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.
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.
- 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 PCOS 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)
OHSS is a significant concern for women with PCOS undergoing fertility treatments, especially where gonadotropins are administered for ovarian stimulation.
- 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.
Signs and Symptoms 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.
- 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 through “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) treatment.
- 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 and 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.
Are you ready to take the next step in your fertility journey and overcome the challenges of PCOS? Contact Sher Fertility Solutions today for expert guidance, personalized treatment, and a path toward improved egg quality and successful IVF. Your dream of motherhood is within reach – let us help you make it a reality. Book a consultation with us to fight against PCOS and start your fertility journey.