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  • Dear Patients,

    I created this forum to welcome any questions you have on the topic of infertility, IVF, conception, testing, evaluation, or any related topics. I do my best to answer all questions in less than 24 hours. I know your question is important and, in many cases, I will answer within just a few hours. Thank you for taking the time to trust me with your concern.

    – Geoffrey Sher, MD

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DHEA & Testosterone Levels

Name: Stephanie W

Hello,

I am wondering what you thoughts were on my situation. I just turned 39 and I have “lean” pcos. I have one living child conceived 6 years ago through medicated timed intercourse. Since then I have had a few miscarriages.

I have read a lot about the importance of adequate androgen levels and egg quality. I got my DHEA – S tested abd it came back as 4.1 umol/l and my testosterone came back at 0.6 nmol/l.
Are these values considered low and indicative of poor egg quality?
Also although I have pcos might supplementing be recommended or could that impact my condition negatively and cause me to be h?

Interested to hear your thoughts.

Thanks.

Author

Answer:

Here is an article I wrote on PCOS an IVF:

Polycystic ovary syndrome (PCOS) is a common hormonal system disorder among women affecting between 5% and 10% of women of reproductive age worldwide.  Women with PCOS may have enlarged ovaries that contain small collections of fluid — called follicles — located in each ovary as seen during an ultrasound. The condition is characterized by abnormal ovarian function (irregular or absent periods, abnormal or absent ovulation and infertility), androgenicity (increased body hair or hirsutism, acne) and increased body weight –body mass index or BMI. The ovaries of women with PCOS characteristically contain multiple micro-cysts often arranged like a “string of pearls” immediately below the ovarian surface (capsule) interspersed by an overgrowth of ovarian connective tissue (stroma).

PCOS is one of the most common causes of menstrual irregularities, infertility, and hirsutism. Despite an enormous effort to define its cause, the etiology of PCOS remains unclear, and there is no definite cure at this time. PCOS is clearly a heterogeneous disorder which often has a familial (genetic) basis. Infertility associated with PCOS has been attributed to numerous factors, including dysfunctional gonadotropin pituitary secretion, peripheral insulin resistance, elevated adrenal and/or ovarian androgen (male hormone) levels, and dysfunction of several growth factors. Women with this condition are often obese and insulin resistant. The compensatory hyperinsulinemia further stimulates ovarian androgen production which may be detrimental to egg maturation and there is a clear link between the degree of insulin resistance and anovulation. PCOS is also a significant long-term health risk for women, thus necessitating vigilance through regular annual examinations (non-insulin dependent diabetes mellitus, hypertension, hypercholesterolemia, cardiovascular disease and endometrial cancer). Whereas PCOS-related infertility is usually manageable through the use of fertility drugs, lifestyle changes (diet and exercise) remain a mainstay of long-term therapy. More recently, ovulation rates, circulating androgens, pregnancy rates and perhaps even first-trimester miscarriage rates have been shown to improve when insulin sensitizers like metformin are used to correct the underlying insulin resistance.

Most patients with PCOS are young and have excellent pregnancy rates with oral clomiphene. Those that require more aggressive treatments with injectable medications probably represent a subgroup of PCOS patients with severe ovarian dysfunction. These women often have explosive response to gonadotropins which can result in serious complications like Severe Ovarian Hyperstimulation Syndrome (OHSS…see below) and high order multiple births. In those women, the ability to perform “prolonged coasting” (see below) and selectively transfer fewer embryos during IVF offers a clear advantage over standard gonadotropin injections.

Egg quality in PCOS

The potential for a woman’s eggs to undergo orderly maturation, successful fertilization and subsequent progression to “good quality embryos” is in large part genetically determined. However, the expression of such potential is profoundly susceptible to numerous influences, especially intra-ovarian hormonal changes during the pre-ovulatory phase of the cycle. Proper follicular stimulation as well as precise timing of egg maturation with LH (Luteinizing Hormone) or hCG (human chorionic gonadotropin) is crucial to optimal egg maturation, fertilization and ultimately embryo quality. Both pituitary gonadotropins, LH and FSH (follicle stimulating hormone) play a pivotal but different role in follicular development. The action of FSH is mainly directed toward granulosa cell (cells lining the inside of the follicle) proliferation and estrogen production (E2). LH, on the other hand, acts primarily on the ovarian stroma (the connective tissue that surrounds the follicle) to produce androgens. While small amounts of ovarian androgens, such as testosterone, enhance egg and follicle development, over-exposure to them can have a deleterious effect. Furthermore, excessive ovarian androgens can also compromise estrogen-induced endometrial growth and development.

Suppressing pituitary secretion of LH with gonadotropin releasing hormone (GnRH) agonists such as Lupron®, is particularly useful in PCOS. In that condition, serum LH levels are elevated, leading to stromal overgrowth, follicular arrests (so-called cysts) and high levels of androgens synthesis. It is therefore not surprising that these follicles often yield poorly developed (“immature”) eggs” at the time of egg retrieval (ET) and that “poor egg/embryo quality”, inadequate endometrial development and high miscarriage rates are common features of this condition. However, contrary to popular belief, this is not due to an intrinsic deficit in “egg quality”. Stimulation protocols geared toward optimizing follicle and egg development and avoiding over exposure to androgens correct these problems ad result in pregnancy rates similar to those of non-PCOS women. Whereas the overuse of LH-containing preparations such as Menopur® and Luveris® further aggravates this effect. In conclusion, to maximize ultimate oocyte maturation, we strongly recommend against the exclusive use of such products in PCOS patients, preferring FSH-dominant products such as Folistim®, Gonal F® or Bravelle® over a period of at least 9 days following pituitary suppression with Lupron®.

PCOS women often have a family history of diabetes and demonstrable insulin resistance (evidenced by high blood insulin levels and an abnormal 2-hour glucose tolerance test).This underlying Diabetes mellitus tendency could play a role in the development of PCOS and contribute to the development of obesity, an abnormal blood lipid profile, and a predisposition to coronary vascular disease. Women with PCOS are slightly more at risk of developing uterine, ovarian and possibly also breast cancer in later life and accordingly should be evaluated for these conditions on a more frequent basis than would ordinarily be recommended to non-PCOS women.

Most women with PCOS either do not ovulate at all or they ovulate irregularly. As a consequence, thereof they in addition usually experience delayed, absent or irregular menstruation. In addition, an inordinate percentage of the eggs produced by PCOS women following ovulation induction, tend to be chromosomally abnormal (aneuploid). Rather than being due to an intrinsic egg defect being inherent in PCOS women, the poor egg quality more than likely the result of over-exposure to male hormones (predominantly, testosterone) produced by the ovarian stroma. These two factors (ovulation dysfunction and poor egg quality) are the main reasons for the poor reproductive performance (infertility and an increased miscarriage rate) in PCOS women.

PCOS patients are at an inordinate risk of severely over-responding fertility drugs, both oral varieties (e.g., Clomiphene, Serophene & Femara) and especially the injectables (e.g., Follistim, Puregon, Gonal F, Menopur and Bravelle) by forming large numbers ovarian follicles. This can lead to life endangering complications associated with sever ovarian hyperstimulation (OHSS). In addition PCOS women receiving fertility drugs often experience multiple ovulations putting them at severe risk (40%+)  of high order multiple pregnancy (i.e. triplets or greater) with often devastating consequences.

VARIETIES OF POLYCYSTIC OVARIAN SYNDROME:

1) Hypothalamic-pituitary-PCOS: This is the commonest form of PCOS and is  often genetically transmitted and is characteristically  associated with a blood concentration of Luteinizing Hormone (LH) that is uncharacteristically much higher than  the Follicle Stimulating Hormone (FSH) level (FSH is normally higher than the LH concentration) as well as high-normal or  blood androgen ( male) hormone  concentrations (e.g. androstenedione, testosterone and dehydroepiandrosterone -DHEA).Hypothalamic-pituitary-ovarian  PCOS is also often associated with insulin resistance and in about 40%-50% of the cases.

2) Adrenal PCOS: Here the excess of male hormones are derived from overactive adrenal glands rather than from the ovaries. Blood levels of testosterone and/or androstenedione raised but here, but here, the blood level of dehydroepiandrosterone (DHEAS) is also raised, clinching the diagnosis.

3) Severe pelvic adhesive disease secondary to severe endometriosis, chronic pelvic inflammatory disease and/or extensive pelvic surgery: Women who have this type of PCOS tend to less likely to hyperstimulate in response to ovulation induction. Their. DHEAS is also is not raised.

 

TREATMENT OF INFERTILITY DUE TO ASSOCIATED OVULATION DYSFUNCTION:

Hypothalamic-pituitary-/ovarian PCOS: Ovulation induction with fertility drugs such as clomiphene citrate, Letrozole (Femara) or gonadotropins, with or without intrauterine insemination (IUI) is often highly successful in establishing pregnancies in PCOS women. However, IVF is fast becoming a treatment of choice (see below).

 

 

In about 40% of cases, 3-6 months of oral Metformin (Glucophage) treatment results in a significant reduction of insulin resistance, lowering of blood androgen levels, an improvement in ovulatory function, and/or some amelioration of androgenous symptoms and signs.

Surgical treatment by “ovarian drilling” of the many small ovarian cysts lying immediately below the envelopment (capsule) of the ovaries, is often used, but is less successful than alternative non-surgical treatment and is only temporarily effective. The older form of surgical treatment, using ovarian wedge resection is rarely used any longer as it can produce severe pelvic adhesion formation.

Adrenal PCOS is treated with steroids such as prednisone or dexamethasone which over a period of several weeks will suppress adrenal androgen production, allowing regular ovulation to take place spontaneously. This is often combined with clomiphene, Letrozole and/or gonadotropin therapy to initiate ovulation.

PCOS attributable to Pelvic Adhesive Disease is one variety which often is associated with compromised ovarian reserve, a raised FSH blood level and ovarian resistance to fertility drugs. In many such cases, high dosage of gonadotropins (FSH-dominant) with “estrogen priming” will often elicit an ovarian response necessary for successful ovulation induction and/or IVF. Neither steroids nor Metformin are helpful in the vast majority of such cases.

PCOS women undergoing ovulation induction usually release multiple eggs following the hCG trigger and are thus at inordinate risk of twin or higher order multiple pregnancies. They are also at risk of developing OHSS.  Many now believe that IVF should be regarded as a primary and preferential treatment for PCOS. The reason is that it is only through this approach that the number of embryos reaching the uterus can be controlled and in this manner the risk of high-order multiples can be minimized and it is only in the course of IVF  treatment that a novel treatment method  known as “prolonged coasting” ( see below) which prevents OHSS, can be implemented

SEVERE OVARIAN HYPERSTIMULATION SYNDROME (OHSS):

As indicated above, there is an inordinate propensity for women with PCOS to hyper-respond to gonadotropin fertility drugs and in the process produce large numbers of ovarian follicles. If left unchecked this can lead to OHSS, a potentially life endangering condition. The onset of OHSS is signaled by the development of a large number of ovarian follicles (usually more than 25 in number). This is accompanied by rapidly rising plasma estradiol (E2) levels, often exceeding 3000pg/ml within 7 or 9 days of stimulation, often rapidly peaking above 6,000 pg/ml prior to hCG administration. When this happens, the risk of OHSS developing is above 80%.

Symptoms and signs of OHSS include: abdominal distention due to fluid collection (ascites), fluid in the chest cavity (hydrothorax), rapid weight gain (of a pound or more per day) due to tissue fluid retention, abdominal pain, lower back ache, nausea, diarrhea, vomiting, visual disturbances such as blurred vision and spots in front of the eyes (scotomata), a rapidly declining urine output, cardiovascular collapse and failure of blood to clot which sometimes results in severe bruising (echymosis) and frank bleeding.  These symptoms and signs may appear before pregnancy can be diagnosed. If pregnancy occurs, the condition is likely to worsen progressively over a period of 3-5 weeks whereupon it rapidly resolves spontaneously over a few days. If no pregnancy occurs, the symptoms and signs all disappear spontaneously within 10-12 days of the hCG injection.

When increasing fluid collection in the abdominal cavity (ascites) starts to compromise breathing raising the head of the bed rose slightly by placing a 4–6-inch block at the base of each head post and using a few additional pillows, will sometimes help ameliorate the problem. In cases where this does not help or symptoms become severe, all or most of the fluid can readily and safely be drained through t transvaginal sterile needle aspiration (vaginal paracentesis-performed once or sometimes twice a week) can be performed once or twice weekly. The problem will usually self corrects within 10-12 days of the hCG shot if pregnancy does not occur or, by the 8th week of pregnancy.

Urine output should be monitored daily to see if it drops below about 500ml a day (about two cups and a half). A chest X-ray, to evaluate for fluid collection in the chest and around the heart should be done weekly along with blood tests for hematocrit, BUN, electrolytes, creatinine, platelet count and fibrin split products (FSP). If indicated on the basis of a deteriorating clinical situation, hospitalization might be needed for close observation and if necessary, to provide intensive care.

In all case of OHSS, the ovaries will invariably be considerably enlarged. This is irrelevant to the final outcome, unless ovarian torsion (twisting of the ovary on its axis), an extremely rare complication occurs. The latter would usually require surgical emergency surgical intervention.

 

 

It is important to know that symptoms and signs of OHSS are severely aggravated by rising hCG levels. Thus such patients should not receive additional hCG injections. 

Does PCOS cause poor egg/embryo quality? It is an undeniable fact that women with PCOS undergoing IVF are commonly found to have poorly developed (“dysmorphic”) eggs, with reduced fertilization potential and yielding “poor quality embryos”. However, in the author’s opinion (which admittedly runs contrary to popular opinion), this is unlikely to be due to an intrinsic deficit in egg quality. Rather, it more likely relates to   intra-ovarian hormonal changes brought about by hyperstimulation and which compromise egg development.  This effect, in the author’s opinion, can often be significantly reduced through implementation of an individualized or customized   ovarian stimulation protocols that minimize exposure of the developing follicles and eggs to excessive LH-induced ovarian androgens. This can be best achieved by limiting the use of LH-containing gonadotropins such as Menopur through selective institution of “prolonged coasting” (see below).

In the past, the onset of OHSS, heralded by the presence of large numbers of developing ovarian follicles and rapidly rising plasma estradiol levels often led the treating physician to prematurely administer hCG in an attempt to abruptly arrest the process and prevent escalation of risk to the patient. However, the premature administration of hCG, while abruptly arresting further proliferation of estrogen producing granulosa cells in the follicles, unfortunately also prematurely arrests egg development. Since the ability of an egg to achieve optimal maturation upon hCG triggering is largely predicated upon it having achieved prior optimal development, the untimely administration of hCG which triggers meiosis, probably increases the risk of numerical chromosomal abnormalities (aneuploidy) of the egg. This in turn would lead to reduced fertilization potential, poor egg/embryo quality and low embryo implantation potential.

In women with PCOS the connective tissue that surrounding the follicles (ovarian stroma) is often characteristically overgrown (stromal hyperplasia). It is the stroma that produces androgens (mainly testosterone) in response to LH. It is this, coupled with the fact that PCOS women also often have elevated blood LH concentrations (see above) results in the excessive production of androgen hormones, which is so characteristic in PCOS. While excessive exposure of developing eggs to ovarian androgens compromises follicle and egg growth it also impairs endometrial response to estrogen, which could explain the common finding of poor endometrial thickening in many PCOS women undergoing IVF.

The obvious remedy for these adverse effects on egg and endometrial development is to employ stimulation protocols that limit ovarian over-exposure to LH and allowing the time necessary for the follicles/eggs to develop optimally, prior to administering hCG through the judicious implementation of   “Prolonged coasting” (PC).

 

 

“PROLONGED COASTING”:

In the early 90’s we were the first to report on “prolonged coasting” (PC), a novel approach that protects egg quality while preventing the development of OHSS. PC has since, gained widespread acceptance as a method of choice for preventing OHSS and has established itself as the “standard of care”. It involves withholding gonadotropin therapy while continuing the administration of the GnRHa and waiting until the plasma estradiol concentration drops below 2,500 pg/ml. Thereupon hCG is administered. In such cases, regardless of the number of developed follicles or the number of eggs retrieved, these women rarely, if ever develop OHSS. It has been reported that while PC virtually eliminates the risk of life-endangering complications associated with OHSS, there are reports in the literature that “the price to pay with PC” is often a poorer fertilization rate and   reduced embryo implantation potential, compromising the pregnancy”. It is the author’s opinion an experience in the development of PC that egg/embryo quality deficit likely has  little to do with the process of PC, itself and can be  explained as follows:  When  PC is initiated too early, follicle growth and development may cease (as evidenced by the estradiol level plateauing or falling immediately, rather than showing an initial continued increase), and when  PC is started  too late, the follicles will often become cystic, measuring >21mm by the time the estradiol level falls below the safe threshold of 2500pg/ml, and so harbor dysmorphic  eggs. Thus precise timing of the initiation of PC is critical. It should in pact be initiated preemptively in all cases when there are more than 25 follicles and the plasma estradiol reaches or exceeds 2,500pg/ml in association, provided that at least 50% of the follicles measuring 14-16mm in mean diameter. Not a day sooner or a day later. If PC is initiated with precise timing, it will usually be followed by a further progressive rise in the estradiol concentration. After a few days, the estradiol level will plateau and then it will start to fall (often rapidly). The temptation to trigger with hCG before the estradiol level falls below 3000picogtrams per milliliter must be resisted …even if the level falls below 1,000pg/ml by the time hCG is given.

Since when using agonist (Cetrotide/Ganirelix/Orgalutron) pituitary suppression throughout the stimulation phase with gonadotropins, the plasma estradiol level often under expressed follicle growth, this method of pituitary blockade should not be used in cases (such as with PCOS) where PC might be required.

 

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

  • A Fresh Look at the Indications for IVF
  • The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
  • Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
  • IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
  • The Fundamental Requirements For Achieving Optimal IVF Success
  • Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
  • Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
  • IVF and the use of Supplementary Human Growth Hormone (HGH) : Is it Worth Trying and who needs it?
  • The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
  • Blastocyst Embryo Transfers Should be the Standard of Care in IVF
  • Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
  • Embryo Transfer: The “Holy Grail in IVF.
  • IVF: Approach to Selecting the Best Embryos for Transfer to the Uterus.
  • Fresh versus Frozen Embryo Transfers (FET) Enhance IVF Outcome
  • Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
  • Genetically Testing Embryos for IVF
  • Staggered IVF
  • 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?
  • Sher Fertility Solutions (SFS): An Exciting New Chapter….
  • Should IVF Treatment Cycles be provided uninterrupted or be Conducted in 7-12 Pre-scheduled “Batches” per Year
  • A personalized, stepwise approach to IVF
  • How Many Embryos should be transferred: A Critical Decision in IVF.
  • Avoiding High Order Multiple Pregnancies (Triplets or Greater) with IVF
  • The Role of Nutritional Supplements in Preparing for IVF
  • Ovarian Hyperstimulation Syndrome (OHS): Its Evolution & Reducing itsIncumbent Risks
  • Taking A Fresh Look at Ovarian Hyperstimulation Syndrome (OHSS), its Presentation, Prevention and Management
  • Preventing Severe Ovarian Hyperstimulation Syndrome (OHSS) with “Prolonged Coasting”
  • IVF Outcome in Patients with Polycystic Ovarian Syndrome (PCOS): Minimizing the Risk of Severe Ovarian Hyperstimulation Syndrome (OHSS) and optimizing Egg/Embryo Quality.
  • Understanding Polycystic Ovarian Syndrome (PCOS) and the Need to Customize Ovarian Stimulation Protocols.
  • IVF & Polycystic Ovarian Syndrome (PCOS): Reducing the Risk of Severe Ovarian Hyperstimulation Syndrome (OHSS), Improving Egg Quality and Optimizing Outcome.

 

 

______________________________________________________

ADDENDUM: PLEASE READ!!

INTRODUCING SHER FERTILITY SOLUTIONS (SFS)

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

 

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

 

PLEASE SPREAD THE WORD ABOUT SFS!

 

Geoff Sher

ADDITIONAL INFORMATION:

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

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

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

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

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

………………………………………………………………..

Poor response to oestrogen

Name: Alyson B

Hello,
My first IVF cycle with embryo adoption has been cancelled due to a thin endometrium as I have not responded well to the oestrogen medication (it was increased to 8mg of Progynova a day in combination with an estraderm patch in the last week). The clinic have said to do a new preparation but what can be done to increase the receptivity of the endometrium?

Previously I had endometrial cancer which was treated with high strength progesterone and the Mirena coil which was removed mid September of this year. I had repeated biopsies taken over two years – I’m concerned this might have damaged the endometrium. Before I was down regulated my endometrium had got to 5.4mm.

I’m concerned that it’s a lost cause. Any help would be gratefully received. Thanks.

Author

Answer:

It is possible that the treatment of your endometrial cancer might have negatively  impacted endometrial thickening in response to estrogen.

This having been said, I would need much  more information in order to provide an authoritative response!

________________________________________________________________________

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

………………………………………………………………..

To set up an online consultation with me, please contact my assistant, Patti Converse at 702-533-2691 or by email: concierge@sherIVF.com

Miscarriage

Name: Ananthy A

I had a term baby at 38years. I was treated with immune protocol – Intralipid, clexane, dexamethasone,aspirin and so on for repeated implantation failure( after 6 failed implantation)
Hla DQ and NK cells normal

At 40 I did ivf again with the same immune protocol with genetically tested embryo but had silent miscarriage at around 16-18 weeks with out any obvious reason.

They could not find the reason.

Could you help me with the reason?

Author

Answer:

I am afraid , I would need a great deal more information to be able to comment authoritatively!.

We should talk!

Geoff Sher

_________________________________________________________-

ADDITIONAL INFORMATION:

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

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

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

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

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

………………………………………………………………..

To set up an online consultation with me, please contact my assistant, Patti Converse at 702-533-2691 or by email: concierge@sherIVF.com

 

3 failed pgs donor fet transfers

Name: Eliana B

Hi Dr. Sher, I have a child conceived naturally at 39 and then two early miscarriages also natural conception (first loss at 6 weeks and second loss at 7 weeks prior to heartbeat being detected) at age 42 and age 43 which were attributed to likely chromosomal abnormalities. Since that time I’ve had one failed round of own egg IVF where none of the fertilized eggs made it blastocyst and one frozen donor egg round where 4 of 6 fertilized eggs made it to blastocyst and three were chromosomally normal. My first FET transfer was a hormonal replacement cycle that resulted in a chemical pregnancy. My second FET was a modified natural transfer that was negative for pregnancy, and now my last transfer was modified natural with autoimmune protocol (baby aspirin, 10 mg Prednisone daily, Claritin 10 mg daily, famotidine 20 mg twice a day, 5 mg estrace starting week of transfer and progesterone 200 mg suppository twice a day for luteal support.) What do you advise should be done next to increase chance of next donor FET transfer being successful? Will add that all my pregnancies have been with my husband who had sperm analysis done with good total sperm count, but less than 2% normal so advised IVF would be best. Thank you.

Author

Answer:

This is highly likely to at least in part, be due to a secondary implantation dysfunction (see below). While not definitive, I suspect an immunologic implantation dysfunction (IID). The fact that you have had a child already means that it if an IID exists, it is possibly alloimmune in origin (see below). You mentioned treatment you received empirically for an IID , however, what you described would in my opinion not have been optimal (see below).

Implantation dysfunction is unfortunately often overlooked as an important cause of IVF failure. In the pursuit of optimizing outcome with IVF, the clinician has a profound responsibility to meticulously assess and address this important issue if IVF success is to be optimized. This is especially relevant in cases of “unexplained IVF failure, Recurrent Pregnancy Loss (RPL) and in women suspected of having underlying anatomical and immunologic factors. Doing so  will not only maximize the chance of a viable pregnancy but enhancing placentation, will at the same time  promote the noble objective of optimizing the quality of life after birth.”

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

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

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

  • Anatomical abnormalities in the uterine cavity  (polyps/scarring/internal fibroids)

Several studies performed both in the United States and abroad have confirmed that a dye X-Ray or hysterosalpingogram (HSG) will fail to identify small endouterine surface lesions in >20% of cases. This is significant because even small uterine lesions have the potential to adversely affect implantation. Hysteroscopy is the traditional method for evaluating the integrity of the uterine cavity in preparation for IVF. It also permits resection of most uterine surface lesions, such as submucous uterine fibroids (myomas), intrauterine adhesions and endometrial or placental polyps. All of these can interfere with implantation by producing a local “inflammatory- type” response similar in nature to that which is caused by an intrauterine contraceptive device. Hysterosonography (syn; HSN/ saline ultrasound examination) and hysteroscopy have all but supplanted HSG to assess the uterine cavity in preparation for IVF. HSN which is less invasive and far less expensive than is than hysteroscopy involves  a small amount of a sterile saline solution is injected into the uterine cavity, whereupon a vaginal ultrasound examination is performed to assess the contour of the uterine cavity.

  • Endometrial Thickness: As far back as in 1989 I first reported  on the finding  that ultrasound assessment of the late proliferative phase endometrium following ovarian stimulation in preparation for IVF, permits better identification of those candidates who are least likely to conceive. We noted that the ideal thickness of the endometrium at the time of ovulation or egg retrieval is >9 mm and that a thickness of less than 8 mm bodes poorly for a successful outcome following IVF.

Then in 1993, I demonstrated that sildenafil (Viagra) introduced into the vagina prior to hCG administration can improve endometrial growth in many women with poor endometrial development. Viagra’s mechanism of action is improvement in uterine blood flow with improved estrogen delivery…thereby enhancing endometrial development.

  • Immunologic factors: These also play a role in IVF failure. Some women develop antibodies to components of their own cells. This “autoimmune” process involves the production of antiphospholipid, antithyroid, and/or anti-ovarian antibodies – all of which may be associated with activation of Natural Killer (NK) cells in the uterine lining. Activated NK cells (NKa) release certain cytokines (TH-I) that if present in excess, often damage the trophoblast (the embryo’s root system) resulting in immunologic implantation dysfunction (IID). This can manifest as “infertility” or as early miscarriages). In other cases (though less common), the problem is due to “alloimmune” dysfunction. Here the genetic contribution by the male partner renders the embryo “too similar” to the mother. This in turn activates NK cells leading to implantation dysfunction. These IID’s are treated using combinations of medications such as heparin, Clexane, Lovenox, corticosteroids and intralipid (IL).

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

 

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

_______________________________________________________________________

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

………………………………………………………………..

To set up an online consultation with me, please contact my assistant, Patti Converse at 702-533-2691 or by email: concierge@sherIVF.com

Infertility/Recurrent loss

Name: Janeé B

Hello Dr. Sher,

Thank you for taking the time to answer my questions. I have 1 daughter (age 16) then loss my son at 23 weeks gestation 2 years later, had 3 ectopic pregnancies and 4 chemical pregnancies. I’ve had a laser done on my cervix after having my daughter , confirmed Endometriosis via laparoscopy, high testosterone/ hair growth/ PCOS. I was put on Metformin, prednisone , progesterone and blood thinner but pregnancy was ectopic. Had HSG test done- remaining tube clear. I also have had immune testing done which came back negative/normal. Clotting tests can back normal as well. All natural pregnancies.

I am currently not on any medications to try to conceive as I am hurt and tired. I am 36 and my husband is 52. The 3 ectopic and last 3 chemical losses was by my husband. My GYN advised that a sperm test was not needed. Any advice on what I should do next?

Thank you in advance!

Author

Answer:

Your underlying PCOS does not explain the losses (chemical or ectopic). You likely have an underlying secondary implantation dysfunction which could be an autoimmune and/or alloimmune, immunologic  implantation dysfunction (IID). The presentation suggests that it possibly is more likely the latter. Endometriosis is associated with an IID in 30% of cases. The fact that you have had immune tests that came up negative, unfortunately does not rule this out because it very much depends on which tests were done and where they were performed.

Please also read the additional Information section at the end of this response:

1. Implantation Dysfunction

Implantation dysfunction is unfortunately often overlooked as an important cause of IVF failure. In the pursuit of optimizing outcome with IVF, the clinician has a profound responsibility to meticulously assess and address this important issue if IVF success is to be optimized. This is especially relevant in cases of “unexplained IVF failure, Recurrent Pregnancy Loss (RPL) and in women suspected of having underlying anatomical and immunologic factors. Doing so  will not only maximize the chance of a viable pregnancy but enhancing placentation, will at the same time  promote the noble objective of optimizing the quality of life after birth.”

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

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

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

  • Anatomical abnormalities in the uterine cavity  (polyps/scarring/internal fibroids)

Several studies performed both in the United States and abroad have confirmed that a dye X-Ray or hysterosalpingogram (HSG) will fail to identify small endouterine surface lesions in >20% of cases. This is significant because even small uterine lesions have the potential to adversely affect implantation. Hysteroscopy is the traditional method for evaluating the integrity of the uterine cavity in preparation for IVF. It also permits resection of most uterine surface lesions, such as submucous uterine fibroids (myomas), intrauterine adhesions and endometrial or placental polyps. All of these can interfere with implantation by producing a local “inflammatory- type” response similar in nature to that which is caused by an intrauterine contraceptive device. Hysterosonography (syn; HSN/ saline ultrasound examination) and hysteroscopy have all but supplanted HSG to assess the uterine cavity in preparation for IVF. HSN which is less invasive and far less expensive than is than hysteroscopy involves  a small amount of a sterile saline solution is injected into the uterine cavity, whereupon a vaginal ultrasound examination is performed to assess the contour of the uterine cavity.

  • Endometrial Thickness: As far back as in 1989 I first reported  on the finding  that ultrasound assessment of the late proliferative phase endometrium following ovarian stimulation in preparation for IVF, permits better identification of those candidates who are least likely to conceive. We noted that the ideal thickness of the endometrium at the time of ovulation or egg retrieval is >9 mm and that a thickness of less than 8 mm bodes poorly for a successful outcome following IVF.

Then in 1993, I demonstrated that sildenafil (Viagra) introduced into the vagina prior to hCG administration can improve endometrial growth in many women with poor endometrial development. Viagra’s mechanism of action is improvement in uterine blood flow with improved estrogen delivery…thereby enhancing endometrial development.

  • Immunologic factors: These also play a role in IVF failure. Some women develop antibodies to components of their own cells. This “autoimmune” process involves the production of antiphospholipid, antithyroid, and/or anti-ovarian antibodies – all of which may be associated with activation of Natural Killer (NK) cells in the uterine lining. Activated NK cells (NKa) release certain cytokines (TH-I) that if present in excess, often damage the trophoblast (the embryo’s root system) resulting in immunologic implantation dysfunction (IID). This can manifest as “infertility” or as early miscarriages). In other cases (though less common), the problem is due to “alloimmune” dysfunction. Here the genetic contribution by the male partner renders the embryo “too similar” to the mother. This in turn activates NK cells leading to implantation dysfunction. These IID’s are treated using combinations of medications such as heparin, Clexane, Lovenox, corticosteroids and intralipid (IL).

2. Endometriosis and IVF

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

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

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

 

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

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

 

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

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

3. Recurrent Pregnancy Loss (RPL)

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

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

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

 

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

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

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

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

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

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

 

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

 

IMMUNOLOGIC IMPLANTATION DYSFUNCTIO-IID (see before)

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

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

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

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

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

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

DIAGNOSING THE CAUSE OF RPL

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

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

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

 

TREATMENT OF RPL

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

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

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

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

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

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

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

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

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

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

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

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

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

The Role of Nutritional Supplements in Preparing for IVF

____________________________________________________________________________

ADDITIONAL INFORMATION:

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

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

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

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

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

_______________________________________________________________________

ADDITIONAL INFORMATION:

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

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

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

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

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

………………………………………………………………..

To set up an online consultation with me, please contact my assistant, Patti Converse at 702-533-2691 or by email: concierge@sherIVF.com

 

 

 

FET Protocol Opinion

Name: Taylor A

Hi, I just wanted a second opinion on what my FET protocol looks like given my personal situation. I was diagnosed with endometriosis via laparoscopy in 2018. I did a total of 6 IUIs in 2021-2022 with my 4th one resulting in a pregnancy (blighted ovum). We did IVF recently and had great egg count – 20 eggs. But had a huge drop off. 12 fertilized (which we were happy with) but only 2 embryos made it to biopsy. My doctor expected better results given my age 28 and my AMH 1.48. After PGA-T testing, only one embryo (6AA) is genetically normal. Given that I have endometriosis and I only have one embryo to work with, what do you think is the best FET protocol approach?

Author

Answer:

This is an inordinate drop off from egg to “competent” embryo. In my opinion, , in spite of your borderline AMH (1.48ng/ml) which would suggest otherwise, you are a high responder to fertility drugs. The most likely explanation for your poor egg to “competent” embryo conversion has to do with the protocoil used for ovarian stimulation (see below).

The second issue is the relationship between endometriosis and immunologic implantation dysfunction (IID). This should also be examined because regardless of embryo quality, you cannot transfer to a “non-receptive endometrium.

1: Why so few “competent” Blastocysts?

One of the commonest questions asked by patients undergoing IVF relates to the likelihood of their eggs fertilizing and the likely “quality of their eggs and embryos. This is also one of the most difficult questions to answer. On the one hand many factors that profoundly influence egg quality; such as the genetic recruitment of eggs for use in an upcoming cycle, the woman’s age and her ovarian reserve, are our outside of our control. On the other hand the protocol for controlled ovarian stimulation (COS) can also profoundly influence egg/embryo development and this is indeed chosen by the treating physician.

First; it should be understood that the most important determinant of fertilization potential, embryo development and blastocyst generation, is the numerical chromosomal integrity of the egg (While sperm quality does play a role, in the absence of moderate to severe sperm dysfunction this is (moderate or severe male factor infertility a relatively small one). Human eggs have the highest rate of numerical chromosomal irregularities (aneuploidy) of all mammals. In fact only about half the eggs of women in their twenties or early thirties, have the required number of chromosomes (euploid), without which upon fertilization they cannot propagate a normal pregnancy. As the woman advances into and beyond her mid-thirties, the percentage of eggs euploid eggs declines progressively such that by the age of 40 years, only about one out of seven or eight are likely to be chromosomally normal and by the time she reaches her mid-forties less than one in ten of her eggs will be euploid.

Second; embryos that fail to develop into blastocysts are almost always aneuploid and not worthy of being transferred to the uterus because they will either not implant, will miscarry or could even result in a chromosomally abnormal baby (e.g. Down syndrome). However, it is incorrect to assume that all embryos reaching the blastocyst stage will be euploid (“competent”).  ). It is true that since many aneuploid embryos are lost during development and that those failing to survive to the blastocyst stage are far more likely to be competent than are earlier (cleaved) embryos.  What is also true is that the older the woman who produces the eggs, the less likely it is that a given blastocyst will be “competent”. As an example, a morphologically pristine blastocyst derived from the egg of a 30-year-old woman would have about a 50:50 chance of being euploid and a 30% chance of propagating a healthy, normal baby, while a microscopically comparable blastocyst-derived through fertilization of the eggs from a 40-year-old, would be about half as likely to be euploid and/or propagate a healthy baby.

While the effect of species on the potential of eggs to be euploid at ovulation is genetically preordained and nothing we do can alter this equation, there is, unfortunately, a lot we can (often unwittingly) do to worsen the situation by selecting a suboptimal protocol of controlled ovarian stimulation (COS). This, by creating an adverse intra-ovarian hormonal environment will often disrupt normal egg development and lead to a higher incidence of egg aneuploidy than otherwise might have occurred.  Older women, women with diminished ovarian reserve (DOR) and those with polycystic ovarian syndrome (PCOS) are especially vulnerable in this regard.

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 (tissue surrounding ovarian follicles) during the pre-ovulatory phase of the cycle enhance late follicle development, estrogen production by the granulosa 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 COS protocols should be individualized and geared toward optimizing follicle growth and development time while avoiding excessive ovarian androgen (testosterone) production and that the hCG “trigger shot” should be carefully timed.

2: The role of ovarian protocol selection on egg/embryo competency and IVF outcome

The importance of the IVF stimulation protocol on egg/embryo quality cannot be overstated. This factor seems often to be overlooked or discounted by t 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. 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.

Gonadotropins (LH and FSH), whether produced by the pituitary gland or administered by way of fertility drugs, have different “targeted” sites of action in the ovary. FSH targets cells that line the inner wall of the follicle (granulosa cells) and also form the cumulus cells that bind the egg to the inner surface of the follicle. Granulosa cells are responsible for estrogen production.

LH, on the other hand, targets the ovarian connective tissue (stroma/theca) that surrounds ovarian follicles resulting in the production of male hormones such as testosterone (predominantly), androstenedione and DHEA. These androgens are then transported to the granulosa cells of the adjacent follicles in a “bucket brigade fashion”. There FSH converts testosterone to estradiol, causing granulosa cells to multiply (proliferate) and produce estradiol, follicles to  grows and eggs to develop (ovogenesis) It follows that  ovarian androgens (mainly testosterone) is absolutely indispensable to follicle/ egg growth and development.

However, the emphasis is on a “normal” amount of testosterone. Over-exposure of the follicle to testosterone can in my opinion,  compromise egg development and lead to an increased likelihood of chromosomal irregularities (aneuploid) following LH/hCG-induced egg maturational division (meiosis) and compromise embryo “competency/quality.

Ovarian androgens can also reach the uterine lining where they sometimes will compromise estrogen receptor -induced endometrial growth and development.

A significant percentage of  older women and those who have diminished ovarian reserve (DOR) have increased LH activity is increased. Such women either over-produce LH and/or the LH produced is far more biologically active. Chronically increased LH activity leads to overgrowth of ovarian connective tissue (stroma/theca). This condition, which is often referred to as Stromal Hyperplasia or hyperthecosis can result in  excessive ovarian androgen/testosterone production and poorer egg-embryo quality/competency, Similarly, women with polycystic ovarian syndrome (PCOS), also characteristically have Stromal hyperplasia/hyperthecosis due to chronically increased LH activity. Thus they too often manifest with increased ovarian androgen production. It is therefore not surprising that “poor egg/embryo quality” is often also a feature of PCOS.

In my opinion, the over-administration of LH-containing menotropins such as Menopur, [which is comprised of roughly equal amount of FSH and   hCG ,which acts similar to LH)], to older women, women with DOR and those who have PCOS can also lead to reduced egg/embryo competency . Similarly, drugs such as clomiphene or Letrozole that cause the pituitary gland to release excessive amounts of LH, are also potentially harmful to egg development and in my opinion, are best omitted from IVF COS protocols. This is especially the case when it comes to older women and those with DOR, who in my opinion should preferably be stimulated using FSH-dominant products such as Follistim, Puregon, Fostimon and Gonal-F.

Gonadotropin releasing hormone agonists (GnRHa): GnRHa such as Lupron, Buserelin, Superfact, Gonopeptyl etc. are often used to launch ovarian stimulation cycles. They act by causing an initial outpouring followed by a depletion of pituitary gonadotropins. This results in LH levels falling to low concentrations, within 4-7 days, thereby establishing a relatively “LH-free environment”. When GnRHa are administered for about 7 days prior to initiating gonadotropin stimulation (“long” pituitary down-regulation”), the LH depletion that will exist when COS is initiated, will usually be protective of subsequent egg development. In contrast, when the GnRHa administration commences along with the initiation of gonadotropin therapy, there will be a resultant immediate surge in the release of pituitary LH with  the potential to increase ovarian testosterone to egg-compromising levels , from the outset of COS. This, in my opinion could be particularly harmful when undertaken in older women and those who have DOR.

GnRH-antagonists such as Ganirelix, Cetrotide and Orgalutron, on the other hand, act very rapidly (within hours) to block pituitary LH release. The purpose in using GnRH antagonists is to prevent the release of LH during COS. In contrast, the LH-lowering effect of GnRH agonists develops over a number of days.

GnRH antagonists are traditionally given, starting after  5th -7th day of gonadotropin stimulation. However, when this is done in older women and those (regardless of age) who have DOR, LH-suppression might be reached too late to prevent the deleterious effect of excessive ovarian androgen production on egg development in the early stage of ovarian stimulation. This is why, it is my preference to administer GnRH-antagonists, starting at the initiation of gonadotropin administration.

Preferred Protocols for Controlled Ovarian Stimulation (COS):

  • Long GnRH Agonist Protocols: The most prescribed protocol for agonist/gonadotropin administration is the so-called “long protocol”. An agonist (usually, Lupron) is given either in a natural cycle, starting 5-7 days prior to menstruation or is overlapped with the BCP for two days whereupon the latter is stopped and the Lupron, continued until menstruation ensues. The agonist precipitates a rapid rise in FSH and LH level, which is rapidly followed by a precipitous decline in the blood level of both, to near zero. This is followed by uterine withdrawal bleeding (menstruation) within 5-7 days of starting the agonist treatment, whereupon gonadotropin treatment is initiated (preferably within 7-10 days of the onset of menses) while daily Lupron injections continue, to ensure a relatively “low LH- environment”. Gonadotropin administration continues until the hCG trigger.
  • Short (“Flare”) GnRH-agonist (GnRHa) Protocol: Another GnRHa usage for COS is the so called “(micro) flare protocol”. This involves initiating gonadotropin therapy commensurate with initiation of gonadotropin administration. The supposed objective 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 “springboard effect” constitutes “a double-edged sword”. 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/thecal androgen production which could potentially compromise egg quality, especially when it comes to older women and women with DOR. 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 when it comes to COS in older women, and in women with diminished ovarian reserve. Accordingly, I do not prescribe such protocols to my IVF patients
  • Long-Agonist/Antagonist Conversion Protocol (A/ACP):With a few (notable) exceptions I preferentially advocate this protocol for many of my patients. With the A/ACP, as with the long protocol (see above) the woman again prepares to launch her stimulation cycle by taking a BCP for at least ten days before overlapping with an agonist such as Lupron. However, when about 5-7 days later her menstruation starts, she supplants the agonist with a with 250 mcg) of an antagonist (e.g. Ganirelix, Orgalutron or Cetrotide). Within a few days of this switch-over, gonadotropin stimulation is commenced. Both the antagonist and the gonadotropins are then continued until the hCG trigger. The purpose in switching from agonist to antagonist is to intentionally allow only a very small amount of the woman’s own pituitary LH to enter her blood and reach her ovaries, while at the same time preventing a large amount of LH from reaching her ovaries. This is because while a small amount of LH is essential to promote and optimize FSH-induced follicular growth and egg maturation, a large concentration of LH can trigger over-production of ovarian stromal testosterone, with an adverse effect of follicle/egg/embryo quality. Moreover, since testosterone also down-regulates estrogen receptors in the endometrium, an excess of testosterone can also have an adverse effect on endometrial growth. Also, since agonists might suppress some ovarian response to the gonadotropin stimulation, antagonists do not do so. It is for this reason that the A/ACP is so well suited to older women and those with some degree of diminished ovarian reserve.
  • Agonist/antagonist conversion protocol with estrogen priming:Patients start their treatment cycle on a combined (monophasic) birth control pill-BCP (e.g., Marvelon, Desogen, Orthonovum 135; Low-Estrin…etc.)  for at least 8-10 days (depending on individual circumstances), before commencing controlled ovarian stimulation for IVF. With this approach, a GnRH agonist (e.g. Lupron/Superfact/Buserelin/Decapeptyl etc.) is continued until menstruation ensues (usually 5-7 days after commencement of the GnRH-agonist). At this point, the GnRH-agonist is SUPPLANTED with 250mcg GnRH antagonist (e.g. Ganirelix/Cetrotide, Orgalutron) and daily estradiol(E2) “priming” commences using either E2 skin-patches or intramuscular estradiol valerate (Delestrogen) injections, twice weekly while continuing the administration of the GnRH antagonist. Seven (7) days after commencing the E2 skin patches or intramuscular Delestrogen, daily injections of recombinant FSH-(e.g., Follistim/Gonal-F/Puregon)  + menotropin (e.g., Menopur)  therapy begins.. This is continued at a modified dosage, along with E2 patches or Delestrogen injections) until the “hCG trigger”. The egg retrieval is performed 36 hours later.

There are a few potential drawback to the use of the A/ACP. We have learned that prolonged use of a GnRH antagonist throughout the ovarian stimulation process can compromise the predictive value of serial plasma E2 measurements to evaluate follicle growth and development. It appears that when the antagonist is given throughout stimulation, the blood E2 levels tend to be significantly lower than when the agonist alone is used or where antagonist treatment is only commenced 5-7 days into the ovarian stimulation process. The reason for this is presently unclear. Accordingly, when the A/ACP is employed, we rely more on follicle size monitoring than on serial blood E2 trends to assess progress.

Also, younger women (under 30 years) and women with absent, irregular or dysfunctional ovulation, and those with polycystic ovarian syndrome are at risk of developing life-threatening Severe Ovarian Hyperstimulation Syndrome (OHSS). The prediction of this condition requires daily access to accurate blood E2 levels. Accordingly, we currently tend to refrain from prescribing the A/ACP in such cases, preferring instead use the “standard long-protocol” approach.

  • Short-GnRH antagonist protocols:The use of GnRH antagonists as currently prescribed in ovarian stimulation cycles (i.e. the administration of 250mcg daily starting on the 6th or 7th day of stimulation with gonadotropins) may be problematic, especially in women over 39 yrs., women with diminished ovarian reserve (i.e. “poor responders” to gonadotropins), and women with PCOS. Such women tend to have higher levels of LH to start with and as such the initiation of LH suppression with GnRH antagonists so late in the cycle (usually on day 6-7) of stimulation fails to suppress LH early enough to avoid compromising egg development. This can adversely influence egg/embryo quality and endometrial development. As is the case with the “microflare” approach (see above) the use of GnRH antagonist protocols in younger women who have normal ovarian reserve, is acceptable. Again, for reasons of caution, and because I see no benefit in doing so, I personally never prescribe this approach for my patients. Presumably, the reason for the suggested mid-follicular initiation of high dose GnRH antagonist is to prevent the occurrence of the so called “premature LH surge”, which is known to be associated with “follicular exhaustion” and poor egg/embryo quality. However the term “premature LH surge” is a misnomer and the concept of this being a “terminal event” or an isolated insult is erroneous. In fact, the event is the culmination (end point) of the progressive escalation in LH (“a staircase effect”) which results in increasing ovarian stromal activation with commensurate growing androgen production. Trying to improve ovarian response and protect against follicular exhaustion by administering GnRH antagonists during the final few days of ovarian stimulation is like trying to prevent a shipwreck by removing the tip of an iceberg.
  • Short-GnRH-agonist (“micro-flare”) protocols:Another approach to COH is by way of so-called “microflare protocols”. This involves initiating gonadotropin therapy simultaneously with the administration of GnRH agonist. The intent is to deliberately allow Lupron to affect an initial surge (“flare”) in pituitary FSH release 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 concomitant (excessive) rise in LH levels that could evoke excessive production of male hormone by the ovarian stroma. The latter in turn could potentially compromise egg quality, especially in women over 39 years of age, women with diminished ovarian reserve, and in women with polycystic ovarian syndrome (PCOS) – all of whose ovaries have increased sensitivity to LH. In this way, “microflare protocols” can potentially hinder egg/embryo development and reduce IVF success rates. While microflare protocols usually are not harmful in younger women and those with normal ovarian reserve, I personally avoid this approach altogether for safety’s sake. The follicles/eggs of women on GnRH-agonist “micro-flare protocols” can be exposed to exaggerated agonist-induced LH release, (the “flare effect”) while the follicles/eggs of women, who receive GnRH antagonists starting 6-8 days following the initiation of stimulation with gonadotropins can likewise be exposed to pituitary LH-induced ovarian male hormones (especially testosterone). While this is not necessarily problematic in younger women and those with adequate ovarian reserve (“normal responders”) it could be decidedly prejudicial in “poor responders” and older women where there is increased follicle and egg vulnerability to high local male hormone levels.
  • The “Trigger Shot”- A Critical Decision:The egg goes through maturational division (meiosis) during the 36-hour period that precedes ovulation or retrieval. The efficiency of this process will determine the outcome of reproduction. It follows that when it comes to ovulation induction, aside from selecting a suitable protocol for COS one of the most important decisions the clinician has to make involves choosing and implementing with logic and precision, the “trigger shot” by which to facilitate meiosis.
    • Urinary versus recombinant hCG:Until quite recently, the standard method used to initiate the “trigger shot” was through the administration of 10,000 units of hCGu. More recently, a recombinant form of hCGr (Ovidrel) was introduced and marketed in 250 mcg doses. But clinical experience strongly suggests that 250 mcg of Ovidrel is most likely not equivalent in biological potency to 10,000 units of hCG. It probably at best only has 60%of the potency of a 10,000U dose of hCGu and as such might not be sufficient to fully promote meiosis, especially in cases where the woman has numerous follicles. For this reason, I firmly believe that when hCGr is selected as the “trigger shot” the dosage should be doubled to 500 mcg, at which dosage it will probably have an equivalent effect on promoting meiosis as would 10,000 units of hCGu.
    • The dosage of hCG used: Some clinicians, when faced with a risk of OHSS developing will deliberately elect to reduce the dosage of hCG administered as a trigger in the hope that by doing so, the risk of developing critical OHSS will be lowered. It is my opinion that such an approach is not optimal because a low dose of hCG (e.g., 5000 units hCGu or 25omcg hCGr) is likely inadequate to optimize the efficiency of meiosis, particularly when it comes to cases such as this where there are numerous follicles. In my opinion a far better approach is to use a method that I first described in 1989, known as “prolonged coasting”
    • Use of hCG versus a GnRHa(e.g., Lupron/Buserelin/Superfact) as the trigger shot: It has been suggested that the use of an “agonist ( Lupron) trigger” in women at risk of developing severe ovarian hyperstimulation syndrome (OHSS) could potentially reduce the risk of the condition becoming critical and thereby placing the woman at risk of developing life-endangering complications. It is for this reason that many RE’s prefer to trigger meiosis in this way (using an agonist-Lupron) rather than through the use of hCG. The agonist promptly causes the woman’s pituitary gland to expunge a large amount of LH over a short period of time and it is this LH “surge” that triggers meiosis. The problem with this approach, in my opinion, is that it is hard to predict how much LH will be released in by the pituitary gland of a given patient receiving an agonist trigger shot, especially if the woman was down-regulated using an agonist, or in cases where an antagonist was used to block pituitary LH release. For this reason, I personally prefer to use hCGu for the trigger, even in cases of ovarian hyperstimulation, with one important proviso…that she underwent “prolonged coasting” in order to reduce the risk of critical OHSS prior to the 10,000 unit hCGu “trigger”.
    • Combined use of hCG +GnRHa; This approach is preferable to the use of a GnRHa, alone. However, in my opinion is inferior to the appropriate and correct use of hCG, alone.
    • The timing of the trigger shot to initiate meiosis:This should coincide with the majority of ovarian follicles being >15 mm in mean diameter with several follicles having reached 18-22 mm. Follicles of larger than 22 mm will usually harbor overdeveloped eggs which in turn will usually fail to produce good quality eggs. Conversely, follicles less than 15 mm will usually harbor underdeveloped eggs that are more likely to be aneuploid and incompetent following the “trigger”.

Severe Ovarian Hyperstimulation Syndrome (OHSS) and prolonged Coasting”

OHSS is a life-endangering condition that usually occurs in women undergoing COS where the blood E2 level rises to above 4,000pg/ml. The risk escalates to greater than 80% in cases where the E2 level rises above 6,000pg/ml. It rarely occurs in normally ovulating women or older (>39Y) women and is more commonly encountered in:

  • Young women (under 30y) who have a high ovarian reserve(based upon basal FSH and AMH.
  • Women with polycystic Ovarian Syndrome (PCOS)
  • Non-PCOS women who do not ovulate spontaneously

The treating physician should be alerted to the possibility of hyperstimulation when encountering a woman who develops >25 ovarian follicles of 14mm-16mm in mean diameter, in association with a blood E2 level of above 2,5000pg/ml prior to the hCG “trigger”.

OHSS is a self-limiting condition. Its development is linked to the effect of hCG and thus does not occur until the “hCG trigger” is administered. In fact, there is virtually no risk of OHSS until the hCG “trigger” is administered.

Prolonged Coasting” is a procedure I introduced in 1991. It involves abruptly stopping gonadotropin therapy while continuing to administer the GnRH agonist (e.g. Lupron, Buserelin) deferring the hCG “trigger” until the woman is out of risk (as evidenced by a fall in plasma estradiol level to below 2,500pg/ml).

It is important that “prolonged coasting” be initiated as soon as two or more follicles have attained a greater diameter than 18mm with at least 50% of the remaining follicles having attained 14-16mm. To start the process of “prolonged coasting” any earlier or any later, while it would still protect against the development of OHSS, would almost certainly result in compromised egg and embryo quality with ultimate failure of the IVF cycle. Simply stated, the precise timing of initiating the process is critical. Proper implementation of PC will almost always prevent OHSS without seriously compromising egg/embryo quality.

Use of the Birth Control Pill (BCP) to launch IVF-COS.

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

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

3. Endometriosis and Immunologic  Implantation Dysfunction (IID):

More than half of women who have endometriosis harbor antiphospholipid antibodies (APA) that can compromise development of the embryo’s root system (trophoblast). In addition and far more serious, is the fact that in about one third of cases endometriosis, regardless of its severity is associated with NKa and cytotoxic uterine lymphocytes (CTL) which can seriously jeopardize implantation. This immunologic implantation dysfunction (IID) is diagnosed by testing the woman’s blood for APA, for NKa (using the K-562 target cell test or by endometrial biopsy for cytokine activity) and, for CTL (by a blood immunophenotype). Activated NK cells attack the invading trophoblast cells (developing “root system” of the embryo/early conceptus) as soon as it tries to gain attachment to the uterine wall. In most cases, this results in rejection of the embryo even before the pregnancy is diagnosed and sometimes, in a chemical pregnancy or an early miscarriage. As such, many women with endometriosis, rather than being infertile, in the strict sense of the word, often actually experience repeated undetected “mini-miscarriages”.

Women who harbor APA’s often experience improved IVF birth rates when heparinoids (Clexane/Lovenox) are administered from the onset of ovarian stimulation with gonadotropins until the 10th week of pregnancy. NKa is treated with a combination of Intralipid (IL) and steroid therapy: Intralipid (IL) is a solution of small lipid droplets suspended in water. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, alpha-linolenic acid (ALA), an omega-3 fatty acid.IL is made up of 20% soybean oil/fatty acids (comprising linoleic acid, oleic acid, palmitic acid, linolenic acid and stearic acid) , 1.2% egg yolk phospholipids (1.2%), glycerin (2.25%)  and water (76.5%).IL exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating NKa.

The therapeutic effect of IL/steroid therapy is likely due to an ability to suppress pro-inflammatory cellular (Type-1) cytokines such as interferon gamma and TNF-alpha. IL/steroids down-regulates NKa within 2-3 weeks of treatment the vast majority of women experiencing immunologic implantation dysfunction. In this regard IL is just as effective as Intravenous Gamma globulin (IVIg) but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for 4-9 weeks when administered in early pregnancy.

The toxic pelvic environment caused by endometriosis, profoundly reduces natural fertilization potential. As a result normally ovulating infertile women with endometriosis and patent Fallopian tubes are much less likely to conceive naturally, or by using fertility agents alone (with or without intrauterine (IUI) insemination. The only effective way to bypass this adverse pelvic environment is through IVF. I am not suggesting here that all women who have endometriosis require IVF! Rather, I am saying that  in cases where  the condition is further compromised by an IID associated with NKa and/or for older women(over 35y)  who have  diminished ovarian reserve (DOR) where time is of the essence, it is my opinion that IVF is the treatment of choice.

4. Frozen Embryo Transfer (FET)

Until less than a decade ago, most women undergoing IVF would have embryos transferred to the uterus in the same cycle that the egg retrieval was performed (“Fresh” Embryo Transfer). This was because embryo cryopreservation (freezing) was a hazardous undertaking.  In fact, it resulted in about 30% not surviving the freezing process and those that did, having about one half the potential of “fresh embryos to implant and propagate a viable pregnancy. The main reason for the high attrition rate associated with embryo cryopreservation is that the “conventional” freezing” process that was done slowly and this resulted in ice forming within the embryo’s cells, damaging or destroying them. The introduction of an ultra-rapid cryopreservation process (vitrification) freezes the embryos so rapidly as to avoid ice crystals from developing. As a result, >90% survive the freeze/thaw process in as good a condition as they were prior to being frozen and thus without being compromised in their ability to propagate a viable pregnancy.

Recently, there have been several articles that have appeared in the literature suggest that an altered hormonal environment may be the reason for this effect.  There have also been reports showing that when singletons (pregnancy with one baby) conceived naturally are compared to singletons conceived through a “fresh” embryo transfers they tend to have a greater chance of low birth weight/prematurity. This difference was not observed in babies born following FET.  Hence, there is a suspicion that the altered hormonal environment during the fresh cycle may be the causative factor.

Available evidence suggests that FET (of pre-vitrified blastocysts) is at least as successful as is the transfer of “fresh” embryos and might even have the edge. The reason for this is certainly unlikely to have anything to do with the freezing process itself. It more than likely  has to do with two factors:

  1. An ever increasing percentage of FET’s involve the transfer of PGS-tested, fully karyotyped, euploid blastocysts that have a greater potential to propagate viable pregnancies, than is the case with “fresh” ET’s where the embryos have rarely undergone prior PGS selection for “competency”…and,
  2. With targeted hormone replacement therapy for FET, one is far better able to better to optimally prepare the endometrium for healthy implantation than is the case where embryos are transferre3d following ovarian stimulation with fertility drugs.

There are additional factors other than method used for embryo cryopreservation that influence outcome following FET. These include

  • An emerging trend towards selective transferring only advanced (day 5-6) embryos (blastocysts).
  •  (PGS) to allow for the selective transfer of genetic competent (euploid) embryos
  • Addressing underlying causes of implantation dysfunction (anatomical and immunologic uterine factors) and
  •  Exclusive use of ultrasound guidance for delivery of embryos transferred to the uterus.

Against this background, the use of FET has several decided advantages:

  • The ability to cryostore surplus embryos left over after fresh embryo transfer
  • The ability to safely hold embryos over for subsequent transfer in a later frozen embryo transfer (FET) cycle (i.e. Staggered IVF) in cases where:
    1. Additional time is needed to perform preimplantation Genetic testing for embryo competency.
    2. In cases where ovarian hyperstimulation increases the risk of life-endangering complications associated with critically severe ovarian hyperstimulation syndrome (OHSS).
    3. To bank (stockpile) embryos for selective transfer of karyotypically normal embryos in older women or those who are diminished ovarian reserve
    4. The ability to store embryos in cases of IVF with third party parenting (Egg Donation; Gestational Surrogacy and Embryo donation) and so improve convenience for those couples seeking such services.

Preimplantation Genetic Sampling with FET:

The introduction of preimplantation genetic sampling (PGS) to karyotyping of embryos for selective transfer of the most “competent” embryos, requires in most cases that the tested blastocysts be vitribanked while awaiting test results and then transferred to the uterus at a later date. Many IVF programs have advocated the routine use of PGS in IVF purported to improve IVF outcome. But PGS should in my opinion should only be used selectively. I do not believe that it is needed for all women undergoing IVF. First there is the significant additional cost involved and second it will not benefit everyone undergoing IVF, in my opinion.

While PGS is a good approach for older women and those with diminished ovarian reserve (DOR) and also for woman who experience recurrent pregnancy loss (RPL) or “unexplained” recurrent IVF failure recent data suggests that it will not improve IVF success rates in  women under 36Y  who have normal ovarian reserve, who represent the majority of women seeking IVF treatment. Nor is it needed in women (regardless of their age) undergoing IVF with eggs donated by a younger donor.  This is because in such women about 1:2/3 of their eggs/embryos are usually chromosomally normal, and in most cases will upon fertilization produce multiple blastocysts per IVF attempt, anyway. Thus in such cases the transfer of 2 blastocysts will likely yield the same outcome regardless of whether the embryos had been subjected to PGS or not. The routine use of

It is another matter when it comes to women who have diminished ovarian reserve and/or DOR contemplating embryo banking and for women with unexplained recurrent IVF failure, recurrent pregnancy loss and women with alloimmune implantation dysfunction who regardless of their age or ovarian reserve require PGS for diagnostic reasons.

Embryo Banking: Some IVF centers are doing embryo banking cycles with Preimplantation Genetic Screening (PGS).  With Embryo Banking” several IVF cycles are performed sequentially (usually about 2 months apart), up to the egg retrieval stage. The eggs are fertilized and the resulting advanced embryos are biopsied. The biopsy specimens are held over until enough 4-8 blastocysts have been vitribanked, thus providing a reasonable likelihood that one or more will turn out to be PGS-normal. At this point the biopsy specimens (derived all banking cycles) are sent for PGS testing at one time (a significant cost-saver), the chromosomally normal blastocysts are identified and the women are scheduled for timed FET procedures….. with a good prospect of  a markedly improved chance of success as well as a reduced risk of miscarriage.

Standard (proposed) Regimen for preparing the uterus for frozen embryo transfer FET) is as follows:

The recipient’s cycle is initiated with an oral contraceptive-OC (e.g. Marvelon/Lo-Estrin; Lo-Ovral etc) for at least 10 days. This is later overlapped with 0.5 mg. (10 units) Lupron/Lucrin (or Superfact/Buserelin) daily for 3 days. Thereupon the OC is withdrawn and daily 0.25 mg (5 units) of Lupron/Lucrin/Superfact injections are continued. Menstruation will usually ensue within 1 week. At this point, an ultrasound examination is performed to exclude ovarian cyst(s) and a blood estradiol measurement is taken (it needs to be <70pg/ml) until daily progesterone administration is initiated some time later. The daily Lupron/Lucrin/Superfact is continued until the initiation of progesterone therapy (see below).

 

Four milligram (4mg) Estradiol valerate (Delestrogen) IM is injected SC, twice weekly (on Tuesday and Friday), commencing within a few days of Lupron/Lucrin/Superfact-induced menstruation. Blood is drawn on Monday and Thursday for measurement of blood [E2].  This allows for planned adjustment of the E2V dosage scheduled for the next day. The objective is to achieve a plasma E2 concentration of 500-1,000pg/ml and an endometrial lining of >8mm, as assessed by ultrasound examination done after 10 days of estrogen exposure i.e. a day after the 3rd dosage of Delestrogen..  The twice weekly, final (adjusted) dosage of E2V is continued until pregnancy is discounted by blood testing or an ultrasound examination. Dexamethasone 0.75 mg is taken orally, daily with the start of the Lupron/Lucrin/Superfact. Oral folic acid (1 mg) is taken daily commencing with the first E2V injection and is continued throughout gestation. Patients also receive Ciprofloxin 500mg BID orally starting with the initiation of Progesterone therapy and continuing for 10 days.

Luteal support commences 6 days prior to the ET, with intramuscular progesterone in oil (PIO) at an initial dose of 50 mg (P4-Day 1).  Starting on progesterone administration-Day 2, PIO is increased to 100 mg daily continuing until the 10th week of pregnancy, or until a blood pregnancy test/negative ultrasound (after the 6-7th gestational week), discounts a viable pregnancy.

Also, commencing on the day following the ET, the patient inserts one (1) vaginal progesterone suppository (100 mg) in the morning + 2mg E2V vaginal suppository (in the evening) and this is continued until the 10th week of pregnancy or until pregnancy is discounted by blood testing or by an ultrasound examination after the 6-7th gestational week. Dexamethasone o.75mg is continued to the 10th week of pregnancy (tailed off from the 8th to 10th week) or as soon as pregnancy is ruled out. With the obvious exception of the fact that embryo recipients do not receive an hCG injections, luteal phase and early pregnancy hormonal support and immuno-suppression is otherwise the same as for conventional IVF patients.  Blood pregnancy tests are performed 13 days and 15 days after the first P4 injection was given.

Note: One (1) vaginal application of Crinone 8% is administered on the 1st day (referred to as luteal phase day 0 – LPO). On LP Day 1, they will commence the administration of Crinone 8% twice daily (AM and PM) until the day of embryo transfer.  Withhold Crinone on the morning of the embryo transfer and resume Crinone administration in the PM.   Crinone twice daily is resumed from the day after embryo transfer. Contingent upon positive blood pregnancy tests, and subsequently upon the ultrasound confirmation of a viable pregnancy, administration of Crinone twice daily are continued until the 10th week of pregnancy.

Regime for Thawing and Transferring Cryopreserved Embryos/Morulae/Blastocysts:

 

Patients undergoing ET with cryopreserved embryos/morulas/blastocysts will have their embryos thawed and transferred by the following regimen.

 

  Day 2 (P4) Day 6 (P4)
PN Thaw ET
Day 3 Embryo   ET
Blastocysts frozen on day 5 post-ER   FET
Blastocysts frozen on day 6, post-ER   FET

 

Read the information above and once having done so, might I suggest you contact my assistant, Patti Converse (702-533-2691) and set up an online consultation with me. I think I can help you!

 

Geoff Sher

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