response to ovarian stimulation. This is not the case, provided that the BCP is overlapped with administration of an agonist (e.g. Lupron, Buserelin, Superfact) for several days leading up to the start of menstruation and the initiation of ovarian stimulation cycle with gonadotropin drugs. If the latter precaution is not taken, and the cycle of stimulation is initiated coming directly off the BCP the response will often be blunted and subsequent egg quality could be adversely affected. The explanation for this is that in natural (unstimulated) as well as in cycles stimulated with fertility drugs, the ability of follicles to properly respond to FSH stimulation is dependent on their having developed FSH-responsive receptors . Pre-antral follicles (PAF) do not have such primed FSH receptors and thus cannot respond properly to FSH stimulation with gonadotropins. The acquisition of FSH receptor responsivity requires that the pre-antral follicles be exposed to FSH, for a number of days (5-7) during which time they attain “FSH-responsivity” and are now known as antral follicles (AF). These AF’s are now able to respond properly to stimulation with administered FSH-gonadotropins. In regular menstrual cycles, the rising FSH output from the pituitary gland insures that PAFs convert tor AF’s. The BCP (as well as prolonged administration of estrogen/progesterone) suppresses FSH. This suppression needs to be countered by artificially causing blood FSH levels to rise in order to cause PAF to AF conversion prior to COS commencing, otherwise pre-antral-to –antral follicle conversion will not take place in an orderly fashion, the duration of ovarian stimulation will be prolonged and both follicle and egg development may be compromised. GnRH agonists (e.g. Lupron, Buserelin, Superfact) , cause an immediate surge in release of FSH by the pituitary gland thus causing conversion from PAF to SAF. This is why, women who take a BCP to launch a cycle of COS need to have an overlap of the BCP with an agonist. By overlapping the BCP with an agonist for a few days prior to menstruation the early recruited follicles are able to complete their developmental drive to the AF stage and as such, be ready to respond appropriately to optimal ovarian stimulation. Using this approach, the timing of the initiation of the IVF treatment cycle can readily and safely be regulated and controlled by varying the length of time that the woman is on the BCP.

Since optimizing follicular response to COS requires that prior to stimulation with gonadotropins, FSH-induced conversion from PAF to AF’s first be  completed and the BCP suppresses FSH, it follows when it comes to women launching COS coming off a BCP something needs to be done to cause a rise in FSH for 5-7 days prior to menstruation heralding the cycle of CO S.This is where overlapping the BCP with an agonist (e.g. Lupron/Superfact/Buserelin) comes in. The agonist causes FSH to be released by the pituitary gland and if overlapped with the BCP for several days and this will  (within 2-5 days) facilitate PAF to AF conversion…. in time to start COS with the onset of menstruation. Initiating ovarian stimulation in women taking a BCP, without doing this is suboptimal

I believe it to be essential regardless of the protocol of COS protocol being contemplated, for women who launching ovarian stimulation coming off a BCP to overlap with an agonist for several days in advance of initiating ovarian stimulation with the onset of menstruation,

Geoff Sher

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ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

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

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

Unfortunately, this is not a sperm: egg matching issue. It has to do with genotypic  matching between the fertilizing sperm and the host……. So using donor egg will likely not help matters.

Geoff Sher

Geoff Sher

Absolutely we do.Simply call the clinic (contact info is on website).

Good luck!

Geoff Sher

Please re-post in English!

Geoff Sher

__________________________________________________________________

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

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

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

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Unless the laparoscopy is intended to alleviate symptoms by  ablating lesions, freeing pelvic adhesions or removing an ovarian endometrioma, I would NOT go that route. I would do IVF.

When women with infertility due to endometriosis seek treatment, they are all too often advised to first try ovarian stimulation (ovulation Induction) with intrauterine insemination (IUI) ………as if to say that this would be just as likely to result in a baby as would in vitro fertilization (IVF). Nothing could be further from reality It is time to set the record straight. And hence this communication!

Bear in mind that the cost of treatment comprises both financial and emotional components and that it is the cost of having a baby rather than cost of a procedure. Then consider the fact that regardless of her age or the severity of the condition, women with infertility due to endometriosis are several fold more likely to have a baby per treatment cycle of IVF than with IUI. It follows that there is a distinct advantage in doing IVF first, rather than as a last resort.

So then, why is it that ovulation induction with or without IUI is routinely offered proposed preferentially to women with mild to moderately severe endometriosis? Could it in part be due to the fact that most practicing doctors do not provide IVF services but are indeed remunerated for ovarian stimulation and IUI services and are thus economically incentivized to offer IUI as a first line approach? Or is because of the often erroneous belief that the use of fertility drugs will in all cases induce the release (ovulation) of multiple eggs at a time and thereby increase the chance of a pregnancy. The truth however is that while normally ovulating women (the majority of women who have mild to moderately severe endometriosis) respond to ovarian stimulation with fertility drugs by forming multiple follicles, they rarely ovulate > 1 (or at most 2) egg at a time. This is because such women usually only develop a single dominant follicle which upon ovulating leaves the others intact. This is the reason why normally ovulating women who undergo ovulation induction usually will not experience improved pregnancy potential, nor will they have a marked increase in multiple pregnancies. Conversely, non-ovulating women (as well as those with dysfunctional ovulation) who undergo ovulation induction, almost always develop multiple large follicles that tend to ovulate in unison. This increases the potential to conceive along with an increased risk multiple pregnancies.

So let me take a stab at explaining why IVF is more successful than IUI or surgical correction in the treatment of endometriosis-related infertility:

1. The toxic pelvic factor: Endometriosis is a condition where the lining of the uterus (the endometrium) grows outside the uterus. While this process begins early in the reproductive life of a woman, with notable exceptions, it only becomes manifest in the 2ndhalf of her reproductive life. After some time, these deposits bleed and when the blood absorbs it leaves a visible pigment that can be identified upon surgical exposure of the pelvis. Such endometriotic deposits invariably produce and release toxins” into the pelvic secretions that coat the surface of the membrane (the peritoneum) that envelops all abdominal and pelvic organs, including the uterus, tubes and ovaries. These toxins are referred to as “the peritoneal factor”. Following ovulation, the egg(s) must pass from the ovary (ies), through these toxic secretions to reach the sperm lying in wait in the outer part the fallopian tube (s) tube(s) where, the sperm lie in waiting. In the process of going from the ovary(ies) to the Fallopian tube(s) these eggs become exposed to the “peritoneal toxins” which alter s the envelopment of the egg (i.e. zona pellucida) making it much less receptive to being fertilized by sperm. As a consequence, if they are chromosomally normal such eggs are rendered much less likely to be successfully fertilized. Since almost all women with endometriosis have this problem, it is not difficult to understand why they are far less likely to conceive following ovulation (whether natural or induced through ovulation induction). This “toxic peritoneal factor impacts on eggs that are ovulated whether spontaneously (as in natural cycles) or following the use of fertility drugs and serves to explain why the chance of pregnancy is so significantly reduced in normally ovulating women with endometriosis.
2. The Immunologic Factor: About one third of women who have endometriosis will also have an immunologic implantation dysfunction (IID) linked to activation of uterine natural killer cells (NKa).  This will require selective immunotherapy with Intralipid infusions, and/or heparinoids (e.g. Clexane/Lovenox) that is much more effectively implemented in combination with IVF.
3. Surgical treatment of mild to moderate endometriosis does not usually improve pregnancy potential:. The reason is that endometriosis can be considered to be a “work in progress”. New lesions are constantly developing. So it is that for every endometriotic seen there are usually many non-pigmented deposits that are in the process of evolving but are not yet visible to the naked eye and such evolving (non-visible) lesions can also release the same “toxins that compromise fertilization. Accordingly, even after surgical removal of all visible lesions the invisible ones continue to release “toxins” and retain the ability to compromise natural fertilization. It also explains why surgery to remove endometriotic deposits in women with mild to moderate endometriosis usually will fail to significantly improve pregnancy generating potential. In contrast, IVF, by removing eggs from the ovaries prior to ovulation, fertilizing these outside of the body and then transferring the resulting embryo(s) to the uterus, bypasses the toxic pelvic environment and is therefore is the treatment of choice in cases of endometriosis-related infertility.
4. Ovarian Endometriomas: Women, who have advanced endometriosis, often have endometriotic ovarian cysts, known as endometriomas. These cysts contain decomposed menstrual blood that looks like melted chocolate…hence the name “chocolate cysts”. These space occupying lesions can activate ovarian connective tissue (stroma or theca) resulting in an overproduction of male hormones (especially testosterone). An excess of ovarian testosterone can severely compromise follicle and egg development in the affected ovary. Thus there are two reasons for treating endometriomas. The first is to alleviate symptoms and the second is to optimize egg and embryo quality. Conventional treatment of endometriomas involves surgical drainage of the cyst contents with subsequent removal of the cyst wall (usually by laparoscopy), increasing the risk of surgical complications. We recently reported on a new, effective and safe outpatient approach to treating endometriomas in women planning to undergo IVF. We termed the treatment ovarian Sclerotherapy.  The process involves; needle aspiration of the “chocolate colored liquid content of the endometriotic cyst, followed by the injection of 5% tetracycline hydrochloride into the cyst cavity. Such treatment will, more than 75% of the time result in disappearance of the lesion within 6-8 weeks. Ovarian sclerotherapy can be performed under local anesthesia or under conscious sedation. It is a safe and effective alternative to surgery for definitive treatment of recurrent ovarian endometriomas in a select group of patients planning to undergo IVF

 I am not suggesting that all women with infertility-related endometriosis should automatically resort to IVF. Quite to the contrary…. In spite of having reduced fertility potential, many women with mild to moderate endometriosis can and do go on to conceive on their own (without treatment). It is just that the chance of this happening is so is much lower than normal.

IN SUMMARY: For young ovulating women (< 35 years of age ) with endometriosis, who have normal reproductive anatomy and have fertile male partners, expectant treatment is often preferable to IUI or IVF. However, for older women, women who (regardless of their age) have any additional factor (e.g. pelvic adhesions, ovarian endometriomas, male infertility, IID or diminished ovarian reserve-DOR) IVF should be the primary treatment of choice.

I strongly recommend that you visit www.DrGeoffreySherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select.  Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.

• The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation (COS)
• The Fundamental Requirements For Achieving Optimal IVF Success
• Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF:
• The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 1-Background
• Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 2- Making a Diagnosis
• Immunologic Dysfunction (IID) & Infertility (IID): PART 3-Treatment
• Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
• Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management: (Case Report)
• Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
• Intralipid (IL) Administration in IVF: It’s Composition; how it Works; Administration; Side-effects; Reactions and Precautions
• Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
• Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas
• Should IVF Treatment Cycles be provided uninterrupted or be Conducted in 7-12 Pre-scheduled “Batches” per Year
• A personalized, stepwise approach to IVF
• How Many Embryos should be transferred: A Critical Decision in IVF?
• Endometriosis and Immunologic Implantation Dysfunction (IID) and IVF
• Endometriosis and Infertility: Why IVF Rather than IUI or Surgery Should be the Treatment of Choice.
• Endometriosis and Infertility: The Influence of Age and Severity on Treatment Options
• Early -Endometriosis-related Infertility: Ovulation Induction (with or without Intrauterine Insemination) and Reproductive Surgery Versus IVF
• Treating Ovarian Endometriomas with Sclerotherapy.
• Effect of Advanced Endometriosis with Endometriotic cysts (Endometriomas) on IVF Outcome & Treatment Options.
• Deciding Between Intrauterine Insemination (IUI) and In Vitro Fertilization (IVF).
• Intrauterine Insemination (IUI): Who Needs it & who Does Not: Pro’s &
• Induction of Ovulation with Clomiphene Citrate: Mode of Action, Indications, Benefits, Limitations and Contraindications for its use
• Clomiphene Induction of Ovulation: Its Use and Misuse!

______________________________________________________

ADDENDUM: PLEASE READ!!

INTRODUCING SHER FERTILITY SOLUTIONS (SFS)

Founded in April 2019, Sher Fertility Solutions (SFS) offers online (Skype/FaceTime) consultations to patients from > 40 different countries. All consultations are followed by a detailed written report presenting my personal recommendations for treatment of what often constitute complex Reproductive Issues.

If you wish to schedule an online consultation with me, please contact my assistant (Patti Converse) by phone (800-780-7437/702-533-2691), email (concierge@SherIVF.com) or,  enroll online on then home-page of my website (www.SherIVF.com). 

PLEASE SPREAD THE WORD ABOUT SFS!

Geoff Sher

___________________________________________________________________________________________

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

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

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

………………………………………………………………..

A heterozygous MTHFR mutation will in my opinion, not cause early pregnancy loss.

When it comes to reproduction, humans are the poorest performers of all mammals. In fact we are so inefficient that up to 75% of fertilized eggs do not produce live births, and up to 30% of pregnancies end up being lost within 10 weeks of conception (in the first trimester). RPL is defined as two (2) or more failed pregnancies. Less than 5% of women will experience two (2) consecutive miscarriages, and only 1% experience three or more.

Pregnancy loss can be classified by the stage of pregnancy when the loss occurs:

• Early pregnancy loss (first trimester)
• Late pregnancy loss (after the first trimester)
• Occult “hidden” and not clinically recognized, (chemical) pregnancy loss (occurs prior to ultrasound confirmation of pregnancy)
• Early pregnancy losses usually occur sporadically (are not repetitive).

In more than 70% of cases the loss is due to embryo aneuploidy (where there are more or less than the normal quota of 46 chromosomes). Conversely, repeated losses (RPL), with isolated exceptions where the cause is structural (e.g., unbalanced translocations), are seldom attributable to numerical chromosomal abnormalities (aneuploidy). In fact, the vast majority of cases of RPL are attributable to non-chromosomal causes such as anatomical uterine abnormalities or Immunologic Implantation Dysfunction (IID).

Since most sporadic early pregnancy losses are induced by chromosomal factors and thus are non-repetitive, having had a single miscarriage the likelihood of a second one occurring is no greater than average. However, once having had two losses the chance of a third one occurring is double (35-40%) and after having had three losses the chance of a fourth miscarriage increases to about 60%. The reason for this is that the more miscarriages a woman has, the greater is the likelihood of this being due to a non-chromosomal (repetitive) cause such as IID. It follows that if numerical chromosomal analysis (karyotyping) of embryonic/fetal products derived from a miscarriage tests karyotypically normal, then by a process of elimination, there would be a strong likelihood of a miscarriage repeating in subsequent pregnancies and one would not have to wait for the disaster to recur before taking action. This is precisely why we strongly advocate that all miscarriage specimens be karyotyped.

There is however one caveat to be taken into consideration. That is that the laboratory performing the karyotyping might unwittingly be testing the mother’s cells rather than that of the conceptus. That is why it is not possible to confidently exclude aneuploidy in cases where karyotyping of products suggests a “chromosomally normal” (euploid) female.

Late pregnancy losses (occurring after completion of the 1st trimester/12th week) occur far less frequently (1%) than early pregnancy losses. They are most commonly due to anatomical abnormalities of the uterus and/or cervix. Weakness of the neck of the cervix rendering it able to act as an effective valve that retains the pregnancy (i.e., cervical incompetence) is in fact one of the commonest causes of late pregnancy loss. So also are developmental (congenital) abnormalities of the uterus (e.g., a uterine septum) and uterine fibroid tumors. In some cases intrauterine growth retardation, premature separation of the placenta (placental abruption), premature rupture of the membranes and premature labor can also causes of late pregnancy loss.

Much progress has been made in understanding the mechanisms involved in RPL. There are two broad categories:

1. Problems involving the uterine environment in which a normal embryo is prohibited from properly implanting and developing. Possible causes include:

• Inadequate thickening of the uterine lining
• Irregularity in the contour of the uterine cavity (polyps, fibroid tumors in the uterine wall, intra-uterine scarring and adenomyosis)
• Hormonal imbalances (progesterone deficiency or luteal phase defects). This most commonly results in occult RPL.
• Deficient blood flow to the uterine lining (thin uterine lining).
• Immunologic implantation dysfunction (IID). A major cause of RPL. Plays a role in 75% of cases where chromosomally normal preimplantation embryos fail to implan
• Interference of blood supply to the developing conceptus can occur due to a hereditary clotting disorder known as Thrombophili

1. Genetic and/or numerical chromosomal abnormalities(aneuploidy) of the embryo are far away the commonest overall causes of miscarriages. But this only applies to sporadic pregnancy losses (which comprises the majority of all miscarriages. However, recurrent, (consecutive) pregnancy losses are much more likely due to implantation dysfunction than to embryo-related issues, where implantation dysfunction (usually anatomical or immunologic) factors usually underly the problem.
2. Genetic or Structural chromosomal abnormalities (which only occur in about 1% of cases) can also cause RPL. This is referred to as an unbalanced translocation and they result from part of one chromosome detaching and then fusing with another chromosome. Additionally, genetic defects (unrelated to chromosomal abnormalities) can also affect embryo quality and pregnancy outcome. Damaged sperm DNA can sometimes be diagnosed using the SCSA (see before) which primarily measures the sperm DNA fragmentation index (DFI).

IMMUNOLOGIC IMPLANTATION DYSFUNCTIO-IID (see before)

Autoimmune IID: Here an immunologic reaction is produced by the individual to his/her body’s own cellular components. The most common antibodies that form in such situations are APA and antithyroid antibodies

Alloimmune IID, i.e., where there is an immunologic reaction to antigens derived from another member of the same species (i.e. the woman’s immune system reacts to the paternal antigens in the sperm (see above) .

*It is important to recognize that alloimmune (rather than autoimmune) IID is more commonly associated with RPL.

Autoimmune IID is often genetically transmitted. Thus, it should not be surprising to learn that it is more likely to exist in women who have a family (or personal) history of primary autoimmune diseases such as lupus erythematosus (LE), scleroderma or autoimmune hypothyroidism (Hashimoto’s disease), autoimmune hyperthyroidism (Grave’s disease), rheumatoid arthritis, etc. Reactionary (secondary) autoimmunity can occur in conjunction with any medical condition associated with widespread tissue damage. One such gynecologic condition is endometriosis. Since autoimmune IID is usually associated with activated NK and T-cells from the outset, it usually results in such very early destruction of the embryo’s root system that the patient does not even recognize that she is pregnant. Accordingly, the condition usually presents as “unexplained infertility” or “unexplained IVF failure” rather than as a miscarriage.

Alloimmune IID, on the other hand, usually starts off presenting as unexplained miscarriages (often manifesting as RPL). Over time as NK/T cell activation builds and eventually becomes permanently established the patient often goes from RPL to “infertility” due to failed implantation. RPL is more commonly the consequence of alloimmune rather than autoimmune implantation dysfunction.

However, regardless, of whether miscarriage is due to autoimmune or alloimmune implantation dysfunction the final blow to the pregnancy is the result of activated NK cells and CTL in the uterine lining that damage the developing embryo’s “root system” (trophoblast) so that it can no longer sustain the growing conceptus. This having been said, it is important to note that autoimmune IID is readily amenable to reversal through timely, appropriately administered, selective immunotherapy, and alloimmune IID is not. It is much more difficult to treat successfully, even with the use of immunotherapy. In fact, in some cases the only solution will be to revert to selective immunotherapy plus using donor sperm (provided there is no “match” between the donor’s DQ alpha/HLA profile and that of the female recipient) or alternatively to resort to gestational surrogacy.

DIAGNOSING THE CAUSE OF RPL

In the past, women who miscarried were not evaluated thoroughly until they had lost several pregnancies in a row. This was because sporadic miscarriages are most commonly the result of embryo numerical chromosomal irregularities (aneuploidy) and thus not treatable. However, a consecutive series of miscarriages points to a repetitive cause that is non-chromosomal and is potentially remediable. Since RPL is most commonly due to a uterine pathology or immunologic causes that are potentially treatable, it follows that early chromosomal evaluation of products of conception could point to a potentially treatable situation. Thus, we strongly recommend that such testing be done in most cases of miscarriage. Doing so will avoid a great deal of unnecessary heartache for many patients.

Establishing the correct diagnosis is the first step toward determining effective treatment for couples with RPL. It results from a problem within the pregnancy itself or within the uterine environment where the pregnancy implants and grows. Diagnostic tests useful in identifying individuals at greater risk for a problem within the pregnancy itself include:

• Karyotyping (chromosome analysis) both prospective parents
• Assessment of the karyotype of products of conception derived from previous miscarriage specimens
• Ultrasound examination of the uterine cavity after sterile water is injected or sonohysterogram, fluid ultrasound, etc.
• Hysterosalpingogram (dye X-ray test)
• Hysteroscopic evaluation of the uterine cavity
• Full hormonal evaluation (estrogen, progesterone, adrenal steroid hormones, thyroid hormones, FSH/LH, )
• Immunologic testing to include:
  • Antiphospholipid antibody (APA) panel
  • Antinuclear antibody (ANA) panel
  • Antithyroid antibody panel (i.e., antithyroglobulin and antimicrosomal antibodies)
  • Reproductive immunophenotype
  • Natural killer cell activity (NKa) assay (i.e., K562 target cell test)
  • Alloimmune (DQ alpha/HLA) testing of both the male and female partners

TREATMENT OF RPL

Treatment for Anatomic Abnormalities of the Uterus: This involves restoration through removal of local lesions such as fibroids, scar tissue, and endometrial polyps or timely insertion of a cervical cerclage (a stitch placed around the neck of the weakened cervix) or the excision of a uterine septum when indicated.

Treatment of Thin Uterine Lining: A thin uterine lining has been shown to correlate with compromised pregnancy outcome. Often this will be associated with reduced blood flow to the endometrium.  Such decreased blood flow to the uterus can be improved through treatment with sildenafil and possibly aspirin.

Sildenafil (Viagra) Therapy (see above). Viagra has been used successfully to increase uterine blood flow. To date, we have seen significant improvement of the thickness of the uterine lining in about 70% of women treated. Successful pregnancy resulted in almost half of those women who responded to the Viagra. It should be borne in mind that most of these women had previously experienced repeated IVF failures.

Use of Aspirin: This is an anti-prostaglandin that improves blood flow to the endometrium. It is administered at a dosage of 81 mg orally, daily from the beginning of the cycle until ovulation.

Treating Immunologic Implantation Dysfunction with Selective Immunotherapy: Modalities such as IL/IVIg, heparinoids (Lovenox/Clexane), and corticosteroids can be used in select cases depending on autoimmune or alloimmune dysfunction.

The Use of IVF in the Treatment of RPL. In the following circumstances, IVF is the preferred option:

• When in addition to a history of RPL, another standard indication for IVF (e.g., tubal factor, endometriosis, and male factor infertility) is superimposed.
• In cases where selective immunotherapy is needed to treat an immunologic implantation dysfunction.

The reason for IVF being a preferred approach in such cases is that in order to be effective, the immunotherapy needs to be initiated well before spontaneous or induced ovulation. Given the fact that in the absence of IVF the anticipated birthrate per cycle of COS with or without IUI is at best about 15%, it follows that short of IVF, to have even a reasonable chance of a live birth, most women with immunologic causes of RPL would need to undergo immunotherapy repeatedly, over consecutive cycles. Conversely, with IVF, the chance of a successful outcome in a single cycle of treatment is several times greater and, because of the attenuated and concentrated time period required for treatment, IVF is far safer and thus represents a more practicable alternative

Since embryo aneuploidy is a common cause of miscarriage, the use of PGS/PGT-A can provide a valuable diagnostic and therapeutic advantage in cases of RPL. PGD requires IVF to provide access to embryos for testing.

There are a few cases of intractable alloimmune dysfunction due to “complete DQ alpha matching where Gestational Surrogacy or use of Donor  Sperm could represent the only viable recourse, other than abandoning treatment altogether and/or resorting to adoption. Other non-immunologic factors such as an intractably thin uterine lining or severe uterine pathology might also warrant that last resort consideration be given to gestational surrogacy.

The good news is that if a couple with RPL is open to all of the diagnostic and treatment options referred to above, a live birthrate of 70%–80% is ultimately achievable.

I strongly recommend that you visit www.SherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select.  Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.

• The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
• The Fundamental Requirements For Achieving Optimal IVF Success
• Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the “Conventional” Antagonist Approach
• Ovarian Stimulation in Women Who have Diminished Ovarian Reserve (DOR): Introducing the Agonist/Antagonist Conversion protocol
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
• Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
• The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
• Blastocyst Embryo Transfers Should be the Standard of Care in IVF
• IVF: How Many Attempts should be considered before Stopping?
• “Unexplained” Infertility: Often a matter of the Diagnosis Being Overlooked!
• IVF Failure and Implantation Dysfunction:
• The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 1-Background
• Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 2- Making a Diagnosis
• Immunologic Dysfunction (IID) & Infertility (IID):PART 3-Treatment
• Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
• Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management:(Case Report
• Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
• Intralipid (IL) Administration in IVF: It’s Composition; How it Works; Administration; Side-effects; Reactions and Precautions
• Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
• Endometrial Thickness, Uterine Pathology and Immunologic Factors
• Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
• Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
• A personalized, stepwise approach to IVF
• How Many Embryos should be transferred: A Critical Decision in IVF.
• The Role of Nutritional Supplements in Preparing for IVF

______________________________________________________

ADDENDUM: PLEASE READ!!

INTRODUCING SHER FERTILITY SOLUTIONS (SFS)

Founded in April 2019, Sher Fertility Solutions (SFS) offers online (Skype/FaceTime) consultations to patients from > 40 different countries. All consultations are followed by a detailed written report presenting my personal recommendations for treatment of what often constitute complex Reproductive Issues.

If you wish to schedule an online consultation with me, please contact my assistant (Patti Converse) by phone (800-780-7437/702-533-2691), email (concierge@SherIVF.com) or,  enroll online on then home-page of my website (www.SherIVF.com). 

PLEASE SPREAD THE WORD ABOUT SFS!

Geoff Sher

________________________________________________________________________________

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  authored …… for your reading pleasure:

• “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

………………………………………………………………..

It is highly unlikely the the elevated aCL alone would lead to secondary recurrent pregnancy loss (RPL). I would venture an educated guess that there is a non-immunologic cause for implantation dysfunction (perhaps the integrity of the uterine cavity or a thin uterine lining). More likely however is that you were not properly evaluated for an immunologic implantation dysfunction (IID)…see below:

Currently, with few exceptions, practitioners of assisted reproduction tend to attribute “unexplained and/or repeated” IVF failure(s), almost exclusively to poor embryo quality, advocating adjusted protocols for ovarian stimulation and/or gamete and embryo preparation as a potential remedy. The idea, having failed IVF, that all it takes to ultimately succeed is to keep trying the same recipe is over-simplistic.

The implantation process begins six or seven days after fertilization of the egg. At this time, specialized embryonic cells (i.e., trophoblasts), that later become the placenta begin growing into the uterine lining. When the trophoblast and the uterine lining meet, they, along with immune cells in the lining, become involved in a “cross talk” through mutual exchange of hormone-like substances called cytokines. Because of this complex immunologic interplay, the uterus can foster the embryo’s successful growth. Thus, from the earliest stage, the trophoblast establishes the very foundation for the nutritional, hormonal and respiratory interchange between mother and baby.  In this manner, the interactive process of implantation is not only central to survival in early pregnancy but also to the quality of life after birth.

There is an ever growing realization, recognition, and acceptance of the fact that uterine immunologic dysfunction can lead to immunologic implantation dysfunction (IID) with “unexplained” infertility, IVF failure, and recurrent pregnancy loss (RPL).

DIAGNOSIS 

Because immunologic problems may lead to implantation failure, it is important to properly evaluate women with risk factors such as:

• Unexplained or recurrent IVF failures
• Unexplained infertility or a family history of autoimmune diseases (e.g., rheumatoid arthritis, lupus erythematosus and hypothyroidism).
• Recurrent Pregnancy Loss (RPL)
• Endometriosis
• A personal or family history of autoimmune conditions, e.g., Rheumatoid Arthritis, Lupus erythematosus, autoimmune hypothyroidism (Hashimoto’s disease) etc.

Considering its importance, it is not surprising that the failure of a properly functioning immunologic interaction during implantation has been implicated as a cause of recurrent miscarriage, late pregnancy fetal loss, IVF failure and infertility. A partial list of immunologic factors that may be involved in these situations includes:

• Antiphospholipid antibodies (APA)
• Antithyroid antibodies (ATA/AMA)
• Activated natural killer cells (NKa)

ACTIVATED NATURAL KILLER CELLS (NKa):

Following ovulation and during early pregnancy, NK cells and T-cells comprise more than 80% of the lymphocyte-immune cells that frequent the uterine lining. These lymphocytes (white blood cells) journey from the bone marrow to the uterus and under hormonal regulation, proliferate there. After exposure to progesterone (due to induced /spontaneous exogenous administration), they begin to produce TH-1 and TH-2 cytokines. TH-2 cytokines are humoral in nature and induce the trophoblast (“root system of the embryo”) to permeate the uterine lining while TH-I cytokines induce a process referred to as apoptosis (cell suicide) thereby confining placental development to the inner part of the uterus. Optimal placental development (placentation) mandates that there be a balance between TH1 and TH-2 cytokines. Most of the cytokine production originates from NK cells (rather than from cytotoxic T-cells/Lymphocytes (CTL)). Excessive production/release of TH-1 cytokines, is toxic to the trophoblast and to endometrial cells, leading to programmed death/suicide (apoptosis) and subsequently to IID.

Functional NK cells reach a maximal concentration in the endometrium by about t day 6-7 days after exposure to progesterone …. This timing corresponds with when the embryo implants into the uterine lining (endometrium).

It is important to bear in mind that measurement of the concentration of blood NK cells has little or no relevance when it comes to assessing NK cell activation (NKa). Rather, it is the NK cell activation that matters. In fact, there are certain conditions (such as with endometriosis) where the NK cell blood concentration is below normal, but NK cell activation is markedly increased.

There are several methods by which NK cell activation (cytotoxicity) can be assessed in the laboratory. Methods such as immunohistochemical assessment of uterine NK cells and/or through measurement of uterine or blood TH-1 cytokines. However, the K-562 target cell blood test still remains the gold standard. With this test, NK cells, isolated from the woman’s blood using Flow Cytometry are incubated in the presence of specific “target cells”. The percentage (%) of “target cells” killed is then quantified. More than 12% killing suggests a level of NK cell activation that usually requires treatment.

Currently, there are less than a half dozen Reproductive Immunology Reference Laboratories in the U.S.A that are capable of performing the K-562 target cell test reliably.

There exists a pervasive but blatant misconception on the part of many, that the addition of IL or IVIg to a concentration of NK cells could have an immediate down-regulatory effect on NK cell activity. Neither IVIg nor IL is capable of significantly suppressing already activated “functional NK cells”. They are believed to work through “regulating” NK cell progenitors which only thereupon will start to propagate down-regulated NK cells. Thus, testing for a therapeutic effect would require that the IL/IVIg infusion be done about 14 days prior to ovulation or progesterone administration…  in order to allow for a sufficient number of normal (non-activated) “functional” NK cell” to be present at the implantation site when the embryos are transferred.

Failure to recognize this reality has, in our opinion, established an erroneous demand by practicing IVF doctors, that Reproductive Immunology Reference Laboratories report on NK cell activity before and again, immediately following laboratory exposure to IVIg and/or IL in different concentrations. Allegedly, this is to allow the treating physician to report back to their patient(s) on whether an  IL or IVIG infusion will be effective in down-regulating their Nka.  But, since already activated NK cells (NKa) cannot be deactivated in the laboratory, effective NKa down-regulation can only be adequately accomplished through deactivation of NK cell “progenitors /parental” NK cells in order too allow them thereupon, to s propagate normal “functional” NK cells and his takes about 10-14 days, such practice  would be of little clinical benefit. This is because even if blood were to be drawn 10 -14 days after IL/IVIg treatment it would require at least  an additional 10 -14days to receive results from the laboratory, by which time it would be far too late to be of practical advantage.

ANTIPHOSPHOLIPID ANTIBODIES:

 Many women who experience “unexplained” IVF failure, women with RPL, those with a personal or family history of autoimmune diseases such as lupus erythematosus, rheumatoid arthritis, scleroderma, and dermatomyositis (etc.)  as well as women who have endometriosis (“silent” or overt) test positive for APAs. More than 30 years ago, we were the first to propose that women who test positive for APA’s be treated with a mini-dose heparin to improve IVF implantation and thus birth rates. This approach was based upon research that suggested that heparin repels APAs from the surface of the trophoblast (the embryo’s “root system) thereby reducing its ant-implantation effects.  We subsequently demonstrated that such therapy only improved IVF outcome in women whose APAs were directed against two specific IgG and/or IgM phospholipids [i.e., phosphatidylethanolamine (PE) and phosphatidylserine (PS)].  More recently low dosage heparin therapy has been supplanted using longer acting low molecular weight heparinoids such as Lovenox and Clexane.   It is very possible that APAs alone do not cause IID but that their presence might help to identify a population at risk due to concomitant activation of uterine natural killer cells (Nka) which through excessive TH-1 cytokine production causes in IID: This is supported by the following observations:

• The presence of female APAs in cases of male factor cases appears to bear no relationship to IID.
• Only APA positive women who also test positive for abnormal NK activity appear to benefit from selective immunotherapy with intralipid/IVIg/ steroids.
• Most APA positive women who have increased NK cell activity also harbor IgG or IgM phosphatidylethanolamine (PE) and phosphatidylserine (PS) antibodies.

ANTITHYROID ANTIBODIES: (ATA).

 A clear relationship has been established between ATA and reproductive failure (especially recurrent miscarriage and infertility).

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

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

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

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

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

TEATMENT OF IID:

The mainstay of treatment involves the selective use of :

• Intralipid (IL) infusion
• IVIg therapy
• Corticosteroids (Prednisone/dexamethasone)
• Heparinoids (Lovenox/Clexane)

Intralipid (IL) Therapy:  IL is a suspension of soybean lipid droplets in water and is primarily used as source of parenteral nutrition. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, and alpha-linolenic acid (ALA), an omega-3 fatty acid.     

It is thought that fatty acids within the emulsion serve as ligands that activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cell cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent.

            Whatever the exact mechanism of action might be, Intralipid acts primarily to suppress NK cell over-production of TH-I cytokines. It exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating cytotoxic /activated natural killer cells (NKa). This effect is enhanced through the concomitant administration of corticosteroids such as dexamethasone, prednisolone and prednisone which augment immune modulation of T cells. The combined effect of IL + steroid therapy suppresses pro-inflammatory cellular TH1 cytokines such as interferon gamma and TNF-alpha that are produced in excess by activated NK cells and cytotoxic lymphocytes/T-cells (CTL).   IL will, in about 80% of cases, successfully down-regulate activated natural killer cells (NKa) over a period of 2-3 weeks. It is likely to be just as effective as IVIg in this respect but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for ~ 4-6 weeks when administered in early pregnancy.

Intralipid is a suspension of soybean lipid droplets in water and is primarily used as source of parenteral nutrition. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, and alpha-linolenic acid (ALA), an omega-3 fatty acid.     

It is thought that fatty acids within the emulsion serve as ligands that activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cell cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent.

            Whatever the exact mechanism of action might be, Intralipid acts primarily to suppress NK cell over-production of TH-I cytokines. It exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating cytotoxic /activated natural killer cells (NKa). This effect is enhanced through the concomitant administration of corticosteroids such as dexamethasone, prednisolone and prednisone which augment immune modulation of T cells. The combined effect of IL + steroid therapy suppresses pro-inflammatory cellular TH1 cytokines such as interferon gamma and TNF-alpha that are produced in excess by activated NK cells and cytotoxic lymphocytes/T-cells (CTL).   IL will, in about 80% of cases, successfully down-regulate activated natural killer cells (NKa) over a period of 2-3 weeks. It is likely to be just as effective as IVIg in this respect but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for ~ 4-6 weeks when administered in early pregnancy.

            Can laboratory testing be used to assess for an immediate effect of IL on Nka suppression?  Since the downregulation of NKa through IL (or IVIg) therapy can take several weeks to become measurable, it follows that there is really no benefit in trying to assess the potential efficacy of such treatment by retesting NKa in the laboratory after adding IL (or IVIg) to the cells being tested.

IVIg Therapy:  Until about a decade ago, the only effective and available way (in the US) to down-regulate activated NK cells was through the intravenous administration of a blood product known as immunoglobulin-G (IVIg). The fear (albeit unfounded) that the administration of this product might lead to the transmission of viral infections such as HIV and hepatitis C, plus the high cost of IVIG along with the fact that significant side effects occurred about 20% of the time, led to bad press and bad publicity for the entire field of reproductive immunology. It was easier for RE’s to simply say “I don’t believe IVIg works” and thereby avoid risk and bad publicity. But the thousands of women who had babies because of NK cell activity being downregulated through its use, attests to IVIg’s efficacy. But those of us who felt morally obligated to many desperate patients who would not conceive without receiving IVIg were facing an uphill battle. The bad press caused by fear mongering took its toll and spawned a malicious controversy. It was only through the introduction of IL less (about 15-20 years ago ), that the tide began to turn in favor of those patients who required low cost, safe and effective immunotherapy to resolve their IID.

 Corticosteroid Therapy (e.g., Prednisone, and Dexamethasone): Corticosteroid therapy has become a mainstay in the treatment of most women undergoing IVF. It is believed by most to enhance implantation due to an overall immunomodulatory effect. Corticosteroids reduce TH-1 cytokine production by CTL. When given in combination with IL or IVIG they augment the implantation process. The prednisone or dexamethasone therapy must commence (along with IL/IVIg)  10-14 days prior to egg retrieval and continue until pregnancy is discounted or until the 10th week of pregnancy.

 Heparinoid Therapy: There is compelling evidence that the subcutaneous administration of low molecular heparin (Clexane, Lovenox) once daily, (starting with the onset of ovarian stimulation) can improve IVF birthrate in women who test positive for APAs and might prevent later pregnancy loss when used to treat certain thrombophilias (e.g. homozygous MTHFR mutation)

What About Baby Aspirin? In our opinion, aspirin has little (if any) value when it comes to IID, and besides, it could even reduce the chance of success. The reason for this is that aspirin thins the blood and increases the potential to bleed. This effect can last for up to a week and could complicate an egg retrieval procedure or result in “concealed” intrauterine bleeding at the time of embryo transfer, thereby potentially compromising IVF success.

TH-1 Cytokine Blockers (Enbrel, Humira): TH-1 cytokine blockers, (Enbrel and Humira) are in our opinion relatively ineffective in the IVF setting. There has to date been no convincing data to support their use. However, these blockers could have a role in the treatment of a threatened miscarriage thought to be due to CTL/NK activation, but not for IVF. The reason is that the very initial phase of implantation requires a cellular response involving TH-1 cytokines. To block them completely (rather than simply restore a TH-1:TH-2 balance as occurs with IL therapy) so very early on could compromise rather than benefit implantation.

Leukocyte Immunization Therapy (LIT): The subcutaneous injection of the male partner’s lymphocytes to the mother is thought to enhance the ability for the mother’s decidua (uterus) to recognize the DQ alpha matching embryo as “self” or “friend” and thereby avert its rejection. LIT has been shown to up-regulate Treg cells and thus down-regulate NK cell activation thereby improving decidual TH-1:TH-2 balance. Thus, there could be a therapeutic benefit from such therapy. However, the same benefit can be achieved through the use of IL plus corticosteroids. Besides, IL is much less expensive, and the use of LIT is prohibited by law in the U.S.A.

There are two categories of immunologic implantation dysfunction (IID) linked to NK cell activation (NKa).

Autoimmune Implantation Dysfunction: Here, the woman will often have a personal or family history of autoimmune conditions such as Rheumatoid arthritis, Lupus Erythematosus, and thyroid autoimmune activity (e.g., Hashimoto’s disease) etc. Autoimmune as well as in about one third of cases of endometriosis, regardless of severity.  Autoimmune sometimes also occurs in the absence of a personal or family history of autoimmune disease.

When it comes to treating  NKa in  IVF cases complicated by autoimmune implantation dysfunction,  the combination of daily oral dexamethasone commencing with the onset of ovarian stimulation and continuing until the 10th week of pregnancy, combined with an initial infusion of IL (100ml, 20% Il dissolved in 500cc of saline solution, 10-14  days prior to PGT-normal embryo transfer and repeated once more (only), as  soon as the blood pregnancy test is positive), the anticipated chance of a viable pregnancy occurring within 2 completed IVF attempts (including fresh + frozen ET’s)  in women under 39Y (who have normal ovarian reserve)  is approximately  65%.

Alloimmune Implantation Dysfunction: Here, NK cell activation results from uterine exposure to an embryo derived through fertilization by a spermatozoon that shares certain genotypic (HLA/DQ alpha) similarities  with that of the embryo recipient.

Partial DQ alpha/HLA match:  Couples who upon genotyping are shown to share only one DQ alpha/HLA gene are labeled as having a “partial match”. The detection of a “partial match” in association with NKa puts the couple at a considerable disadvantage with regard to IVF outcome. It should be emphasized however, that in the absence of associated Nka, DQ alpha/HLA matching whether “partial” or “total (see below) will NOT cause an IID. Since we presently have no way of determining which embryo carries a matching paternal DQ alpha gene, it follows that each embryo transferred will have about half the chance of propagating a viable pregnancy. Treatment of a partial DQ alpha/HLA match (+ Nka) involves the same IL, infusion as for autoimmune-Nka with one important caveat, namely that here we prescribe oral prednisone as adjunct therapy (rather than dexamethasone) and the IL infusion is repeated every 2-4 weeks following the diagnosis of pregnancy and continued until the 24th week of gestation. Additionally, (as alluded to elsewhere) in such cases we transfer a single (1) embryo at a time. This is because, the likelihood is that one out of two embryos will “match” and we are fearful that if we transfer >1 embryo, and one transferred embryos “matches” it could cause further activation of uterine NK cells and so prejudice the implantation of all transferred embryos. Here it should be emphasized that if associated with Nka, a matching embryo will still be at risk of rejection even in the presence of Intralipid (or IVIg) therapy.

Total (complete) DQ alpha Match:   Here the husband’s DQ alpha genotype matches both of that of his partner’s. While this occurs very infrequently, a total alloimmune (DQ alpha) match with accompanying Nka, means that the chance of a viable pregnancy resulting in a live birth at term, is unfortunately greatly diminished.  Several instances in our experience have required the use of a gestational surrogate.

It is indeed unfortunate that so many patients are being denied the ability to go from “infertility to family” simply because (for whatever reason) so many reproductive specialists refuse to embrace the role of immunologic factors in the genesis of intractable reproductive dysfunction. Hopefully this will change, and the sooner the better.

I strongly recommend that you visit www.DrGeoffreySherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select.  Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.

• The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation (COS)
• The Fundamental Requirements for Achieving Optimal IVF Success
• Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
• The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 1-Background
• Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 2- Making a Diagnosis
• Immunologic Dysfunction (IID) & Infertility (IID): PART 3-Treatment
• Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID) Why did my IVF Fail
• Recurrent Pregnancy Loss (RPL): Why do I keep losing my PregnanciesGenetically Testing Embryos for IVF
• Staggered IVF
• Staggered IVF with PGS- Selection of “Competent” Embryos Greatly Enhances the Utility & Efficiency of IVF.
• Embryo Banking/Stockpiling: Slows the “Biological Clock” and offers a Selective Alternative to IVF-Egg Donation
• Preimplantation Genetic Testing (PGS) in IVF: It should be Used Selectively and NOT be Routine.
• IVF: Selecting the Best Quality Embryos to Transfer
• Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
• PGS in IVF: Are Some Chromosomally abnormal Embryos Capable of Resulting in Normal Babies and Being Wrongly Discarded?
• Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management 🙁 Case Report)
• Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
• Intralipid (IL) Administration in IVF: It’s Composition; how it Works; Administration; Side-effects; Reactions and Precautions
• Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
• Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!

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ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

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

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

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That is highly unusual. The ER would not have caused this. Perhaps one of these measurements was not accurate.

It was as far back as 1989, when I first published a study that examined the correlation between the thickness of a woman’s uterine lining (the endometrium), and the subsequent successful implantation of embryos in IVF patients. This study revealed that when the uterine lining measured <8mm in thickness by the day of the “hCG trigger” (in fresh IVF cycles), or at the time of initiating progesterone therapy (in embryo recipient cycles, e.g. frozen embryo transfers-FET, egg donation-IVF etc.) , pregnancy and birth rates were substantially improved. Currently, it is my opinion, that an ideal estrogen-promoted endometrial lining should ideally measure at least 9mm in thickness and that an endometrial lining measuring 8-9mm is “intermediate”. An estrogenic lining of <8mm is in most cases unlikely to yield a viable pregnancy.

A “poor” uterine lining is usually the result of the innermost layer of endometrium (the basal or germinal endometrium from which endometrium grows) ) not being able to respond to estrogen by propagating an outer, “functional” layer thick enough  to support optimal embryo implantation and development of a healthy placenta (placentation). The “functional” layer ultimately comprises 2/3 of the full endometrial thickness and is the layer that sheds with menstruation in the event that no pregnancy occurs.

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

1. Damage to the basal endometrium as a result of:
   1. Inflammation of the endometrium (endometritis) most commonly resulting from infected products left over following abortion, miscarriage or birth
   2. Surgical trauma due to traumatic uterine scraping, (i.e. due to an over-aggressive D & C)
2. Insensitivity of the basal endometrium to estrogen due to:
   1. Prolonged , over-use/misuse of clomiphene citrate
   2. Prenatal exposure to diethylstilbestrol (DES).  This is a drug that was given to pregnant women in the 1960’s to help prevent miscarriage
3. Over-exposure of the uterine lining to ovarian male hormones (mainly testosterone): Older women, women with diminished ovarian reserve (poor responders) and women with polycystic ovarian syndrome -PCOS tend to have raised LH biological activity.. This causes the connective tissue in the ovary (stroma/theca) to overproduce testosterone. The effect can be further exaggerated when certain methods for ovarian stimulation such as agonist (Lupron/Buserelin) “flare” protocols and high dosages of menotropins such as Menopur are used in such cases.
4. Reduced blood flow to the basal endometrium:

Examples include;

1. 1. Multiple uterine fibroids – especially when these are present under the endometrium (submucosal)

1. Uterine adenomyosis (excessive, abnormal invasion of the uterine muscle by endometrial glands).

“The Viagra Connection”

Eighteen years ago years ago, after reporting on the benefit of vaginal Sildenafil (Viagra) for to women who had implantation dysfunction due to thin endometrial linings I was proud to announce the birth of the world’s first “Viagra baby.” Since the introduction of this form of treatment, thousands of women with thin uterine linings have been reported treated and many have gone on to have babies after repeated prior IVF failure.

For those of you who aren’t familiar with the use of Viagra in IVF, allow me to provide some context. It was in the 90’s that Sildenafil (brand named Viagra) started gaining popularity as a treatment for erectile dysfunction.  The mechanism by which it acted was through increasing penile blood flow through increasing nitric oxide activity. This prompted me to investigate whether Viagra administered vaginally, might similarly improve uterine blood flow and in the process cause more estrogen to be delivered to the basal endometrium and thereby increase endometrial thickening. We found that when Viagra was administered vaginally it did just that! However oral administration was without any significant benefit in this regard.  We enlisted the services of a compound pharmacy to produce vaginal Viagra suppositories. Initially, four (4) women with chronic histories of poor endometrial development and failure to conceive following several advanced fertility treatments were evaluated for a period of 4-6 weeks and then underwent IVF with concomitant Viagra therapy. Viagra suppositories were administered four times daily for 8-11 days and were discontinued 5-7 days prior to embryo transfer in all cases.

Our findings clearly demonstrated that vaginal Viagra produced a rapid and profound improvement in uterine blood flow and that was followed by enhanced endometrial development in all four cases. Three (3) of the four women subsequently conceived. I expanded the trial in 2002 and became the first to report on the administration of vaginal Viagra to 105 women with repeated IVF failure due to persistently thin endometrial linings. All of the women had experienced at least two (2) prior IVF failures attributed to intractably thin uterine linings. About 70% of these women responded to treatment with Viagra suppositories with a marked improvement in endometrial thickness. Forty five percent (45%) achieved live births following a single cycle of IVF treatment with Viagra The miscarriage rate was 9%. None of the women who had failed to show an improvement in endometrial thickness following Viagra treatment achieved viable pregnancies.

Following vaginal administration, Viagra is rapidly absorbed and quickly reaches the uterine blood system in high concentrations. Thereupon it dilutes out as it is absorbed into the systemic circulation. This probably explains why treatment is virtually devoid of systemic side effects

It is important to recognize that Viagra will NOT be effective in improving endometrial thickness in all cases. In fact, about 30%-40% of women treated fail to show any improvement. This is because in certain cases of thin uterine linings, the basal endometrium will have been permanently damaged and left unresponsive to estrogen. This happens in cases of severe endometrial damage due mainly to post-pregnancy endometritis (inflammation), chronic granulomatous inflammation due to uterine tuberculosis (hardly ever seen in the United States) and following extensive surgical injury to the basal endometrium (as sometimes occurs following over-zealous D&C’s).

Combining vaginal Viagra Therapy with oral Terbutaline;

In my practice I sometimes recommend combining Viagra administration with 5mg of oral terbutaline. The Viagra relaxes the muscle walls of uterine spiral arteries that feed the basal (germinal) layer of the endometrium while Terbutaline, relaxes the uterine muscle through which these spiral arteries pass. The combination of these two medications interacts synergistically to maximally enhance blood flow through the uterus, thereby improving estrogen delivery to the endometrial lining. The only drawback in using Terbutaline is that some women experience agitation, tremors and palpitations. In such cases the terbutaline should be discontinued. Terbutaline should also not be used women who have cardiac disease or in those who have an irregular heartbeat.

About 75% of women with thin uterine linings see a positive response to treatment within 2-3 days. The ones that do not respond well to this treatment are those who have severely damaged inner (basal/germinal) endometrial linings, such that no improvement in uterine blood flow can coax an improved response. Such cases are most commonly the result of prior pregnancy-related endometrial inflammation (endometritis) that sometimes occurs post abortally or following infected vaginal and/or cesarean delivery.

Viagra therapy has proven to be a god send to thousands of woman who because of a thin uterine lining would otherwise never have been able to successfully complete the journey “from infertility to family”.

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ADDENDUM: PLEASE READ!!

INTRODUCING SHER FERTILITY SOLUTIONS (SFS)

Founded in April 2019, Sher Fertility Solutions (SFS) offers online (Skype/FaceTime) consultations to patients from > 40 different countries. All consultations are followed by a detailed written report presenting my personal recommendations for treatment of what often constitute complex Reproductive Issues.

Patients are encouraged to share the information I provide, with their treating Physicians and/or to avail themselves of my personal hands-on services, provided through batched IVF cycles that I conduct every 3 months at Los Angeles IVF (LAIVF) Clinic, Century City, Los Angeles, CA.

If you wish to schedule an online consultation with me, please contact my assistant (Patti Converse) by phone (800-780-7437/702-533-2691), email (concierge@SherIVF.com) or,  enroll online on then home-page of my website (www.SherIVF.com). 

PLEASE SPREAD THE WORD ABOUT SFS!

Geoff Sher

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ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

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

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

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In my opinion…you would face the same issues . It is not recommended!

This is about your genotype and that of the sperm that fertilized the egg. It is not about egg and sperm.

Read the additional information below!

Geoff Sher

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ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  authored …for your reading pleasure:

• “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link”

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

When it comes to reproduction, humans are the poorest performers of all mammals. In fact we are so inefficient that up to 75% of fertilized eggs do not produce live births, and up to 30% of pregnancies end up being lost within 10 weeks of conception (in the first trimester). RPL is defined as two (2) or more failed pregnancies. Less than 5% of women will experience two (2) consecutive miscarriages, and only 1% experience three or more.

Pregnancy loss can be classified by the stage of pregnancy when the loss occurs:

• Early pregnancy loss (first trimester)
• Late pregnancy loss (after the first trimester)
• Occult “hidden” and not clinically recognized, (chemical) pregnancy loss (occurs prior to ultrasound confirmation of pregnancy)
• Early pregnancy losses usually occur sporadically (are not repetitive).

In more than 70% of cases the loss is due to embryo aneuploidy (where there are more or less than the normal quota of 46 chromosomes). Conversely, repeated losses (RPL), with isolated exceptions where the cause is structural (e.g., unbalanced translocations), are seldom attributable to numerical chromosomal abnormalities (aneuploidy). In fact, the vast majority of cases of RPL are attributable to non-chromosomal causes such as anatomical uterine abnormalities or Immunologic Implantation Dysfunction (IID).

Since most sporadic early pregnancy losses are induced by chromosomal factors and thus are non-repetitive, having had a single miscarriage the likelihood of a second one occurring is no greater than average. However, once having had two losses the chance of a third one occurring is double (35-40%) and after having had three losses the chance of a fourth miscarriage increases to about 60%. The reason for this is that the more miscarriages a woman has, the greater is the likelihood of this being due to a non-chromosomal (repetitive) cause such as IID. It follows that if numerical chromosomal analysis (karyotyping) of embryonic/fetal products derived from a miscarriage tests karyotypically normal, then by a process of elimination, there would be a strong likelihood of a miscarriage repeating in subsequent pregnancies and one would not have to wait for the disaster to recur before taking action. This is precisely why we strongly advocate that all miscarriage specimens be karyotyped.

There is however one caveat to be taken into consideration. That is that the laboratory performing the karyotyping might unwittingly be testing the mother’s cells rather than that of the conceptus. That is why it is not possible to confidently exclude aneuploidy in cases where karyotyping of products suggests a “chromosomally normal” (euploid) female.

Late pregnancy losses (occurring after completion of the 1st trimester/12th week) occur far less frequently (1%) than early pregnancy losses. They are most commonly due to anatomical abnormalities of the uterus and/or cervix. Weakness of the neck of the cervix rendering it able to act as an effective valve that retains the pregnancy (i.e., cervical incompetence) is in fact one of the commonest causes of late pregnancy loss. So also are developmental (congenital) abnormalities of the uterus (e.g., a uterine septum) and uterine fibroid tumors. In some cases intrauterine growth retardation, premature separation of the placenta (placental abruption), premature rupture of the membranes and premature labor can also causes of late pregnancy loss.

Much progress has been made in understanding the mechanisms involved in RPL. There are two broad categories:

1. Problems involving the uterine environment in which a normal embryo is prohibited from properly implanting and developing. Possible causes include:

• Inadequate thickening of the uterine lining
• Irregularity in the contour of the uterine cavity (polyps, fibroid tumors in the uterine wall, intra-uterine scarring and adenomyosis)
• Hormonal imbalances (progesterone deficiency or luteal phase defects). This most commonly results in occult RPL.
• Deficient blood flow to the uterine lining (thin uterine lining).
• Immunologic implantation dysfunction (IID). A major cause of RPL. Plays a role in 75% of cases where chromosomally normal preimplantation embryos fail to implan
• Interference of blood supply to the developing conceptus can occur due to a hereditary clotting disorder known as Thrombophili

1. Genetic and/or numerical chromosomal abnormalities(aneuploidy) of the embryo are far away the commonest overall causes of miscarriages. But this only applies to sporadic pregnancy losses (which comprises the majority of all miscarriages. However, recurrent, (consecutive) pregnancy losses are much more likely due to implantation dysfunction than to embryo-related issues, where implantation dysfunction (usually anatomical or immunologic) factors usually underly the problem.
2. Genetic or Structural chromosomal abnormalities (which only occur in about 1% of cases) can also cause RPL. This is referred to as an unbalanced translocation and they result from part of one chromosome detaching and then fusing with another chromosome. Additionally, genetic defects (unrelated to chromosomal abnormalities) can also affect embryo quality and pregnancy outcome. Damaged sperm DNA can sometimes be diagnosed using the SCSA (see before) which primarily measures the sperm DNA fragmentation index (DFI).

IMMUNOLOGIC IMPLANTATION DYSFUNCTIO-IID (see before)

Autoimmune IID: Here an immunologic reaction is produced by the individual to his/her body’s own cellular components. The most common antibodies that form in such situations are APA and antithyroid antibodies

Alloimmune IID, i.e., where there is an immunologic reaction to antigens derived from another member of the same species (i.e. the woman’s immune system reacts to the paternal antigens in the sperm (see above) .

*It is important to recognize that alloimmune (rather than autoimmune) IID is more commonly associated with RPL.

Autoimmune IID is often genetically transmitted. Thus, it should not be surprising to learn that it is more likely to exist in women who have a family (or personal) history of primary autoimmune diseases such as lupus erythematosus (LE), scleroderma or autoimmune hypothyroidism (Hashimoto’s disease), autoimmune hyperthyroidism (Grave’s disease), rheumatoid arthritis, etc. Reactionary (secondary) autoimmunity can occur in conjunction with any medical condition associated with widespread tissue damage. One such gynecologic condition is endometriosis. Since autoimmune IID is usually associated with activated NK and T-cells from the outset, it usually results in such very early destruction of the embryo’s root system that the patient does not even recognize that she is pregnant. Accordingly, the condition usually presents as “unexplained infertility” or “unexplained IVF failure” rather than as a miscarriage.

Alloimmune IID, on the other hand, usually starts off presenting as unexplained miscarriages (often manifesting as RPL). Over time as NK/T cell activation builds and eventually becomes permanently established the patient often goes from RPL to “infertility” due to failed implantation. RPL is more commonly the consequence of alloimmune rather than autoimmune implantation dysfunction.

However, regardless, of whether miscarriage is due to autoimmune or alloimmune implantation dysfunction the final blow to the pregnancy is the result of activated NK cells and CTL in the uterine lining that damage the developing embryo’s “root system” (trophoblast) so that it can no longer sustain the growing conceptus. This having been said, it is important to note that autoimmune IID is readily amenable to reversal through timely, appropriately administered, selective immunotherapy, and alloimmune IID is not. It is much more difficult to treat successfully, even with the use of immunotherapy. In fact, in some cases the only solution will be to revert to selective immunotherapy plus using donor sperm (provided there is no “match” between the donor’s DQ alpha/HLA profile and that of the female recipient) or alternatively to resort to gestational surrogacy.

DIAGNOSING THE CAUSE OF RPL

In the past, women who miscarried were not evaluated thoroughly until they had lost several pregnancies in a row. This was because sporadic miscarriages are most commonly the result of embryo numerical chromosomal irregularities (aneuploidy) and thus not treatable. However, a consecutive series of miscarriages points to a repetitive cause that is non-chromosomal and is potentially remediable. Since RPL is most commonly due to a uterine pathology or immunologic causes that are potentially treatable, it follows that early chromosomal evaluation of products of conception could point to a potentially treatable situation. Thus, we strongly recommend that such testing be done in most cases of miscarriage. Doing so will avoid a great deal of unnecessary heartache for many patients.

Establishing the correct diagnosis is the first step toward determining effective treatment for couples with RPL. It results from a problem within the pregnancy itself or within the uterine environment where the pregnancy implants and grows. Diagnostic tests useful in identifying individuals at greater risk for a problem within the pregnancy itself include:

• Karyotyping (chromosome analysis) both prospective parents
• Assessment of the karyotype of products of conception derived from previous miscarriage specimens
• Ultrasound examination of the uterine cavity after sterile water is injected or sonohysterogram, fluid ultrasound, etc.
• Hysterosalpingogram (dye X-ray test)
• Hysteroscopic evaluation of the uterine cavity
• Full hormonal evaluation (estrogen, progesterone, adrenal steroid hormones, thyroid hormones, FSH/LH, )
• Immunologic testing to include:
  • Antiphospholipid antibody (APA) panel
  • Antinuclear antibody (ANA) panel
  • Antithyroid antibody panel (i.e., antithyroglobulin and antimicrosomal antibodies)
  • Reproductive immunophenotype
  • Natural killer cell activity (NKa) assay (i.e., K562 target cell test)
  • Alloimmune (DQ alpha/HLA) testing of both the male and female partners

TREATMENT OF RPL

Treatment for Anatomic Abnormalities of the Uterus: This involves restoration through removal of local lesions such as fibroids, scar tissue, and endometrial polyps or timely insertion of a cervical cerclage (a stitch placed around the neck of the weakened cervix) or the excision of a uterine septum when indicated.

Treatment of Thin Uterine Lining: A thin uterine lining has been shown to correlate with compromised pregnancy outcome. Often this will be associated with reduced blood flow to the endometrium.  Such decreased blood flow to the uterus can be improved through treatment with sildenafil and possibly aspirin.

Sildenafil (Viagra) Therapy (see above). Viagra has been used successfully to increase uterine blood flow. To date, we have seen significant improvement of the thickness of the uterine lining in about 70% of women treated. Successful pregnancy resulted in almost half of those women who responded to the Viagra. It should be borne in mind that most of these women had previously experienced repeated IVF failures.

Use of Aspirin: This is an anti-prostaglandin that improves blood flow to the endometrium. It is administered at a dosage of 81 mg orally, daily from the beginning of the cycle until ovulation.

Treating Immunologic Implantation Dysfunction with Selective Immunotherapy: Modalities such as IL/IVIg, heparinoids (Lovenox/Clexane), and corticosteroids can be used in select cases depending on autoimmune or alloimmune dysfunction.

The Use of IVF in the Treatment of RPL. In the following circumstances, IVF is the preferred option:

• When in addition to a history of RPL, another standard indication for IVF (e.g., tubal factor, endometriosis, and male factor infertility) is superimposed.
• In cases where selective immunotherapy is needed to treat an immunologic implantation dysfunction.

The reason for IVF being a preferred approach in such cases is that in order to be effective, the immunotherapy needs to be initiated well before spontaneous or induced ovulation. Given the fact that in the absence of IVF the anticipated birthrate per cycle of COS with or without IUI is at best about 15%, it follows that short of IVF, to have even a reasonable chance of a live birth, most women with immunologic causes of RPL would need to undergo immunotherapy repeatedly, over consecutive cycles. Conversely, with IVF, the chance of a successful outcome in a single cycle of treatment is several times greater and, because of the attenuated and concentrated time period required for treatment, IVF is far safer and thus represents a more practicable alternative

Since embryo aneuploidy is a common cause of miscarriage, the use of PGS/PGT-A can provide a valuable diagnostic and therapeutic advantage in cases of RPL. PGD requires IVF to provide access to embryos for testing.

There are a few cases of intractable alloimmune dysfunction due to “complete DQ alpha matching where Gestational Surrogacy or use of Donor  Sperm could represent the only viable recourse, other than abandoning treatment altogether and/or resorting to adoption. Other non-immunologic factors such as an intractably thin uterine lining or severe uterine pathology might also warrant that last resort consideration be given to gestational surrogacy.

The good news is that if a couple with RPL is open to all of the diagnostic and treatment options referred to above, a live birthrate of 70%–80% is ultimately achievable.

I strongly recommend that you visit www.SherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select.  Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.

• The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
• The Fundamental Requirements For Achieving Optimal IVF Success
• Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the “Conventional” Antagonist Approach
• Ovarian Stimulation in Women Who have Diminished Ovarian Reserve (DOR): Introducing the Agonist/Antagonist Conversion protocol
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
• Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
• The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
• Blastocyst Embryo Transfers Should be the Standard of Care in IVF
• IVF: How Many Attempts should be considered before Stopping?
• “Unexplained” Infertility: Often a matter of the Diagnosis Being Overlooked!
• IVF Failure and Implantation Dysfunction:
• The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 1-Background
• Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 2- Making a Diagnosis
• Immunologic Dysfunction (IID) & Infertility (IID):PART 3-Treatment
• Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
• Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management:(Case Report
• Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
• Intralipid (IL) Administration in IVF: It’s Composition; How it Works; Administration; Side-effects; Reactions and Precautions
• Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
• Endometrial Thickness, Uterine Pathology and Immunologic Factors
• Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
• Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
• A personalized, stepwise approach to IVF
• How Many Embryos should be transferred: A Critical Decision in IVF.
• The Role of Nutritional Supplements in Preparing for IVF

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ADDENDUM: PLEASE READ!!

INTRODUCING SHER FERTILITY SOLUTIONS (SFS)

Founded in April 2019, Sher Fertility Solutions (SFS) offers online (Skype/FaceTime) consultations to patients from > 40 different countries. All consultations are followed by a detailed written report presenting my personal recommendations for treatment of what often constitute complex Reproductive Issues.

If you wish to schedule an online consultation with me, please contact my assistant (Patti Converse) by phone (800-780-7437/702-533-2691), email (concierge@SherIVF.com) or,  enroll online on then home-page of my website (www.SherIVF.com). 

PLEASE SPREAD THE WORD ABOUT SFS!

Geoff Sher

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ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

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

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

This sounds like implantation dysfunction.

Implantation dysfunction is unfortunately often overlooked as an important cause of IVF failure. This is especially relevant in cases of unexplained IVF failure, recurrent pregnancy loss (RPL), and in women with underlying endo-uterine surface lesions, thickness of the uterine lining (endometrium) and /or immunologic factors.

IVF success rates have been improving over the last decade. The average live birth rate per embryo transfer in the U.S.A for women under 40y using their own eggs is currently better than 1:3 women. However, there is still a wide variation from program to program for IVF live birth rates, ranging from 20% to near 50%. Based upon these statistics, most women undergoing IVF in the United States require two or more attempts to have a baby. IVF practitioners in the United States commonly attribute the wide dichotomy in IVF success rates to variability in expertise of the various embryology laboratories. This is far from accurate. In fact, other factors such as wide variations in patient selection and the failure to develop individualized protocols for ovarian stimulation or to address those infectious, anatomical, and immunologic factors that influence embryo implantation are at least equally important.

About 80% of IVF failures are due to “embryo incompetency” that is largely due to aneuploidy      usually related to advancing age of the woman and is further influenced by other factors such as the protocol selected for ovarian stimulation, diminished ovarian reserve (DOR), and severe male factor infertility. However, in about 20% of dysfunctional cases embryo implantation is the cause of failure.

This section will focus on implantation dysfunction and IVF failure due to:

ANATOMICAL ENDO-UTERINE SURFACE LESIONS

            It has long been suspected that anatomical defects of the uterus might result in infertility. While the presence of uterine fibroids, in general, are unlikely to cause infertility, an association between their presence and infertility has been observed in cases where the myomas distort the uterine cavity or protrude through the endometrial lining.  Even small fibroids that lie immediately under the endometrium (submucous fibroids) and protrude into the uterine cavity have the potential to lower embryo implantation.  Multiple fibroids in the uterine wall (intramural fibroids) that encroach upon the uterine cavity can sometimes so compromise blood flow that estrogen delivery is impaired, and the endometrium is unable to thicken properly. This can usually be diagnosed by ultrasound examination during the proliferative phase of the menstrual cycle.  It is likely that any surface lesion in the uterine cavity, whether submucous fibroids, intrauterine adhesions a small endometrial or a placental polyp, has the potential to interfere with implantation by producing a local inflammatory response, not too dissimilar in nature from that which is caused by an intrauterine contraceptive device (IUD).       

            Clearly, since even small uterine lesions have the potential to adversely affect implantation, the high cost (financial, physical, and emotional) associated with IVF and related procedures, justifies the routine performance of diagnostic procedures such as an HSG, hysterosonogram (fluid ultrasound examination), or hysteroscopy prior to initiating IVF.  Identifiable uterine lesions that have the potential of impairing implantation usually require surgical intervention.  In most cases, dilatation and curettage (D & C) or hysteroscopic resection will suffice. Some cases might require the performance of a laparotomy.  Such intervention will often result in subsequent improvement of the endometrial response.      

Sonohysterography [Fluid ultrasonography (FUS)]: Fluid ultrasonography is a procedure whereby a sterile solution of saline is injected via a catheter through the cervix and into the uterine cavity. The fluid-distended cavity is examined by vaginal ultrasound for any irregularities that might point to surface lesions such as polyps, fibroid tumors, scarring, or a uterine septum. If performed by an expert, a FUS is highly effective in recognizing even the smallest lesion and can replace hysteroscopy under such circumstances. FUS is less expensive, less traumatic, and equally as effective as hysteroscopy. The only disadvantage lies in the fact that if a lesion is detected, it may require the subsequent performance of hysteroscopy to treat the problem anyway.

Hysteroscopy: Diagnostic hysteroscopy is an office procedure that is performed under intravenous sedation, general anesthesia, or paracervical block with minimal discomfort to the patient. This procedure involves the insertion of a thin, lighted, telescope like instrument known as a hysteroscope through the vagina and cervix into the uterus to fully examine the uterine cavity. The uterus is first distended with normal saline, which is passed through a sleeve adjacent to the hysteroscope. As is the case with FUS, diagnostic hysteroscopy facilitates examination of the inside of the uterus under direct vision for defects that might interfere with implantation. We have observed that approximately one in eight candidates for IVF have lesions that require attention prior to undergoing IVF in order to optimize the chances of a successful outcome. We strongly recommend that all patients undergo therapeutic surgery (usually by hysteroscopy) to correct the pathology prior to IVF.  Depending on the severity and nature of the pathology, therapeutic hysteroscopy may require general anesthesia and, in such cases, should be performed in an outpatient surgical facility or conventional operating room where facilities are available for laparotomy, a procedure in which an incision is made in the abdomen to expose the abdominal contents for diagnosis, or for surgery should this be required.       

THICKNESS OF THE UTERINE LINING (ENDOMETRIUM):

As far back as in 1989 we first reported on the finding that ultrasound assessment of the late proliferative phase endometrium can identify those candidates who are least likely to conceive. We noted that the ideal thickness of the endometrium at the time of ovulation or egg retrieval is >8 mm and that thinner linings are associated with decreased implantation rates.

More than 30 years ago we first showed that in normal and “stimulated” cycles, pre-ovulatory endometrial thickness and ultrasound appearance is predictive of embryo implantation (pregnancy) potential following ET. With conventional IVF and with FET, endometrial lining at the time of the “trigger shot” or with the initiation of progesterone needs to preferably be at least 8 mm in sagittal thickness with a triple line (trilaminar) appearance. Anything less than an 8mm endometrial thickness       is associated with a reduction in live birth rate per ET. An 8-9mm thickness represents a transitional measurement…a “gray zone”.  Hitherto, attempts to augment endometrial growth in women with poor endometrial linings by bolstering circulating estrogen blood levels (through the administration of increased doses of fertility drugs, aspirin administration and by supplementary estrogen therapy) yielded disappointing results.

            A “poor” uterine lining is usually the result of the innermost layer of endometrium (the basal or germinal endometrium from which endometrium grows) not being able to respond to estrogen by propagating an outer, “functional” layer thick enough to support optimal embryo implantation and development of a healthy placenta (placentation). The “functional” layer ultimately comprises 2/3 of the full endometrial thickness and is the layer that sheds with menstruation if no pregnancy occurs.

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

• Damage to the basal endometrium because of:
• Inflammation of the endometrium (endometritis) most commonly resulting from infected products left over following abortion, miscarriage, or birth
• Surgical trauma due to traumatic uterine scraping, (i.e. due to an over-aggressive D & C)
• Insensitivity of the basal endometrium to estrogen due to:
• Prolonged, over-use/misuse of clomiphene citrate
• Prenatal exposure to diethylstilbestrol (DES). This is a drug that was given to pregnant women in the 1960’s to help prevent miscarriage
• Over-exposure of the uterine lining to ovarian male hormones (mainly testosterone): Older women, women with diminished ovarian reserve (poor responders) and women with polycystic ovarian syndrome -PCOS tend to have raised LH biological activity. This causes the connective tissue in the ovary (stroma/theca) to overproduce testosterone. The effect may be further exaggerated when certain methods for ovarian stimulation such as “flare” protocols and high dosages of Menopur are used in such cases.
• Reduced blood flow to the basal endometrium: Examples include.
• Multiple uterine fibroids – especially when these are present under the endometrium (submucosal)
• Uterine adenomyosis (excessive, abnormal invasion of the uterine muscle by endometrial glands).

Vaginal Viagra: About 35 years ago, after reporting on the benefit of administering vaginal Sildenafil (Viagra) to women who had implantation dysfunction due to thin endometrial linings we announced the birth of the world’s first “Viagra baby.”  Viagra administered vaginally, but not orally, in affected women improves uterine blood flow causing more estrogen to be delivered to the basal endometrium and increasing the endometrial thickening.  Following vaginal administration, Viagra is rapidly absorbed and quickly reaches the uterine blood system in high concentrations. Thereupon it dilutes out as it is absorbed into the systemic circulation. This probably explains why treatment is virtually devoid of systemic side effects.  It is important to recognize that Viagra will NOT be effective in improving endometrial thickness in all cases. In fact, about one third of women treated fail to show any improvement. This is because in certain cases of thin uterine linings, the basal endometrium will have been permanently damaged and left unresponsive to estrogen. This happens in cases of severe endometrial damage due mainly to post-pregnancy endometritis (inflammation), chronic granulomatous inflammation due to uterine tuberculosis (hardly ever seen in the United States) and following extensive surgical injury to the basal endometrium (as sometimes occurs following over-zealous D&C’s).

• Immunologic factors: These also play a role in IVF failure (see “Immunologic factors and Implantation” …see below.

IMMUNOLOGIC IMPLANTATION DYSFUNCTION (IID)

            Currently, with few exceptions, practitioners of assisted reproduction tend to attribute “unexplained and/or repeated” IVF failure(s), almost exclusively to poor embryo quality, advocating adjusted protocols for ovarian stimulation and/or gamete and embryo preparation as a potential remedy. The idea, having failed IVF, that all it takes to ultimately succeed is to keep trying the same recipe is over-simplistic.

            The implantation process begins six or seven days after fertilization of the egg. At this time, specialized embryonic cells (i.e., trophoblasts), that later become the placenta begin growing into the uterine lining. When the trophoblast and the uterine lining meet, they, along with immune cells in the lining, become involved in a “cross talk” through mutual exchange of hormone-like substances called cytokines. Because of this complex immunologic interplay, the uterus can foster the embryo’s successful growth. Thus, from the earliest stage, the trophoblast establishes the very foundation for the nutritional, hormonal and respiratory interchange between mother and baby.  In this manner, the interactive process of implantation is not only central to survival in early pregnancy but also to the quality of life after birth.

There is an ever growing realization, recognition, and acceptance of the fact that uterine immunologic dysfunction can lead to immunologic implantation dysfunction (IID) with “unexplained” infertility, IVF failure, and recurrent pregnancy loss (RPL).

DIAGNOSIS 

Because immunologic problems may lead to implantation failure, it is important to properly evaluate women with risk factors such as:

• Unexplained or recurrent IVF failures
• Unexplained infertility or a family history of autoimmune diseases (e.g., rheumatoid arthritis, lupus erythematosus and hypothyroidism).
• Recurrent Pregnancy Loss (RPL)
• Endometriosis
• A personal or family history of autoimmune conditions, e.g., Rheumatoid Arthritis, Lupus erythematosus, autoimmune hypothyroidism (Hashimoto’s disease) etc.

            Considering its importance, it is not surprising that the failure of a properly functioning immunologic interaction during implantation has been implicated as a cause of recurrent miscarriage, late pregnancy fetal loss, IVF failure and infertility. A partial list of immunologic factors that may be involved in these situations includes:

• Antiphospholipid antibodies (APA)
• Antithyroid antibodies (ATA/AMA)
• Activated natural killer cells (NKa)

ACTIVATED NATURAL KILLER CELLS (NKa):

Following ovulation and during early pregnancy, NK cells and T-cells comprise more than 80% of the lymphocyte-immune cells that frequent the uterine lining. These lymphocytes (white blood cells) journey from the bone marrow to the uterus and under hormonal regulation, proliferate there. After exposure to progesterone (due to induced /spontaneous exogenous administration), they begin to produce TH-1 and TH-2 cytokines. TH-2 cytokines are humoral in nature and induce the trophoblast (“root system of the embryo”) to permeate the uterine lining while TH-I cytokines induce a process referred to as apoptosis (cell suicide) thereby confining placental development to the inner part of the uterus. Optimal placental development (placentation) mandates that there be a balance between TH1 and TH-2 cytokines. Most of the cytokine production originates from NK cells (rather than from cytotoxic T-cells/Lymphocytes (CTL)). Excessive production/release of TH-1 cytokines, is toxic to the trophoblast and to endometrial cells, leading to programmed death/suicide (apoptosis) and subsequently to IID.

Functional NK cells reach a maximal concentration in the endometrium by about t day 6-7 days after exposure to progesterone …. This timing corresponds with when the embryo implants into the uterine lining (endometrium).

It is important to bear in mind that measurement of the concentration of blood NK cells has little or no relevance when it comes to assessing NK cell activation (NKa). Rather, it is the NK cell activation that matters. In fact, there are certain conditions (such as with endometriosis) where the NK cell blood concentration is below normal, but NK cell activation is markedly increased.

There are several methods by which NK cell activation (cytotoxicity) can be assessed in the laboratory. Methods such as immunohistochemical assessment of uterine NK cells and/or through measurement of uterine or blood TH-1 cytokines. However, the K-562 target cell blood test still remains the gold standard. With this test, NK cells, isolated from the woman’s blood using Flow Cytometry are incubated in the presence of specific “target cells”. The percentage (%) of “target cells” killed is then quantified. More than 12% killing suggests a level of NK cell activation that usually requires treatment.

Currently, there are less than a half dozen Reproductive Immunology Reference Laboratories in the U.S.A that are capable of performing the K-562 target cell test reliably.

There exists a pervasive but blatant misconception on the part of many, that the addition of IL or IVIg to a concentration of NK cells could have an immediate down-regulatory effect on NK cell activity. Neither IVIg nor IL is capable of significantly suppressing already activated “functional NK cells”. They are believed to work through “regulating” NK cell progenitors which only thereupon will start to propagate down-regulated NK cells. Thus, testing for a therapeutic effect would require that the IL/IVIg infusion be done about 14 days prior to ovulation or progesterone administration…  in order to allow for a sufficient number of normal (non-activated) “functional” NK cell” to be present at the implantation site when the embryos are transferred.

Failure to recognize this reality has, in our opinion, established an erroneous demand by practicing IVF doctors, that Reproductive Immunology Reference Laboratories report on NK cell activity before and again, immediately following laboratory exposure to IVIg and/or IL in different concentrations. Allegedly, this is to allow the treating physician to report back to their patient(s) on whether an IL or IVIG infusion will be effective in downregulating their Nka.  But, since already activated NK cells (NKa) cannot be deactivated in the laboratory, effective NKa down-regulation can only be adequately accomplished through deactivation of NK cell “progenitors /parental” NK cells in order to allow them thereupon, to s propagate normal “functional” NK cells and his takes about 10-14 days, such practice would be of little clinical benefit. This is because even if blood were to be drawn 10 -14 days after IL/IVIg treatment it would require at least an additional 10 -14days to receive results from the laboratory, by which time it would be far too late to be of practical advantage.

ANTIPHOSPHOLIPID ANTIBODIES:

 Many women who experience “unexplained” IVF failure, women with RPL, those with a personal or family history of autoimmune diseases such as lupus erythematosus, rheumatoid arthritis, scleroderma, and dermatomyositis (etc.)  as well as women who have endometriosis (“silent” or overt) test positive for APAs. More than 30 years ago, we were the first to propose that women who test positive for APA’s be treated with a mini-dose heparin to improve IVF implantation and thus birth rates. This approach was based upon research that suggested that heparin repels APAs from the surface of the trophoblast (the embryo’s “root system) thereby reducing its ant-implantation effects.  We subsequently demonstrated that such therapy only improved IVF outcome in women whose APAs were directed against two specific IgG and/or IgM phospholipids [i.e., phosphatidylethanolamine (PE) and phosphatidylserine (PS)].  More recently low dosage heparin therapy has been supplanted using longer acting low molecular weight heparinoids such as Lovenox and Clexane.   It is very possible that APAs alone do not cause IID but that their presence might help to identify a population at risk due to concomitant activation of uterine natural killer cells (Nka) which through excessive TH-1 cytokine production causes in IID: This is supported by the following observations:

• The presence of female APAs in cases of male factor cases appears to bear no relationship to IID.
• Only APA positive women who also test positive for abnormal NK activity appear to benefit from selective immunotherapy with intralipid/IVIg/ steroids.
• Most APA positive women who have increased NK cell activity also harbor IgG or IgM phosphatidylethanolamine (PE) and phosphatidylserine (PS) antibodies.

ANTITHYROID ANTIBODIES: (ATA).

 A clear relationship has been established between ATA and reproductive failure (especially recurrent miscarriage and infertility).

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

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

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

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

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

TEATMENT OF IID:

The mainstay of treatment involves the selective use of:

• Intralipid (IL) infusion
• IVIg therapy
• Corticosteroids (Prednisone/dexamethasone)
• Heparinoids (Lovenox/Clexane)

Intralipid (IL) Therapy:  IL is a suspension of soybean lipid droplets in water and is primarily used as source of parenteral nutrition. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, and alpha-linolenic acid (ALA), an omega-3 fatty acid.     

It is thought that fatty acids within the emulsion serve as ligands that activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cell cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent.

            Whatever the exact mechanism of action might be, Intralipid acts primarily to suppress NK cell over-production of TH-I cytokines. It exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating cytotoxic /activated natural killer cells (NKa). This effect is enhanced through the concomitant administration of corticosteroids such as dexamethasone, prednisolone and prednisone which augment immune modulation of T cells. The combined effect of IL + steroid therapy suppresses pro-inflammatory cellular TH1 cytokines such as interferon gamma and TNF-alpha that are produced in excess by activated NK cells and cytotoxic lymphocytes/T-cells (CTL).   IL will, in about 80% of cases, successfully down-regulate activated natural killer cells (NKa) over a period of 2-3 weeks. It is likely to be just as effective as IVIg in this respect but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for ~ 4-6 weeks when administered in early pregnancy.

Intralipid is a suspension of soybean lipid droplets in water and is primarily used as source of parenteral nutrition. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, and alpha-linolenic acid (ALA), an omega-3 fatty acid.     

It is thought that fatty acids within the emulsion serve as ligands that activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cell cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent.

            Whatever the exact mechanism of action might be, Intralipid acts primarily to suppress NK cell over-production of TH-I cytokines. It exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating cytotoxic /activated natural killer cells (NKa). This effect is enhanced through the concomitant administration of corticosteroids such as dexamethasone, prednisolone and prednisone which augment immune modulation of T cells. The combined effect of IL + steroid therapy suppresses pro-inflammatory cellular TH1 cytokines such as interferon gamma and TNF-alpha that are produced in excess by activated NK cells and cytotoxic lymphocytes/T-cells (CTL).   IL will, in about 80% of cases, successfully down-regulate activated natural killer cells (NKa) over a period of 2-3 weeks. It is likely to be just as effective as IVIg in this respect but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for ~ 4-6 weeks when administered in early pregnancy.

            Can laboratory testing be used to assess for an immediate effect of IL on Nka suppression?  Since the downregulation of NKa through IL (or IVIg) therapy can take several weeks to become measurable, it follows that there is really no benefit in trying to assess the potential efficacy of such treatment by retesting NKa in the laboratory after adding IL (or IVIg) to the cells being tested.

IVIg Therapy:  Until about a decade ago, the only effective and available way (in the US) to down-regulate activated NK cells was through the intravenous administration of a blood product known as immunoglobulin-G (IVIg). The fear (albeit unfounded) that the administration of this product might lead to the transmission of viral infections such as HIV and hepatitis C, plus the high cost of IVIG along with the fact that significant side effects occurred about 20% of the time, led to bad press and bad publicity for the entire field of reproductive immunology. It was easier for RE’s to simply say “I don’t believe IVIg works” and thereby avoid risk and bad publicity. But the thousands of women who had babies because of NK cell activity being downregulated through its use, attests to IVIg’s efficacy. But those of us who felt morally obligated to many desperate patients who would not conceive without receiving IVIg were facing an uphill battle. The bad press caused by fear mongering took its toll and spawned a malicious controversy. It was only through the introduction of IL less (about 15-20 years ago ), that the tide began to turn in favor of those patients who required low cost, safe and effective immunotherapy to resolve their IID.

 Corticosteroid Therapy (e.g., Prednisone, and Dexamethasone): Corticosteroid therapy has become a mainstay in the treatment of most women undergoing IVF. It is believed by most to enhance implantation due to an overall immunomodulatory effect. Corticosteroids reduce TH-1 cytokine production by CTL. When given in combination with IL or IVIG they augment the implantation process. The prednisone or dexamethasone therapy must commence (along with IL/IVIg) 10-14 days prior to egg retrieval and continue until pregnancy is discounted or until the 10th week of pregnancy.

 Heparinoid Therapy: There is compelling evidence that the subcutaneous administration of low molecular heparin (Clexane, Lovenox) once daily, (starting with the onset of ovarian stimulation) can improve IVF birthrate in women who test positive for APAs and might prevent later pregnancy loss when used to treat certain thrombophilias (e.g., homozygous MTHFR mutation)

What About Baby Aspirin? In our opinion, aspirin has little (if any) value when it comes to IID, and besides, it could even reduce the chance of success. The reason for this is that aspirin thins the blood and increases the potential to bleed. This effect can last for up to a week and could complicate an egg retrieval procedure or result in “concealed” intrauterine bleeding at the time of embryo transfer, thereby potentially compromising IVF success.

TH-1 Cytokine Blockers (Enbrel, Humira): TH-1 cytokine blockers, (Enbrel and Humira) are in our opinion relatively ineffective in the IVF setting. There has to date been no convincing data to support their use. However, these blockers could have a role in the treatment of a threatened miscarriage thought to be due to CTL/NK activation, but not for IVF. The reason is that the very initial phase of implantation requires a cellular response involving TH-1 cytokines. To block them completely (rather than simply restore a TH-1:TH-2 balance as occurs with IL therapy) so very early on could compromise rather than benefit implantation.

Leukocyte Immunization Therapy (LIT): The subcutaneous injection of the male partner’s lymphocytes to the mother is thought to enhance the ability for the mother’s decidua (uterus) to recognize the DQ alpha matching embryo as “self” or “friend” and thereby avert its rejection. LIT has been shown to up-regulate Treg cells and thus down-regulate NK cell activation thereby improving decidual TH-1:TH-2 balance. Thus, there could be a therapeutic benefit from such therapy. However, the same benefit can be achieved through the use of IL plus corticosteroids. Besides, IL is much less expensive, and the use of LIT is prohibited by law in the U.S.A.

There are two categories of immunologic implantation dysfunction (IID) linked to NK cell activation (NKa).

Autoimmune Implantation Dysfunction: Here, the woman will often have a personal or family history of autoimmune conditions such as Rheumatoid arthritis, Lupus Erythematosus, and thyroid autoimmune activity (e.g., Hashimoto’s disease) etc. Autoimmune as well as in about one third of cases of endometriosis, regardless of severity.  Autoimmune sometimes also occurs in the absence of a personal or family history of autoimmune disease.

When it comes to treating  NKa in  IVF cases complicated by autoimmune implantation dysfunction,  the combination of daily oral dexamethasone commencing with the onset of ovarian stimulation and continuing until the 10th week of pregnancy, combined with an initial infusion of IL (100ml, 20% Il dissolved in 500cc of saline solution, 10-14  days prior to PGT-normal embryo transfer and repeated once more (only), as  soon as the blood pregnancy test is positive), the anticipated chance of a viable pregnancy occurring within 2 completed IVF attempts (including fresh + frozen ET’s)  in women under 39Y (who have normal ovarian reserve)  is approximately  65%.

Alloimmune Implantation Dysfunction: Here, NK cell activation results from uterine exposure to an embryo derived through fertilization by a spermatozoon that shares certain genotypic (HLA/DQ alpha) similarities with that of the embryo recipient.

Partial DQ alpha/HLA match:  Couples who upon genotyping are shown to share only one DQ alpha/HLA gene are labeled as having a “partial match”. The detection of a “partial match” in association with NKa puts the couple at a considerable disadvantage with regard to IVF outcome. It should be emphasized however, that in the absence of associated Nka, DQ alpha/HLA matching whether “partial” or “total (see below) will NOT cause an IID. Since we presently have no way of determining which embryo carries a matching paternal DQ alpha gene, it follows that each embryo transferred will have about half the chance of propagating a viable pregnancy. Treatment of a partial DQ alpha/HLA match (+ Nka) involves the same IL, infusion as for autoimmune-Nka with one important caveat, namely that here we prescribe oral prednisone as adjunct therapy (rather than dexamethasone) and the IL infusion is repeated every 2-4 weeks following the diagnosis of pregnancy and continued until the 24th week of gestation. Additionally, (as alluded to elsewhere) in such cases we transfer a single (1) embryo at a time. This is because, the likelihood is that one out of two embryos will “match” and we are fearful that if we transfer >1 embryo, and one transferred embryos “matches” it could cause further activation of uterine NK cells and so prejudice the implantation of all transferred embryos. Here it should be emphasized that if associated with Nka, a matching embryo will still be at risk of rejection even in the presence of Intralipid (or IVIg) therapy.

Total (complete) DQ alpha Match:   Here the husband’s DQ alpha genotype matches both of that of his partner’s. While this occurs very infrequently, a total alloimmune (DQ alpha) match with accompanying Nka, means that the chance of a viable pregnancy resulting in a live birth at term, is unfortunately greatly diminished.  Several instances in our experience have required the use of a gestational surrogate.

It is indeed unfortunate that so many patients are being denied the ability to go from “infertility to family” simply because (for whatever reason) so many reproductive specialists refuse to embrace the role of immunologic factors in the genesis of intractable reproductive dysfunction. Hopefully this will change, and the sooner the better.

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I urge you to  visit my website at  www.SherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select.  Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.

• A Fresh Look at the Indications for IVF
• The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
• The Fundamental Requirements For Achieving Optimal IVF Success
• Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
• Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
• IVF and the use of Supplementary Human Growth Hormone (HGH) : Is it Worth Trying and who needs it?
• The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
• Blastocyst Embryo Transfers Should be the Standard of Care in IVF
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
• IVF: Approach to Selecting the Best Embryos for Transfer to the Uterus.
• Fresh versus Frozen Embryo Transfers (FET) Enhance IVF Outcome
• Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
• Genetically Testing Embryos for IVF
• Staggered IVF
• Staggered IVF with PGS- Selection of “Competent” Embryos Greatly Enhances the Utility & Efficiency of IVF.
• Preimplantation Genetic Testing (PGS) in IVF: It should be Used Selectively and NOT be Routine.
• IVF: Selecting the Best Quality Embryos to Transfer
• Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
• PGS in IVF: Are Some Chromosomally abnormal Embryos Capable of Resulting in Normal Babies and Being Wrongly Discarded?
• PGS and Assessment of Egg/Embryo “competency”: How Method, Timing and Methodology Could Affect Reliability
• Endometrial Receptivity Array (ERA): Is There an actual “There, There”?
• IVF Failure and Implantation Dysfunction:
• Diagnosing and Treating Immunologic Implantation Dysfunction (IID)
• The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 1-Background
• Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 2- Making a Diagnosis
• Immunologic Dysfunction (IID) & Infertility (IID):PART 3-Treatment
• Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
• Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management:(Case Report
• Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
• Intralipid (IL) Administration in IVF: It’s Composition; How it Works; Administration; Side-effects; Reactions and Precautions
• Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
• Endometrial Thickness, Uterine Pathology and Immunologic Factors
• Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
• A Thin Uterine Lining: Vaginal Viagra is Often the Answer (update)
• Cervical Ureaplasma Urealyticum Infection: How can it Affect IUI/IVF Outcome?
• The Role of Nutritional Supplements in Preparing for IVF
• The Basic Infertility Work-Up
• Defining and Addressing an Abnormal Luteal Phase
• Male Factor Infertility
• Routine Fertilization by Intracytoplasmic Sperm Injection (ICSI): An Argument in Favor
• Hormonal Treatment of Male Infertility
• Hormonal Treatment of Male Infertility
• Antisperm Antibodies, Infertility and the Role of IVF with Intracytoplasmic Sperm Injection (ICSI)
• Endometriosis and Infertily
• Endometriosis and Immunologic Implantation Dysfunction (IID) and IVF
• Endometriosis and Infertility: Why IVF Rather than IUI or Surgery Should be the Treatment of Choice.
• Endometriosis and Infertility: The Influence of Age and Severity on Treatment Options
• Early -Endometriosis-related Infertility: Ovulation Induction (with or without Intrauterine Insemination) and Reproductive Surgery  Versus IVF
• Deciding Between Intrauterine Insemination (IUI) and In Vitro Fertilization (IVF).
• Intrauterine Insemination (IUI): Who Needs it & who Does Not: Pro’s & Con’s!IUI-Reflecting upon its Use and Misuse: Time for a Serious “Reality Check
• Mode of Action, Indications, Benefits, Limitations and Contraindications for its ue
• Clomiphene Induction of Ovulation: Its Use and Misuse!
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ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

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

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. 1. 1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

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That sounds like a reasonable approach!

I wish you well!

Geoff Sher

____________________________________________________________________________

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

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

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

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