The need for and scientific management of luteal support in IVF cycles

　　
　　During IVF treatment, surrogate mothers (or mothers-to-be for autologous egg conception) are required to receive intensive luteal support, which is a core component of maintaining early pregnancy. Data show that the miscarriage rate of IVF cycles without luteal support can be as high as 40%-50%, while standardized medication can reduce it to 10%-15%. The following is an in-depth analysis of the indispensability of luteal support from three aspects: physiological mechanism, drug selection and safety.
　　I. Pathologic basis of luteal insufficiency
　　Multiple blows to the corpus luteum by super-ovulation promotion
　　Hormonal disruption of multiple follicular development: Controlled Ovulation Synchronization (COS) induces synchronized growth of 10-20 follicles, resulting in estrogen levels spiking 10-20 times higher than in natural cycles (>5,000 pg/mL). High estrogen inhibits hypothalamic GnRH secretion via negative feedback, which reduces pulsatile pituitary LH secretion and prevents luteal cells from receiving adequate LH support.
　　Residual effects of GnRH agonists/antagonists: it takes 4-6 weeks for pituitary function to recover after the use of down-regulating drugs such as leuprolide, and the luteum is unable to synthesize sufficient progesterone on its own due to insufficient endogenous LH secretion during early pregnancy (4-8 weeks).
　　Mechanical damage during egg retrieval: During follicular aspiration, approximately 30% of the granulosa cells are lost with the follicular fluid, which should have differentiated into luteal cells. Studies have shown that for every 1 mL of follicular fluid lost, luteal phase progesterone production decreases by 15%.
　　Special Needs After Embryo Transfer
　　The artificial cycle protocol in freeze-thawed embryo transfer (FET) cycles is completely dependent on exogenous hormones and lacks the luteal formation that occurs after natural ovulation. Even with natural cycle transfer, endometrial tolerance establishment still requires progesterone concentrations to be maintained at >10 ng/mL.
　　II. Drug selection and mechanism of action of luteal support
　　Progesterone drugs
　　Intramuscular progesterone (oil):
　　Pharmacokinetics: peak blood levels are reached 2 hours after injection, half-life about 16 hours, bioavailability >95%.
　　CLINICAL VALUE: Can stabilize progesterone concentrations in surrogate mothers at 15-40 ng/mL in early pregnancy, reducing the rate of miscarriage to 12%.
　　Limitations: prolonged injections lead to localized sclerosis (60% incidence), seborrhea (5%), and the need for regular replacement of the injection site.
　　Vaginal progesterone preparations:
　　Uterine first-pass effect: after vaginal administration, the local concentration in the endometrium is 10-20 times higher than that of serum, which is more suitable for endometrial tolerance optimization.
　　Dosage form comparison:
　　Micronized progesterone capsules (e.g., Utrogestan): 600-800 mg daily in divided doses to maintain uterine concentrations >20 ng/g;
　　Progesterone sustained-release gel (Crinone 8%): sustained release for 72 hours after a single dose, suitable for those with poor compliance.
　　Oral dextroprogesterone:
　　Molecular advantage: trans progesterone structure avoids cross-talk with glucocorticoid/salocorticoid receptors and is safer.
　　Dosing strategy: 30-40 mg/d orally in divided doses, combined with vaginal dosing reduces breakthrough bleeding (incidence reduced from 25% to 8%).
　　hCG adjuvant regimen
　　Principle of action: hCG binds to LH receptor and directly stimulates progesterone secretion from luteal cells. Indicated for those with mid-luteal phase (day 3 post-transplant) progesterone <10 ng/mL. 　　Risk Management: hCG may induce Ovarian Hyperstimulation Syndrome (OHSS) and is contraindicated in cycles with >15 eggs retrieved.

Individualized design of medication program
　　Natural cycle/microstimulation cycle
　　Progesterone requirement is low, vaginal progesterone (600 mg/d) combined with dextroprogesterone (20 mg/d) is sufficient.
　　Artificial cycle frozen embryo transfer
　　Intensive support required: intramuscular progesterone 50 mg/d + vaginal gel 90 mg/d to maintain progesterone >20 ng/mL.
　　High-risk population
　　History of recurrent miscarriage: add low molecular heparin (e.g., enoxaparin 40 mg/d) to improve endometrial blood flow and improve pregnancy rate by 18%.
　　Low ovarian response: addition of recombinant LH (Luveris 75 IU/d) enhances luteal function and increases live birth rate to 32%.
　　Drug safety and offspring health
　　Risk of teratogenicity excluded
　　Progesterone is an endogenous hormone analog, and no evidence of teratogenicity has been found. Cohort studies of more than 2 million progesterone-exposed pregnancies worldwide showed no difference in the rate of birth defects (2.3%) versus natural pregnancies (2.1%).
　　Neurodevelopmental Effects
　　Seven-year follow-up data showed no statistically significant differences in intelligence quotient (IQ 105±12 vs 103±11) or incidence of behavioral problems (12% vs 14%) in progesterone-exposed offspring.
　　Maternal health management
　　The incidence of systemic side effects (dizziness, somnolence) was <5% for vaginal administration, which was much lower than for intramuscular preparations (35%). Bedtime administration is recommended to minimize discomfort.
　　V. Future technological innovation direction
　　Long-acting sustained-release dosage forms: Microsphere encapsulation technology to maintain effective concentration for 7 days in a single injection (e.g., Prolutex®), which has been approved in the EU.
　　Artificial intelligence monitoring: real-time monitoring of progesterone salivary concentration (correlation with serum concentration r=0.89) through wearable devices, dynamic adjustment of dosage.
　　Gene-guided dosing: CYP2C19 gene polymorphism testing predicts progesterone metabolism rate and guides dose individualization (fast metabolizers need to increase dosage by 30%).
　　Luteal support is the cornerstone of IVF success, and its regimen needs to balance efficacy and safety. Through accurate etiological analysis, drug optimization and full monitoring, 95% of surrogate mothers can achieve stable control of progesterone levels. Any self-reduced or discontinued medication may lead to a sudden drop in hormone levels, causing irreversible pregnancy loss, so strict adherence to the doctor’s instructions is the core guarantee of a successful pregnancy.