Fertility Topics Explained from the Experts at SFS
Given the considerable emotional, physical and financial investment associated with IVF treatment, it is essential that factors known to affect success be identified and regulated in advance of initiating treatment and to always thoroughly and meticulously “plan the trip before taking the ride.” This article addresses the most important considerations in this regard:
As a woman advances beyond 30 years of age, her eggs are progressively more likely to be numerically chromosomally “abnormal” (aneuploid). By way of example, a women < 35 years, is likely to have about 50% of her “mature eggs” being aneuploid at the time of ovulation or egg extraction. By the time she reaches 40 years of age about 90% are likely to be aneuploid and by 45Y of age about 95% of her mature eggs will likely be aneuploid. Bear in mind that upon fertilization, aneuploid eggs will either not fertilize or if they do, will propagate aneuploid and “incompetent” embryos which will either arrest during development, fail to attach to the uterine will be lost early in gestation as chemical pregnancies or as miscarriages. Infrequently, an aneuploid embryo will attach and develop further, to produce a chromosomally defective babies (e.g. Down syndrome).This inevitable increase in the rapid rise in the prevalence of infertility, miscarriage, and birth defects that occur as the age of conception increases beyond the age of 35 years. The progressive decline in the woman’s egg population or DOR also serves to explain the accompanied decline in response to fertility drugs and in large part, why treatment of infertility becomes progressively less successful with advancing maternal age. Simply stated, egg (rather than sperm) aneuploidy is a primary rate-limiting factor in human reproduction. While DOR and declining egg quality both commonly occur as the woman approaches her 40’s, there is often a tendency to believe that DOR and a decline in egg quality go hand in hand. This is a misconception because often times the climacteric and DOR will set in at a younger age, before age related egg aneuploidy becomes a factor. Thus, a 38-40 year old woman who has a normal basal FSH/AMH (i.e. has not yet entered the climacteric) would probably respond relatively well to modest ovarian stimulation with fertility drugs, produce numerous growing follicles/eggs and embryos, while woman B, also 40 years of age has entered the climacteric (with elevated basal FSH and low AMH) and thus has DOR would produce significantly fewer follicles/eggs in response to aggressive ovarian stimulation with fertility drugs. However, provided the protocol used for ovarian stimulation used were optimal selected, both women, would likely have the same incidence of egg/embryo aneuploidy. However, since Woman A would probably yield more eggs/embryos than woman B, the former likely have more available from which to select the best quality embryos for transfer, she would have more embryos available for transfer and thus the chance of her having a chromosomally normal embryos transferred would be greater than for Woman B and her chance of success would likewise be improved. Since egg aneuploidy precipitates embryo aneuploidy and the latter is at the root of the age-related decline in IVF success, many IVF programs recommend preimplantation genetic sampling (PGS) of embryos for chromosomal integrity. PGS methods such as next generation gene sequencing (NGS) and comparative genomic hybridization (CGH) allow for evaluation of all 23 pairs of chromosomes. Embryos that have all 46 chromosomes intact (euploid) have a much higher chance of propagating a viable pregnancy and are far less likely to result in early pregnancy loss and chromosomal birth defects. For those women whose age and/or degree of ovarian resistance make 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.
In order for any organism to attain an optimal state of maturation (ripening) it must first undergo full growth and development. A fruit plucked from a tree before having developed fully ,or a poorly developed fruit, might still ripen (mature) on the shelf and might even appear as enticing as one that had previously undergone proper development, but it will lack the same quality. The same principle applies to the optimal maturation of human eggs. Proper development as well as precise timing of the initiation of egg maturation through meiosis (a process that in nature, is triggered by the LH surge, and in IVF, by the administration of hCG), is a vital requirement for optimal maturation, fertilization and ultimately to embryo quality. In fact, in cases where follicle/egg development is compromised or hCG (which initiates maturational division of egg chromosomes-meiosis), is administered prematurely or too late, the incidence of aneuploidy can rise well above the age-related threshold level, compromising IVF outcome. 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, while small amounts of ovarian male hormones (androgens) such as testosterone, enhance egg and follicle development, over-exposure to excessive concentrations of the same hormones can seriously compromise egg ( and subsequently, also) embryo quality . 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 toward granulosa cells (which line the inside of the follicles) proliferation and estrogen production. LH, on the other hand, acts primarily on the ovarian stroma (the connective tissue that surrounds the follicles) to produce male hormones (predominantly testosterone). Only a small amount of testosterone is necessary for optimal estrogen production while over--production has 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. It follows that protocols for controlled ovarian stimulation (COS) should be geared toward optimizing follicle and egg development while avoiding over exposure to testosterone The fulfillment of these objectives requires an individualized approach to COS and that the administration of human chorionic gonadotropin (hCG) to “trigger” ovulation, be timed precisely. In conditions such as polycystic ovarian syndrome (PCOS), which is characterized by increased blood LH biological availability there is also an increased ovarian male hormone (androgen) production. It is therefore not surprising that “poor egg/embryo quality” is often a feature of this condition. The use of an LH/hCG -containing preparation such as Menopur can in my opinion, further aggravate this effect. Thus I recommend against the exclusive use of Menopur (and similar menotropins), in PCOS patients, preferring FSH-dominant products such as Follistim, Puregon and Gonal F. While it would seem prudent to limit LH/hCG exposure in all cases of COS, this appears to be most needed in older women, women with DOR and PCOS women who tend all to have increased LH biological activity. Use of GnRH-Agonists (e.g. Lupron/ Buserelin) and GnRH-Antagonists (e.g. Cetrotide, Ganirelix, Orgalutron): It is common practice to administer gonadotropin releasing hormone (GnRH) agonists and more recently, GnRH-antagonists to prevent the “premature” release of LH late in the cycle of ovarian stimulation with gonadotropins. GnRH agonists exert their LH-lowering effect over a number of days. They act by causing an initial outpouring and then depletion of pituitary gonadotropins. This results in the LH level falling to within negligible concentrations, within 4-7 days, thereby establishing a relatively “LH-free environment”. GnRH Antagonists, on the other hand, act by rapidly (within a few hours) blocking pituitary LH release, so as to achieve the same effect. The most commonly used protocols for ovarian stimulation:
Selecting embryos for transfer to the uterus:
While in the vast majority of cases embryo aneuploidy results from egg rather than sperm problems, few would argue that sperm quality is also a very important factor in insuring embryo quality. Nevertheless, the advent of intracytoplasmic sperm injection (ICSI) has all but removed male infertility as an impediment to IVF success. The procedure of ICSI, involves the direct injection of a single sperm into each egg under direct microscopic vision. Initially ICSI was only used to achieve fertilization in cases of male infertility. However, today it is often used routinely to optimize the fertilization rate in all cases of IVF. When ICSI is conducted in cases of male infertility, there is a slight increase in the risk of chromosomal deletions leading to miscarriage. However, when ICSI is done in the absence of male infertility the miscarriage and IVF birth rate appears to be unaffected. It is relevant however that when ICSI is performed for male infertility there might well be a subsequent increased risk of male factor infertility in the offspring.
While there are many factors that affect implantation, the most important boil down to the following four (4)
While the presence of myomas (fibroids) in the uterine wall, are unlikely to cause infertility, an association between their presence and infertility has been observed in cases where they distort the uterine cavity, or protrude as submucous polyps through the endometrial lining. It would appear that even small submucous myomas have the potential to prejudice implantation. It is likely that any surface lesion in the uterine cavity, whether an endometrial, placental or fibroid polyp (no matter how small), or intrauterine adhesions, has the potential to interfere with implantation by producing a local inflammatory response. Unfortunately, a hysterosalpingogram (HSG) will miss the diagnosis in approximately 20% of cases. The only reliable methods for diagnosing even the smallest of such lesions, is through the performance of a sonohysterogram (fluid ultrasound) or by hysteroscopy. Either such procedure should ideally be performed within a year of doing IVF.
Considering its importance to successful procreation, it is not surprising that failure of proper function of this immunologic interaction during implantation has been implicated as a cause of implantation dysfunction leading to IVF failure, unexplained infertility, and recurrent pregnancy loss (RPL). A partial list of immunologic factors that may be involved in these situations includes anti-phospholipid antibodies (APA), antithyroid antibodies (ATA), and, perhaps most importantly, activated natural killer cells (NKa). Presently, these immunologic markers in the blood, can be adequately measured by only a few (less than a half dozen) highly specialized reproductive immunology laboratories in the United States:
In the final analysis, the transfer of embryos is the “holy grail”. It would not matter whether the embryos are ”competent” or whether the uterus is anatomically and immunologically “receptive” or not, if they are not transferred using optimal technique and by someone with dexterity, experience and dedicated commitment. First, as stated above, it is my opinion that with few exceptions only day 5 or 6 blastocysts should be transferred. Second, the transfer should be conducted under ultrasound guidance with the woman having a full bladder and finally the assistant performing the ultrasound examination for the transfer needs to be experienced or at the very least should be supervised by someone who has seasoning and expertise. Reporting of Clinic-Specific IVF Success Rates: Currently IVF success rates are reported by the society for Assisted Reproductive Technology (SART) and the CDC annually, on their respective websites. Unfortunately the reporting process currently in use is seriously lacks proper of accountability and oversight. Moreover, by presenting IVF outcome as a function of pregnancy or birth rate per completed cycle of IVF, per egg retrieval or per embryo transfer procedure performed does not serve to compare IVF programs on a level playing. This is because it leaves the door open for even the most honest and well intentioned IVF practitioners to attempt to try and look better by simply altering the mix of the patients they treat and report on or by increasing the number of embryos transferred per procedure. One way to remove such tendencies while still being able to readily compare and evaluate IVF success rates would in my opinion be to express IVF outcome in terms of pregnancy and birth rates (in various age and demographic categories) per embryo that is transferred. This, would immediately allow for reported success rates to be assessed using a level playing field. At the same time, it would discourage the transfer of multiple embryos at a time, and would lead to a further and much needed drop in the still unacceptably high national NF multiple birth rate. In my opinion, by using this approach and expressing IVF success as Viable Conception Rate (VCR) and/or Live Birth Rate (LBR) per embryo being transferred would immediately transfer responsibility for reporting, from the clinical team to the embryology laboratory, where such data is already accessible. This would make it simple for governing bodies to cross-check reported outcomes using existing embryology laboratory oversight mechanisms already in place through the College of American Pathologists (CAP) and in the process, remove one of SART's biggest impediments to reliable IVF outcome data collection. Our practice has had some of the highest rates of IVF success in the world. I have been working in this field for over thirty years and have helped bring more than 18,000 babies into the arms of loving families. If you have any questions about IVF, fertility, or any other specific concerns, I would be happy to answer them on my open forum, or in a private Skype consultation.
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