Current Status and Applicable Population Analysis of Mild Stimulation Ovulation Induction Technology in China

I. Mild Stimulation Ovulation Induction Protocol Under Physician Decision-Making Logic

In a reproductive clinic, when a 38-year-old woman with an AMH of 0.9 ng/mL asks, "Can I still use my own eggs for IVF?", the physician usually reviews her previous stimulation records — if a conventional protocol yielded only 3-4 oocytes with poor embryo quality, or if she had been hospitalized for OHSS, then the mild stimulation protocol enters the discussion. This is not a "better" or "worse" choice, but a decision-making path based on ovarian biological characteristics.

1. Core Features of the Mild Stimulation Protocol

Mild stimulation ovulation induction (also known as gentle stimulation, low-dose stimulation) uses lower than conventional doses of gonadotropins (FSH/HMG), with or without oral ovulation induction medications (clomiphene, letrozole), targeting 1-6 follicles. Unlike conventional protocols aiming for 10-15 follicles, mild stimulation focuses more on follicle quality and endometrial synchronicity.

2. Why Choose Mild Stimulation? Clinical Judgment Criteria

Physicians decide to use a mild stimulation protocol based on one or more of the following indicators:

• Diminished Ovarian Reserve (DOR): AMH ≤ 1.2 ng/mL or Antral Follicle Count (AFC) ≤ 6. In this case, the ovary has a limited response to high-dose stimulation, and increasing the dose does not linearly increase oocyte yield but may instead reduce follicle quality.
• Poor Previous Conventional Stimulation Response: A previous cycle using 300 IU FSH yielded only 2-3 oocytes with poor embryo quality (high fragmentation rate, slow development).
• High OHSS Risk Population: Women with Polycystic Ovary Syndrome (PCOS), a history of OHSS, or AMH > 5 ng/mL. Mild stimulation can significantly reduce the incidence of OHSS.
• Advanced Age (≥40 years): Limited follicular pool. Mild stimulation can reduce excessive ovarian consumption and lower the cycle cancellation rate.

II. Specific Process and Timeline for Mild Stimulation Ovulation Induction

1. Standardized Process (Using a Combined Protocol as an Example)

Commonly used mild stimulation protocols in domestic reproductive centers currently include: Clomiphene + Low-dose FSH, Letrozole + Low-dose FSH, and Low-dose FSH alone. The most common clomiphene combination protocol is as follows:

1. Menstrual Cycle Day 2-3: Blood test for sex hormone panel (FSH, LH, E2, P, T, PRL) + transvaginal ultrasound to confirm no cysts and endometrial thickness < 5 mm.
2. Menstrual Cycle Day 3-5: Oral clomiphene 50-100 mg/day for 5 days; simultaneously or starting from day 5, add FSH 75-150 IU/day subcutaneously.
3. Menstrual Cycle Day 8-9: First follicle monitoring (ultrasound + E2, LH). Adjust FSH dose based on follicle size.
4. When the leading follicle diameter reaches 16-18 mm: Discontinue FSH, administer HCG or GnRH-a trigger, and retrieve oocytes 36 hours later.
5. After Oocyte Retrieval: Decide on fresh transfer or freeze-all embryos based on embryo status.

2. Timeline Reference

III. Differences in Mild Stimulation Application Across Age Groups

The efficacy of the mild stimulation protocol varies significantly with age and ovarian reserve status. The clinical characteristics of three typical populations are as follows:

Note: The above data are from published multicenter retrospective studies, and individual variability is significant. For women ≥ 40 years old, the significance of mild stimulation lies in obtaining transferable embryos at a lower cost, rather than pursuing the number of oocytes retrieved. If no transferable embryos are obtained after two consecutive mild stimulation cycles, the physician will recommend discussing the possibility of egg donation or cycle discontinuation.

IV. Most Easily Overlooked Details and Clinical Pitfalls

1. Trigger Timing and Luteal Function

In mild stimulation cycles, clomiphene occupies estrogen receptors, leading to decreased endometrial receptivity. Therefore, luteal phase support after the trigger needs to be stronger — typically using progesterone injection 40-60 mg/day + estrogen patches, rather than oral progesterone alone. Ignoring this detail can shift the implantation window and reduce implantation rates.

2. Prevention of Premature Follicle Emptying

Since the LH surge may occur prematurely in mild stimulation cycles, especially when using clomiphene, about 8-12% of patients experience a premature LH surge. Therefore, monitoring LH from menstrual cycle day 7 is crucial, and adding a GnRH antagonist (e.g., Cetrotide 0.25 mg/day) to suppress LH is necessary if indicated.

3. Embryo Transfer Strategy

Mild stimulation cycles yield fewer oocytes and thus a limited number of embryos. The current mainstream approach is freeze-all embryos + elective transfer, because the endometrium in the fresh cycle is affected by clomiphene, resulting in lower implantation rates compared to frozen-thawed cycles. However, if the patient is > 42 years old and embryo quality is average, some centers may attempt a fresh transfer to avoid freeze-thaw damage.

V. Frequently Asked Questions About the Mild Stimulation Protocol

VI. Management Strategies for Special Situations

1. Extremely Low Ovarian Reserve (AMH < 0.5 ng/mL)

For such patients, even with mild stimulation, the number of oocytes retrieved may be only 1-2. The physician might attempt a dual-start protocol: starting oral letrozole + low-dose FSH from cycle day 2. If follicular development is slow, increase FSH to 150 IU from cycle day 8. If no transferable embryos are obtained after two consecutive cycles, egg donation or adoption should be discussed.

2. Previous Mild Stimulation Failure (No Oocytes Retrieved or Empty Follicles)

If follicles develop during a mild stimulation cycle but empty follicles are found at retrieval, it may be related to trigger timing, drug absorption, or follicle maturation disorders. Management options include: ① Changing the trigger medication (switch from HCG to GnRH-a or dual trigger); ② Adjusting the type of stimulation medication (e.g., changing from FSH to HMG); ③ Increasing the waiting time after trigger (36-40 hours).

3. Polycystic Ovary Syndrome (PCOS) with High OHSS Risk

For PCOS patients, mild stimulation can indeed reduce the risk of OHSS. A common protocol: Letrozole 5 mg/day × 5 days + FSH starting at 75 IU. Add an antagonist when the follicle diameter reaches 14 mm, and trigger with GnRH-a. The incidence of OHSS with this protocol can be controlled below 1%, but the number of oocytes retrieved is typically 4-8.

VII. Practitioner Observation: The Real Application Status of Mild Stimulation in China

As a physician working in a reproductive center for 10 years, I have observed significant regional differences in the use of mild stimulation protocols in China. In top-tier reproductive centers in Beijing, Shanghai, Guangzhou, and Shenzhen, mild stimulation accounts for about 15-25% of cycles, primarily targeting advanced age and DOR populations. In some prefectural and municipal hospitals, due to the older average patient age and limited financial capacity, the proportion of mild stimulation can reach over 40%.

A noteworthy phenomenon is that many patients actively request "mild stimulation because they heard it is less harmful." However, actual evaluation reveals that about 30% of them have completely normal ovarian reserve and are more suitable for conventional stimulation. This indicates that mild stimulation should be based on objective indicators, not subjective preference. Physicians have a responsibility to provide individualized recommendations after thorough communication, rather than simply catering to the patient's desire for a "gentle" protocol.

Furthermore, mild stimulation cycles have higher requirements for embryo culture conditions. Because fewer oocytes are retrieved, each one is precious. The laboratory needs to have mature Intracytoplasmic Sperm Injection (ICSI) and blastocyst culture techniques to maximize the use of limited resources. The lower success rates of mild stimulation in some smaller reproductive centers stem not from the protocol itself, but from insufficient laboratory capabilities.

VIII. Factors Influencing the Cost of Mild Stimulation Protocols

The cost of a mild stimulation cycle varies depending on the medication protocol, number of monitoring visits, and regional differences. The following is a rough estimate (using a public tertiary hospital as an example):

• Medication Costs: 1500-3500 RMB (FSH + oral medications + antagonist)
• Monitoring Costs: 1200-2000 RMB (4-6 ultrasounds + 3-4 blood tests)
• Surgical Costs: 5000-8000 RMB (oocyte retrieval + embryo culture + transfer)
• Total Cost (Single Cycle): Approximately 8000-13500 RMB

Compared to conventional stimulation (approximately 15000-25000 RMB per cycle), mild stimulation saves about 30-50% in costs. However, if multiple cycles are needed to accumulate embryos, the total expenditure may approach or exceed that of a conventional protocol. Patients should confirm the expected cumulative pregnancy rate with their physician before treatment, rather than focusing solely on the cost per cycle.

IX. Precautions and Risk Reminders

Although mild stimulation ovulation induction is relatively gentle, it must still be performed under the guidance of a professional reproductive physician. The following are key reminders:

• Do not purchase or administer medications yourself: The dosage of ovulation induction medications needs to be adjusted daily based on hormone levels and follicular growth dynamics. Self-medication can lead to failed follicular development or ovarian hyperstimulation.
• Monitoring frequency cannot be reduced: In mild stimulation cycles, follicular growth rate may be uneven, and the LH surge may appear prematurely. Reducing monitoring frequency can lead to missed trigger timing.
• Endometrial receptivity needs assessment: Clomiphene can affect endometrial thickness and morphology. Endometrial receptivity assessment (ERA or endometrial morphology examination) should be performed before transfer.
• Applicability of Preimplantation Genetic Testing (PGT): Mild stimulation yields fewer oocytes. If PGT is performed simultaneously, there may be insufficient embryos to complete the testing. Discuss the necessity and feasibility of PGT with a genetic counselor before treatment.
• Psychological expectation management: The cycle cancellation rate for mild stimulation (due to poor follicular development or premature ovulation) is about 10-20%, higher than for conventional protocols. Patients need to be mentally prepared and develop a Plan B with their physician (e.g., consecutive cycle protocol).