Ovarian Stimulation (COS)

What is Controlled Ovarian Stimulation?

Controlled Ovarian Stimulation involves using medications to stimulate the ovaries, encouraging the development of multiple eggs. This process is utilized in timed intercourse, IUI, and IVF to increase the chances of successful conception. By producing more eggs, the likelihood of fertilization and pregnancy is heightened. This method helps control and optimize the timing of fertility treatments.

Role of Ovarian Stimulation in OI-TI and IUI

In timed intercourse or IUI treatment, the objective of ovarian stimulation is to stimulate the ovaries to release one or two mature eggs, maximizing the chances of fertilization. Basiclly, this technique is commonly employed in cases of unexplained infertility, ovulatory disorders, or when the male partner has mild fertility issues.

Role of Ovarian stimulation in IVF

In IVF treatment, the objective of controlled ovarian stimulation is to stimulate the ovaries to produce multiple eggs, increasing the chances of successful fertilization and embryo development. As a result of retrieving more eggs, there are more embryos available for selection and transfer, which improves the likelihood of achieving a successful pregnancy in IVF.

What are IVF stimulation protocols (ovarian stimulation protocols)?

The IVF stimulation protocols involve various approaches to stimulate the ovaries and produce multiple eggs for the procedure. The specific medications are given at different times during the IVF cycle for each protocol. The goal is to maximize the number and quality of eggs retrieved while minimizing the risk of complications.

How does a fertility specialist select the best protocol for me?

The selection of the best IVF stimulation protocol depends on various factors. Above all the fertility specialist would consider the patient’s age, ovarian reserve, previous response to stimulation, reproductive history, medical conditions, cost, religious and ethical concerns, and personalized assessment.

What are the commonly used IVF protocols?

Commonly used IVF protocols are:

• For patients with normal ovarian reserve (normoresponders) and different infertility diagnoses such as tubal factor infertility, male factor infertility, and uterine factor infertility, common IVF stimulation protocols include the Antagonist Protocol, Long GnRH Agonist Protocol, Short GnRH Agonist Protocol (rarely used in modern fertility practice), and Mild Stimulation Protocol.
• For patients with diminished or poor ovarian reserve, the following protocols are used: Agonist/Antagonist Conversion Protocol, Minimal Stimulation Protocol, Natural Cycle IVF, Modified Natural Cycle, Dual Stim Protocol, and Progesterone Primed Ovarian Stimulation.
• For patients at risk of hyper-response, such as those diagnosed with PCOS, the protocols used are the Antagonist Protocol, Minimal Stimulation Protocol, and Progesterone Primed Ovarian Stimulation.

Understanding Ovarian Stimulation Protocols used in IVF

Antagonist Protocol

The Antagonist Protocol is widely used in IVF. Above all, it involves administering GnRH antagonists to control the release of luteinizing hormone and prevent premature ovulation. This protocol is suitable for women with regular menstrual cycles and good ovarian reserve.

Pros of the Antagonist Protocol:

1. Shorter treatment duration: The protocol basically has a shorter treatment duration, making it more convenient for some patients.
2. Reduced risk of OHSS: The risk of ovarian hyperstimulation syndrome (OHSS) is generally lower with this protocol.
3. Lower gonadotropin doses: It often requires lower doses of gonadotropin medications. As a result this translate to a lower costs and fewer side effects.
4. Fewer injections: Patients may require fewer daily injections compared to other IVF protocols.

Cons of the Antagonist Protocol:

1. Lower egg yield: In some cases, it may result in a lower number of eggs retrieved compared to other IVF protocols.
2. Fewer embryos: There may be fewer embryos available for selection and transfer.
3. Higher cancellation rate: If patients experience premature ovulation, it may then lead to cycle cancellation.
4. Increased risk of cycle disruption: Occasionally it may lead to cycle disruptions and the need for alternative protocols in certain cases.

Patients where the Antagonist Protocol is effective:

Patients with regular menstrual cycles and normal ovarian function are suitable candidates for ovarian stimulation. Additionally, younger patients with good ovarian reserve can also benefit from this approach. Moreover, ovarian stimulation is particularly beneficial for patients at risk of OHSS. However, it may also be considered by patients who prefer a shorter treatment duration or fewer injections.

The Minimal Stimulation Protocol

The Minimal Stimulation Protocol, also known as Mini-IVF, involves using lower doses of fertility medications. It is ideal for older women, those with diminished ovarian reserve, or individuals who are more sensitive to fertility drugs.

Pros of the Minimal Stimulation Protocol:

1. Reduced medication dosage: Lower doses of fertility medications result in decreased side effects and lower treatment costs.
2. Lower risk of OHSS: The risk of OHSS is generally lower with fewer medications.
3. Shorter treatment duration: The protocol is typically shorter compared to conventional IVF.
4. Fewer multiple pregnancies: The risk of multiple pregnancies is reduced.

Cons of the Minimal Stimulation Protocol:

1. Lower egg yield: Due to lower medication doses, it may yield fewer eggs, impacting the success rates.
2. Fewer embryos for selection: Fewer eggs retrieved may lead to fewer embryos available for selection and transfer.
3. Reduced success rates: It may not be as effective as standard IVF protocols in achieving pregnancy.

Patients where the Minimal Stimulation Protocol is effective:

Patients with good ovarian reserve and younger age can benefit from ovarian stimulation. Additionally, it is a suitable option for patients who want to avoid high medication doses or seek to reduce treatment costs. Moreover, ovarian stimulation is particularly beneficial for patients at risk of OHSS. However, it may also be considered by patients who prefer a shorter treatment duration or a more conservative approach. Both younger patients and those at risk of OHSS can find ovarian stimulation to be a viable solution. Whether seeking cost-effective treatment or a more conservative approach, ovarian stimulation offers various advantages to patients.

Progesterone-Primed Ovarian Stimulation (PPOS) protocol

The Progesterone-Primed Ovarian Stimulation (PPOS) protocol is a newer approach used in IVF treatments. Instead of using GnRH agonist or antagonist to suppress natural ovulation, a low dose of progesterone is administered during the early follicular phase.

Pros of the Progesterone-Primed Ovarian Stimulation (PPOS) protocol:

1. Improved follicular synchronization: Better synchronization of follicle development leads to a more uniform cohort of mature eggs.
2. Reduced cancelation rates: Lower cycle cancelation rates due to improved patient responsiveness to fertility medications.
3. Lower gonadotropin dosage: This protocol may require lower doses of gonadotropin medications, reducing risks and cost.
4. Enhanced egg quality: Better egg quality potentially results in improved embryo development and pregnancy rates.
5. Potentially reduced risk of OHSS: Using a more natural approach to ovarian stimulation may lower the risk of OHSS.

Cons of the Progesterone-Primed Ovarian Stimulation (PPOS) protocol:

1. Limited clinical data: The PPOS protocol is relatively new, with limited long-term clinical data.
2. Individual variability: Response to the PPOS protocol can vary from patient to patient.
3. Longer treatment duration: It may require a longer treatment duration due to a more gradual stimulation process.
4. Not suitable for all patients: The PPOS protocol may not be appropriate for all patient populations.

Patients for whom the Progesterone-Primed Ovarian Stimulation (PPOS) protocol may be effective:

Poor responders may benefit from PPOS as an alternative approach to conventional protocols. Additionally, PPOS may be suitable for older women with diminished ovarian reserve. Moreover, some patients with PCOS may respond well to the PPOS approach. For patients with previous IVF failures, PPOS offers a viable option to consider. It is worth noting that PPOS may be particularly beneficial for patients with low ovarian reserve. Whether dealing with poor response, diminished ovarian reserve, or previous IVF failures, PPOS presents itself as a viable option for these individuals. Another key point to consider is that PPOS can be a promising choice for patients with specific challenges in conventional protocols.

Natural Cycle IVF protocol

The Natural Cycle IVF protocol uses little to no fertility medications to stimulate the ovaries. It focuses on retrieving one naturally selected egg produced in the natural menstrual cycle.

Pros of the Natural Cycle IVF Protocol:

1. No or minimal medications: Reduced risk of side effects and lower treatment costs.
2. Lower risk of OHSS: Less use of fertility medications lowers the risk of OHSS.
3. Safer for certain patients: Natural cycle IVF may be safer for patients at risk of OHSS or those who may not tolerate medications well.
4. Reduced health risks: Avoids potential long-term health risks associated with high-dose ovarian stimulation.

Cons of the Natural Cycle IVF Protocol:

1. Lower success rates: Success rates are generally lower compared to conventional IVF due to fewer eggs retrieved.
2. Uncertain egg retrieval: The naturally selected egg may not develop adequately, leading to cycle cancelation.
3. Frequent monitoring: Regular monitoring is required to determine the timing of ovulation.
4. Multiple cycles needed: Patients may require multiple cycles to achieve a viable pregnancy.

Patients for whom the Natural Cycle IVF Protocol may be effective:

Natural cycle IVF can be a suitable option for various patient groups. Chiefly, poor responders, who have experienced limited success with conventional IVF, may find benefits in this approach. Additionally, older women with diminished ovarian reserve can explore natural cycle IVF as an alternative. Furthermore, patients at risk of OHSS may consider it as a safer option. Besides, individuals with religious or ethical concerns may prefer this protocol due to its minimalist approach. Another key point to consider is that patients seeking a more natural and less invasive process may find natural cycle IVF appealing. Altogether, natural cycle IVF offers a viable and attractive choice for patients with specific needs and preferences. As I have noted, it can be an advantageous alternative for a range of individuals in the IVF journey.

Modified Natural Cycle IVF protocol

The Modified Natural Cycle IVF protocol involves using minimal medications to support the natural menstrual cycle. Some medications are used to enhance the process and improve success.

Pros of the Modified Natural Cycle IVF:

1. Minimal medications: Lower potential risks and side effects compared to conventional IVF.
2. More natural approach: Offers a more natural approach to fertility treatment.
3. Lower cost: Fewer medications lead to cost savings.
4. Reduced risk of OHSS: Safer alternative for patients at higher risk of OHSS.

Cons of the Modified Natural Cycle IVF:

1. Lower success rates: Generally lower compared to conventional IVF due to only one egg being retrieved.
2. Uncertain egg retrieval: The naturally selected egg may not develop adequately.
3. Frequent monitoring: Regular monitoring is required to determine ovulation timing.
4. Multiple cycles needed: Patients may require multiple cycles to achieve pregnancy.

Patients for whom Modified Natural Cycle IVF may be effective:

Natural cycle IVF is a versatile option, and it can be beneficial for various patient groups. Firstly, it is suitable for patients at risk of OHSS, offering a safer alternative for those prone to developing the syndrome. Additionally, it may be a suitable option for older women with diminished ovarian reserve. Moreover, poor responders, who have not experienced favorable outcomes with conventional IVF, may find natural cycle IVF advantageous. Another key point is that patients seeking a more natural and less invasive approach can find it appealing. Altogether, natural cycle IVF addresses the needs of multiple patient categories, making it a valuable choice in the realm of fertility treatments. As a matter of fact, it offers a wide array of benefits and possibilities for those considering IVF.

Long GnRH Agonist Protocol (Long Protocol)

The Long GnRH Agonist Protocol involves using GnRH agonist medication to suppress the natural menstrual cycle before starting ovarian stimulation to ensure multiple mature eggs are available for retrieval.

Pros of the Long GnRH Agonist Protocol:

1. Improved control and synchronization: Better control and synchronization of the ovarian stimulation process.
2. Reduced risk of premature ovulation: Suppression with GnRH agonist prevents premature ovulation.
3. Suitable for patients with normal ovarian reserve: Commonly used in patients with normal ovarian function.
4. Higher chances of success: More eggs retrieved increase the chances of obtaining good-quality embryos for transfer.
5. Better timing for egg retrieval: Allows for precise timing of egg retrieval for optimal maturity.

Cons of the Long GnRH Agonist Protocol:

1. Longer treatment duration: The protocol typically involves a longer treatment duration.
2. Potential over-suppression: Prolonged use may lead to excessive ovarian suppression and reduced response.
3. Risk of cycle cancellation: Despite suppression, there is still a risk of cycle cancellation.
4. Increased gonadotropin use: May require higher doses of gonadotropin medications.

Patients for whom the Long GnRH Agonist Protocol may be effective:

Long GnRH protocol is effective in patients with normal ovarian reserve. Additionally, it is most commonly used in patients with normal ovarian function.

Moreover, younger women with a higher number of antral follicles may benefit from this protocol. Both regular menstrual cycles and patients with previous IVF failures are suitable candidates for this approach.

Furthermore, the long GnRH protocol may be a viable option for women with a history of good ovarian response to stimulation. Altogether, it provides a promising alternative for patients seeking improved IVF outcomes.

Dual Stim Protocol

The Dual Stim Protocol involves two separate stimulation cycles in one menstrual cycle and is used for women with poor ovarian response, cancer, or a history of IVF failure.

Pros of the Dual Stim Protocol:

1. Increased egg retrieval: Produces two waves of follicular development, leading to more eggs retrieved.
2. Higher number of embryos: More eggs mean an increased chance of obtaining embryos for transfer.
3. Suitable for poor responders: Particularly beneficial for patients with poor response to conventional IVF.
4. Tailored treatment: Allows individualized treatment based on the patient’s response.

Cons of the Dual Stim Protocol:

1. Increased medication use: Requires higher doses of gonadotropins, increasing cost and side effects.
2. Longer treatment duration: Involves two separate stimulation cycles within one menstrual cycle.
3. More frequent monitoring: Requires more frequent visits to the clinic for monitoring.
4. Risk of OHSS: Higher medication doses may increase the risk of OHSS.

Patients for whom the Dual Stim Protocol may be effective:

Dual Stim protocol is effective in poor responders, as it has shown positive outcomes for patients with a history of poor response to conventional IVF.

Additionally, it may be suitable for younger women with good ovarian reserve, catering to their specific needs.

Moreover, patients with previous IVF failures may find this protocol beneficial, offering a potential solution for their past challenges.

Furthermore, women with adequate ovarian response to stimulation are likely to benefit from the Dual Stim approach, providing them with improved chances of success.

Altogether, the Dual Stim protocol allows for an individualized assessment, ensuring customized treatment plans based on each patient’s unique response. This comprehensive approach ensures optimal outcomes for patients seeking fertility treatments.

Agonist/Antagonist Conversion Protocol

The Agonist/Antagonist Conversion Protocol combines elements of both the GnRH agonist and antagonist protocols to optimize ovarian response and improve IVF success rates.

Pros of the Agonist/Antagonist Conversion Protocol:

1. Improved ovarian response: Combining GnRH agonist and antagonist may lead to a more robust response.
2. Precise timing of egg retrieval: Introduction of GnRH antagonist prevents premature ovulation for better timing.
3. Reduced risk of OHSS: GnRH antagonist helps lower the risk of OHSS.
4. Suitable for patients with normal ovarian reserve: Commonly used in patients with normal ovarian function.
5. Individualized treatment: Allows for tailored treatment based on the patient’s response.

Cons of the Agonist/Antagonist Conversion Protocol:

1. Increased medication use: Uses both GnRH agonist and antagonist medications.
2. Longer treatment duration: Involves a longer treatment duration.
3. Risk of cycle cancellation: Despite careful monitoring, cycle cancellation may occur.
4. More frequent monitoring: Requires more frequent visits to the clinic for monitoring.

Patients for whom the Agonist/Antagonist Conversion Protocol may be effective:

The Agonist/Antagonist conversion protocol is effective in patients with normal ovarian reserve, making it a commonly used approach for those with normal ovarian function.

Additionally, younger women with good ovarian reserve may also benefit from this protocol, offering them a potential solution for their fertility needs.

Moreover, patients with previous IVF failures may find this protocol beneficial, providing them with renewed hope for successful outcomes.

Furthermore, women with an adequate ovarian response to stimulation are likely to benefit from the Agonist/Antagonist conversion protocol, as it optimizes their chances of success.

All things considered, this protocol allows for an individualized assessment, enabling customized treatment plans based on each patient’s unique response. This personalized approach ensures the best possible outcomes for patients seeking fertility treatments.

Ovarian Stimulation: Understanding Medications and Risks

Oral Ovulogens:

These tablets stimulate the ovaries during timed intercourse, IUI, or IVF (minimal stimulation protocol). Common types include:

1. Clomiphene Citrate
2. Letrozole (preferred for certain medical conditions or poor responders)
3. Tamoxifen (alternative for hormone-sensitive breast cancer patients seeking fertility preservation).

Adverse effects may include:

• Risk of multiple pregnancies
• Hot flashes
• Mood swings
• Bloating
• Abdominal discomfort

Gonadotropins:

FSH and LH stimulate ovaries to produce multiple follicles. Common types are:

2. Recombinant FSH (Follitropin Alfa, Follitropin Beta)
3. Menotropins (hMG derived from postmenopausal women)
4. Urofollitropin (highly purified FSH).

Adverse effects may include:

• Bloating
• Abdominal discomfort
• Injection site reactions
• OHSS
• Risk of multiple pregnancies

GnRH Agonists:

Buserelin, Leuprolide, Triptorelin act on the pituitary to modulate FSH and LH. They cause a “flare-up” response initially but suppress FSH and LH with prolonged exposure.

Used in Long GnRH Agonist Protocol, GnRH Agonist/Antagonist conversion protocol, and as GnRH Agonist “Trigger” for OHSS risk patients.

Adverse effects may include:

• Hot flashes
• Headache
• Mood swings
• Vaginal dryness
• Injection site reactions

GnRH Antagonists:

Cetrorelix, Ganirelix prevent premature ovulation, allowing optimal trigger shot timing. Used in antagonist, GnRH Agonist/Antagonist Conversion, mild stimulation, and dual stim protocols.

Adverse effects may include:

• Injection site reactions
• Headache
• Nausea
• Transient ovarian cysts
• Fatigue

Human Chorionic Gonadotropin (hCG):

Triggers final egg maturation. Common brands: Ovitrelle, Pregnyl, Lupi-HCG, Zyhcg, Corion, Proficure. Used in most IVF protocols.

Adverse effects may include:

• Injection site reactions
• OHSS
• Early pregnancy-like symptoms
• Mood swings
• Headache

Adjuvants Used in Ovarian Stimulation:

Growth Hormone (GH):

Enhances ovarian response and pregnancy rates in poor responders or those with diminished ovarian reserve.

Adverse events may include:

• Injection site reactions
• Headache
• Nausea
• Fluid retention

Coenzyme Q10 (CoQ10)

Improves ovarian response, egg quality, and mitochondrial function.

Adverse events may include:

• Gastrointestinal upset
• Allergic reaction

Dehydroepiandrosterone (DHEA):

Improves ovarian response and egg quality.

Adverse events may include:

• Acne
• Hair growth
• Mood changes
• Menstrual irregularities

Risks and Complications of Ovarian Stimulation:

• Ovarian Hyperstimulation Syndrome (OHSS): Potentially serious complication with enlarged ovaries and fluid accumulation in the abdomen.
• Multiple Pregnancies: Increased risk of twins or higher-order multiples.
• Ovarian Torsion: Enlarged ovaries increase the risk of ovarian twisting.
• Allergic Reactions: Rare cases of allergic reactions to medications.