IVF – Friend of Ivan Sher

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I am flattered that Ivan referred you to me and will do my best to advise. The response will be lengthy but please read it carefully:

There are several issues that apply here

1, AGE: It is primarily the egg (rather than the sperm) that determines the chromosomal integrity (karyotype) of the embryo, the most important determinant of egg/embryo competency”. A “competent” egg is therefore one that has a normal karyotype and has the best potential to propagate a “competent” embryo. In turn, a “competent embryo is one that possesses the highest potential to implant and develop into a normal, healthy, baby.

When it comes to reproductive performance, humans are the least efficient of all mammals. Even in young women under 35y, at best only 2 out of 3 eggs are chromosomally numerically normal (euploid). The remainder will have an irregular number of chromosomes (aneuploid) and are thus “incompetent”. The incidence of egg aneuploidy increases with age such by age 39 years, 3 in 4 are “competent”, and by the mid-forties, at best one in 10 are likely to be aneuploid. The fertilization of an aneuploid egg will inevitably lead to embryo aneuploidy (“incompetence”). As previously stated,   an aneuploid embryo cannot propagate a normal pregnancy s. For the embryo to have exactly 46 chromosomes (the euploid number), both the mature egg and mature spermatozoon must contain exactly 23 chromosomes. Only such euploid embryos are “competent” (capable of developing into healthy babies). Those with an irregular number of chromosomes (aneuploid embryos) are “incompetent” and are incapable of propagating healthy babies. While embryo “incompetence” can result from either egg or sperm aneuploidy, it usually stems from egg aneuploidy. However, in cases of moderate or severe male factor infertility, the sperm’s contribution to aneuploidy of the embryo can be significantly greater.

While embryo ploidy (numerical chromosomal integrity) is not the only determinant of its “competency, it is by far the most important and in fact is a rate-limiting factor in human reproduction. It is causal in the vast majority of cases of “failed nidation which in turn is responsible for most cases of a failed pregnancy (natural or assisted) and causes most sporadic early pregnancy losses (both chemical gestations and miscarriages) as well as  many chromosomal birth defects such as Turner syndrome (X-monosomy ) Down syndrome (trisomy 21) and Edward syndrome (trisomy 18) . In most cases, embryos that develop too slowly as well as those that grow too fast (i.e. ones that by day 3 post-fertilization comprise fewer than 6 cells or more than 9 cells) and/or embryos that contain cell debris or “fragments” are usually aneuploid and are thus unable to propagate a healthy pregnancy (i.e. they are “incompetent”). Additionally, embryos that fail to survive in culture to the blastocyst stage are also almost always aneuploid/”incompetent”. .Advancing chronologic age ais almost invariably associated  increased incidence of egg/embryo “incompetence” due to aneuploidy

The ovaries and developing eggs of older women are highly susceptible to the adverse effect of excessive Luteinizing Hormone (LH)-induced, ovarian overproduction of male hormones (e,g. testosterone and androstenedione). While a little testosterone produced by the ovaries is essential because for normal  and orderly egg development excessive testosterone has a converse effect. That is an important reason why older women who almost invariably have  excessive LH bioavailability and thus, increased ovarian testosterone production are at greater risk of propagating aneuploid eggs/embryos. Especially in such women, the use of individualized stimulation protocols that down- regulate LH production and so regulate ovarian testosterone will help to  improve egg yield, development and chromosomal integrityl and thereby    also embryo competency. Conversely, in such women, the use of ovarian stimulation protocols that fail to down-regulate LH activity prior to initiating ovarian stimulation with gonadotropins, often prejudices egg/embryo yield, quality and IVF outcome. This can manifest as an inordinately high yield of aneuploid embryos and/or low blastocyst propagation (bear in mind that egg which upon fertilization fail to propagate blastocysts are almost always aneuploid and “incompetent”. The only way to try to minimize this effect is by using indidualizing  protocols of ovarian stimulation, that down-regulate the LH-nduced effect.

• The conventional long pituitary down regulation protocol: BCP are commenced early in the cycle and continued for at least 10 days. Starting 3 days before the BCP is to be discontinued, it is overlapped with an agonist such as Lupron 10U daily for three (3) days and continued until menstruation begins (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 to exclude a functional ovarian cyst. Daily Lupron (10U) is continued and an FSH-dominant gonadotropin such as Follistim, Puregon or Gonal-f daily is administered daily falong with 37.5U of Menopur (an FSH/LH combination) for 2 days. On the 3^rd day the gonadotropin dosage is reduced by about one half and the dosage of Menopur is increased to 75U daily. Daily ultrasound and blood estradiol measurements are conducted starting on the 7^th or 8^th day of gonadotropin administration and continued until daily ultrasound follicle assessments indicate that most follicles have fully developed. At this point egg maturation is “triggered” using an intramuscular injection of a recombinant hCGr (Ovidrel) 500mcg or urinary derived hCGu (Pregnyl/Profasi/Novarel) 10,000U. And an egg retrieval is scheduled for 36h later.
• The agonist/antagonist conversion protocol (A/ACP): This is essentially the same as the conventional long down regulation protocol (see “a”-as above), except that with the onset of post-BCP menstruation, the agonist is supplanted by daily administration of a GnRH antagonist (e.g. Ganirelix, Cetrotide or Orgalutron) at a dosage of 250mcg daily until the day of the “trigger”. When it comes to women who have DOR I favor the use of the A/ACP, adding supplementary human growth hormone (HGH). In cases where the DOR is regarded as severe (AMH=<0.2), I often augment  the AACP protocol by using estrogen priming for 7-9 days prior to or with the commencement of gonadotropin therapy; For this I prescribe E2 skin patches  or intramuscular  estradiol valerate (Delestrogen), prior to or sometimes concurrent with, the  commencement of the GnRH antagonist administration
• The following Ovarian stimulation protocols are in my opinion best avoided in stimulating olderf women and /or thosed who regardless of age , have  DOR :

1. Agonist (e.g. Lupron/Superfact/Buserelin) “flare” protocols which result in an out-pouring of pituitary-LH at the critical time that ovarian follicles and eggs start developing/growing.
2. High dosages of LH -containing fertility drugs (e.g. Menopur) can also prejudice egg development and “competency”. Similarly, augmentation of the stimulation with LH0analogues such as hCG is in my opinon, likewise best avoided.
3. Supplementation with preparations that are testosterone-based such as Androgel are also, in my opinion, ill advised.
4. Supplementation with DHEA (which is converted to testosterone in the ovaries.
5. Clomiphene citrate or Letrozole which cause increased release of LH and thus increase ovarian male hormone (testosterone and androstenedione output are in my opinion, best avoided.
6. “Triggering” egg maturation using too low a dosage of hCG (e.g. 5,000U rather than 10,000U) or Ovidrel (e.g. 250mcg of Ovidrel rather than 500mcg)
7. “Triggering” with an agonist (alone) such as Lupron Superfact/ Buserelin/Aminopeptidyl/Decapeptyl will result in the expunging of LH from the pituitary gland with resultant increased production of ovarian testosterone.

B. ADENOMYOSIS: This condition cannot be disanosed by ultrasound or hysteroscopy. It required performance of pelvic MRI. And, in my opinion, prolonged down-regulation with Lupron has little , if any benefit when it comes to procuring pregnancy. Adenomyosis is a condition where endometrial glands develop outside the uterine lining (endometrium), within the muscular wall of the uterus (myometrium). Definitive diagnosis of adenomyosis is difficult to make. The condition should be suspected when a premenopausal woman (usually>25 years of age) presents with pelvic pain, heavy painful periods, pain with deep penetration during intercourse, “unexplained infertility” or repeated miscarriages and thereupon, when on digital pelvic examination she is found to have an often smoothly enlarged (bulky) soft tender uterus. Previously, a definitive diagnosis was only possible after a woman had her uterus removed (hysterectomy) and it this was inspected under a microscope. However the use of uterine magnetic resonance imaging (MRI) now permits reliable diagnosis. Ultrasound examination of the uterus on the other hand , while not permitting definitive diagnosis, is a very helpful tool in raising a suspicion of the existence of adenomyosis. Criteria used to make a diagnosis of adenomyosis on transvaginal ultrasound:

• Smooth generalized enlargement of the uterus.
• Asymmetrical thickening of one side of the (myometrium) as compared to another side.
• Thickening (>12mm) of the junctional zone between the endometrium and myometrium with increased blood flow.
• Absence of a clear line of demarcation between the endometrium and the myometrium
• Cysts in the myometrium
• One or more non discrete (not encapsulated) tumors (adenomyomas) in the myometrium.

Since there is no proven independent relationship between adenomyosis and egg/embryo quality any associated reproductive dysfunction (infertility/miscarriages) might be attributable to an implantation dysfunction. It is tempting to postulate that this is brought about by adenomyosis-related anatomical pathology at the endometrial-myometrial junction. However, many women with adenomyosis, do go on to have children without difficulty. Given that 30%-70% of women who have adenomyosis also have endometriosis…. a known cause of infertility, it is my opinion that infertility caused by adenomyosis is likely linked to endometriosis where infertility is at least in part due to a toxic pelvic environment that compromises egg fertilization potential and/or due to an immunologic implantation dysfunction (IID) linked to activation of uterine natural killer cells (NKa). Thus, in my opinion all women who are suspected of having adenomyosis-related reproductive dysfunction (infertility/miscarriages) should be investigated for endometriosis and for IID. The latter, if confirmed would make them candidates for selective immunotherapy (using intralipid/steroid/heparin) in combination with IVF.

Surgery: Conservative surgery to address adenomyosis-related infertility involves excision of portions of the uterus with focal or nodular adenomyosis and/or excision of uterine adenomyomas. It is very challenging and difficult to perform because adenomyosis does not have distinct borders that distinguish normal uterine tissue from the lesions. In addition, surgical treatment for adenomyosis-related reproductive dysfunction is of questionable value and of course is  not an option for diffuse adenomyosis.

Medical treatment: There are three approaches.

• GnRH agonists (Buserelin/Lupron) which is thought to work by lowering estrogen levels.
• Aromatase inhibitors such as Letrozole have also been tried with limited success
• Inhibitors of angiogenesis: The junctional zone in women with adenomyosis may grow blood vessels more readily that other women (i.e. angiogenesis). A hormone known as VEGF can drive this process. It is against this background that it has been postulated that use of drugs that reduce the action of VEGF and thereby counter blood vessel proliferation in the uterus could have a therapeutic benefit. While worth trying in some cases, thus far such treatment has been rather disappointing
• Immunotherapy to counter IID: The use of therapies such as Intralipid (or IVIG)/steroids/heparin in combination with IVF might well hold promise in those women with adenomyosis who have NKa.

Fortunately, not all women with adenomyosis are infertile. For those who are, treatment presents a real problem. Even when IVF is used and the woman conceives, there is still a significant risk of miscarriage. Since the condition does not compromise egg/embryo quality, women with adenomyosis-related intractable reproductive dysfunction who fail to benefit from all options referred to above…(including IVF) might as a last resort consider  Gestational surro resort consider  Gestational surrogacy.

C: GENETIC/CHROMOSOMAL EMBRYO TESTING:

Adenomyosis is a condition where endometrial glands develop outside the uterine lining (endometrium), within the muscular wall of the uterus (myometrium). Definitive diagnosis of adenomyosis is difficult to make. The condition should be suspected when a premenopausal woman (usually>25 years of age) presents with pelvic pain, heavy painful periods, pain with deep penetration during intercourse, “unexplained infertility” or repeated miscarriages and thereupon, when on digital pelvic examination she is found to have an often smoothly enlarged (bulky) soft tender uterus. Previously, a definitive diagnosis was only possible after a woman had her uterus removed (hysterectomy) and it this was inspected under a microscope. However the use of uterine magnetic resonance imaging (MRI) now permits reliable diagnosis. Ultrasound examination of the uterus on the other hand , while not permitting definitive diagnosis, is a very helpful tool in raising a suspicion of the existence of adenomyosis.

I would mbe happy to have an online consultation with you. Feel free to set this up by contacting my assistant, Patti Concerse (702-522-2691)

Geoff Sher

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ADDITIONAL INFORMATION:

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

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

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

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

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

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