Raised DHEA is not a real problem . it is a raised DHEAS that xcouyld be problematic as it would point to a possible adrenal contribution to the PCOS equation.

Navigating Polycystic Ovary Syndrome: Understanding, Hope, and Treatment

Geoffrey Sher MD

Understanding the intricate interplay of hormones and the impact on egg development empowers us to create personalized protocols, offering hope for improved egg quality and ultimately optimizing the chances of successful IVF for women with PCOS.

Polycystic ovary syndrome (PCOS) is a widespread hormonal disorder affecting 5% to 10% of reproductive-age women globally. Women with PCOS often have enlarged ovaries containing multiple small fluid-filled collections (micro-cysts) arranged in a “string of pearls” pattern below the ovarian surface, intertwined with an overgrowth of ovarian connective tissue.

PCOS is marked by abnormal ovarian function causing absent, irregular or dysfunctional ovulation and menstruation,  infertility, increased body hair (hirsutism), acne, and higher body weight as indicated by an above normal body mass index (BMI). 

Despite substantial research efforts to identify its cause, the origins of PCOS remain elusive, and a definite cure is yet to be found. This disorder is notably diverse and often has a genetic basis within families. 

Infertility related to PCOS is attributed to various factors, including irregular gonadotropin (FSH and LH) pituitary secretion, peripheral insulin resistance, elevated levels of adrenal and/or ovarian androgens (male hormones), and dysfunction in growth factors. Individuals with PCOS often battle obesity and insulin resistance. The compensatory surge in insulin levels further stimulates ovarian androgen production, potentially hampering egg maturation. Notably, the degree of insulin resistance is closely linked to anovulation. 

PCOS also poses long-term health risks, underscoring the need for vigilant annual health check-ups to monitor potential conditions like non-insulin-dependent diabetes mellitus, hypertension, hypercholesterolemia, cardiovascular disease, and endometrial cancer.

Though PCOS-related infertility is typically manageable with fertility drugs, lifestyle modifications involving diet and exercise are fundamental for long-term management. Recent advancements have shown improvements in ovulation rates, androgen levels, pregnancy rates, and even a reduction in first-trimester miscarriage rates through the use of insulin sensitizers like Metformin to address underlying insulin resistance.

Most PCOS patients are young and often experience successful pregnancies with oral clomiphene or Letrozole/Femara. However, a subset of PCOS patients with severe ovarian ovulatory dysfunction and those requiring IVF treatment, will usually require injectable gonadotropin medications such as Follistim, Gonal-F, Menopur, etc. These treatments can trigger an exaggerated  response to gonadotropins, potentially leading to complications such as Severe Ovarian Hyperstimulation Syndrome (OHSS) and high-order multiple births ( triplets or greater). For these cases, employing strategies like “prolonged coasting” (see below) and/or delaying embryo transfer for a month or two  in order to allow the ovaries to recover from ovarian stimulation,  and selectively transferring fewer embryos present clear advantages..

PCOS and Egg/Embryo Quality:

PCOS and Egg/Embryo “Competency”.

A woman’s potential for successful egg maturation and embryo development is largely determined by genetics. However, this potential can also be significantly influenced by hormonal changes within the ovaries during the pre-ovulatory phase of her menstrual cycle. Achieving the right stimulation of the follicles and precise timing for egg maturation with the LH (Luteinizing Hormone) “surge” or through hCG (human chorionic gonadotropin) administration is crucial for optimal egg quality, fertilization, and subsequent embryo development.

Two key hormones, LH and FSH (follicle stimulating hormone), play vital but distinct roles in the development of eggs and follicles. FSH mainly stimulates granulosa cells (lining the follicles) and estrogen production (E2). On the other hand, LH primarily acts on the ovarian stroma (connective tissue around the follicle) to produce androgens ( predominantly testosterone and androstenedione). While a small amount of androgen supports egg and follicle development, excessive exposure can be harmful. Too much androgen can also hinder estrogen-induced growth of the uterine lining.

PCOS is commonly associated with elevated LH levels, leading to excess stromal growth, follicle overgrowth (referred to as cysts), and heightened androgen production. Accordingly, suppressing LH secretion using gonadotropin releasing hormone (GnRH) agonists like Lupron/ Buserelin/Superfact and decapeptyl proves beneficial. However, it is important to understand that  some LH is essential for optimal egg and follicle development. Excessive  LH on the other hand results in over-production of LH-induced ovarian androgens, which upon reaching the follicular fluid often  compromises both follicle and egg development.  Consequently, PCOS women who commonly over-produce LH and ovarian androgens  frequently propagate poorly developed follicles and  “dysmature/immature” eggs leading to  poor fertilization and embryo quality as well as an androgen-induced insufficient uterine lining that might prejudice embryo implantation, It is in my opinion, that the compromised egg quality is not necessarily due to an inherent “egg defect “ but  rather due to an adverse ovarian hormonal milieu which can often be avoided by  tailoring stimulation protocols so as to avoid excessive LH-induced androgens, Avoiding .

Varieties of PCOS:

Polycystic Ovary Syndrome (PCOS) comes in various forms, each requiring tailored treatment. Here, I wish to shed light on the main types and how infertility linked to ovulation dysfunction can be managed.

• Hypothalamic-Pituitary-PCOS:
  • Most common form with genetic roots.
  • Characterized by high levels of Luteinizing Hormone (LH) and androgen hormones.
  • Often associated with insulin resistance.
• Adrenal PCOS:
  • Excess male hormones come from overactive adrenal glands.
  • Elevated testosterone and/or androstenedione levels, along with increased dehydroepiandrosterone (DHEAS) levels, confirm diagnosis.
• Pelvic Adhesive Disease-Related PCOS:
  • Linked to severe endometriosis, pelvic inflammatory disease, or extensive pelvic surgery.
  • Lower response to ovulation induction.
  • Notably, DHEAS levels remain unaffected.

Treating Infertility Due to Ovulation Dysfunction:

• Hypothalamic-Pituitary-/Ovarian PCOS:
  • Successful treatment with fertility drugs like clomiphene citrate, Letrozole, or gonadotropins.
  • In-vitro Fertilization (IVF) is increasingly favored.
  • Oral Metformin can help reduce insulin resistance and androgen levels.
• Adrenal PCOS:
  • Treated with steroids like prednisone or dexamethasone to suppress adrenal androgen production.
  • Combined with fertility drugs for induced ovulation.
• PCOS due to Pelvic Adhesive Disease:
  • Often linked to compromised ovarian reserve and higher FSH levels.
  • Requires high doses of gonadotropins and “estrogen priming” for effective ovulation induction or IVF.

The Risks of Treatment

• High-order multiple pregnancies (triplets, or greater):

PCOS patients undergoing ovulation induction are at greater risk of multiple pregnancies which are especially treacherous both mother and offspring occur with the occurrence of high-order multiple pregnancies. This risk is not preventable when ovulation induction alone is used (with or without IUI) since there is no ability to regulate the number of eggs that are ovulated. Conversely, IVF  allows for the  number of embryos transferred to the uterus to be deliberately regulated. 

• Severe Ovarian Hyperstimulation (OHSS)
  1. OHSS is a significant concern for women with PCOS undergoing fertility treatments , especially where gonadotropins are administered for ovarian stimulation.
  2. Understanding OHSS:
     • Women with PCOS tend to hyper-respond to fertility drugs, often producing excessive ovarian follicles.;
     • his can escalate into OHSS, posing life-threatening risks.

Indicators of OHSS:

• OHSS begins with an abundance of ovarian follicles (often more than 25).
• Rapid rise in estradiol (E2) levels, sometimes exceeding 3000pg/ml within 7-9 days of stimulation.
• The risk of OHSS exceeds 80% when the peak blood estradiol level exceeds 6000pg/ml.

Symptoms and Signs of OHSS:

• Abdominal swelling due to fluid accumulation (ascites).
• Sometimes fluid in the chest cavity (hydrothorax) and even around the heart ( pericardial effusion)
• Rapid weight gain (more than a pound per day) due to fluid retention.
• Abdominal pain and lower backache.
• Nausea, diarrhea, and vomiting.
• Visual disturbances like blurred vision and spots in front of the eyes.
• Reduced urine output.
• Cardiovascular complications and bleeding tendencies.

Managing OHSS:

• If fluid accumulation compromises breathing, elevating the head of the bed often helps.
• Drainage of excess fluid through transvaginal sterile needle aspiration (vaginal paracentesis) may be necessary.
• Symptoms typically subside within 10-12 days of hCG shot if pregnancy doesn’t occur or by the 8th week of pregnancy.
• Monitor urine output and perform chest X-rays and blood tests regularly to assess the condition.
• In severe cases, hospitalization and intensive care might be necessary.

Avoiding OHSS while protecting egg quality though  “Prolonged Coasting”

In the early 1990s, I introduced  a game-changing approach to the prevention of OHSS, called “Prolonged Coasting” (PC) . The method avoids the life-endangering risks associated with this complication while to largely protecting  egg quality . PC  has now become a standard treatment for OHSS prevention. However, the effective success of PC is very largely dependent on meticulous implementation and proper timing.

What is “Prolonged Coasting” (PC)?

• PC involves a strategic pause in administering gonadotropin therapy, while continuing GnRHa (Lupron/Buserelin/Superfact/decapeptyl)
• This method significantly reduces the risk of OHSS, a life-threatening condition associated with excessive follicle growth.
• Balancing Act for Egg Quality:
• While PC is highly effective in averting OHSS, concerns were raised about potential impacts on fertilization rates and embryo implantation.
• Experience suggests that the perceived egg/embryo quality deficit isn’t directly caused by PC but is more about precise timing.
• Timing is Crucial: It is initiated when a woman with >25 follicles (total) with an estradiol measurement of >2500pg/ml has at least 50% of her follicles at 14mm diameter. It ends when the rising E2 plateaus and then drops. The key is to wait until the plasma estradiol concentration drops below 2,500 pg/ml before administering hCG. Initiating PC too early or too late can either halt follicle growth abruptly or lead to cystic follicles, both affecting egg quality. The timing allows for a progressive rise in estradiol levels followed by a plateau before a controlled decline, optimizing egg maturation. Even if the estradiol level falls below 1,000 pg/ml by hCG trigger time, resisting the urge to trigger prematurely with hCG is vital. This ensures eggs have adequate time for optimal development, increasing the chances of successful fertilization and embryo quality.

:

Words of caution:

• Pituitary suppression with GnRH antagonists (Ganirelix, Cetrotide, Orgalutron) can falsely suppress E2 levels and in my opinion, is not be suitable, especially in cases like PCOS a decision on timing for PC in large part hinges on the accurate determination of serial blood estradiol levels…Accordingly, I caution against their use in patients with PCOS where “prolonged coasting is contemplated being used.
• The standard practice of administering hCG (human chorionic gonadotropin) in an attempt to prematurely arrest further follicle growth and so prevent Severe Ovarian Hyperstimulation Syndrome (OHSS) can, by abruptly halting egg development, impact their maturation, prejudice their “competency” and in turn compromise embryo competency”, as well. Mastering the art of “Prolonged Coasting” is a critical step forward in fertility treatments. Precise timing and a patient-centered approach can make a world of difference, providing hope and improved outcomes for women on their journey towards motherhood.

In summary, when it comes to managing infertility in PCOS women, it is  crucial to tailor stimulation protocols during IVF to minimize exposure to excessive LH-induced ovarian androgens. By limiting the use clomiphene snd Letrozole/Femara  as well as LH-containing gonadotropins like Menopur and incorporating “prolonged coasting,” we can provide the necessary time for optimal follicle and egg development before administering hCG. This approach can potentially enhance egg quality and improve outcomes in IVF for women with PCOS.

_____________________________________________________________________

Herewith are  online links to 2  E-books 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

I invite you to visit my very recently launched “Podcast”,  “HAVE A BABY” on RUMBLE;   https://rumble.com/c/c-3304480

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\

No, I do not think you need to go on Lovenox and use own eggs/embryos.

Hereditary Clotting Defects (Thrombophilia)

Geoffrey Sher MD

Thrombophilia (Hereditary Clotting Defect) is defined as the genetic predisposition to developing intravascular thrombosis. It is due to hypercoagulability of blood leading to impairment of initial vascularization that takes place during implantation.

Thrombophilia affects as many as one in five people in the United States and is responsible for pregnancy loss (most particularly after the 1st trimester) and “unexplained” infertility, as well as being a factor in some cases of “unexplained” IVF failure. Whether (and/or the extent to which) thrombophilia causes 1st trimester recurrent pregnancy loss (RPL) is the subject of debate and is controversial. In fact, first-trimester RPL is far more likely to be due to immunologic implantation dysfunction (IID) and/or irregularities in the contour of the uterine cavity or insufficient thickness of its lining (a thin endometrium). Thrombophilia has also been associated with late pregnancy-induced complications such as preeclampsia, premature separation of the placenta (abruptio placenta), placental insufficiency with intrauterine growth retardation, and in “unexplained” intrauterine death.

This having been said, it is a fact that most women with a thrombophilia go on to experience healthy pregnancies.

Diagnosis of Throbophilia

Thrombophilia is diagnosed when one or more of the following is detected:

• Mutational defect involving methylenetetrahydrofolate reductase (MTHFR), which occurs in at least 20% of affected cases. Homozygosity for a common C677T mutation in the MTHFR gene that is associated with hyperhomocysteinemia is the most common form of hereditary thrombophilia leading to a 3-fold increase in risk of complications.
• Mutation of factor V Leiden (FVL),
• A mutation of prothrombin G20210A,
• Deficiency of antithrombin III
• Deficiency of protein C
• Deficiency of protein S

Risk Factors

• Pregnant women with predisposing factors such as:
• A personal or family history of thromboembolism (deep vein thrombosis), pulmonary embolism (blood clot in the lung), cerebrovascular accidents (i.e. strokes)
• A personal history of pregnancy complications such as unexplained intrauterine death, preeclampsia, abruptio placenta, intrauterine growth retardation, placental insufficiency, should be tested for the condition.

Treatment

Treatment should be initiated as soon as possible after pregnancy is diagnosed biochemically (blood or urine hCG test) and be continued throughout gestation.

Severe thrombophilias (e.g. homozygous MTHFR mutations, protein C deficiency, prothrombin G20210A mutation) as well as cases of mild thrombophilias associated  with one or more of the pregnancy complications mentioned above, are best treated with low-molecular weight heparin (LMWH) taken throughout pregnancy.

For other (milder) thrombophilias and no history of prior pregnancy complications: Low-dose aspirin with the B vitamins folic acid, B6 and B12.

_________________________________________________________________________________________________________________

Herewith are  online links to 2  E-books 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

I invite you to visit my very recently launched “Podcast”,  “HAVE A BABY” on RUMBLE;   https://rumble.com/c/c-3304480

Frankly, I would not be overly concerned. And no,there is in my opinion nothing to do here. except follow up with ultrasound evaluations intermittently.

Good luck!

Geoff Sher

___________________________________________________________

Herewith are  online links to 2  E-books 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

I invite you to visit my very recently launched “Podcast”,  “HAVE A BABY” on RUMBLE;   https://rumble.com/c/c-3304480

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 concur. I would collect as many eggs as possible in advance.

“Empowering Choices: Embryo Banking vs. Egg Banking for Fertility Preservation“

Geoffrey Sher MD

It’s crucial for women to make informed decisions about preserving their fertility. Delaying trying to conceive, relying on egg freezing, or assuming the biological clock can be paused are misconceptions. As women age, egg quality declines, affecting the chance of a successful, healthy pregnancy.

Let’s break down the key points:

1. Age and Egg Quality: As women progress past their mid-thirties, the quality of their eggs declines rapidly. This impacts conception rates, leading to higher miscarriage and chromosomal abnormalities like Down syndrome.
2. Comparing Chances:

1. • At 30, the natural conception rate is around 15-20%, with a 10-15% miscarriage rate and a 1:1000 chance of Down syndrome.
   • At 45, natural conception drops to 1-2%, with a 50-60% miscarriage rate and a 1:40 chance of Down syndrome.

1. IVF and Age:

1. • IVF success rates are better at younger ages, with a 50-60% conception rate for 30-year-olds and a 3-5% chance for 45-year-olds.
   • However, IVF doesn’t eliminate the increased risk of miscarriage or chromosomal abnormalities as women age.

1. IVF Realities:

1. • The success of IVF dramatically decreases with age, making informed decisions crucial.

Preimplantation Genetic Screening (PGS)/Preimplantation Genetic Testing for aneuploidy (PGT-A) is a breakthrough in fertility treatment, aiding the selection of the most viable embryos for a successful pregnancy. By analyzing all chromosomes, it significantly boosts the success rates of IVF. PGS/PGT-A not only increases the chance of a healthy baby per embryo transfer but also reduces the risks of miscarriages and chromosomal birth defects, regardless of the woman’s age.

Who Benefits from PGS/PGT-A?

PGS/PGT-A) has revolutionized embryo evaluation, especially for those facing unexplained IVF failure, infertility, recurrent pregnancy loss (RPL), and older women with diminished ovarian reserve (DOR).

Empowering Older Women: Embryo Banking

PGS/PGT-A is especially beneficial for women over 39 years of age and those with DOR, as it allows the storage (banking) of healthy embryos over multiple cycles, countering the ticking biological clock.. Selective banking of PGS-normal embryos over multiple cycles is a game-changer. It minimizes the impact of age on egg quality, giving these women a chance to make the most of their remaining time to conceive a healthy baby.

Egg Freezing: Factors to Consider

Eggs are vulnerable cells, and freezing a single egg is less effective than freezing a multi-cellular embryo. Additionally, a significant portion of eggs (especially in older women) have chromosomal abnormalities. This makes egg freezing less efficient and  embryo freezing, far more successful, especially when selectively freezing PGS/PGT-A-normal blastocysts.

Choosing the Right Path

Importantly, considering the decline in reproductive potential with age, it’s essential for women and couples to explore their fertility options before the age of 35. An aggressive approach, like moving to assisted reproduction and IVF can significantly improve outcomes. For younger women (<35y) who have normal egg reserves, especially those who are not married,  have not as yet settled on la “permanent” male partner or a do not feel secure with their existing male partner fathering a child with them might preferentially choose egg freezing . Conversely,  women who are comfortable with a designated male partner, older women and those who have DOR might rather select embryo banking.

In the choice between egg and embryo freezing, caution is advised. Current methods for egg selection lack chromosomal analysis. Conversely the performance of PGSGT-A allows for identification of the healthiest embryos for subsequent FET..

Either way, “timing” is a very important consideration.

By understanding these options, you can make an informed decision to maximize your chances of a healthy, happy family. Remember, knowledge is power in the journey to parenthood.

_____________________________________________________________________

Herewith are  online links to 2  E-books 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

I invite you to visit my very recently launched “Podcast”,  “HAVE A BABY” on RUMBLE;   https://rumble.com/c/c-3304480

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\

You will need to be evaluated as to the reason for your not having periods. Only then could treatment be contemplated. Go an see your primary OB/GYN.

Geoff Sher

In my opinion, this is likely due to the protocol used for ovarian stimulation (see below

EGG/ EMBRYO QUALITY IN IVF & HOW SELECTION OF THE IDEAL PROTOCOL FOR OVARIAN STIMULATION INFLUENCES  EGG/EMBRYO QUALITY AND  OUTCOME.

Geoffrey Sher MD

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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Herewith are  online links to 2  E-books 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

I invite you to visit my very recently launched “Podcast”,  “HAVE A BABY” on RUMBLE;   https://rumble.com/c/c-3304480

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\