Ask Our Doctors – Archive
Our Medical Directors are outstanding physicians that you will find to be very personable and compassionate, who take care to ensure that you have the most cutting-edge fertility treatments at your disposal. This is your outlet to ask your questions to the doctors.
Dear Dr Sher,
Please let me know if ut us mandatory to use prednisone along with intralipids in case of elevated natural killer cells.What is the purpose of prednisone and when it should be used.Thank you!
Intralipid (IL) is a solution of small lipid droplets suspended in water. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, alpha-linolenic acid (ALA), an omega-3 fatty acid. It is made up of 20% soybean oil/fatty acids (comprising linoleic acid, oleic acid, palmitic acid, linolenic acid and stearic acid), 1.2% egg yolk phospholipids (1.2%), glycerin (2.25%) and water (76.5%).
Possible Mode of Action:
It is thought that fatty acids within the emulsion serve as ligands to activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK 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. Interestingly, similar to Intralipid 1% Propofol also contains the same concentration of soybean oil, and purified egg phospholipid, with glycerin. Perhaps its use offers a fringe benefit in cases of immunologic implantation dysfunction.
Whatever the exact mechanism of action might be, IL 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 in my opinion do so by immune modulation of T cells . The combined effect of IL + steroid therapy is thought to suppresses pro-inflammatory cellular (Type-1) cytokines such as interferon gamma and TNF-alpha, produced in excess by activated NK cells and cytotoxic T cells.
IL will in about 80% of cases, successfully down-regulats activated natural killer cells (NKa) within 2-3 weeks. In this regard it is likely to be just as effective as IVIg but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for 4-9 weeks when administered in early pregnancy.
Can in-vitro (laboratory) tests assess for an immediate benefit of IL on Nka?
Since the down-regulation of NKa through IL (or IVIg) therapy can take several weeks to become detectable, 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.
Treatment of NKa Using IL:
•Autoimmune Implantation Dysfunction: When it comes to 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 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 80%.
•Alloimmune Implantation Dysfunction
oPartial DQ alpha match: IVF patients who have NKa associated with a partial alloimmune implantation dysfunction (DQ alpha match between partners) we use the same IL, infusion as with autoimmune-NKa, only here we prescribe oral prednisone rather than dexamethasone until the 10th week of pregnancy and IL infusions are repeated every 2-4 weeks following the chemical diagnosis of pregnancy until the 24th week. Additionally, (as alluded to elsewhere) in such cases we transfer only a single embryo at a time. This is because in such cases, 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. Since we presently have no way of determining which embryo carries the matching paternal DQ alpha gene and thus would transfer only one embryo at a time, it follows that the anticipated viable pregnancy rate per cycle will be much lower than with autoimmune implantation dysfunction. It also follows the only way to improve success with a single embryo being transferred would be to perform PGS on the embryos in advance of ET and then selectively transfer a “chromosomally normal-euploid (“competent”) embryos.
oTotal (complete) DQ alpha Match: In cases where the partners have a total alloimmune (DQ alpha) match with accompanying NKa the chance of a viable pregnancy occurring or (if it does) resulting in a live birth at term, is so small as to be an indication for using a non-matching sperm donor or resorting to gestational surrogacy would in our opinion be preferable by far.
Contra-Indications and Cautions with Intralipid Infusion:
IL is only contraindicated in conditions associated with severely disordered fat metabolism (e.g. severe liver damage, acute myocardial infarction and shock,
Rarely, hypersensitivity has been observed in patients allergic to soybean protein, egg yolk and egg whites and where fat metabolism may be disturbed (e.g. renal insufficiency, uncontrolled diabetes, certain metabolic disorders and in cases oif severe infection (sepsis) sepsis
Adverse Reactions During Infusions of IL (rare):
Adverse reactions (rare) reported to occur during and/or following infusion of Intralipid include: transient fever, chills, nausea, vomiting, headache, back or chest pain with dyspnea and cyanosis.
In cases of verified or suspected liver insufficiency, liver function must be closely followed. If increased levels of transaminases, alkaline phosphatases or bilirubin appear, infusion of Intralipid should be withheld or postponed, until normalization is achieved.
Very rare cases of hypersensitivity have been observed in patients allergic to soybean protein, egg yolk and egg whites.
Fat metabolism may be disturbed in conditions such as renal insufficiency, uncompensated diabetes, certain forms of liver insufficiency, metabolic disorders and sepsis.
Administration:
The drip rate is adjusted to 500 ml of a 20% solution should be infused over about 3 hours. The infusion should be started at half the infusion rate during the first 30 minutes, under supervision.
Geoff Sher
Hi Dr Sher,
My wife just had a failed I’ve cycle. 14 eggs were harvested and all but three were immature. With the remainder there was no fertilisation. Is it just that our sperm and egg don’t like each other or could there be natural killer antibodies etc?
Whenever a patient fails to achieve a viable pregnancy following embryo transfer (ET), the first question asked is why! Was it simply due to, bad luck?, How likely is the failure to recur in future attempts and what can be done differently, to avoid it happening next time?.
It is an indisputable fact that any IVF procedure is at least as likely to fail as it is to succeed. Thus when it comes to outcome, luck is an undeniable factor. Notwithstanding, it is incumbent upon the treating physician to carefully consider and address the causes of IVF failure before proceeding to another attempt:
1.Age: The chance of a woman under 35Y of age having a baby per embryo transfer is about 35-40%. From there it declines progressively to under 5% by the time she reaches her mid-forties. This is largely due to declining chromosomal integrity of the eggs with advancing age…”a wear and tear effect” on eggs that are in the ovaries from birth.
2.Embryo Quality/”competency (capable of propagating a viable pregnancy)”. As stated, the woman’s age plays a big role in determining egg/embryo quality/”competency”. This having been said, aside from age the protocol used for controlled ovarian stimulation (COS) is the next most important factor. It is especially important when it comes to older women, and women with diminished ovarian reserve (DOR) where it becomes essential to be aggressive, and to customize and individualize the ovarian stimulation protocol.
We used to believe that the uterine environment is more beneficial to embryo development than is the incubator/petri dish and that accordingly, the earlier on in development that embryos are transferred to the uterus, the better. To achieve this goal, we used to select embryos for transfer based upon their day two or microscopic appearance (“grade”). But we have since learned that the further an embryo has advanced in its development, the more likely it is to be “competent” and that embryos failing to reach the expanded blastocyst stage within 5-6 days of being fertilized are almost invariably “incompetent” and are unworthy of being transferred. Moreover, the introduction into clinical practice about a decade ago, (by Levent Keskintepe PhD and myself) of Preimplantation Genetic Sampling (PGS), which assesses for the presence of all the embryos chromosomes (complete chromosomal karyotyping), provides another tool by which to select the most “competent” embryos for transfer. This methodology has selective benefit when it comes to older women, women with DOR, cases of unexplained repeated IVF failure and women who experience recurrent pregnancy loss (RPL).
3.The number of the embryos transferred: Most patients believe that the more embryos transferred the greater the chance of success. To some extent this might be true, but if the problem lies with the use of a suboptimal COS protocol, transferring more embryos at a time won’t improve the chance of success. Nor will the transfer of a greater number of embryos solve an underlying embryo implantation dysfunction (anatomical molecular or immunologic).Moreover, the transfer of multiple embryos, should they implant, can and all too often does result in triplets or greater (high order multiples) which increases the incidence of maternal pregnancy-induced complications and of premature delivery with its serious risks to the newborn. It is for this reason that I rarely recommend the transfer of more than 2 embryos at a time and am moving in the direction of advising single embryo transfers …especially when it comes to transferring embryos derived through the fertilization of eggs from young women.
4.Implantation Dysfunction (ID): Implantation dysfunction is a very common (often overlooked) cause of “unexplained” IVF failure. This is especially the case in young ovulating women who have normal ovarian reserve and have fertile partners. Failure to identify, typify, and address such issues is, in my opinion, an unfortunate and relatively common cause of repeated IVF failure in such women. Common sense dictates that if ultrasound guided embryo transfer is performed competently and yet repeated IVF attempts fail to propagate a viable pregnancy, implantation dysfunction must be seriously considered. Yet ID is probably the most overlooked factor. The most common causes of implantation dysfunction are:
a.A“ thin uterine lining”
b.A uterus with surface lesions in the cavity (polyps, fibroids, scar tissue)
c.Immunologic implantation dysfunction (IID)
d.Endocrine/molecular endometrial receptivity issues
Certain causes of infertility are repetitive and thus cannot readily be reversed. Examples include advanced age of the woman; severe male infertility; immunologic infertility associated with alloimmune implantation dysfunction (especially if it is a “complete DQ alpha genetic match between partners plus uterine natural killer cell activation (NKa).
I strongly recommend that you visit http://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.
•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 Aproach
•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.
•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
•Traveling for IVF from Out of State/Country–
•A personalized, stepwise approach to IVF
•How Many Embryos should be transferred: A Critical Decision in IVF.
Please call or email Julie Dahan, my patient concierge. She will guide you on how to set up an in-person or Skype consultation with me. You can reach Julie at on her cell phone or via email at any time:
Julie Dahan
•Email: Julied@sherivf.com
•Phone: 702-533-2691
?800-780-7437
Geoff Sher
I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.
Hi Dr, Sher,
I am currently doing IVF for the first time after being unsuccessful for the past 7 years in getting pregnant as well as 4 failed IUI’s. Last year, I did find out that I had a moderate case of endometriosis which was addressed with a laparoscopy. I’m 39 and my FSH just started to rise recently where my eggs showed signs of aging. for the cycle, I stimmed for 12 days and was on Gonal-F (225 IU morning and night as well as 10 mcg of mf Lupron taken morning and night as well as 30 IU of ldhcg every evening. My blood levels looked good on day 12 ..my E2 was 1634 and HCG 274, LH level 1.46 and P4 level 1.85. I went for egg retrieval on day 15, which was yesterday. 4 eggs were able to be retrieved (though when they were monitoring me they said there were 6 follicles). Just heard today that 2 eggs fertilized out of the 4. Initially my husband and I were going to do the PGS testing and still would prefer that route. However the Dr is recommending a day 3 transfer based upon the low # of embyros. They are saying they would have a better shot inside my uterus vs outside. Any suggestions on this? Does it make sense to transfer on day 3? We really want to have a baby. Also… is it normal that I would have only produced 4 eggs? Is it possible if I try again I might have a better outcome if I changed medications etc? Any other insight that you could offer would be greatly appreciated:). Thank you soo much for your time and help!
1. First, Endometriosis is associated with several Fertility related issues that need to be considered/addressed upfront. Endometriosis is a condition that occurs when the uterine lining (endometrium) grows not only in the interior of the uterus but in other areas, such as the Fallopian tubes, ovaries and the bowel.
Endometriosis is a complex condition where, the lack or relative absence of an overt anatomical barrier to fertility often belies the true extent of reproductive problem(s).
All too often the view is expounded that the severity of endometriosis-related infertility is inevitably directly proportionate to the anatomical severity of the disease itself, thereby implying that endometriosis causes infertility primarily by virtue of creating anatomical barriers to fertilization. This over-simplistic and erroneous view is often used to support the performance of many unnecessary surgeries for the removal of small innocuous endometriotic lesions, on the basis of such “treatment” evoking an improvement in subsequent fertility.
It is indisputable that even the mildest form of endometriosis can compromise fertility. It is equally true that, mild to moderate endometriosis is by no means a cause of absolute “sterility”.
Rather, when compared with normally ovulating women of a similar age who do not have endometriosis, women with mild to moderate endometriosis are about four to six times less likely to have a successful pregnancy.
Endometriosis often goes unnoticed for many years. Such patients are frequently, erroneously labeled as having “unexplained infertility”, until the diagnosis is finally clinched through direct visualization of the lesions at the time of laparoscopy or laparoscopy. Not surprisingly, many patients with so called “unexplained” infertility, if followed for a number of years, will ultimately reveal endometriosis.
Women who have endometriosis are much more likely to be infertile. There are several reasons for this:
•First-Ovulation Dysfunction: In about 25 – 30% of cases, endometriosis is associated with ovulation dysfunction. Treatment requires controlled ovarian stimulation (COS). The problem is that the toxic pelvic environment markedly reduces the likelihood that anything other than IVF will enhance pregnancy potential.
•Second- Toxic Pelvic environment that compromises Fertilization Endometriosis is associated with the presence of toxins in peritoneal secretions while it is tempting to assert that normally ovulating women with mild to moderate endometriosis would have no difficulty in conceiving if their anatomical disease is addressed surgically or that endometriosis-related infertility is confined to cases with more severe anatomical disease…nothing could be further from the truth. The natural conception rate for healthy ovulating women in their early 30’s (who are free of endometriosis) is about 15% per month of trying and 70% per year of actively attempting to conceive. Conversely, the conception rate for women of a comparable age who have mild or moderate pelvic endometriosis (absent or limited anatomical disease) is about 5-6% per month and 40% after 3 years of trying. As sperm and egg(s) travel towards the fallopian tubes they are exposed to these toxins which compromise the fertilization process. In fact it has been estimated that there is a 5-6 fold reduction in fertilization potential because of these toxins which cannot be eradicated. Frankly, it really does not matter whether an attempt is made to remove endometriosis deposits surgically as this will not improve pregnancy potential. The reason is that for every deposit observed, there are numerous others that are in the process of developing and are not visible to the naked eye and whether visible or not, such translucent deposits still produce toxins. This also explains why surgery to remove visible endometriosis deposits, controlled ovarian stimulation with or without intrauterine insemination will usually not improve pregnancy potential. Only IVF, through removing eggs before they are exposed to the toxic pelvic environment, fertilizing them in-vitro and then transferring the embryos to the uterus represents the only way to enhance pregnancy potential.
•Third-Pelvic adhesions and Scarring: In its most severe form, endometriosis is associated with scarring and adhesions in the pelvis, resulting in damage to, obstruction or fixation of the fallopian tubes to surrounding structures, thereby preventing the union of sperm and eggs.
•Fourth-Ovarian Endometriomas, Advanced endometriosis is often associated with ovarian cysts (endometriomas/chocolate cysts) that are filled with altered blood and can be large and multiple. When these are sizable (>1cm) they can activate surrounding ovarian connective tissue causing production of excessive male hormones (androgens) such as testosterone and androstenedione. Excessive ovarian androgens can compromise egg development in the affected ovary (ies) resulting in an increased likelihood of numerical chromosomal abnormalities (aneuploidy) and reduced egg/embryo competency”. In my opinion large ovarian endometriomas need to be removed surgically or rough sclerotherapy before embarking on IVF.
•Fifth- Immunologic Implantation Dysfunction (IID). Endometriosis, regardless of its severity is associated with immunologic implantation dysfunction linked to activation of uterine natural killer cells (NKa) and cytotoxic uterine lymphocytes (CTL) in about 30 of cases. This is diagnosed by testing the woman’s blood for NKa using the K-562 target cell test or by endometrial biopsy for cytokine analysis, and, for CTL by doing a blood immunophenotype. These NKa attack the invading trophoblast cells (developing “root system” of the embryo/early conceptus) as soon as it tries to gain attachment to the uterine wall. In most cases, this results in death of the embryo even before the pregnancy is diagnosed and sometimes, in a chemical pregnancy or even an early miscarriage. . As such, many women with endometriosis, rather than being infertile, in the strict sense of the word, often actually experience repeated undetected “mini-miscarriages”.
Advanced Endometriosis: In its most advanced stage, anatomical disfiguration is causally linked to the infertility. In such cases, inspection at laparoscopy or laparoscopy will usually reveal severe pelvic adhesions, scarring and “chocolate cysts”. However, the quality of life of patients with advanced endometriosis is usually so severely compromised by pain and discomfort, that having a baby is often low on the priority list. Accordingly, such patients are usually often more interested in relatively radical medical and surgical treatment options (might preclude a subsequent pregnancy), such as removal of ovaries, fallopian pubis and even the uterus, as a means of alleviating suffering.
Moderately Severe Endometriosis. These patients have a modest amount of scarring/ adhesions and endometriotic deposits which are usually detected on the ovaries, fallopian tubes, bladder surface and low in the pelvis, behind the uterus. In such cases, the fallopian tubes are usually opened and functional.
Mild Endometriosis: These patients who at laparoscopy or laparotomy are found to have no significant distortion of pelvic anatomy are often erroneously labeled as having “unexplained” infertility. To hold that the there can only infertility can only be attributed to endometriosis if significant anatomical disease can be identified, is to ignore the fact that, biochemical, hormonal and immunological factors profoundly impact fertility. Failure to recognize this salient fact continues to play havoc with the hopes and dreams of many infertile endometriosis patients.
TREATMENT:
The following basic concepts apply to management of endometriosis-related infertility:
1.Controlled Ovulation stimulation (COS) with/without intrauterine insemination (IUI): Toxins in the peritoneal secretions of women with endometriosis exert a negative effect on fertilization potential regardless of how sperm reaches the fallopian tubes. This helps explain why COS with or without IUI will usually not improve the chances of pregnancy (over no treatment at all) in women with endometriosis. IVF is the only way by which to bypass this problem.
2.Laparoscopy or Laparotomy Surgery aimed at restoring the anatomical integrity of the fallopian tubes does not counter the negative influence of toxic peritoneal factors that inherently reduce the chances of conception in women with endometriosis four to six fold. Nor does it address the immunologic implantation dysfunction (IID) commonly associated with this condition. Pelvic surgery is relatively contraindicated for the treatment of infertility associated with endometriosis, when the woman is more than 35 years of age. With the pre-menopause approaching, such women do not have the time to waste on such less efficacious alternatives. In contrast, younger women who have time on their side might consider surgery as a viable option. Approximately 30 -40 percent of women under 35 years of age with endometriosis will conceive with in two to three years following corrective pelvic surgery.
3.Sclerotherapy for ovarian endometriomas (“chocolate” cysts). About 15 years ago I introduced “sclerotherapy”, a relatively non-invasive, safe and effective outpatient method to permanently eliminate endometriomas without surgery being required. Sclerotherapy for ovarian endometriomas involves needle aspiration of the liquid content of the endometriotic cyst, followed by the injection of 5% tetracycline into the cyst cavity. Treatment results in disappearance of the lesion within 6-8 weeks, in more than 75% of cases so treated. Ovarian sclerotherapy can be performed under local anesthesia or under general anesthesia. It has the advantage of being an ambulatory office- based procedure, at low cost, with a low incidence of significant post-procedural pain or complications and the avoidance of the need for laparoscopy or laparotomy
4.The role of selective immunotherapy More than half of women who have endometriosis harbor antiphospholipid antibodies (APA) that can compromise development of the embryo’s root system (trophoblast). In addition and far more serious, is the fact that in about one third of cases endometriosis, regardless of its severity is associated with NKa and cytotoxic uterine lymphocytes (CTL) which can seriously jeopardize implantation. This immunologic implantation dysfunction (IID) is diagnosed by testing the woman’s blood for APA, for NKa (using the K-562 target cell test or by endometrial biopsy for cytokine activity) and, for CTL (by a blood immunophenotype). Activated NK cells attack the invading trophoblast cells (developing “root system” of the embryo/early conceptus) as soon as it tries to gain attachment to the uterine wall. In most cases, this results in rejection of the embryo even before the pregnancy is diagnosed and sometimes, in a chemical pregnancy or an early miscarriage. . As such, many women with endometriosis, rather than being infertile, in the strict sense of the word, often actually experience repeated undetected “mini-miscarriages”.
Women who harbor APA’s often experience improved IVF birth rates when heparinoids (Clexane/Lovenox) are administered from the onset of ovarian stimulation with gonadotropins until the 10th week of pregnancy. NKa is treated with a combination of Intralipid (IL) and steroid therapy: Intralipid (IL) is a solution of small lipid droplets suspended in water. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, alpha-linolenic acid (ALA), an omega-3 fatty acid.IL is made up of 20% soybean oil/fatty acids (comprising linoleic acid, oleic acid, palmitic acid, linolenic acid and stearic acid) , 1.2% egg yolk phospholipids (1.2%), glycerin (2.25%) and water (76.5%).IL exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating NKa.
The therapeutic effect of IL/steroid therapy is likely due to an ability to suppress pro-inflammatory cellular (Type-1) cytokines such as interferon gamma and TNF-alpha. IL/steroids down-regulates NKa within 2-3 weeks of treatment the vast majority of women experiencing immunologic implantation dysfunction. In this regard IL is just as effective as Intravenous Gamma globulin (IVIg) but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for 4-9 weeks when administered in early pregnancy.
5.The role of IVF: The toxic pelvic environment caused by endometriosis, profoundly reduces natural fertilization potential. As a result normally ovulating infertile women with endometriosis and patent Fallopian tubes are much less likely to conceive naturally, or by using fertility agents alone (with or without intrauterine (IUI) insemination. The only effective way to bypass this adverse pelvic environment is through IVF. I am not suggesting here that all women who have endometriosis require IVF! Rather, I am saying that in cases where the condition is further compromised by an IID associated with NKa and/or for older women(over 35y) who have diminished ovarian reserve (DOR) where time is of the essence, it is my opinion that IVF is the treatment of choice.
2. Ovarian stimulation needs to be individualized..in my opinion.
Two main factors determine the quality of a woman’s eggs at ovulation or egg retrieval. First is her age and second is the protocol used for ovarian stimulation. With the possible the exception of cases where there is severe sperm dysfunction, it is the chromosomal integrity of the egg rather than the sperm that will ultimately determine the chromosomal integrity of the embryo (i.e. its “competency”, or its potential to propagate a healthy babies). It therefore follows that the only way by which to influence embryo “competence” is through the selection and implementation of an optimal protocol for ovarian stimulation. Since older women (=35 years) and those who have diminished ovarian reserve (DOR) are at greatest risk of yielding “incompetent” eggs, they are the ones that require special attention. This article will highlight the reasons why such women are the ones most prone to produce poor quality eggs and embryos and how best to address ovarian stimulation in an attempt to minimize this risk.
Cells that have a full chromosomal component are termed euploid while those that do not, are aneuploid. Most euploid eggs are “competent”, that is, they are the one’s that are most likely to propagate euploid, “competent” embryos. Aneuploid, “incompetent” eggs will invariably develop into aneuploid, “incompetent” embryos. There is a progressive increase in the incidence in egg/embryo aneuploidy with advancing age. To put numbers to the equation; by time a woman reaches 35 yrs; approximately 60% of her eggs are likely to be aneuploid. By the time she reaches her mid 40’s the incidence will be greater than 85%.
For example, a woman of 43 years would be fortunate if six (6) or eight (8), of her eggs would upon being fertilized, result in one (1) “competent” embryo. As the woman gets older, the inevitable decline in egg/embryo quality results in her having a reduced ability to conceive naturally, a declining IVF success rates, an increase in miscarriages, and a rising incidence of having her baby affected by chromosomal birth defects such as Trisomy 21 (Down’s syndrome). This is why for such a woman, the anticipated IVF birth rate per egg retrieval is less than 10% (i.e. >70% lower than at age 35), the miscarriage rate increases from about 15% at 35y to >40% at age above 40y.and why her risk of having a baby with Down’s syndrome is about 0 2% at 35y as compared to 2% at 44y).
The anticipation of poor IVF outcome statistics for women in their mid-40’s makes IVF with ovum donation the most rational approach. Yet, in spite of this, many older women still elect to use their own eggs as long as there is even the slightest chance of having their own genetic offspring.
As a woman approaches and then engages her 40’s, her ability to produce “competent” eggs progressively declines. At the same time she experiences diminishing ovarian reserve that results in a progressive fall-off in the number of eggs she is likely to produce at egg retrieval. As a result, there will be a commensurate drop of in the number of “competent” embryos available for transfer to her uterus.
The following IVF stimulation protocols are the ones most commonly used for COS in older women and those with DOR:
1.GnRHa Flare (“Short”) protocol: Some IVF physicians advocate the use of gonadotropin releasing hormone-agonist (GnRHa)- flare protocols in which the administration of GnRHa (e.g. Lupron, Buserelin, Nafarelin, Synarel) therapy begins at the same time that ovarian stimulation with gonadotropins is started (usually with the onset of menstruation). The proposed benefit of such an approach is that the GnRHa will cause the woman’s pituitary gland to release large amounts of follicle stimulating hormone (FSH), which would augment the administered dosage of FSH and thereby synergizing the growth of ovarian follicles.
The problem associated with this “flare” approach is that concurrent with the GnRHa-induced FSH luteinizing hormone (LH) also surges. In older women and those who have diminished ovarian reserve, the out-pouring of LH can cause the ovarian connective tissue (stroma or theca) which produces excessive male hormones (predominantly, testosterone). While some testosterone is essential for optimal follicle growth, too much testosterone can compromise its development as well as egg/embryo quality. Since older women and women with diminished ovarian reserve often have increased LH production as well as an overgrown of ovarian stroma/theca (i.e. hyperthecosis), a further GnRHa-induced increase in LH can so elevate local ovarian testosterone levels as to severely compromise egg/ embryo “competency”.
2.Combined Clomiphene or Letrazole) /Gonadotropin Stimulation: This approach when used in older women and women with diminished ovarian reserve is also potentially harmful to egg/embryo quality. The reason is that like GnRHa, clomiphene and Letrazole also cause LH to be released in large amounts. Since these medications are given at the start of ovarian stimulation they, as with “flare protocols” can elicit ovarian over-production of testosterone. As such this approach is in my opinion far less than ideal for older women and women who have diminished ovarian reserve.
3.Mid-follicular GnRH-antagonist protocol: With this approach, stimulation with gonadotropins is commenced with the onset of the cycle. Then, several days later, once the majority of follicles have reached about 12mm in size, GnRH antagonist (e.g. Ganirelix, Cetrotide, Cetrorelix, and Orgalutron) is added. The intent in adding the antagonist is to abruptly block pituitary LH release and so prevent a “premature LH surge” with its effect of causing increased ovarian testosterone and impaired follicle and egg development.
The problem with such a regime is that women with diminished ovarian reserve already have too much of their own LH around at the beginning of the cycle. Accordingly, blocking LH release only 6-7 days into the stimulation does nothing to prevent the early adverse effects of too much LH-induced ovarian testosterone on early egg/embryo development. It should be borne in mind that eggs are often at their most vulnerable, early on in the cycle. Thus, in my opinion such protocols are also less than optimal for older women and for those with diminished ovarian reserve.
4.GnRHa (“Long”) Pituitary down-Regulation Protocol:
a)The “Standard” Long Protocol Approach: This protocol, which is the mainstay of ovarian stimulation for IVF, is either initiated about 1 week after natural ovulation (a “luteal phase start”) or is launched off a monophasic birth control pill (a “BCP start”). In the case of the latter, the BCP is taken for at least 8 days before, GnRHa (e.g. Lupron/Superfact/Buserelin) is added daily. Two days after starting the GnRHa, the BCP is stopped. Menstruation usually ensues within 3-5 days. GnRHa administration is continued and gonadotropin (Follistim/Gonal-F/Puregon, Bravelle, and Menopur) stimulation is initiated. Both daily Gonadotropin stimulation and GnRHa are continued until the day of the “hCG trigger”.
The initial administration of agonist serves to rapidly expunge pituitary FSH and LH causing an immediate rise in the blood levels of both hormones. Then, within a few days, having virtually exhausted/depleted pituitary gonadotropin stores, the blood levels of FSH and LH both rapidly decline, such that by the time menstruation occurs, the levels are very low. The initial premenstrual GnRHa-induced rise in FSH helps recruit ovarian antral follicles for the upcoming cycle, while the ultimate virtual depletion of LH serves to prevent excessive ovarian testosterone production and protects egg quality.
I prefer to use pure FSHr (Folistim, Puregon, Gonal F) for ovarian stimulation for IVF with the initial dosage being reduced by about 25% within a few days. Thereupon 75U Menopur is added daily, up until the hCG trigger.
b)Modified Long Protocols:
i.Agonist/Antagonist Conversion protocol (A/ACP): Agonists might competitively inhibit follicle response to FSH. Therefore, in an attempt to improve follicle response to FSH we modified the “standard approach” (a- above) as follows: Rather than continuing to give GnRHa throughout the stimulation protocol, we here supplant GnRHa with low dosage GnRH antagonist starting with the initiation of menstruation, continuing throughout stimulation until the day of the “hCG trigger” at which point both the antagonist and gonadotropins are discontinued. We have had very good results using the A/ACP modification of the “standard long pituitary down-regulation protocol”. In fact it has become my preferred approach for most women with a normal ovarian reserve, who undergo ovarian stimulation for IVF.
ii.Agonist/Antagonist Conversion Protocol (A/ACP) +“Estrogen Priming” (LA10-E2V): Estrogen primes follicle FSH receptors, thereby enhancing response to FSH. This forms the basis of the “estrogen priming” approach in women with diminished ovarian response. The approach involves administering estradiol by daily injection, or by skin patch starting about 10 days prior to initiating high dosage gonadotropin stimulation. As with the standard A/ACP, the estrogen priming protocol is initiated a week post-ovulation (luteal phase start) or is launched off a birth control pill regime of at least 10 days. It also starts with GnRHa administration for about 5 days whereupon menstruation ensues and the agonist is supplanted by an antagonist. But this is where things change slightly such that instead of directly initiating FSHr (Follistim/Gonal-F/Puregon) injections, the patient, while continuing to take the GnRH antagonist now receives twice weekly estradiol valerate injections or daily estradiol skin patches (I prefer the former) for a period of about 10 days. Thereupon, daily high dosage FSHr (750U) is administered once daily. Four to five days later, 75U Menopur daily is added. “Estrogen priming” is continued until more than 50% of the follicles are at least 12mm in size whereupon it is discontinued.
5. Mini-IVF or Natural Cycle IVF for women with DOR? It is quite understandable that many women with DOR are easily persuaded that less (or no) ovarian stimulation offers a more “natural” and less “stressful” approach on eggs than a robust, high gonadotropin-based, long-pituitary down regulation approach. This, in my opinion is a fallacy and can compromise rather than benefit IVF outcome in such cases. Even in young women in their early or mid-30’s, the IVF success rate per fresh “natural” or “mini” IVF cycle is much lower (<15%) than that which can be achieved through the use of conventional long down-regulation protocols, where the anticipated success is at least double this rate (30%). Mini-IVF is usually conducted using clomiphene or Femara, alone or in combination with Menopur, all of which is associated with the production of excessive LH-induced ovarian testosterone. Furthermore, low dosage stimulation will result in fewer eggs being available, thus further reducing the odds of IVF success per egg retrieval conducted. Natural cycle IVF is in my opinion also not in the best interest of women with DOR, because with such an approach, nothing is done to control the exaggerated production of LH by the woman’s own pituitary gland.
Addendum:
Human Growth Hormone (HGH) Supplementation. Recently, I began selectively adding human growth hormone (HGH) supplementation to simulation protocols in women with DOR, in cases where there is a history of the woman repeatedly producing poor quality eggs and in older women (>38Y) undergoing IVF. There is evidence that this might enhance mitochondrial activity and thus improve egg maturational division (meiosis).
3. In my opinion, Blastocyst transfer is the way to go:
Embryo transfer (ET) is undoubtedly a rate limiting factor when it comes to IVF outcome. In fact, in my opinion, it is the single most important procedural step in IVF. Optimal performance of ET takes practice, confidence, dexterity, timing, gentility and skill. Of all the hands-on procedures involved in the IVF process, embryo transfer is by far the most difficult to teach. In fact, any women fail to conceive simply because the practicing physician did (could) not perform this procedure optimally.
The issue of whether it is better to transfer early (day 2-3,post fertilization) cleaved embryos rather than (day 5-6) blastocysts continues to rage. Here I wish to focus on the reasons why I favor transferring blastocysts.
Not too long ago, it was believed that the sooner an embryo was transferred into the “natural environment” of the uterus, the greater would be the chance of it implanting and propagating a viable pregnancy. Thus most IVF physicians advocated day 2 or day 3 embryo transfers preferentially. About 20 years ago, we began to realize that there was no validity to the belief that an embryo would develop better and have a greater chance of propagating a baby by being inside the uterus earlier than it would by being allowed to first develop into a blastocyst in an incubator. About a decade later, it was realized that cleaved embryos that fail to develop into blastocysts are with few exceptions numerically chromosomally “incompetent” (aneuploid) such that had they been transferred earlier, they almost certainly would not have developed into blastocysts and would not have propagated a pregnancy anyway. Now most of us practicing in this field believe it to be preferential to selectively transfer blastocysts rather than earlier cleaved embryos. Don’t get me wrong! I am not saying that there is never a place for doing earlier pre-blastocyst transfers. Patients that only have one or two cleaved embryos available might as well transfer them early.
The recent popularization of full preimplantation genetic sampling (PGS) using methods such as comparative genomic hybridization (CGH), next generation gene sequencing (NGS) and SNP array, now allow us to identify those blastocysts that are the most “competent”. Selective transfer of such embryos improves the implantation rate per embryo by a factor of 2-3.
It is important to bear in mind that morphologically good looking day 3 embryos/blastocysts that are determined microscopically to be of a “high grade” , are by no means always numerically chromosomally “competent” euploid , and the likelihood of such embryos being “competent” diminishes progressively with advancing age of the woman. Only through the performance of full PGS can his age-related discrepancy be reduced.
While it would be acceptable to me to transfer 2 PGS-untested blastocysts to women under 39 years, and to transfer 3 to older women, I would not recommend transferring more than 2 PGS-normal embryos at any age.
The following are arguments in favor of performing blastocysts transfers:
•By waiting to day 5-6 many unworthy, many aneuploid and “incompetent” embryos can be culled out, thereby allowing for the transfer of fewer embryos and minimizing the risk of high order multiple pregnancies.
•Diagnostic Advantages:
o Failure of the expected number of cleaved embryos to advance to the blastocyst stage of development in culture, raises the suspicion of underlying inherent embryo “incompetence”, which is usually (but not exclusively) egg-related rather than due to a sperm factor. While age of the woman is the most important factor involved, it can also be due to the wrong protocol of ovarian stimulation being used).
oIt facilitates the performance of PGS to identify and then selectively transfer only most “competent” (euploid) blastocysts. In such cases, provided there is no underlying uterine implantation dysfunction implantation and pregnancy rate is enhanced significantly.
I strongly recommend that you visit http://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.
•Blastocyst Embryo Transfers Should be the Standard of Care in IVF
•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!
•Traveling for IVF from Out of State/Country–
•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
•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
•Treating Ovarian Endometriomas with Sclerotherapy.
Please call or email Julie Dahan, my patient concierge. She will guide you on how to set up an in-person or Skype consultation with me. You can reach Julie at on her cell phone or via email at any time:
Julie Dahan
•Email: Julied@sherivf.com
•Phone: 702-533-2691
?800-780-7437
Geoff Sher
I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.
:
Hello Dr. Geoffrey Sheri, I just had surgery to open my Fallopian tubes after have a Chemical pregnancy and 2001. My left Fallopian tube is absolute. My ivf doctor told me I can do IUI do to my right Fallopian being open. I will be take fertility drugs$ 2400 + paying for the IUI. I’m 39 soon to be 40. I do have 2 children ages 19 and 16. I have been pregnant 6 times in the pass this includes my 2 children. Others then my Fallopian tubes I’m a health female. My concern is I don’t want to do the IUI and it doesn’t work I don’t knw if I should go straight to ivf. I don’t knw if my right tube is open. The surgery was done this pass July.
Hi Tee,
At 39y I would go directly to IVF if I were you. Remember, the fact that you had a chemical pregnancy only indicates that an embryo was starting to attach but it does not tell you if the attachment was in the uterus or in the Fallopian tube. Both would present the same way.
I strongly recommend that you visit http://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.
•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 Aproach
•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
•Why did my IVF Fail
•IVF Should Supplant Tubal Fertility Surgery.
Please call or email Julie Dahan, my patient concierge. She will guide you on how to set up an in-person or Skype consultation with me. You can reach Julie at on her cell phone or via email at any time:
Julie Dahan
•Email: Julied@sherivf.com
•Phone: 702-533-2691
?800-780-7437
Geoff Sher
I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.
Dear Dr Sher
I have persistent problems with thin endometrial lining. I do not have natural cycles due to PCOS so my lining doesn’t develop in a non medicated cycles. My lining doesn’t get above 6mm in an ovulation induction cycle (low dose Gonal-F, not Clomid). My lining responds poorly to exogenous oestrogen – a medicated FET was cancelled after my lining failed to get above 6mm following transdermal, vaginal and oral administration of oestrogen (IM oestrogen is unavailable in the UK)
Hysteroscopy confirmed no adhesions, and Doppler scans show excellent uterine blood flow. My issues appear to be oestrogen related, as my lining HAS however responded in my fresh IVF cycles, under the influence of supraphysiological levels of endogenous oestrogen. After cancelled medicated and ovulation induction FET cycles, we undertook a cycle of COS to thicken my endometrium via the means that has worked in the past. 150iu Gonal-F produced 17 follicles: which, combined with the administration of additional progynova tablets and vaginal viagra pessaries, and a Neupogen uterine wash, meant we attained just under the desired 9mm at hCG trigger.
We transferred a euploid blastocyst, however I had a chemical pregnancy. We are already treating and retesting for IID due to NKa (prednisolone, intralipids, clexane), however it seems likely that I have a lining issue at play. In addition to issues with lining thickness, we also have questions over my lining quality. After my May IVF cycle, despite endometrial thickness of >10mm, I did not menstruate properly – the lining did not shed as a normal bleed, but as black clots and brown spotting.
Our next step is to do another hysteroscopy, and undertake a period of extended oestrogen priming, with the addition of a copper IUD and co administration of pentoxifylline and tocopherol
Would you recommend the addition of vaginal viagra to this protocol for endometrial preparation, over an extended period of time (min 1-2 months)?
Do you have any thoughts as to what we can do for an endometrium that will only respond to high levels of endogenous oestrogen, and not to exogenous oestrogen (via multiple routes of adminstration)?
Kind regards
Katy
Women with PCOS often have elevated ovarian testosterone (that wont necessarily show up in peripheral blood sampling). The high pelvic testosterone levels (from the ovaries) often blunt endometrial receptor response to estrogen resulting in a thin lining. Treatment with Viagra and estrogen in stimulated cycles often does not reverse this. Treatment requires a few months on the BCP to lower LH which causes the ovaries to produce the testosterone and then follow with a long pituitary down regulation protocol overlapping the BCP with Lupron and then stimulate with purified FSH. This will lower LH-induced testosterone and often will result in enhanced endometrial response to estrogen.
I strongly recommend that you visit http://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.
•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
•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
•Endometrial Thickness, Uterine Pathology and Immunologic Factors
•Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
•Traveling for IVF from Out of State/Country–
•A personalized, stepwise approach to IVF
•Understanding Polycystic Ovarian Syndrome (PCOS) and the Need to Customize Ovarian Stimulation Protocols.
•“Triggering” Egg Maturation in IVF: Comparing urine-derived hCG, Recombinant DNA-hCG and GnRH-agonist:
•The “Lupron Trigger” to Prevent Severe OHSS: What are the Pro’s and Con’s?
Please call or email Julie Dahan, my patient concierge. She will guide you on how to set up an in-person or Skype consultation with me. You can reach Julie at on her cell phone or via email at any time:
Julie Dahan
•Email: Julied@sherivf.com
•Phone: 702-533-2691
?800-780-7437
Geoff Sher
I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.