The journey of in vitro fertilization can be a rollercoaster of emotions for many patients. Often times they have to face the harsh reality that the number and quality of eggs retrieved has fallen short of their expectations. Then, should fertilization of these eggs not propagate  chromosomally normal (euploid), “competent” embryos suitable for transfer to the uterus, many such patients find themselves in a state of emotional distress. They grapple with the inevitable questions of why this happened and how to prevent it from occurring again in the future. This article aims to delve into these queries, providing insights, rational explanations, and therapeutic options. It is an invitation to explore the light at the end of the tunnel. Readers are urged to carefully absorb the entirety of the article in the hope of finding valuable information and renewed hope.

• The Importance of Chromosomal Integrity: While sperm quality is an important factor, egg quality is by far the most important when it comes to the generation of embryos that are capable of propagating healthy babies (“competent”). In this regard, chromosomal integrity of the egg and embryo, although it is not the only factor , is certainly the main determinant of such competency.
• The woman’s age: About two thirds of a woman’s eggs in her twenties or early thirties have the correct number of chromosomes, which is necessary for a healthy pregnancy. As a woman gets older, the percentage of eggs with the right number of chromosomes decreases. By age 40, only about one in every 5-6 eggs is likely to be normal, and by the mid-forties, less than one in ten eggs will be normal.
• Ovarian Reserve (number of available in the ovaries): A woman is born with all the eggs she will ever have. She starts using these eggs when she begins ovulating during puberty. At first, the eggs are used up quickly, but as she gets older, the number of eggs starts to run out. Her brain and pituitary gland try to stimulate the production of more eggs by increasing the output of Follicle Stimulating Hormone (FSH), but unfortunately, this often doesn’t work. When the number of remaining eggs in her ovaries falls below a certain level (which can be different for each woman), her FSH level rises, and production of the ovarian hormone, AMH decreases. This is the start of diminishing ovarian reserve (DOR). Most women experience the onset of DOR in their late 30s or early 40s, but it can happen earlier for some. The lower the ovarian reserve, the lower the AMH level will be, and the fewer eggs will be available for harvesting during IVF-egg retrieval. In such cases, a higher dosage of fertility drugs might be needed to promote better egg production in future attempts. . On the other hand, higher AMH levels mean more eggs are available, and lower doses of fertility drugs are usually needed. DOR is commonly associated with increased bioactivity of pituitary gland-produced LH. This LH activates production of ovarian male hormones (androgens)…predominantly testosterone by ovarian connective tissue (stroma) . While a small amount of  ovarian testosterone is absolutely necessary for optimal follicle and egg development, excessive ovarian testosterone will often access the follicle , and compromise both egg quality and follicle growth and development. In some cases, rapidly increasing  LH-release (“premature LH-surge”) with excessive induced ovarian testosterone can lead to “premature luteinization”  of the follicles with cessation in growth and even to“ premature ovulation”.
• Importance of Individualized Controlled Ovarian Stimulation (COS) Protocol: It’s not surprising that DOR is more common in older women, but regardless of age, having DOR makes a woman’s eggs more likely to be compromised during controlled ovarian stimulation (COS). The choice of the COS protocol is crucial to preventing unintentional harm to egg and embryo quality. The wrong protocol can disrupt normal egg development and increase the risk of abnormal embryos. That’s why it’s important to tailor the COS protocol to each individual’s needs. This helps optimize follicle growth and the quality of eggs and embryos. The timing of certain treatments is also important for successful outcomes.
• Embryo Competency and Blastocyst Development: Embryos that don’t develop into blastocysts by day 6 after fertilization are usually chromosomally abnormal or aneuploid (”incompetent”) and not suitable for transfer. However, not all blastocysts are guaranteed to be normal and capable of developing into a healthy baby. As a woman gets older, the chances of a her embryos being chromosomally normal blastocyst decreases. For example, a blastocyst from a 30-year-old woman is more likely to be normal compared to one from a 40-year-old woman.

The IVF stimulation protocol has a big impact on the quality of eggs and embryos especially in women with DOR. Unfortunately, many IVF doctors use the same COS “recipe approach” for everyone without considering individual differences. Using personalized protocols can greatly improve the success of IVF. While we can’t change genetics or reverse a woman’s age, a skilled IVF specialist can customize the COS protocol to meet each patient’s specific needs.

GONADOTROPIN RELEASING HORMONE AGONISTS (GNRHA) AND GNRH-ANTAGONISTS:

• Gonadotropin releasing hormone agonists (GnRHa). Examples are Lupron, Buserelin, Superfact, and Decapeptyl . These are commonly used to launch  ovarian stimulation cycles. They work by initially causing a release of pituitary gonadotropins, followed by a decrease in LH and FSH levels within 4-7 days. This creates a relatively low LH environment when COS begins, which is generally beneficial for egg development. However, if GnRHa are administered starting concomitant with gonadotropin stimulation (see GnRHa –“flare protocol” -below) it can cause an immediate surge in LH release, potentially leading to high levels of ovarian testosterone that can harm egg quality, especially in older women and those with diminished ovarian reserve (DOR).
• Gonadotropin releasing hormone antagonists (GnRH-antagonists) : Examples are Ganirelix, Cetrotide, and Orgalutron. GnRH antagonists (take days  work quickly (within hours) to block pituitary LH release. Their purpose is to prevent excessive LH release during COS. In contrast, the LH-lowering effect of GnRH agonists takes several days to develop. Traditionally, GnRH antagonists are given starting on the 5th-7th day of gonadotropin stimulation. However, in older women and those with DOR, suppressing LH might happen too late to prevent excessive ovarian androgen production that can negatively impact egg development in the early stages of stimulation. That’s why I prefer to administer GnRH-antagonists right from the beginning of gonadotropin administration.

USING BIRTH CONTROL PILLS TO START OVARIAN STIMULATION:

Patients are often told that using birth control pills (BCP) to begin ovarian stimulation will suppress the response of the ovaries. This is true, but only if the BCP is not used correctly. Here’s the explanation:

In natural menstrual cycles and cycles stimulated with fertility drugs, the follicles in the ovaries need to develop receptors that respond to follicle-stimulating hormone (FSH) in order to properly respond to FSH stimulation. Pre-antral follicles (PAFs) do not have these receptors and cannot respond to FSH stimulation. The development of FSH responsivity requires exposure of the pre-antral follicles to FSH for several days, during which they become antral follicles (AFs) and gain the ability to respond to FSH-gonadotropin stimulation. In regular menstrual cycles, the rising FSH levels naturally convert PAFs to AFs. However, the combined BCP suppresses FSH. To counter this suppression, we need to promote increased  FSH production several days before starting COS. This allows the orderly conversion from PAFs to AFs, ensuring proper follicle and egg development.

GnRHa causes an immediate surge in FSH release by the pituitary gland, promoting the conversion from PAF to AF. Therefore, when women take the BCP control pill to launch a cycle of COS, they need to overlap the BCP with a GnRHa for a few days before menstruation. This allows the early recruited PAFs to complete their development and reach the AF stage, so they can respond appropriately to ovarian stimulation. By adjusting the length of time, the woman is on the birth control pill, we can regulate and control the timing of the IVF treatment cycle. Without this step, initiating ovarian stimulation in women coming off birth control pills would be suboptimal.

PROTOCOLS FOR CONTROLLED OVARIAN STIMULATION (COS):

• GnRH Agonist Ovarian Stimulation Protocols:
  • The long GnRHa protocol: Here, a GnRHa (usually Lupron or Superfact) is given either in a natural cycle, starting 5-7 days before menstruation, overlapping with the BCP for three days. Thereupon, the pill is stopped, while daily  GnRHa injections continue until menstruation occurs (usually 5-7 days later). The GnRHa causes a rapid rise in FSH and LH levels. This is followed about 3-4 days later , by a progressive decline in FSH and LH to near zero levels,  with a concomitant drop in ovarian estradiol and progesterone. This, in turn triggers uterine withdrawal bleeding (menstruation) within 5-7 days of starting the GnRHa administration. Gonadotropin treatment is then initiated while daily GnRHa injections continue to maintain a relatively low LH environment. Gonadotropin administration continues until the hCG “trigger” (see below).
  • Short GnRH-Agonist (“Flare”) Protocol: This protocol involves starting hormone therapy and using GnRH agonist at the same time. The goal is to boost FSH so that with concomitant stimulation with FSH-gonadotropins + the GnRHa-induced surge in pituitary gland FSH release, will augment follicle development. However, this surge also leads to a rise in LH levels, which can cause an excessive production of ovarian male hormones (e.g., testosterone). This could potentially adversely affect the quality of eggs, especially in women over 39 years old, those with low ovarian reserve, and women with PCOS or DOR who already have increased LH sensitivity. In this way, these “flare protocols” can potentially decrease the success rates of IVF. While they are generally safe for younger women with normal ovarian reserve, I personally avoid using this approach on the off chance that even patients with normal ovarian reserve, might experience poor egg quality.
• GnRH Antagonist-Ovarian Stimulation Protocols:
  • Conventional GnRH Antagonist Protocol: In this approach, daily GnRH antagonist injections are given from the 5th to the 8th day of COS with gonadotropins to the day of the “trigger” (see below). Accordingly, although rapidly acting to lower LH , this effect of GnRH- antagonist only starts suppressing LH from well into the COS cycle which means the ovarian follicles are left exposed and unshielded from pituitary gland -produced, (endogenous) LH during the first several days of stimulation. This can be harmful, especially in the early stage of COS when eggs and follicles are most vulnerable to the effects of over-produced LH-induced excessive ovarian testosterone. Therefore, I believe the Conventional GnRH Antagonist Protocol is not ideal for older women, those with low ovarian reserve, and women with PCOS who already have elevated LH activity. However, this protocol is acceptable for younger women with normal ovarian reserve, although I personally avoid using this approach on the off chance that even patients with normal ovarian reserve, might experience poor egg quality.

It’s important to note that the main reason for using GnRH antagonists is to prevent a premature LH surge, which is associated with poor egg and embryo quality due to follicular exhaustion. However, calling it a “premature LH surge” is misleading because it actually represents the culmination of a progressive increase in LH-induced ovarian testosterone. A better term would be “premature luteinization”. In some such cases, the rise in LH can precipitate “premature ovulation”.

• Agonist/Antagonist Conversion Protocol (A/ACP): I recommend this protocol for many of my patients, especially for older women and those with DOR or PCOS. The woman starts by taking a BCP for 7-10 days. This overlapped with a GnRHa for 3 days and continued until menstruation ensues about 5-7 days later. At this point  she “converts” from the GnRH-agonist to a GnRH-antagonist (Ganirelix, Orgalutron, or Cetrotide). A few days after this conversion from agonist to antagonist, COS with  gonadotropin stimulation starts. Both the antagonist and the gonadotropins are continued together until the hCG trigger. The purpose is to suppress endogenous LH release throughout the COS process and so  avoid over-exposure of follicles and eggs to LH-induced  excessive ovarian testosterone which as previously stated, can compromise egg and follicle growth and development.   Excessive ovarian testosterone can also adversely affect estrogen-induced growth of the uterine lining (endometrium). Unlike GnRH-agonists, antagonists do not suppress ovarian response to the gonadotropin stimulation. This is why the A/ACP is well-suited for older women and those with diminished ovarian reserve.
• A/ACP with estrogen priming: This is a modified version of the A/ACP protocol used for women with very low ovarian reserve (AMH=<0.2ng/ml). Estrogen priming is believed to enhance the response of follicles to gonadotropins. Patients start their treatment cycle by taking a combined birth control pill (BCP) for 7-10 days. After that, they overlap daily administration of a GnRH agonist with the BCP for 3 days. The BCP is then stopped, and the daily agonist continues until menstruation ensues (usually 5-7 days later). At this point, the GnRH agonist is supplanted by daily injections of  GnRH antagonist and  Estradiol (E2) “priming” begins using E2 skin patches or intramuscular estradiol valerate injections twice weekly, while continuing the GnRH antagonist. Seven days after starting the estrogen priming COS begins using recombinant FSHr such as Follistim, Gonal-F or Puregon) +menotropin (e.g., Menopur) . The estrogen “priming” continues to the day of the “trigger” (see below).  Egg retrieval is performed 36 hours after the trigger.

Younger women (under 30 years) and women with absent, irregular, or dysfunctional ovulation, as well as those with polycystic ovarian syndrome (PCOS), are at risk of developing a severe condition called Ovarian Hyperstimulation Syndrome (OHSS), which can be life-threatening. To predict this condition, accurate daily blood E2 level monitoring is required.

TRIGGERING “EGG MATURATION PRIOR TO EGG RETRIEVAL”

• The hCG “trigger”: When it comes to helping eggs mature before retrieval, one of the important decisions the doctor needs to make is choosing the “trigger shot” to facilitate the process. Traditionally, hCG (human chorionic gonadotropin) is derived from the urine of pregnant women (hCGu) while a newer recombinant hCG (hCGr), Ovidrel was recently The ideal dosage of hCGu is 10,000U and for Ovidrel, the recommended dosage is 500mcg. Both have the same efficacy. The “trigger” is usually administered by intramuscular injection, 34-36 hours prior to egg retrieval.

Some doctors may choose to lower the dosage of hCG if there is a risk of severe ovarian hyperstimulation syndrome (OHSS). However, I believe that a low dose of hCG (e.g., 5000 units of hCGu or 250 mcg of hCGr ( Ovidrel) might not be enough to optimize egg maturation, especially when there are many follicles. Instead, I suggest using a method called “prolonged coasting” to reduce the risk of OHSS.

• Using GnRH antagonist alone or combined with hCG as the trigger: Some doctors may prefer to use a GnRH- agonist trigger instead of hCG to reduce the risk of OHSS. The GnRHa “trigger” acts by inducing a “surge of pituitary gland-LH. However, it is difficult to predict the amount of LH that is released in response to a standard agonist trigger. In my opinion, using hCG is a better choice, even in cases of ovarian hyperstimulation, with the condition that “prolonged coasting” is implemented beforehand.
• Combined use of hCG + GnRH agonist: This approach is better than using a GnRH agonist alone but still not as effective as using the appropriate dosage of hCG.
• Timing of the trigger: The trigger shot should be given when the majority of ovarian follicles have reached a size of more than 15 mm, with several follicles measuring 18-22 mm. Follicles larger than 22 mm often contain overdeveloped eggs, while follicles smaller than 15 mm usually have underdeveloped and potentially abnormal eggs.

SEVERE OVARIAN HYPERSTIMULATION SYNDROME (OHSS) & “PROLONGED COASTING”

OHSS is a life-threatening condition that can occur during controlled ovarian stimulation (COS) when the blood E2 (estradiol) level rises too high. It is more common in young women with high ovarian reserve, women with polycystic ovarian syndrome (PCOS), and young women who do not ovulate spontaneously. To prevent OHSS, some doctors may trigger egg maturation earlier, use a lower dosage of hCG, or “trigger” using a GnRHa. However, these approaches can compromise egg and embryo quality and reduce the chances of success.

To protect against the risk of OHSS while optimizing egg quality, Physicians can use one of two options. The first is “prolonged coasting,” a procedure I introduced more than three decades ago. It involves stopping gonadotropin therapy while continuing to administer the GnRHa until the risk of OHSS has decreased. The precise timing of “prolonged coasting” is critical. It should be initiated when follicles have reached a specific size accompanied and the  blood estradiol has reached a certain peak.  The second option is to avoid fresh embryo transfer and freeze all “competent” embryos for later frozen embryo transfers (FETs) at a time when the risk of OHSS has subsided. By implementing these strategies, both egg/embryo quality and maternal well-being can be maximized.

In the journey of fertility, a woman is blessed with a limited number of eggs, like precious treasures awaiting their time. As she blossoms into womanhood, these eggs are gradually used, and the reserves start to fade. Yet, the power of hope and science intertwines, as we strive to support the development of these eggs through personalized treatment. We recognize that each woman is unique, and tailoring the protocol to her individual needs can unlock the path to success. We embrace the delicate timing, understanding that not all embryos are destined for greatness. With age, the odds may shift, but our dedication remains steadfast, along with our ultimate objective, which is  to do everything possible to propagate  of a normal pregnancy while optimizing the  quality of that life after birth and all times, minimizing risk to the prospective parents.

______________________________________________________________

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) “

https://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

If you are interested in having an online consultation with me, please contact my assistant, Patti Converse at 702-533-2691 or email her at concierge@sherivf.com

………………………………………………………………..

The journey of in vitro fertilization can be a rollercoaster of emotions for many patients. Often times they have to face the harsh reality that the number and quality of eggs retrieved has fallen short of their expectations. Then, should fertilization of these eggs not propagate  chromosomally normal (euploid), “competent” embryos suitable for transfer to the uterus, many such patients find themselves in a state of emotional distress. They grapple with the inevitable questions of why this happened and how to prevent it from occurring again in the future. This article aims to delve into these queries, providing insights, rational explanations, and therapeutic options. It is an invitation to explore the light at the end of the tunnel. Readers are urged to carefully absorb the entirety of the article in the hope of finding valuable information and renewed hope.

• The Importance of Chromosomal Integrity: While sperm quality is an important factor, egg quality is by far the most important when it comes to the generation of embryos that are capable of propagating healthy babies (“competent”). In this regard, chromosomal integrity of the egg and embryo, although it is not the only factor , is certainly the main determinant of such competency.
• The woman’s age: About two thirds of a woman’s eggs in her twenties or early thirties have the correct number of chromosomes, which is necessary for a healthy pregnancy. As a woman gets older, the percentage of eggs with the right number of chromosomes decreases. By age 40, only about one in every 5-6 eggs is likely to be normal, and by the mid-forties, less than one in ten eggs will be normal.
• Ovarian Reserve (number of available in the ovaries): A woman is born with all the eggs she will ever have. She starts using these eggs when she begins ovulating during puberty. At first, the eggs are used up quickly, but as she gets older, the number of eggs starts to run out. Her brain and pituitary gland try to stimulate the production of more eggs by increasing the output of Follicle Stimulating Hormone (FSH), but unfortunately, this often doesn’t work. When the number of remaining eggs in her ovaries falls below a certain level (which can be different for each woman), her FSH level rises, and production of the ovarian hormone, AMH decreases. This is the start of diminishing ovarian reserve (DOR). Most women experience the onset of DOR in their late 30s or early 40s, but it can happen earlier for some. The lower the ovarian reserve, the lower the AMH level will be, and the fewer eggs will be available for harvesting during IVF-egg retrieval. In such cases, a higher dosage of fertility drugs might be needed to promote better egg production in future attempts. . On the other hand, higher AMH levels mean more eggs are available, and lower doses of fertility drugs are usually needed. DOR is commonly associated with increased bioactivity of pituitary gland-produced LH. This LH activates production of ovarian male hormones (androgens)…predominantly testosterone by ovarian connective tissue (stroma) . While a small amount of  ovarian testosterone is absolutely necessary for optimal follicle and egg development, excessive ovarian testosterone will often access the follicle , and compromise both egg quality and follicle growth and development. In some cases, rapidly increasing  LH-release (“premature LH-surge”) with excessive induced ovarian testosterone can lead to “premature luteinization”  of the follicles with cessation in growth and even to“ premature ovulation”.
• Importance of Individualized Controlled Ovarian Stimulation (COS) Protocol: It’s not surprising that DOR is more common in older women, but regardless of age, having DOR makes a woman’s eggs more likely to be compromised during controlled ovarian stimulation (COS). The choice of the COS protocol is crucial to preventing unintentional harm to egg and embryo quality. The wrong protocol can disrupt normal egg development and increase the risk of abnormal embryos. That’s why it’s important to tailor the COS protocol to each individual’s needs. This helps optimize follicle growth and the quality of eggs and embryos. The timing of certain treatments is also important for successful outcomes.
• Embryo Competency and Blastocyst Development: Embryos that don’t develop into blastocysts by day 6 after fertilization are usually chromosomally abnormal or aneuploid (”incompetent”) and not suitable for transfer. However, not all blastocysts are guaranteed to be normal and capable of developing into a healthy baby. As a woman gets older, the chances of a her embryos being chromosomally normal blastocyst decreases. For example, a blastocyst from a 30-year-old woman is more likely to be normal compared to one from a 40-year-old woman.

The IVF stimulation protocol has a big impact on the quality of eggs and embryos especially in women with DOR. Unfortunately, many IVF doctors use the same COS “recipe approach” for everyone without considering individual differences. Using personalized protocols can greatly improve the success of IVF. While we can’t change genetics or reverse a woman’s age, a skilled IVF specialist can customize the COS protocol to meet each patient’s specific needs.

GONADOTROPIN RELEASING HORMONE AGONISTS (GNRHA) AND GNRH-ANTAGONISTS:

• Gonadotropin releasing hormone agonists (GnRHa). Examples are Lupron, Buserelin, Superfact, and Decapeptyl . These are commonly used to launch  ovarian stimulation cycles. They work by initially causing a release of pituitary gonadotropins, followed by a decrease in LH and FSH levels within 4-7 days. This creates a relatively low LH environment when COS begins, which is generally beneficial for egg development. However, if GnRHa are administered starting concomitant with gonadotropin stimulation (see GnRHa –“flare protocol” -below) it can cause an immediate surge in LH release, potentially leading to high levels of ovarian testosterone that can harm egg quality, especially in older women and those with diminished ovarian reserve (DOR).
• Gonadotropin releasing hormone antagonists (GnRH-antagonists) : Examples are Ganirelix, Cetrotide, and Orgalutron. GnRH antagonists (take days  work quickly (within hours) to block pituitary LH release. Their purpose is to prevent excessive LH release during COS. In contrast, the LH-lowering effect of GnRH agonists takes several days to develop. Traditionally, GnRH antagonists are given starting on the 5th-7th day of gonadotropin stimulation. However, in older women and those with DOR, suppressing LH might happen too late to prevent excessive ovarian androgen production that can negatively impact egg development in the early stages of stimulation. That’s why I prefer to administer GnRH-antagonists right from the beginning of gonadotropin administration.

USING BIRTH CONTROL PILLS TO START OVARIAN STIMULATION:

Patients are often told that using birth control pills (BCP) to begin ovarian stimulation will suppress the response of the ovaries. This is true, but only if the BCP is not used correctly. Here’s the explanation:

In natural menstrual cycles and cycles stimulated with fertility drugs, the follicles in the ovaries need to develop receptors that respond to follicle-stimulating hormone (FSH) in order to properly respond to FSH stimulation. Pre-antral follicles (PAFs) do not have these receptors and cannot respond to FSH stimulation. The development of FSH responsivity requires exposure of the pre-antral follicles to FSH for several days, during which they become antral follicles (AFs) and gain the ability to respond to FSH-gonadotropin stimulation. In regular menstrual cycles, the rising FSH levels naturally convert PAFs to AFs. However, the combined BCP suppresses FSH. To counter this suppression, we need to promote increased  FSH production several days before starting COS. This allows the orderly conversion from PAFs to AFs, ensuring proper follicle and egg development.

GnRHa causes an immediate surge in FSH release by the pituitary gland, promoting the conversion from PAF to AF. Therefore, when women take the BCP control pill to launch a cycle of COS, they need to overlap the BCP with a GnRHa for a few days before menstruation. This allows the early recruited PAFs to complete their development and reach the AF stage, so they can respond appropriately to ovarian stimulation. By adjusting the length of time, the woman is on the birth control pill, we can regulate and control the timing of the IVF treatment cycle. Without this step, initiating ovarian stimulation in women coming off birth control pills would be suboptimal.

PROTOCOLS FOR CONTROLLED OVARIAN STIMULATION (COS):

• GnRH Agonist Ovarian Stimulation Protocols:
  • The long GnRHa protocol: Here, a GnRHa (usually Lupron or Superfact) is given either in a natural cycle, starting 5-7 days before menstruation, overlapping with the BCP for three days. Thereupon, the pill is stopped, while daily  GnRHa injections continue until menstruation occurs (usually 5-7 days later). The GnRHa causes a rapid rise in FSH and LH levels. This is followed about 3-4 days later , by a progressive decline in FSH and LH to near zero levels,  with a concomitant drop in ovarian estradiol and progesterone. This, in turn triggers uterine withdrawal bleeding (menstruation) within 5-7 days of starting the GnRHa administration. Gonadotropin treatment is then initiated while daily GnRHa injections continue to maintain a relatively low LH environment. Gonadotropin administration continues until the hCG “trigger” (see below).
  • Short GnRH-Agonist (“Flare”) Protocol: This protocol involves starting hormone therapy and using GnRH agonist at the same time. The goal is to boost FSH so that with concomitant stimulation with FSH-gonadotropins + the GnRHa-induced surge in pituitary gland FSH release, will augment follicle development. However, this surge also leads to a rise in LH levels, which can cause an excessive production of ovarian male hormones (e.g., testosterone). This could potentially adversely affect the quality of eggs, especially in women over 39 years old, those with low ovarian reserve, and women with PCOS or DOR who already have increased LH sensitivity. In this way, these “flare protocols” can potentially decrease the success rates of IVF. While they are generally safe for younger women with normal ovarian reserve, I personally avoid using this approach on the off chance that even patients with normal ovarian reserve, might experience poor egg quality.
• GnRH Antagonist-Ovarian Stimulation Protocols:
  • Conventional GnRH Antagonist Protocol: In this approach, daily GnRH antagonist injections are given from the 5th to the 8th day of COS with gonadotropins to the day of the “trigger” (see below). Accordingly, although rapidly acting to lower LH , this effect of GnRH- antagonist only starts suppressing LH from well into the COS cycle which means the ovarian follicles are left exposed and unshielded from pituitary gland -produced, (endogenous) LH during the first several days of stimulation. This can be harmful, especially in the early stage of COS when eggs and follicles are most vulnerable to the effects of over-produced LH-induced excessive ovarian testosterone. Therefore, I believe the Conventional GnRH Antagonist Protocol is not ideal for older women, those with low ovarian reserve, and women with PCOS who already have elevated LH activity. However, this protocol is acceptable for younger women with normal ovarian reserve, although I personally avoid using this approach on the off chance that even patients with normal ovarian reserve, might experience poor egg quality.

It’s important to note that the main reason for using GnRH antagonists is to prevent a premature LH surge, which is associated with poor egg and embryo quality due to follicular exhaustion. However, calling it a “premature LH surge” is misleading because it actually represents the culmination of a progressive increase in LH-induced ovarian testosterone. A better term would be “premature luteinization”. In some such cases, the rise in LH can precipitate “premature ovulation”.

• Agonist/Antagonist Conversion Protocol (A/ACP): I recommend this protocol for many of my patients, especially for older women and those with DOR or PCOS. The woman starts by taking a BCP for 7-10 days. This overlapped with a GnRHa for 3 days and continued until menstruation ensues about 5-7 days later. At this point  she “converts” from the GnRH-agonist to a GnRH-antagonist (Ganirelix, Orgalutron, or Cetrotide). A few days after this conversion from agonist to antagonist, COS with  gonadotropin stimulation starts. Both the antagonist and the gonadotropins are continued together until the hCG trigger. The purpose is to suppress endogenous LH release throughout the COS process and so  avoid over-exposure of follicles and eggs to LH-induced  excessive ovarian testosterone which as previously stated, can compromise egg and follicle growth and development.   Excessive ovarian testosterone can also adversely affect estrogen-induced growth of the uterine lining (endometrium). Unlike GnRH-agonists, antagonists do not suppress ovarian response to the gonadotropin stimulation. This is why the A/ACP is well-suited for older women and those with diminished ovarian reserve.
• A/ACP with estrogen priming: This is a modified version of the A/ACP protocol used for women with very low ovarian reserve (AMH=<0.2ng/ml). Estrogen priming is believed to enhance the response of follicles to gonadotropins. Patients start their treatment cycle by taking a combined birth control pill (BCP) for 7-10 days. After that, they overlap daily administration of a GnRH agonist with the BCP for 3 days. The BCP is then stopped, and the daily agonist continues until menstruation ensues (usually 5-7 days later). At this point, the GnRH agonist is supplanted by daily injections of  GnRH antagonist and  Estradiol (E2) “priming” begins using E2 skin patches or intramuscular estradiol valerate injections twice weekly, while continuing the GnRH antagonist. Seven days after starting the estrogen priming COS begins using recombinant FSHr such as Follistim, Gonal-F or Puregon) +menotropin (e.g., Menopur) . The estrogen “priming” continues to the day of the “trigger” (see below).  Egg retrieval is performed 36 hours after the trigger.

Younger women (under 30 years) and women with absent, irregular, or dysfunctional ovulation, as well as those with polycystic ovarian syndrome (PCOS), are at risk of developing a severe condition called Ovarian Hyperstimulation Syndrome (OHSS), which can be life-threatening. To predict this condition, accurate daily blood E2 level monitoring is required.

TRIGGERING “EGG MATURATION PRIOR TO EGG RETRIEVAL”

• The hCG “trigger”: When it comes to helping eggs mature before retrieval, one of the important decisions the doctor needs to make is choosing the “trigger shot” to facilitate the process. Traditionally, hCG (human chorionic gonadotropin) is derived from the urine of pregnant women (hCGu) while a newer recombinant hCG (hCGr), Ovidrel was recently The ideal dosage of hCGu is 10,000U and for Ovidrel, the recommended dosage is 500mcg. Both have the same efficacy. The “trigger” is usually administered by intramuscular injection, 34-36 hours prior to egg retrieval.

Some doctors may choose to lower the dosage of hCG if there is a risk of severe ovarian hyperstimulation syndrome (OHSS). However, I believe that a low dose of hCG (e.g., 5000 units of hCGu or 250 mcg of hCGr ( Ovidrel) might not be enough to optimize egg maturation, especially when there are many follicles. Instead, I suggest using a method called “prolonged coasting” to reduce the risk of OHSS.

• Using GnRH antagonist alone or combined with hCG as the trigger: Some doctors may prefer to use a GnRH- agonist trigger instead of hCG to reduce the risk of OHSS. The GnRHa “trigger” acts by inducing a “surge of pituitary gland-LH. However, it is difficult to predict the amount of LH that is released in response to a standard agonist trigger. In my opinion, using hCG is a better choice, even in cases of ovarian hyperstimulation, with the condition that “prolonged coasting” is implemented beforehand.
• Combined use of hCG + GnRH agonist: This approach is better than using a GnRH agonist alone but still not as effective as using the appropriate dosage of hCG.
• Timing of the trigger: The trigger shot should be given when the majority of ovarian follicles have reached a size of more than 15 mm, with several follicles measuring 18-22 mm. Follicles larger than 22 mm often contain overdeveloped eggs, while follicles smaller than 15 mm usually have underdeveloped and potentially abnormal eggs.

SEVERE OVARIAN HYPERSTIMULATION SYNDROME (OHSS) & “PROLONGED COASTING”

OHSS is a life-threatening condition that can occur during controlled ovarian stimulation (COS) when the blood E2 (estradiol) level rises too high. It is more common in young women with high ovarian reserve, women with polycystic ovarian syndrome (PCOS), and young women who do not ovulate spontaneously. To prevent OHSS, some doctors may trigger egg maturation earlier, use a lower dosage of hCG, or “trigger” using a GnRHa. However, these approaches can compromise egg and embryo quality and reduce the chances of success.

To protect against the risk of OHSS while optimizing egg quality, Physicians can use one of two options. The first is “prolonged coasting,” a procedure I introduced more than three decades ago. It involves stopping gonadotropin therapy while continuing to administer the GnRHa until the risk of OHSS has decreased. The precise timing of “prolonged coasting” is critical. It should be initiated when follicles have reached a specific size accompanied and the  blood estradiol has reached a certain peak.  The second option is to avoid fresh embryo transfer and freeze all “competent” embryos for later frozen embryo transfers (FETs) at a time when the risk of OHSS has subsided. By implementing these strategies, both egg/embryo quality and maternal well-being can be maximized.

In the journey of fertility, a woman is blessed with a limited number of eggs, like precious treasures awaiting their time. As she blossoms into womanhood, these eggs are gradually used, and the reserves start to fade. Yet, the power of hope and science intertwines, as we strive to support the development of these eggs through personalized treatment. We recognize that each woman is unique, and tailoring the protocol to her individual needs can unlock the path to success. We embrace the delicate timing, understanding that not all embryos are destined for greatness. With age, the odds may shift, but our dedication remains steadfast, along with our ultimate objective, which is  to do everything possible to propagate  of a normal pregnancy while optimizing the  quality of that life after birth and all times, minimizing risk to the prospective parents.

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ADDITIONAL INFORMATION:

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

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

https://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

If you are interested in having an online consultation with me, please contact my assistant, Patti Converse at 702-533-2691 or email her at concierge@sherivf.com

………………………………………………………………..

It is positive news!

Good luck!

Geoff Sher

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TIMING AND INTERPRETATION OF hCG BLOOD PREGNANCY TESTS
Geoffrey Sher MD

Going through IVF is a major investment, emotionally, physically, and financially, for every patient or couple. One of the most crucial moments is receiving the result of the blood test for human chorionic gonadotropin (hCG) pregnancy. It’s a big deal! The days after the embryo transfer, waiting for this result, can be extremely stressful. That’s why it’s crucial for the IVF doctor and staff to handle this information with care and professionalism. They should be accessible to the patient/couple and provide results promptly and sensitively.

Testing urine or blood to check for human chorionic gonadotropin (hCG) is the best way to confirm pregnancy. Urine tests are cheaper and more commonly used. They are also more convenient because they can be done anywhere. However, blood tests are more reliable and sensitive than urine tests. They can detect pregnancy earlier and at lower hCG levels. Blood tests are also more accurate and can track changes in hCG levels over time. Urine tests can detect hCG when blood levels are above 20IU, which is about 16-18 days after ovulation or 2-3 days after a missed period. Blood tests can measure any concentration of hCG about 12-13 days after ovulation.

Detecting hCG in the blood early on and tracking its increase is especially useful for women undergoing fertility treatments like controlled ovarian stimulation or in vitro fertilization. The sooner hCG is detected and measured, the more information can be gathered about the success of implantation and the health of the developing embryo.

Typically, two beta hCG blood tests are done, spaced 2-4 days apart. It’s best to wait for the results of the second test before reporting on the pregnancy. This is because an initial result can change, even from equivocal or negative to positive. Sometimes a normal embryo takes longer to implant, and the hCG level can be initially low or undetectable. Regardless of the initial level, the test should be repeated after two days to check for a significant rise in hCG. A significant rise usually indicates that an embryo is implanting, which suggests a possible pregnancy. Waiting for the second test result helps avoid conveying false hope or disappointment.

It’s important to note that beta hCG levels don’t double every two days throughout pregnancy. Once the levels rise above 4,000U, they tend to increase more slowly. Except in specific cases like IVF using an egg donor or transfer of genetically tested embryos, the birth rate following IVF in younger women is around 40% per embryo transfer. Patients need to have realistic expectations and should be informed about how and when they will receive the news, as well as counseling in case of a negative outcome.

When an embryo starts to implant, it releases the pregnancy hormone hCG into the woman’s bloodstream. Around 12 days after egg retrieval, 9 days after a day 3 embryo transfer, or 7 days after a blastocyst transfer, a woman should have a quantitative beta hCG blood pregnancy test performed. By that time, most of the hCG injected to prepare the eggs for retrieval should have cleared from the bloodstream. So, if the test detects more than 10 IU of hCG per ml of blood, it indicates that the embryo has attempted to implant. In third-party IVF (e.g., ovum donation, gestational surrogacy, embryo adoption, or frozen embryo transfers), no hCG trigger is administered, so any amount of hCG detected in the blood is considered significant.

Sometimes, there is a slow initial rise in hCG between the first and second tests (failure to double every 48 hours). In such cases, a third and sometimes a fourth hCG test should be done at two-day intervals. A failure to double on the third and/or fourth test is a poor sign and could indicate a failed or dysfunctional implantation. In some cases, a progressively slow rising hCG level might indicate an ectopic pregnancy, which requires additional testing and follow-up.

In certain situations, the first beta hCG level starts high, drops with the second test, and then starts doubling again. This could suggest that initially, multiple embryos started to implant but only one survived to continue a healthy implantation.

It’s customary for the IVF clinic staff to inform the patient/couple and the referring physician about the hCG pregnancy test results. Often, the IVF physician or nurse-coordinator coordinates with the referring physician to arrange all necessary pregnancy tests. If the patient/couple prefer to make their own arrangements, the program should provide detailed instructions.

In some cases, when the two blood pregnancy tests show that one or more embryos are implanting, certain programs recommend daily injections of progesterone or the use of vaginal hormone suppositories for several weeks to support the implantation process. Others give hCG injections three times a week until the pregnancy can be confirmed by ultrasound examination. Some IVF programs don’t prescribe any hormones after the embryo transfer.

Patients with appropriate doubling of hCG levels within two days after frozen embryo transfer (FET) or third-party IVF procedures such as surrogacy or egg donation may receive estradiol and progesterone injections, often along with vaginal hormone suppositories, for 10 weeks after the implantation is diagnosed by blood pregnancy testing.

A positive Beta hCG blood pregnancy test indicates the possibility of conception, but ultrasound confirmation is needed to confirm the pregnancy. Until then, it is referred to as a “chemical pregnancy.” Only when ultrasound examination confirms the presence of a gestational sac, clinical examination establishes a viable pregnancy, or after abortion when products of conception are detected, is it called a clinical intrauterine pregnancy.

A significantly elevated  hCG blood level without concomitant detection of an gestational sac inside the uterus by ultrasound after 5 weeks gestation raises the suspicion of an ectopic (tubal) pregnancy.

The risk of miscarriage gradually decreases once a viable clinical pregnancy is diagnosed (a conceptus with a regular heartbeat of 110-180 beats per minute). From this point onward, the risk of miscarriage is usually 10- 15% for women under 40 years old and around 35% for women in their early forties.

Dealing with successful IVF cases is relatively easy as everyone feels happy and validated. The real challenge lies in handling unsuccessful cases. Setting rational expectations from the beginning is crucial. In some cases (fortunately rare), emotional pressure may overwhelm the patient/couple, leading to a need for counseling or psychiatric therapy. I always advise my patients that receiving optimal care doesn’t always guarantee the desired outcome. There are many variables beyond our control, especially the unpredictable nature of fate. With around 36 years of experience in this field, I strongly believe that when it comes to IVF, the saying “man proposes while God disposes” always holds.

There are a few important things to consider when interpreting blood hCG levels. Levels can vary widely, ranging from 5mIU/ml to over 400mIU/ml, 10 days after ovulation or egg retrieval. The levels double every 48-72 hours until the 6th week of pregnancy, after which the doubling rate slows down to about 96 hours. By the end of the 1st trimester, hCG levels reach 13,000-290,000 IU and then slowly decline to around 26,000-300,000 IU at full term. Here are the average hCG levels during the first trimester:

• 3 weeks after the last menstrual period (LMP): 5-50 IU
• 4 weeks LMP: 5-426 IU
• 5 weeks LMP: 18-7,340 IU
• 6 weeks LMP: 1,080-56,500 IU
• 7-8 weeks LMP: 7,650-229,000 IU
• 9-12 weeks LMP: 25,700-288,000 IU

Most doctors wait until around the 7th week to perform an ultrasound to confirm pregnancy. By that time, the heartbeat should be clearly visible, providing a more reliable assessment of the pregnancy’s viability.

In some cases, blood hCG levels can be unusually high or increase faster than normal. This could indicate multiple pregnancies or a molar pregnancy. Rarely, conditions unrelated to pregnancy, such as certain ovarian tumors or cancers, can cause detectable hCG levels in both blood and urine.

To summarize, testing urine or blood for hCG is the most reliable way to confirm pregnancy. Urine tests are more common and convenient, while blood tests are more accurate and can detect pregnancy earlier. Tracking hCG levels in the blood is especially important for women undergoing fertility treatments. It’s essential to wait for the results of a second blood test before confirming pregnancy to avoid false hope or disappointment. Interpreting hCG levels requires considering various factors, and doctors usually perform an ultrasound around the 7th week for a more accurate assessment. Unusually high hCG levels may indicate multiple pregnancies or other conditions unrelated to pregnancy. Providing sensitive and timely communication of results is crucial for IVF clinics to support patients through the emotional journey.

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ADDITIONAL INFORMATION:

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

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

https://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

If you are interested in having an online consultation with me, please contact my assistant, Patti Converse at 702-533-2691 or email her at concierge@sherivf.com

………………………………………………………………..

think we should talk. Please call my assistant, Patti Converse (702-533-2691) and set up ,an online consultation to discuss.

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) “

https://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

If you are interested in having an online consultation with me, please contact my assistant, Patti Converse at 702-533-2691 or email her at concierge@sherivf.com

………………………………………………………………..

I think we should talk. Please call my assistant, Patti Converse (702-533-2691) and set up ,man online consultation to discuss.

Geoff Sher

______________________________________________________________________

Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining

Geoffrey Sher

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About 25 years ago, after reporting on the benefit of vaginal Sildenafil (Viagra) for to women who had implantation dysfunction due to thin endometrial linings I was proud to announce the birth of the world’s first “Viagra baby.”  For those of you who aren’t familiar with the use of Viagra in IVF, allow me to provide some context.

It was as far back as 1989, when I first published a study that examined the correlation between the thickness of a woman’s uterine lining (the endometrium), and the subsequent successful implantation of embryos in IVF patients. This study revealed that when the uterine lining measured <8mm in thickness by the day of the “hCG trigger” (in fresh IVF cycles), or at the time of initiating progesterone therapy (in embryo recipient cycles, e.g.  frozen embryo transfers, egg donation-IVF etc.) , pregnancy and birth rates were substantially improved. Currently, it is my opinion, that an ideal estrogen-promoted endometrial lining should ideally measure at least 9mm in thickness and that an endometrial lining measuring 8-9mm is “intermediate”. An estrogenic lining of <8mm is in most cases unlikely to yield a viable pregnancy.

A “poor” uterine lining is usually the result of the innermost layer of endometrium (the basal or germinal endometrium from which endometrium grows) ) not being able to respond to estrogen by propagating an outer, “functional” layer thick enough  to support optimal embryo implantation and development of a healthy placenta (placentation). The “functional” layer ultimately comprises 2/3 of the full endometrial thickness and is the layer that sheds with menstruation in the event that no pregnancy occurs.

The main causes of a “poor” uterine lining are:

1. Damage to the basal endometrium as a result of:
   1. Inflammation of the endometrium (endometritis) most commonly resulting from infected products left over following abortion, miscarriage or birth
   2. Surgical trauma due to traumatic uterine scraping, (i.e. due to an over-aggressive D & C)
2. Insensitivity of the basal endometrium to estrogen due to:
   1. Prolonged , over-use/misuse of clomiphene citrate
   2. Prenatal exposure to diethylstilbestrol (DES).  This is a drug that was given to pregnant women in the 1960’s to help prevent miscarriage
3. Over-exposure of the uterine lining to ovarian male hormones (mainly testosterone): Older women, women with diminished ovarian reserve (poor responders) and women with polycystic ovarian syndrome -PCOS tend to have raised LH biological activity.. This causes the connective tissue in the ovary (stroma/theca) to overproduce testosterone. The effect can be further exaggerated when certain methods for ovarian stimulation such as agonist (Lupron/Buserelin) “flare” protocols and high dosages of menotropins such as Menopur are used in such cases.
4. Reduced blood flow to the basal endometrium:

Examples include;

1. 1. Multiple uterine fibroids – especially when these are present under the endometrium (submucosal)

1. Uterine adenomyosis (excessive, abnormal invasion of the uterine muscle by endometrial glands).

“The Viagra Connection”

Treatments such supplementary estrogen therapy, aspirin administration and/or administration of high dosage gonadotropin fertility drugs, aimed at improving endometrial development have all yielded disappointing results.

It was in the 90’s that Sildenafil (brand named Viagra) was gaining popularity as a treatment for erectile dysfunction.  The mechanism by which it acted was through increasing penile blood flow through increasing nitric oxide activity. This prompted me to investigate whether Viagra administered vaginally, might similarly improve uterine blood flow and in the process cause more estrogen to be delivered to the basal endometrium and thereby increase endometrial thickening. We found that when Viagra was administered vaginally it did just that! However oral administration was without any significant benefit in this regard.  We enlisted the services of a compound pharmacy to produce vaginal Viagra suppositories. Initially, four (4) women with chronic histories of poor endometrial development and failure to conceive following several advanced fertility treatments were evaluated for a period of 4-6 weeks and then underwent IVF with concomitant Viagra therapy. Viagra suppositories were administered four times daily for 8-11 days and were discontinued 5-7 days prior to embryo transfer in all cases.

Our findings clearly demonstrated that vaginal Viagra produced a rapid and profound improvement in uterine blood flow and that was followed by enhanced endometrial development in all four cases. Three (3) of the four women subsequently conceived. . I expanded the trial in 2002 and became the first to report on the administration of vaginal Viagra to 105 women with repeated IVF failure due to persistently thin endometrial linings. All of the women had experienced at least two (2) prior IVF failures attributed to intractably thin uterine linings. About 70% of these women responded to treatment with Viagra suppositories with a marked improvement in endometrial thickness. Forty five percent (45%) achieved live births following a single cycle of IVF treatment with Viagra The miscarriage rate was 9%. None of the women who had failed to show an improvement in endometrial thickness following Viagra treatment achieved viable pregnancies.

Following vaginal administration, Viagra is rapidly absorbed and quickly reaches the uterine blood system in high concentrations. Thereupon it dilutes out as it is absorbed into the systemic circulation. This probably explains why treatment is virtually devoid of systemic side effects

Since the introduction of this form of treatment, thousands of women with thin uterine linings have been reported treated and many have gone on to have babies after repeated prior IVF failure.

It is important to recognize that Viagra will NOT be effective in improving endometrial thickness in all cases. In fact, about one third of women treated fail to show any improvement. This is because in certain cases of thin uterine linings, the basal endometrium will have been permanently damaged and left unresponsive to estrogen. This happens in cases of severe endometrial damage due mainly to post-pregnancy endometritis (inflammation), chronic granulomatous inflammation due to uterine tuberculosis (hardly ever seen in the United States) and following extensive surgical injury to the basal endometrium (as sometimes occurs following over-zealous D&C’s).

To be effective, Viagra must be administered vaginally. It is NOT effective when taken orally. We prescribe 20mg vaginal suppositories to be inserted four times per day. Treatment is commenced soon after menstruation ceases and is continued until the day of the “hCG trigger.”  While ideally the treatment should be sustained throughout the first half of the cycle, most women will respond within 48-72 hours. For this reason, Viagra can be used to “rescue” a poor lining after the cycle has already started, provided that there is enough time remaining prior to ovulation, egg retrieval or progesterone administration.

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ADDITIONAL INFORMATION:

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

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

https://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

If you are interested in having an online consultation with me, please contact my assistant, Patti Converse at 702-533-2691 or email her at concierge@sherivf.com

………………………………………………………………..

With a  notable exception (Pelvic Tuberculosis—(which is VERY rare in the USA), I am NOT a believer in chronic endometritis as a cause of IVF failure. The reason is that menstruation purges the endometrium every moth , preventing a chronic inflammatory process from taking hold.

Good luck !

Geoff Sher

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W

If you’ve undergone in vitro fertilization (IVF) and didn’t achieve a successful pregnancy, you may be wondering why. It’s important to know that IVF outcomes can be unpredictable, but there are factors that can affect your chances. Let’s explore some common reasons for IVF failure in simpler terms.

1. Age: A woman’s age is a significant factor in IVF success. Generally, women under 35 have a higher chance of getting pregnant through IVF, around 35-40% per embryo transfer. However, this success rate decreases as women get older. For women in their mid-forties, the success rate drops to under 5%. This decline is mainly because the quality of eggs decreases as women age, affecting their ability to develop normally.

1. Egg/Embryo Competency: Apart from age, the quality and competency of embryos also affect IVF success. The quality of eggs and embryos is influenced by a woman’s age. However, for older women or those with fewer eggs, the specific IVF protocol used to stimulate the ovaries becomes crucial. A more aggressive approach may be needed to maximize the chances of success. Previously, it was thought that the uterus was better for embryo development than the lab environment. So, early-stage embryos were transferred to the uterus based on their appearance. However, we now know that embryos that have progressed further in development are more likely to be successful. Embryos that don’t reach the blastocyst stage within 5-6 days after fertilization are considered less competent and not suitable for transfer. Additionally, Preimplantation Genetic Sampling / Testing (PGS/T) allows us to check the chromosomes of embryos. This technique helps select the most competent embryos for transfer, especially for older women, those with fewer eggs, repeated IVF failures, and recurrent pregnancy loss.

1. Number of Embryos Transferred: Some people believe that transferring more embryos increases the chances of success. While this may have some truth, it’s essential to know that if the problem lies with the ovarian stimulation protocol, transferring more embryos won’t solve it. Also, transferring more embryos doesn’t fix issues related to embryo implantation dysfunction, such as anatomical or immunologic problems. Moreover, multiple embryos can lead to higher-order multiple pregnancies, which pose risks. To minimize these risks, it’s generally recommended to transfer a maximum of two embryos, or even just one, especially when using eggs from young women.

1. Implantation Dysfunction (ID): Implantation dysfunction is often overlooked as a cause of unexplained IVF failure, especially in young women with normal ovarian reserve and fertile partners. Failure to identify and address these issues can result in repeated IVF failures. If transferring competent embryos repeatedly fails to result in a viable pregnancy, implantation dysfunction should be considered. The most common causes include:

1. 1. Thin Uterine Lining: When the lining of the uterus is too thin, it can affect the embryo’s ability to implant and grow.
   2. Surface Lesions in the Uterus: Polyps, fibroids, or scar tissue in the uterus can interfere with embryo implantation.
   3. Immunologic Implantation Dysfunction (IID): Sometimes, the immune system can mistakenly attack the embryo, preventing successful implantation.
   4. Endocrine/Molecular Endometrial Receptivity Issues: Hormonal or molecular issues in the uterine lining can impact the embryo’s ability to attach and develop.
   5. Ureaplasma Urealyticum (UU) Infection: This infection in the cervical mucous and uterine lining can lead to unexplained early pregnancy loss or IVF failure. Both partners should be tested and treated if positive to prevent transmission.

Certain causes of infertility are difficult or impossible  to reverse, e.g.; advanced age of the woman, severe male infertility, and immunologic implantation dysfunction associated with certain specific genetic factors.

Understanding the common factors contributing to IVF failure can help you have informed discussions with your doctor and make decisions for future attempts. Factors like the number of embryos transferred and implantation dysfunction play significant roles. While success cannot be guaranteed, knowing these factors can guide you in maximizing your chances and addressing potential issues.

____________________________________________________________________________________

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) “

https://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

If you are interested in having an online consultation with me, please contact my assistant, Patti Converse at 702-533-2691 or email her at concierge@sherivf.com

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