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,
Two days ago, I had my egg retrieval. They got 14 eggs. Yesterday the called me and told me that 10 fertilized but only 3 normally. I think 3 out of 14 is a very low number. What do you think?
They told me they had issues since my egg quality (I am 31) and the sperm of my husband has a bad quality. Do you the 3 normal fertilized will also be affected in a negative way and increases the risk that we will not have a blastocyst? Or does this not necessarily mean that also those 3 are from a bad quality?
At 31 years with normal ovarian reserve, you should perhaps have done better. Your response in my opinion, has likely less to do with inherent egg-quality issues than with the protocol used for ovarian stimulation. Please consider the following:
Maturation (ripening) is the final step in biological development that a system or organism must undergo in order to prepare for optimal function. Ultimately the functional efficiency of the system and/or organism will be predicated upon its state of readiness to undergo such maturational fine tuning. A poorly developed system/organism can thus never attain optimal functionality. The same concept applies with regard to the development and maturation of a woman’s eggs. Since it is predominantly the egg rather than the sperm that determines the potential of an embryo (the fertilized egg) to develop into a healthy baby (embryo “competence”), it is little wonder that egg development/maturation is a major determinant of human reproductive performance.
A woman is born with all the eggs she will ever produce. She uses them up through her reproductive life and when they are gone, her reproductive potential ends. It is interesting that a woman’s eggs are already stored in her ovaries 6 months before she is born and in fact she starts losing her eggs at a furious rate from the get go such that by the time she born more than half of her eggs have absorbed. This process of egg attrition continues after birth but at a slower rate. By the time the woman reaches puberty and begins to menstruate (the menarche) and then ovulate, her egg population has dropped from more than 5 million (at 3 months post-conception) to on average, less than 1 million. The number of eggs present at the time of puberty when the woman’s reproductive potential is launched is genetically determined.
Each immature egg stored in the “ovarian repository” is enveloped by a thin layer of cells. Batches of these so called “primordial follicles are sequentially “recruited” to embark upon what represents a 4 month developmental journey, during which time they undergo complex and magnificent developmental changes designed to prepare them for “service” in a single, designated ovulation cycle. During this “journey” many primordial follicles succumb to a process of culling. Those primordial follicles that ultimately survive this 4-month “recruitment process” each develop a central collection of fluid lined by a few layers of hormonally active “granulosa cells” and measure a few millimeters in diameter. At this point they are referred to as “antral follicles”. The number of antral follicles available for hormonally induced growth in the very next ovulation cycle (her” recruitment potential”)t starts off at quite a large number (as many as 20-50) but then declines with advancing age as with more and more usage, the primordial follicle population in the ovaries, progressively declines.
The recruited antral follicles grow in response to stimulation by follicle stimulating hormone (FSH), a hormone produced by the pituitary gland (a cherry-sized structure located just above the roof of the mouth, which hangs from the base of the brain). FSH stimulates the cells lining the inner wall of the follicle. These, so called granulosa cells start to produce the female hormone, estrogen in ever increasing amounts. Estrogen makes the lining of the uterus (endometrium) thicken in preparation for ovulation. Within the first 5 or 6 days of the cycle, one (sometimes two), antral follicles start to grow faster than other members of the cohort, differentiating from them. About five days into the cycle, these selected follicle(s) continue enlarging while all the others begin a downward spiral and ultimately die off within a week or so. Once the selected follicle(s) attain(s) a certain size (approximately 18-20 mm in diameter) and their estrogen output reaches a crescendo, a sudden surge of another pituitary hormone called Luteinizing hormone (LH) occurs, the follicle(s) rupture(s) and the egg(s) is/are release(d). Ovulation has taken place.. .Under the influence of LH the granulosa cells in the ovary undergo transformation (luteinization) and now, in addition to estrogen the in addition produce progesterone. It id the combined effect of estrogen and progesterone causes secretion in the hitherto developed endometrial glands, that further prepares the endometrium to receive the fertilized egg (embryo) about 5-6 days after ovulation.
With every 4 month “recruitment journey” the number ovarian primordial follicles (eggs) that a woman has available declines and the fewer antral follicles she will have available use in any cycle. Over a period of 2 decades or so, the progressive erosion in the number of ovarian primordial follicles/eggs is accompanied by such a profound reduction in the woman’s recruitment potential that the pituitary gland in a frantic attempt to restore recruitment increases its output of FSH. This manifests in a rising blood FSH concentrations. At a certain point, a reciprocal rise in basal LH follows. The rising basal FSH and LH level signals the onset of the “climacteric”, a period of roughly 6-8 years in the woman’s reproductive career, during which time the number of primordial follicles (and eggs) in the ovaries having declined below a critical threshold, triggers certain profound changes. These include (but are not necessarily limited to) hot flashes, ovulation becoming irregular and dysfunctional, menstrual cycles becoming more and more irregular and less and less frequent and a decline in egg quality. The latter is accompanied by reduced fertility an increased risk of miscarriages. Ultimately the follicle recruitment process trickles to a halt, ovulation and menstruation cease altogether…The “menopause” has arrived.
.
A few additional pieces of information are needed here:
.
1.The ovary has two well defined hormone producing “compartments”. The first, the follicle houses the egg and has an inner lining of granulosa cells which in response to FSH produce estrogen. The second is the stroma or theca, connective tissue that surrounds the follicles and produces male hormone (predominantly testosterone).
2.Testosterone is the building block from which granulosa cells manufacture estrogen. It is carried in a “bucket brigade” fashion from the stroma to the follicle. LH promotes production of testosterone by the stroma.
3.Some LH is essential. In fact, neither follicle growth with estrogen production, nor proper egg development and maturation is possible without some delivery of testosterone to the follicle granulosa cells. However, too much LH-by causing overproduction of stromal (thecal) male hormones (predominantly testosterone) can however have a detrimental effect on follicle growth (as evidenced by a decline in estrogen production) with egg development which in turn ultimately interferes with egg maturation. In such cases, when the eggs fertilize (if indeed they even do), the resulting embryo(s) are much more likely to have an irregular chromosome number (i.e. aneuploidy) and thus be “incompetent”.
4.There are situations such as advanced age above 40 years, diminishing ovarian reserve and polycystic ovarian syndrome (PCOS) which are all associated with a sustained elevation in LH as well as an overgrowth of ovarian stroma (stromal hyperplasia or hyperthecosis). In such cases the overgrowth of ovarian stroma/theca serves as an enlarged target for LH activity and thus will over-produce testosterone with adverse effects on egg development and embryo quality.
Simply stated, the potential for a woman’s eggs to undergo orderly development and maturation, successful fertilization and subsequent progression to “competent” embryos while genetically determined is also profoundly influenced by ovarian hormonal influences such as overproduction of ovarian (stromal/thecal) testosterone which can have an adverse influence on follicle development, egg quality and ultimately on embryo “competence.
It follows those protocols for controlled ovarian stimulation (COS) must strike a balance between optimizing follicle growth and development and avoidance of excessive ovarian testosterone production. We do have access to medications that act as agonists (Lupron, Buserelin, Superfact, etc.) and antagonists (Cetrotide, Orgalutron, Ganirelix etc.) , by which it is possible to pharmacologically regulate pituitary release of LH . We also have pure DNA recombinant FSH (Follistim, Puregon and Gonal F) and pure recombinant LH preparations (Luveris). By prescribing customized protocols of ovarian stimulation it is now possible to avoid over-exposure to testosterone in women at risk (e.g. those with diminished ovarian reserve, older women and those who have PCOS) and in the process improve egg/embryo quality. So why then do some still persist in using high dosages of fertility drugs such as drugs that contain high concentrations of LH such as Menopur, in such cases and, why use protocols that promote LH over-exposure (Flare protocols).
There is an unfortunate tendency on the part of many IVF practitioners to place the blame for “poor quality embryos” on the embryology laboratory, The truth of the matter is that while the IVF embryology laboratory plays a pivotal, role in achieving optimal fertilization and embryo quality, no embryologist, regardless of expertise, can produce “good quality embryos” from “poor quality eggs”.
It is important to recognize that the chromosomal configuration of the embryo that determines its “competence”. A “competent embryo” is one that is euploid (has all its 46 chromosomes), and upon being transferred to a “receptive uterus” is most likely to propagate a viable pregnancy. Embryos that are aneuploid (an irregular number of chromosomes) are incapable of propagating “competent” embryos. The fact is that less than 50% of embryos resulting from fertilization of even young women’s’ eggs. As women get older this gets progressively worse such that by her mid-40 the number drops to less than 10%.
The above serves to explain the progressive decline in IVF birthrates that starts in the mid-thirties, greatly and accelerates after 40. For those women whose age and/or degree of ovarian resistance makes having a baby with their own eggs unappealing or unlikely, ovum donation (using donated eggs from a young donor (usually compatible and anonymous) is an excellent option. In fact IVF-ovum donation is one of the most successful methods of achieving pregnancy, regardless of the woman’s age.
•Controlled ovarian (COS) protocols:
Protocols for controlled ovarian stimulation (COS) should be geared toward optimizing follicle and egg development and avoiding over exposure to ovarian androgens (mainly testosterone). The fulfillment of these objectives requires an individualized approach to COS and that the administration of human chorionic gonadotropin (hCG) or recombinant luteinizing hormone (LHr) to “trigger” ovulation, be timed precisely.
A.Long Protocols:
I routinely use long pituitary down Regulation protocols on my patients.. It is common practice to administer gonadotropin releasing hormone (GnRH) agonists (Lupron, Buserelin, Superfact) that act by causing an initial outpouring and then, over 4-5 days, a depletion of Pituitary FSH and LH and GnRH-antagonists (e.g. Orgalutron, Ganirelix, Cetrotide). GnRH- antagonists that block pituitary LH release within a few hours of administration:
a.Conventional Pituitary down-regulation with a GnRH agonist (GnRHa):
Long Pituitary down regulation protocol: I mostly recommend this protocol, for women with normal ovarian reserve (AMH=>2.0ng/ml/15pmol/L). My patients start on a BCP, and overlapping it with a GnRHa, (e.g. Lupron 10U daily) for three (3) days and then stop the BCP but continuing on with daily Lupron 10u daily and await a period (which should ensue within 5-7 days of stopping the BCP). At that point an US examination is done along with a baseline measurement of blood estradiol (which needs to be <70pg/ml) to exclude a functional ovarian cyst and simultaneously, the Lupron dosage is reduced to 5U daily and then continued until the hCG (10,000u) trigger. An FSH-dominant gonadotropin such as Follistim/ Puregon/ Gonal-f, daily is started with the period for 2 days and then the gonadotropin dosage is reduced and a 37.5U-75U of Menopur (daily) is added. This is continued until US and blood estradiol levels indicate that the hCG trigger be given, whereupon an ER is done 36h later.
b.GnRH antagonist Protocols: There are 3 variations on this theme:
i.Late antagonist protocol: I do not use this approach. Here the antagonist therapy is initiated about 6-8 days after starting gonadotropin therapy
ii.The agonist/antagonist conversion protocol (A/ACP): I mostly recommend this for women who have diminishing ovarian reserve (AMH=<2.0ng/ml). Here, as with the long pituitary down regulation protocol, a BCP launches the cycled and this is overlapped with a GnRHa (e.g. Lupron). A menstrual bleed will usually follow within <7days. At this point, the GnRHa is supplanted with an antagonist which is continued through to the day of the hCG trigger. at The initial administration of GnRHa is designed to take advantage of the GnRHa-induced pre-cycle surge in pituitary FSH output that is necessary to promote antral follicle recruitment while at the same time allowing the concomitant surge in LH to wear off (down-regulate) over 4-5 days in an attempt to establish a relatively “LH-free environment”, prior to initiating gonadotropin therapy.
iii.A/ACP + Estrogen priming: I mostly prescribe this for women with very severely diminished ovarian reserve (AMH=<0.2ng/ml).This variation of the A/ACP involves “estrogen priming” prior to initiating gonadotropins. Here estradiol is administered by injection (estradiol valerate/Delestrogen) starting after menstruation begins, for 8-10 days prior to initiating high dosage FSH-dominant/Menopur, gonadotropin therapy and is then continued for another 7-10 days during the stimulation. The intent is to prime ovarian follicle FSH receptors in an attempt to augment response to gonadotropins in women who have diminished ovarian reserve.
It is remarkable, that while using the A/ACP + E2V in “poor responders “ whose FSH levels were often well above threshold limits, our cycle cancellation has consistently been below 10% (i.e. much lower than expected). Many such patients who had previously been told that they should give up on using their own eggs, and switch to egg donation because of “poor ovarian reserve”, have subsequently achieved viable pregnancies at SIRM using the A/ACP with “estrogen priming”.
B. Short Protocol/ “Flare “protocol/ Microdose-Lupron(MDL) protocol
I rarely, if ever recommend this approach and here is the explanation as to why: When a GnRHa such as Lupron is used this is often referred to as the microdose Lupron (MDL) flare protocol. Here, administration of GnRHa is initiated after spontaneous menstruation, virtually at the same time that gonadotropin therapy commences. The intent is to deliberately allow Lupron to affect an initial surge (“flare”) in pituitary FSH release, so as to augment ovarian response to the gonadotropin medication. Unfortunately, this approach represents “a double edged sword” as the resulting increased release of FSH is likely to be accompanied by a similar rise in blood LH levels that could evoke excessive ovarian stromal androgen production. The latter could potentially compromise egg quality, especially in older women, and to women with conditions like polycystic ovarian syndrome (PCOS) whose ovaries have increased sensitivity to LH. In my opinion, it is in this way that such “flare protocols” can suppress endometrial development; compromise egg/embryo quality and reduce IVF success rates….especially if used in older women (>40y) and those who have declining or diminished ovarian reserve –DOR (AMH<2.0ng/ml/<15pmol/L.
I strongly recommend that you visit http://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.
•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?
•Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
•IVF & Diminished Ovarian Reserve (DOR): A Rational Basis for COS Protocol Selection.
• A Rational Basis for selecting Controlled Ovarian Stimulation (COS) protocols in women with Diminished Ovarian Reserve (DOR)
•Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)
•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
I urge you to set up a Skype or an in-person consultation with me. To do so, simply call 1-800-780-7437 (if you reside in the U.S.A or Canada) or 702-533-2691 (if you reside elsewhere). Alternatively you can enroll online by going to the home page of the Sher-IVF website, http://www.SherIVF.com where, upon completing an enrollment form), you will immediately be eligible
Hi Dr. Sher,
I just found out I was pregnant last weekend and have had the following bloodwork done starting on 1/7 which was approximately 14/15 DPO:
-1/7 at 10:30 am
HCG: 79, Progesterone: 33
-1/9 at 8 am:
HCG: 118
-1/10 at 11:30 am
HCG: 167
-1/12 at 5:30 pm
HCG: 326
I am wondering if I should be concerned about the rate of increase? My doctor told me that the rate of increase between 1/7 and 1/9, though not a full 48 hours was concerning but the rates do seem to be increasing faster since. Also,
I have a 30 day cycle and may have ovulated a day or two off but was wondering if my level at 326 at just around 5 weeks seems too low? I am worried about Ectopic as they were not able to identify anything on an ultrasound yesterday and have had dull one-sided back discomfort, though it is still early.
Thank you in advance!
Frankly, I am guardedly optimistic for you!
Good luck!
Geoff Sher
Hello Dr. Sher.
I have read on your blog that long down regulation protocol may produce cysts. This is what happened to me-after Synarel downregulation I developed 40mm cyst. My question-is short protocol with 1-3 days antagonist suppression before stims have less probability of cyst formation?
Thank you
Kind regards
Anna
Protocols for controlled ovarian stimulation (COS) should be geared toward optimizing follicle and egg development and avoiding over exposure to ovarian androgens (mainly testosterone). The fulfillment of these objectives requires an individualized approach to COS and that the administration of human chorionic gonadotropin (hCG) or recombinant luteinizing hormone (LHr) to “trigger” ovulation, be timed precisely.
A.LONG PROTOCOLS:
I routinely use long pituitary down Regulation protocols on my patients.. It is common practice to administer gonadotropin releasing hormone (GnRH) agonists (Lupron, Buserelin, Superfact) that act by causing an initial outpouring and then, over 4-5 days, a depletion of Pituitary FSH and LH and GnRH-antagonists (e.g. Orgalutron, Ganirelix, Cetrotide). GnRH- antagonists that block pituitary LH release within a few hours of administration:
A.Conventional Pituitary down-regulation with a GnRH agonist (GnRHa):
i.Long Pituitary down regulation protocol: I mostly recommend this protocol, for women with normal ovarian reserve (AMH=>2.0ng/ml/15pmol/L). My patients start on a BCP, and overlapping it with a GnRHa, (e.g. Lupron 10U daily) for three (3) days and then stop the BCP but continuing on with daily Lupron 10u daily and await a period (which should ensue within 5-7 days of stopping the BCP). At that point an US examination is done along with a baseline measurement of blood estradiol (which needs to be <70pg/ml) to exclude a functional ovarian cyst and simultaneously, the Lupron dosage is reduced to 5U daily and then continued until the hCG (10,000u) trigger. An FSH-dominant gonadotropin such as Follistim/ Puregon/ Gonal-f, daily is started with the period for 2 days and then the gonadotropin dosage is reduced and a 37.5U-75U of Menopur (daily) is added. This is continued until US and blood estradiol levels indicate that the hCG trigger be given, whereupon an ER is done 36h later.
ii.GnRH antagonist(GnRHa) protocols:
i.Late antagonist protocol: I do not use this approach. Here the antagonist therapy is initiated about 6-8 days after starting gonadotropin therapy
ii.The agonist/antagonist conversion protocol (A/ACP): I mostly recommend this for women who have diminishing ovarian reserve (AMH=<2.0ng/ml). Here, as with the long pituitary down regulation protocol, a BCP launches the cycled and this is overlapped with a GnRHa (e.g. Lupron). A menstrual bleed will usually follow within <7days. At this point, the GnRHa is supplanted with an antagonist which is continued through to the day of the hCG trigger. at The initial administration of GnRHa is designed to take advantage of the GnRHa-induced pre-cycle surge in pituitary FSH output that is necessary to promote antral follicle recruitment while at the same time allowing the concomitant surge in LH to wear off (down-regulate) over 4-5 days in an attempt to establish a relatively “LH-free environment”, prior to initiating gonadotropin therapy.
iii.A/ACP + Estrogen priming: I mostly prescribe this for women with very severely diminished ovarian reserve (AMH=<0.2ng/ml).This variation of the A/ACP involves “estrogen priming” prior to initiating gonadotropins. Here estradiol is administered by injection (estradiol valerate/Delestrogen) starting after menstruation begins, for 8-10 days prior to initiating high dosage FSH-dominant/Menopur, gonadotropin therapy and is then continued for another 7-10 days during the stimulation. The intent is to prime ovarian follicle FSH receptors in an attempt to augment response to gonadotropins in women who have diminished ovarian reserve.
It is remarkable, that while using the A/ACP + E2V in “poor responders “ whose FSH levels were often well above threshold limits, our cycle cancellation has consistently been below 10% (i.e. much lower than expected). Many such patients who had previously been told that they should give up on using their own eggs, and switch to egg donation because of “poor ovarian reserve”, have subsequently achieved viable pregnancies at SIRM using the A/ACP with “estrogen priming”.
B. SHORT FROTOCOL/ “Flare “protocol/ Microdose-Lupron(MDL) protocol
I rarely, if ever recommend this approach and here is the explanation as to why: When a GnRHa such as Lupron is used this is often referred to as the microdose Lupron (MDL) flare protocol. Here, administration of GnRHa is initiated after spontaneous menstruation, virtually at the same time that gonadotropin therapy commences. The intent is to deliberately allow Lupron to affect an initial surge (“flare”) in pituitary FSH release, so as to augment ovarian response to the gonadotropin medication. Unfortunately, this approach represents “a double edged sword” as the resulting increased release of FSH is likely to be accompanied by a similar rise in blood LH levels that could evoke excessive ovarian stromal androgen production. The latter could potentially compromise egg quality, especially in older women, and to women with conditions like polycystic ovarian syndrome (PCOS) whose ovaries have increased sensitivity to LH. In my opinion, it is in this way that such “flare protocols” can suppress endometrial development; compromise egg/embryo quality and reduce IVF success rates….especially if used in older women (>40y) and those who have declining or diminished ovarian reserve –DOR (AMH<2.0ng/ml/<15pmol/L.
I strongly recommend that you visit http://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.
•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?
•Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
•IVF & Diminished Ovarian Reserve (DOR): A Rational Basis for COS Protocol Selection.
• A Rational Basis for selecting Controlled Ovarian Stimulation (COS) protocols in women with Diminished Ovarian Reserve (DOR)
•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
I urge you to set up a Skype or an in-person consultation with me. To do so, simply call 1-800-780-7437 (if you reside in the U.S.A or Canada) or 702-533-2691 (if you reside elsewhere). Alternatively you can enroll online by going to the home page of the Sher-IVF website, http://www.SherIVF.com where, upon completing an enrollment form), you will immediately be eligible to download my new book, “Recurrent Pregnancy Loss (RPL) and unexplained IVF Failure: The Immunologic Link”, free of charge.
Geoffrey Sher MD
We know that egg quality decreases as a woman ages; does AMH and antral follicle count mean much of anything to egg quality for a woman in the 42, 43, 44 year old age range? In other words, if the AMH is good and she has an antral count somewhere between 10 and 15, does this bode well or does it not matter anyway because the egg quality will be compromised regardless of how many are retrieved?
The impact of advancing age on egg/embryo quality is linked to the increasing incidence of egg karyotype (numerical chromosomal integrity). However, this is largely independent of ovarian reserve (as measured by basal AMH/FSH/LH/E2) which is an index of egg availability. However when there is diminished ovarian reserve in combination of advancing age, the effect on egg competency is magnified. Thus it is essential to use an individualized and strategic protocol for ovarian stimulation in such cases.
The potential for a woman’s eggs to undergo orderly development and maturation, while in large part being genetically determined can be profoundly influenced by the woman’s age, her “ovarian reserve” and proximity to menopause. It is also influenced by the protocol used for controlled ovarian stimulation (COH) which by fashioning the intra-ovarian hormonal environment, profoundly impacts egg development and maturation.
After the menarche (age at which menstruation starts) a monthly process of repeatedly processing eggs continues until the menopause, by which time most eggs will have been used up, and ovulation and menstruation cease. When the number of eggs remaining in the ovaries falls below a certain threshold, ovarian function starts to wane over a 5 to10-years. This time period is referred to as the climacteric. With the onset of the climacteric, blood Follicle Stimulating Hormone (FSH) and later also Luteinizing Hormone (LH) levels begin to rise…. at first slowly and then more rapidly, ultimately culminating in the complete cessation of ovulation and menstruation (i.e. menopause).
One of the early indications that the woman has entered the climacteric and that ovarian reserve is diminishing DOR) , is the detection of a basal blood FSH level above 9.0 MIU/ml and/ or an AMH level og <2.0ng/ml.
Prior to the changes that immediately precede ovulation, virtually all human eggs have 23 pairs (i.e. 46) of chromosomes. Thirty six to forty hours prior to ovulation, a surge occurs in the release of LH by the pituitary gland. One of the main e purposes of this LH surge is to cause the chromosomes in the egg to divide n half (to 23 in number) in order that once fertilized by a mature sperm ends up having 23 chromosomes) the resulting embryo will be back to having 46 chromosomes. A “competent” mature egg is one that has precisely 23 chromosomes, not any more or any less. It is largely the egg, rather than the sperm that determines the chromosomal integrity of the embryo and only an embryo that has a normal component of 46 chromosomes (i.e. euploid) is “competent” to develop into a healthy baby. If for any reason the final number of chromosomes in the egg is less or more than 23 (aneuploid), it will be incapable of propagating a euploid, “competent” embryo. Thus egg/embryo aneuploidy (“incompetence”) is the leading cause of human reproductive dysfunction which can manifest as: arrested embryo development and/or failed implantation (which often presents as infertility), early miscarriage or chromosomal birth defects (e.g. Down’s syndrome). While most aneuploid (“incompetent”) embryos often fail to produce a pregnancy, some do. However, most such pregnancies miscarry early on. On relatively rare occasions, depending on the chromosome pair involved, aneuploid embryos can develop into chromosomally defective babies (e.g. Down’s syndrome).
Up until a woman reaches her mid- thirties, at best, 1:2 of her eggs will likely be chromosomally normal. As she ages beyond her mid-thirties there will be a a progressive decline in egg quality such that by age 40 years only about 15%-20% of eggs are euploid and, by the time the woman reaches her mid-forties, less than 10% of her eggs are likely to be chromosomally normal. While most aneuploid embryos do appear to be microscopically abnormal under the light microscope, this is not invariably so. In fact, many aneuploid embryos a have a perfectly normal appearance under the microscope. This is why it is not possible to reliably differentiate between competent and incompetent embryos on the basis of their microscopic appearance (morphologic grade) alone.
The process of natural selection usually precludes most aneuploid embryos from attaching to the uterine lining. Those that do attach usually do so for such only a brief period of time. In such cases the woman often will not even experience a postponement of menstruation. There will be a transient rise in blood hCG levels but in most cases the woman will be unaware of even having conceived (i.e. a “chemical pregnancy”). Alternatively, an aneuploid embryo might attach for a period of a few weeks before being expelled (i.e. a “miscarriage”). Sometimes (fortunately rarely) an aneuploid embryo will develop into a viable baby that is born with a chromosomal birth defect (e.g. Down’s syndrome).
The fact that the incidence of embryo aneuploidy invariably increases with advancing age serves to explain why reproductive failure (“infertility”, miscarriages and birth defects), also increases as women get older.
It is an over-simplification to represent that diminishing ovarian reserve as evidenced by raised FSH blood levels (and other tests) and reduced response to stimulation with fertility drugs is a direct cause of “poor egg/ embryo quality”. This common misconception stems from the fact that poor embryo quality (“incompetence”) often occurs in women who at the same time, because of the advent of the climacteric also have elevated basal blood FSH/LH levels and reduced AMH. But it is not the elevation in FSH or the low AMH that causes embryo “incompetence”. Rather it is the effect of advancing age (the “biological clock”) resulting a progressive increase in the incidence of egg aneuploidy, which is responsible for declining egg quality. Simply stated, as women get older “wear and tear” on their eggs increases the likelihood of egg and thus embryo aneuploidy. It just so happens that the two precipitating factors often go hand in hand.
The importance of the IVF stimulation protocol on egg/embryo quality cannot be overstated. This factor seems often to be overlooked or discounted by those IVF practitioners who use a “one-size-fits-all” approach to ovarian stimulation. My experience is that the use of individualized/customized COS protocols can greatly improve IVF outcome in patients at risk – particularly those with diminished ovarian reserve (“poor responders”) and those who are “high responders” (women with PCOS , those with dysfunctional or absent ovulation, and young women under 25 years of age).
While no one can influence underlying genetics or turn back the clock on a woman’s age, any competent IVF specialist should be able to tailor the protocol for COS to meet the individual needs of the patient.
During the normal ovulation cycle, ovarian hormonal changes are regulated to avoid irregularities in production and interaction that could adversely influence follicle development and egg quality. As an example, small amounts of androgens (male hormones such as testosterone) that are produced by the ovarian stroma (the tissue surrounding ovarian follicles) during the pre-ovulatory phase of the cycle enhance late follicle development, estrogen production by the granulosa cells (cells that line the inner walls of follicles), and egg maturation.
However, over-production of testosterone can adversely influence the same processes. It follows that protocols for controlled ovarian stimulation (COS should be geared toward optimizing follicle growth and development (without placing the woman at risk from overstimulation), while at the same time avoiding excessive ovarian androgen production. Achievement of such objectives requires a very individualized approach to choosing the protocol for COS with fertility drugs as well as the precise timing of the “trigger shot” of hCG.
It is important to recognize that the pituitary gonadotropins, LH and FSH, while both playing a pivotal role in follicle development, have different primary sites of action in the ovary. The action of FSH is mainly directed towards the cells lining the inside of the follicle that are responsible for estrogen production. LH, on the other hand, acts primarily on the ovarian stroma to produce male hormones/ androgens (e.g. androstenedione and testosterone). A small amount of testosterone is necessary for optimal estrogen production. Over-production of such androgens can have a deleterious effect on granulosa cell activity, follicle growth/development, egg maturation, fertilization potential and subsequent embryo quality. Furthermore, excessive ovarian androgens can also compromise estrogen-induced endometrial growth and development.
In conditions such as polycystic ovarian syndrome (PCOS), which is characterized by increased blood LH levels, there is also increased ovarian androgen production. It is therefore not surprising that “poor egg/embryo quality” is often a feature of this condition. The use of LH-containing preparations such as Menopur further aggravates this effect. Thus we recommend using FSH-dominant products such as Follistim, Puregon, and Gonal-F in such cases. While it would seem prudent to limit LH exposure in all cases of COS, this appears to be more vital in older women, who tend to be more sensitive to LH
It is common practice to administer gonadotropin releasing hormone agonists (GnRHa) agonists such as Lupron, and, GnRH-antagonists such as Ganirelix and Orgalutron to prevent the release of LH during COS. GnRH agonists exert their LH-lowering effect over a number of days. They act by causing an initial outpouring followed by a depletion of pituitary gonadotropins. This results in the LH level falling to low concentrations, within 4-7 days, thereby establishing a relatively “LH-free environment”. GnRH Antagonists, on the other hand, act very rapidly (within a few hours) to block pituitary LH release, so as achieve the same effect.
Long Agonist (Lupron/Buserelin) Protocols: The most commonly prescribed protocol for Lupron/gonadotropin administration is the so-called “long protocol”. Here, Lupron is given, starting a week or so prior to menstruation. This results in an initial rise in FSH and LH level, which is rapidly followed by a precipitous fall to near zero. It is followed by uterine withdrawal bleeding (menstruation), whereupon gonadotropin treatment is initiated while daily Lupron injections continue, to ensure a “low LH” environment. A modification to the long protocol which I prefer using in cases of DOR, is the Agonist/Antagonist Conversion Protocol (A/ACP) where, upon the onset of a Lupron-induced bleed , this agonist is supplanted by an antagonist (Ganirelix/Cetrotide/Orgalutron) and this is continued until the hCG trigger. In many such cases I supplement with human growth hormone (HGH) to try and further enhance response and egg development.
Lupron Flare/Micro-Flare Protocol: Another approach to COS is by way of so-called “(micro) flare protocols”. This involves initiating gonadotropin therapy simultaneous with the administration of GnRH agonist (e.g. Lupron/Buserelin). The intent here is to deliberately allow Lupron to elicit an initial surge (“flare”) in pituitary FSH release in order to augment FSH administration by increased FSH production. Unfortunately, this “spring board effect” represents “a double edged sword” because while it indeed increases the release of FSH, it at the same time causes a surge in LH release. The latter can evoke excessive ovarian stromal androgen production which could potentially compromise egg quality, especially in older women and women with PCOS, whose ovaries have increased sensitivity to LH. I am of the opinion that by evoking an exaggerated ovarian androgen response, such “(micro) flare protocols” can harm egg/embryo quality and reduce IVF success rates, especially in older women, and in women with diminished ovarian reserve. Accordingly, I do not prescribe them at all.
Estrogen Priming – My approach for “Poor Responders” Our patients who have demonstrated reduced ovarian response to COS as well as those who by way of significantly raised FSH blood levels are likely to be “poor responders”, are treated using a “modified” long protocol. The approach involves the initial administration of GnRH agonist for a number of days to cause pituitary down-regulation. Upon menstruation and confirmation by ultrasound and measurement of blood estradiol levels that adequate ovarian suppression has been achieved, the dosage of GnRH agonist is drastically lowered and the woman is given twice-weekly injections of estradiol for a period of 8. COS is thereupon initiated using a relatively high dosage of FSH-(Follistim, Bravelle, Puregon or Gonal F) which is continued along with daily administration of GnRH agonist until the “hCG trigger.” By this approach we have been able to significantly improve ovarian response to gonadotropins in many of hitherto “resistant patients”.
The “Trigger”: hCG (Profasi/Pregnyl/Novarel) versus Lupron: With ovulation induction using fertility drugs, the administration of 10,000U hCGu (the hCG “trigger”) mimics the LH surge, sending the eggs (which up to that point are immature (M1) and have 46 chromosomes) into maturational division (meiosis) This process is designed to halve the chromosome number , resulting in mature eggs (M2) that will have 23 chromosomes rather that the 46 chromosomes it had prior to the “trigger”. Such a chromosomally normal, M2 egg, upon being fertilized by mature sperm (that following maturational division also has 23 chromosomes) will hopefully propagate embryos that have 46 chromosomes and will be “:competent” to propagate viable pregnancies. The key is to trigger with no less than 10,000U of hCGu (Profasi/Novarel/Pregnyl) and if hCGr (Ovidrel) is used, to make sure that 500mcg (rather than 250mcg) is administered. In my opinion, any lesser dosage will reduce the efficiency of meiosis, and increase the risk of the eggs being chromosomally abnormal. . I also do not use the agonist (Lupron) “trigger”. This approach which is often recommended for women at risk of overstimulation, is intended to reduce the risk of OHSS. The reason for using the Lupron trigger is that by inducing a surge in the release of LH by the pituitary gland it reduces the risk of OHSS. This is true, but this comes at the expense of egg quality because the extent of the induced LH surge varies and if too little LH is released, meiosis can be compromised, thereby increasing the percentage of chromosomally abnormal and of immature (M1) eggs. The use of “coasting” in such cases) can obviate this effect
.I strongly recommend that you visit http://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
•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 “Biological Clock” and how it should Influence the Selection and Design of Ovarian Stimulation Protocols for IVF.
• A Rational Basis for selecting Controlled Ovarian Stimulation (COS) protocols in women with Diminished Ovarian Reserve (DOR)
•Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)
•Ovarian Stimulation in Women Who have Diminished Ovarian Reserve (DOR): Introducing the Agonist/Antagonist Conversion protocol
•Controlled Ovarian Stimulation (COS) in Older women and Women who have Diminished Ovarian Reserve (DOR): A Rational Basis for Selecting a Stimulation Protocol
•Optimizing Response to Ovarian Stimulation in Women with Compromised Ovarian Response to Ovarian Stimulation: A Personal Approach.
•Egg Maturation in IVF: How Egg “Immaturity”, “Post-maturity” and “Dysmaturity” Influence IVF Outcome:
•Commonly Asked Question in IVF: “Why Did so Few of my Eggs Fertilize and, so Many Fail to Reach Blastocyst?”
•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?
•Staggered IVF
•Staggered IVF with PGS- Selection of “Competent” Embryos Greatly Enhances the Utility & Efficiency of IVF.
•Staggered IVF: An Excellent Option When. Advancing Age and Diminished Ovarian Reserve (DOR) Reduces IVF Success Rate
•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?
•PGS and Assessment of Egg/Embryo “competency”: How Method, Timing and Methodology Could Affect Reliability
•IVF outcome: How Does Advancing Age and Diminished Ovarian Reserve (DOR) Affect Egg/Embryo “Competency” and How Should the Problem be addressed.
I urge you to set up a Skype or an in-person consultation with me. To do so, simply call 1-800-780-7437 (if you reside in the U.S.A or Canada) or 702-533-2691 (if you reside elsewhere). Alternatively you can enroll online by going to the home page of the Sher-IVF website, http://www.SherIVF.com where, upon completing an enrollment form), you will immediately be eligible to download my new book, “Recurrent Pregnancy Loss (RPL) and unexplained IVF Failure: The Immunologic Link”, free of charge.
Geoffrey Sher MD
Hello Dr. Sher,
I have just turned 47. Met my husband at age 41 and within about 6 months we began trying to conceive. We had two miscarriages (both at 6 weeks), and started going to a fertility clinic to begin IVF. They discovered I had fibroids. Waited over a year before I was able to get in for myomectomy to get those out, and another 6 months to recover from that. Then I was diagnosed with transverse myelitis/possible MS after an acute attack of neuropathy. At the moment this is under control, only one lesion, but I do have little autoimmune-type rashes that flare up, blood shows autoimmune antibodies. Long story short all of this held up our IVF journey. In September of 2018 at age 46 I conceived naturally but miscarried again at 6 weeks (my third miscarriage). In November we finally began our first IVF cycle. My AMH showed high ovarian reserve. The protocol was Rekovelle + Menopur + Saizen and then Orgalutran beginning on day 6 until trigger shot. We retrieved 10 eggs, 5 fertilized, all made it to day 3 but none made it to day 5. I just turned 47, this past December. I feel healthy and I eat well and take all the supplements – Ubiquinol, high-quality fish oil, vit D, etc. My clinic is willing to do another IVF cycle (with PGS) and I am as well, but my husband is hesitant because of my age and our history. I also wonder about my autoimmune issues and miscarriage. Of course we are considering donor egg but I’m struggling to let go of “just one more try” with my own eggs, given that I seem to still have a decent reserve.
I wonder if you have thoughts or advice on the best approach at this point? Thanks very much!
Given your age, the chance of success with own eggs (regardless of your ovarian reserve)is dismal. Advancing age increases the likelihood of egg/embryo chromosomal aberrations (aneuploidy), compounding the risk of failed implantation and increasing the livelihood of early pregnancy loss.
Egg donation is the process by which a woman donates eggs for purposes of assisted reproduction or biomedical research. For assisted reproduction purposes, egg donation typically involves in vitro fertilization (IVF) technology, with the eggs being fertilized in the laboratory, unfertilized eggs may be frozen and stored for later use. Egg donation is a third party reproduction as part of assisted reproductive technology (ART).
For many women, disease and/or diminished ovarian reserve precludes achieving a pregnancy with their own eggs. Since the vast majority of such women are otherwise quite healthy and physically capable of bearing a child, egg donation (ED) provides them with a realistic opportunity of going from infertility to parenthood.
Egg donation is associated with definite benefits. Firstly, in many instances, more eggs are retrieved from a young donor than would ordinarily be needed to complete a single IVF cycle. As a result, there are often supernumerary (leftover) embryos for cryopreservation and storage. Secondly, since eggs derived from a young woman are less likely than their older counterparts to produce aneuploid (chromosomally abnormal) embryos, the risk of miscarriage and birth defects such as Down’s syndrome is considerably reduced.
Egg Donation-related, fresh and frozen embryo transfer cycles account for 10%-15% of IVF performed in the United States. The vast majority of egg donation procedures performed in the U.S involve women with declining ovarian reserve. While some of these are done for premature ovarian failure, the majority are undertaken in women over 40 years of age. Recurrent IVF failure due to “poor quality” eggs or embryos is also a relatively common indication for ED in the U.S. A growing indication for ED is in cases of same-sex relationships (predominantly female) where both partners wish to share in the parenting experience by one serving as egg provider and the other, as the recipient.
Ninety percent of egg donation in the U.S is done through the solicitation of anonymous donors who are recruited through a state-licensed egg donor agency. It is less common for recipients to solicit known donors through the services of a donor agency, although this does happen on occasion. It is also not easy to find donors who are willing to enter into such an open arrangement. Accordingly, in the vast majority of cases where the services of a known donor is solicited, it is by virtue of a private arrangement. While the services of non-family members are sometimes sought, it is much more common for recipients to approach close family members to serve as their egg donor.
Some recipients feel the compulsion to know or at least to have met their egg donor, so as to gain first hand familiarity with her physical characteristics, intellect, and character. This having been said, in the U.S. it is much more common to seek the services of anonymous donors. In terms of disclosure to their family, friends and child(ren), recipients using anonymous donors tend to be far more open than those of known donors about the nature of the child’s conception. Most, if not all, egg donor agencies provide a detailed profile, photos, medical and family history of each prospective donor for the benefit and information of the recipient. Agencies generally have a website through which recipients can access donor profiles in the privacy of their own homes in order to select the ideal donor.
Interaction between the recipient and the egg donor program may be conducted in-person, by telephone or online in the initial stages. Once the choice of a donor has been narrowed down to two or three, the recipient is asked to forward all relevant medical records to their chosen IVF physician. Upon receipt of her records, a detailed medical consultation will subsequently held and a physical examination by the treating physician or by a designated alternative qualified counterpart is scheduled. This entire process is usually overseen, facilitated and orchestrated by one of the donor program’s nurse coordinators who, in concert with the treating physician, will address all clinical, financial and logistical issues, as well as answering any questions. At the same time, the final process of donor selection and donor-recipient matching is completed.
Egg donor agencies usually limit the age of egg donors to women under 35 years with normal ovarian reserve in an attempt to minimize the risk of ovarian resistance and negate adverse influence of the “biological clock” (donor age) on egg quality.
No single factor instills more confidence regarding the reproductive potential of a prospective egg donor than a history of her having previously achieved a pregnancy on her own, or that one or more recipients of her eggs having achieved a live birth. Moreover, such a track record makes it far more likely that such an ED will have “good quality eggs”. Furthermore, the fact that an ED readily conceived on her own lessens the likelihood that she herself has tubal or organic infertility. This having been said, the current shortage in the supply of egg donors makes it both impractical and unfeasible, to confine donor recruitment to those women who could fulfill such stringent criteria for qualification.
It is not unheard of for a donor who, at some point after donating eggs, finds herself unable to conceive on her own due to pelvic adhesions or tubal disease, to blame her infertility on complications caused by the prior surgical egg retrieval process. She may even embark upon legal proceedings against the IVF physician and program. It should therefore come as no surprise that it provides a measurable degree of comfort to ED program when a prospective donor is able to provide evidence of having experienced a relatively recent, trouble free spontaneous pregnancy.
Screening of Donors
Genetic Screening: The vast majority of IVF programs in the U.S. follow the recommendations and guidelines of the American Society of Reproductive Medicine (ASRM) for selectively genetic screening of prospective egg donors for conditions such as sickle cell trait or disease, thalassemia, cystic fibrosis and Tay Sachs disease, when medically indicated. Consultation with a geneticist is available through about 90% of programs.
Most recipient couples place a great deal of importance on emotional, physical, ethnic, cultural and religious compatibility with their chosen egg donor. In fact they often will insist that the egg donor be heterosexual.
Psychological Screening: Americans tend to place great emphasis on psychological screening of egg donors. Since most donors are “anonymous,” it is incumbent upon the ED agency or the IVF program to determine the donor’s degree of commitment as well as her motivation for deciding to provide this service. I have on occasions encountered donors who have buckled under the stress and defaulted mid-stream during their cycle of stimulation with gonadotropins. In one case, a donor knowingly stopped administering gonadotropins without informing anyone. She simply awaited cancellation, which was effected when follicles stopped growing and her plasma E2 concentration failed to rise.
Such concerns mandate that assessment of donor motivation and commitment be given appropriate priority. Most recipients in the U.S. tend to be very much influenced by the “character” of the prospective egg donor, believing that a flawed character is likely to be carried over genetically to the offspring. In reality, unlike certain psychoses such as schizophrenia or bipolar disorders, character flaws are usually neuroses and are most likely to be determined by environmental factors associated with upbringing. They are unlikely to be genetically transmitted. Nevertheless, egg donors should be subjected to counseling and screening and should be selectively tested by a qualified psychologists. When in doubt, they should be referred to a psychiatrist for more definitive testing. Selective use of tests such as the MMPI, Meyers-Briggs and NEO-Personality Indicator are used to assess for personality disorders. Significant abnormalities, once detected, should lead to the automatic disqualification of such prospective donors.
When it comes to choosing a known egg donor, it is equally important to make sure that she was not coerced into participating. We try to caution recipients who are considering having a close friend or family member serve as their designated egg donor, that in doing so, the potential always exists that the donor might become a permanent and an unwanted participant in the lives of their new family.
Drug Screening: Because of the prevalence of substance abuse in our society, we selectively call for urine and/or serum drug testing of our egg donors.
Screening for STDs: FDA and ASRM guidelines recommend that all egg donors be tested for sexually transmittable diseases before entering into a cycle of IVF. While it is highly improbable that DNA and RNA viruses could be transmitted to an egg or an embryo through sexual intercourse or IVF, women infected with viruses such as hepatitis B, C, HTLV, HIV etc, must be disqualified from participating in IVF with egg donation due to the (abeit remote) possibility of transmission, as well as the potential legal consequences of the egg donation process being blamed for their occurrence.
In addition, evidence of prior or existing infection with Chlamydia or Gonococcus introduces the possibility that the egg donor might have pelvic adhesions or even irreparably damaged fallopian tubes that might have rendered her infertile. As previously stated, such infertility, subsequently detected might be blamed on infection that occurred during the process of egg retrieval, exposing the caregivers to litigation. Even if an egg donor or a recipient who carries a sexually transmittable viral or bacterial agent is willing to waive all rights of legal recourse, a potential risk still exists that a subsequently affected offspring might in later in life sue for wrongful birth.
Screening of the Recipient
Medical Evaluation: while advancing age, beyond 40 years, is indeed associated with an escalating incidence of pregnancy complications, such risks are largely predicable through careful medical assessment prior to pregnancy. The fundamental question namely: “is the woman capable of safely engaging a pregnancy that would culminate in the safe birth of a healthy baby” must be answered in the affirmative, before any infertility treatment is initiated. For this reason, a thorough cardiovascular, hepatorenal, metabolic and anatomical reproductive evaluation must be done prior to initiating IVF in all cases.
Infectious Screening: the need for careful infectious screening for embryo recipients cannot be overemphasized. Aside from tests for debilitating sexually transmittable diseases, there is the important requirement that cervical mucous and semen be free of infection with ureaplasma urealyticum. This organism which rarely causes symptoms frequents the cervical glands of 15-20% of women in the U.S. The introduction of an embryo transfer catheter via a so infected cervix might transmit the organism into an otherwise sterile uterine cavity leading to early implantation failure and/or first trimester miscarriage.
Immunologic Screening: Certain autoimmune and alloimmune disorders (see elsewhere) can be associated with immunologic implantation dysfunction (IID). In order to prevent otherwise avoidable treatment failure, it is advisable to evaluate the recipient for autoimmune IDD and also to test both the recipient and the sperm provider for alloimmune similarities that could compromise implantation.
Disclosure and Consent
Preparation for egg donation requires full disclosure to all participants regarding what each step of the process involves from start to finish, as well as potential medical and psychological risks. This necessitates that significant time be devoted to this task and that there be a willingness to painstakingly address all questions and concerns posed by all parties involved in the process. An important component of full disclosure involves clear interpretation of the medical and psychological components assessed during the evaluation process. All parties should be advised to seek independent legal counsel so as to avoid conflicts of interest that might arise from legal advice given by the same attorney. Appropriate consent forms are then reviewed and signed independently by the donor and the recipient couple.
Most embryo recipients fully expect their chosen donor to yield a large number of mature, good quality eggs, sufficient to provide enough embryos to afford a good chance of pregnancy as well as several for cryopreservation (freezing) and storage. While such expectations ore often met, this is not always the case. Accordingly, to minimize the trauma of unexpected and usually unavoidable disappointment, it is essential that in the process of counseling and of consummating agreements, the respective parties be fully informed that by making best efforts to provide the highest standards of care, the caregivers can only assure optimal intent and performance in keeping with accepted standards of care. No one can ever promise an optimal outcome. All parties should be made aware that no definitive representation can or will be made as to the number or quality of ova and embryos that will or are likely to become available, the number of supernumerary embryos that will be available for cryopreservation or the subsequent outcome of the IVF donor process.
TYPES OF EGG DONATION
Conventional Egg Donation: This is the basic format used for conducting the process of egg donor IVF. It involves synchronizing the menstrual cycles of both the recipient and the donor by placing the donor and the recipient on a birth control pill so that both parties start stimulation with fertility drugs simultaneously. This ultimately allows for precise timing of the fresh embryo transfer. Using this approach, the anticipated egg donation birth rate is >50% per cycle.
Preimplantation Genetic Sampling (PGS)-Egg Donation: The recent introduction of complete numerical chromosomal assessment (karyotyping) using metaphase Comparative Genomic Hybridization (mCGH) and Next Generation Gene sequencing (NGS) has the potential to change the manner in which egg donation will be performed in the future. CGH/NGS allows full egg/embryo chromosome analysis providing a 70- 80% assurance that the embryo(s) so selected for transfer are highly likely to be “competent” (i.e. capable of producing a healthy baby). Such PGS-egg selection provides about a 50% chance of a baby per transfer of an embryo derived through fertilization of a pre-vitrified euploid egg. This is at least double that reported when conventional egg donation is used. As a result, mCGH/NGS-Egg Donation allows for excellent results when one or two embryos are transferred, virtually eliminating the risk of “high order” multiple pregnancies (triplets or greater). Moreover, since numerical chromosomal irregularities (aneuploidy) are responsible for most miscarriages, the use of CGH also significantly reduces this dreaded complication.
PGS egg selection of necessity mandates the use of Staggered (ST)- IVF. Here the egg donor cycle is divided into two parts. The first involves the egg retrieval, fertilization, embryo biopsy for PGS analysis and embryo cryostorage. The second part involving warming or thawing of the frozen embryo(s) and the subsequent transfer of “competent” embryo(s) to the recipient’s uterus is conducted electively at least several weeks later once the results of PGS testing are available. Since, with St-IVF the egg retrieval and embryo transfer are separated in time, the retrieval can be performed without first having to synchronize the menstrual cycles of the recipient and the egg the donor. In fact, the recipient does not even have to be available when the egg donor is going through cycle. All that is needed is for designated sperm to be available (fresh or frozen) on the day of egg retrieval. This avoids unnecessary travel and inconvenience, and minimizes stress and cost.
Donor Egg Banking: Another imminent advance is the introduction of egg banking. Being able to freeze and bank donor eggs would solve most of these challenges. By using PGS in combination with a egg vitrification (ultra-rapid freezing), we are now capable of improving the birth rate per warmed/thawed egg by a factor of 3-4 fold (from a previous average of <8% per egg to about 27%). Through an electronic catalogue, recipients will be able to select and purchase 1-3 CGH-normal eggs from the comfort of their homes. Thereupon, the selective transfer of 1 or 2 embryos derived from such chromosomally normal eggs could achieve a 50-60% pregnancy rate without the risk of initiating high-order multiple pregnancies in the process. Through this process, the cost, inconvenience and risks associated with “conventional” fresh egg donor cycles would also be reduced significantly.
Financial Considerations
The fee paid to the egg donor agency per cycle usually ranges between $2,000 and $8,000. This does not include the cost associated with psychological and clinical pre-testing, fertility drugs, and donor insurance, which commonly range between $3,000 and $6,000. The medical service costs of the IVF treatment cycle ranges between $8,000 and $14,000. The donor stipend can range from $2,000 too as high $50,000 depending upon the exotic requirements of the recipient couple as well as supply and demand. Thus the total out of pocket expenses for an egg donor cycle in the United States range between $15,000 and $78,000, putting egg donation outside the financial capability of most couples needing this service.
The growing gap between need and affordability has spawned a number of creative ways to try and make IVF with egg donation more affordable. Here are a few examples:
•Egg banking (see above)
•Egg Donor Sharing, where one comprehensive fee is shared between two recipients and the eggs are then divided between them. The downside is that fewer eggs are available embryos for transfer and/or cryopreservation.
•Egg Bartering, where in the course of conventional IVF, a woman undergoing IVF remits some of her eggs to the clinic (who in turn provides it to a recipient patient) in exchange for a deferment of some or all of the IVF fee. In my opinion, such an arrangement can be fraught with problems. For example, in the event that the woman donating some of her eggs fails to conceive while the recipient of her eggs does, it is very possible that she might suffer emotional despair and even go so far as to seek out her genetic offspring. Such action could be very damaging to both her and the recipient, as well as the child.
•Financial Risk Sharing. Certain IVF programs offer financial risk sharing (FRS) which most recipient couples favor greatly. FRS offers qualifying candidates a refund of fees paid if egg donation is unsuccessful. FRS is designed to spread the risk between the providers, and the recipient couple.
Moral, Legal & Ethical Considerations: The “Uniform Parentage Act” which has been adopted by most states in the United States declares that the woman who gives birth to the child will be regarded as the rightful mother. Accordingly, there has to date not been any grounds for legal dispute when it comes to maternal custody of a child born through IVF with egg donation in the majority of states. In a few states such as Mississippi and Arizona the law is less clear but nevertheless, as yet, has not been contested.
The moral-ethical and religious implications of egg donation are diverse and have a profound effect on cultural acceptance of this process. The widely held view that everyone is entitled to their own opinion and has the right to have such opinions respected, governs much of the attitude towards this process in the U.S. The extreme views on each end of the spectrum hold the gentle central swing of the pendulum in place. This attitude is a reflection of the general acceptance in the united states of diverse views and opinions and the willingness to allow free expression of such views and beliefs provided that they don’t infringe on the rights of others.
So where do we go from here? Can and should we, cryopreserve and store eggs or ovarian tissue from a young woman wishing to defer procreation until it becomes convenient? And if we do this, would it be acceptable to eventually have a woman give birth to her own sister or aunt? Can or should we store viable ovarian tissue through generations. Should egg donation simply become a future source of embryos generated for the purpose of providing stem cells, to be used in the treatment of disease states or to “manufacture” fetuses as a source of spare body parts? If the answer to even some of these questions is yes…what about the checks and balances. Who will exercise control and where what form should such control take? Are we willing to engage this slippery slope where the disregard for the dignity of the human embryo leads us to the point where the rights of a human being are more readily ignored? …………………… Personally, I hope not.
I urge you to set up a Skype or an in-person consultation with me. To do so, simply call 1-800-780-7437 (if you reside in the U.S.A or Canada) or 702-533-2691 (if you reside elsewhere). Alternatively you can enroll online by going to the home page of the Sher-IVF website, http://www.SherIVF.com where, upon completing an enrollment form), you will immediately be eligible to download my new book, “Recurrent Pregnancy Loss (RPL) and unexplained IVF Failure: The Immunologic Link”, free of charge.
Geoffrey Sher MD
Addendum #1:
Optimizing International Access to Sher-IVF Services in Las Vegas.
Geoffrey Sher MD
Couples from all over the world seek access to IVF services at Sher-IVF in Las Vegas, NV. In fact about 70% of our patients emanate from out-of-state or from abroad. Most tend to be older, have failed IVF numerous times, have had repeated pregnancy losses or have complex reproductive issues. This article explains how we treat such patients at Sher-IVF and how we are able to provide seamless care in a caring and non-stressful environment. In one case, after experiencing 22 consecutive IVF failures, a couple who journeyed to see me from Melbourne, Australia, had a baby following a single IVF attempt. My approach is to individualize care and target those factors that adversely affect IVF outcome.
At Sher-IVF, IVF cycles are batched into about 8-10, 1-2 week cycles per year (dependent on whether we do fresh embryo transfers or frozen embryo transfers (FET)…which means that patients will almost always know well in advance of treatment, when they need to be at our centers for IVF. This makes the process very convenient for both patients and staff. It also allows us to quality assure the embryology laboratory between cycle batches and so optimize care and outcome.
HOW SHER-IVF PROVIDES OPTIMAL TREATMENT AT A DISTANCE:
•Setting Up a Skype Consultation
The initial step in treatment is to schedule a consultation with me. Patients living outside of the geographic catchment area of our Sher-IVF, (Las Vegas, NV) clinic generally schedule a consultation via Skype. I find that this is much more personal than a telephone consultation and is the closest thing to meeting me in person. You can schedule this consultation by going to my website, http://www.SherIVF.com where you can enroll online, by calling the Sher-IVF at 1-800-780-7437, or by emailing Julie Dahan (patient Concierge) at JulieD@sherIVF.com. Prior to your consultation with me you will be sent a questionnaire that asks for information relating to your medical and reproductive history. You will also be asked to provide copies of whatever medical records (from prior treatment and procedures) you might have available. If you have difficulty in completing the Questionnaire, please contact Julie by phone or email her and she will help you do this.
•The Initial Physician Consultation
You will thereupon be scheduled for initial Skype or an in-person consultation with me at which time I will review all available medical records, ask additional relevant questions and offer a preliminary opinion. I will at that time provide you with my personal cell phone # and will request that you contact me immediately with any future questions or concerns, so that I can address these immediately and in so doing, avoid any misunderstandings. This will be followed by one or more free, follow-up consultations with me to endorse or revise that opinion contingent upon supportive clinical and laboratory testing that I might recommend be performed in the interim. Within 24 hours of our initial consultation, you will receive a follow-up email from me which summarizes your case, my opinion and recommends tests needed. The email communication will also provide you with a list of suggested, supportive articles that I have written on my blog, http://www.SherIVF.com, along with directions on how to access these.
•The Consultation w/Clinical Director and Financial Advisor
Within one or two working days of our initial meeting, you be contacted by my office to set up a consultation with our Office Administrator to cover the logistical and financial considerations associated with doing IVF with me at Sher-IVF in Las Vegas. This consultation is free and in no way binds you to us. It is simply intended to provide you with relevant information, in case you should choose to do IVF here in Las Vegas, with me. At the same time, you will be familiarized with the logistics, time constraints, structure and process involved in an IVF cycle at Sher-IVF. Our approach enables patients to plan their treatment with precision, even months in advance. We will also go over our protocols for performing IVF in 1-2 week batches or “cycles” throughout the year so that our patients rarely need to spend more than two (2) weeks away from home to complete a full cycle of treatment. A Clinical Coordinator will be assigned to chaperone you through your IVF cycle and she will interact with you and your primary care OB/GYN (as required) on a regular and ongoing basis.
•Reaching the Crossroad: The Decision on Whether to Proceed
After completion of the above consultations, you will be asked to contact us with a firm decision as to whether/when you wish to undergo IVF treatment at Sher-IVF. Only after making such a commitment will you be expected to make a modest financial commitment to secure your place on our IVF calendar at a designated and mutually agreed upon time.
•The consultation with a Nurse, Case manager:
Once you have committed to, and have committed to a specific IVF cycle, you (and your partner…as applicable) will be scheduled to have a detailed consultation with a Nurse Coordinator who will develop a detailed, color-coded electronic calendar outlining all aspects of your management and treatment. This will include all diagnostic steps and therapeutic procedures required to ensure that that your planned cycle of IVF can be conducted as scheduled, and without a hitch. The Clinical Coordinator and her team of nursing and administrative personnel will in effect, hand-hold and triage you through all required steps and thereupon will schedule you with follow-up consultations. You will also be provided with contact information by which to reach the Clinical Coordinator, at will.
•Follow-up Physician consultation:
Once all records are available, test results are in, and your IVF cycle is scheduled, you will again consult with me for a free, follow-up consultation at which time we will review everything in detail and if needed make adjustments. Thereupon I might require further free consultations with you and you would of course be free to visit with, or call me on my cell phone with any issues. I ask is that you do not email or text me. I prefer to be contacted by phone so that we can discuss matters of concern rather than have me respond with one-liners via electronic communication.
•Ongoing Interaction and Follow-up
Our staff will at all times endeavor be affable and available to you upon request and will endeavor to maintain regular contact with you throughout. However, we are all human, and thus are capable of erring at times ….So, if anything is not in keeping with your expectations, I ask that you bring the matter(s) to our/my attention immediately so that we can address any/all issues in a timely manner.
•How to Reach Us and Where to Stay
We will gladly advise and assist you in obtaining the most affordable transportation and accommodations. Couples who elect to undergo IVF will find that accommodations in, and airfare (especially if scheduled well in advance) to Las Vegas, likely be relatively reasonable. In fact, we can assist you in obtaining very affordable quality accommodations in close proximity to our facilities.
•Getting You Ready to Go…Conveniently and On Time
We work with you to get all of your required tests done through your own doctor’s office. Remember, your primary OB/GYN is just as capable as we to facilitate or perform virtually all the necessary tests and procedures you may need, in your hometown environment.
Once we have reviewed all your test results, a customized protocol of treatment will be developed and then be emailed to you. Your assigned Clinical Coordinator will provide you with a detailed calendar and will review it with you in person or by telephone, prior to initiating your IVF cycle of treatment.
•The IVF Cycle:
Your cycle begins with the Birth Control Pill (BCP),starting no later than day 7 of menstruation. Depending upon your scheduled date for IVF, you will continue taking the BCP Pill for 11-30 days. This will be outlined in detail on the calendar we provide you with. It will also direct you when to begin your injections. Once you have taken an agonist (e.g. the Lupron, Superfact, Buserelin) for 3-5 days, the BCP will be stopped. You can expect to menstruate 3-8 days after stopping the BCP. Your blood estradiol (E2) level will be measured at the onset of menstruation. An E2 level of less than 70 pg/ml (200pmol/L) provides relative assurance that you have not formed an ovarian cyst and that you are ready to begin Gonadotropin (fertility hormone medication) injections. You will also have an ultrasound examination to ensure that you have no obvious cysts.
Depending on the stimulation protocol selected, you will at this point either continue with daily agonist injections (The conventional down-regulation protocol) or switch to an antagonist (Ganirelix, Cetrotide, Orgalutron) daily injections (the Agonist/Antagonist Conversion Protocol-A/ACP). Once again, your calendar will direct you as to when you should start the injections at home and plan on arriving at the center in Las Vegas for monitoring 7-8 days later. Please note that you will also be taking other medications during your cycle of treatment. This may include daily human growth hormone (HGH) until the day of hCG “trigger” and/or , low dosage oral steroid therapy (dexamethasone/prednisone) starting early in the stimulation and continuing to the 10th week of pregnancy,
If you have a thin uterine lining, you might receive vaginal sildenafil (Viagra) suppositories from the early stage of ovarian stimulation to the day of the hCG “trigger” . In the case of embryo recipient cycles (e.g. egg donation, gestational surrogacy, low dosage oral steroid therapy (dexamethasone/prednisone) will start early in the stimulation and continue to the 10th week of pregnancy. Treatment of an underlying immunologic implantation dysfunction (IID) may in addition require that you receive an intravenous infusion of 20% Intralipid (IL) about 10-14 days prior to embryo transfer (ET) and/or low molecular heparinoid (Lovenox or Clexane). This might need to be repeated one or more times after a positive beta-hCG pregnancy test depending on the type of immune issue involved in your case.
Once you arrive at Sher-IVF in Las Vegas for treatment, regular (usually daily) monitoring of blood E2 levels will begin along with ultrasound monitoring of your ovarian response and development of your uterine lining. Typically, egg retrieval will take place 2-8 days after your arrival at the clinic for monitoring. Fresh ET usually involv