Introduction
Infertility remains one of the most challenging medical and social issues of modern times. Assisted reproductive technologies (ART), particularly in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), have transformed the landscape of reproductive medicine. At the heart of these interventions lies ovarian stimulation, a carefully orchestrated pharmacological process designed to produce multiple mature oocytes in a single cycle. The European Society of Human Reproduction and Embryology (ESHRE) has provided comprehensive guidelines that synthesize available evidence and expert consensus, creating a framework for clinicians to optimize outcomes while minimizing risks.
The aim of ovarian stimulation is deceptively simple: encourage the ovaries to produce more eggs than a natural menstrual cycle would allow. In practice, however, the process is nuanced, requiring precise balancing of efficacy, safety, patient-specific variables, and the evolving body of evidence. The 2020 ESHRE guideline offers 84 recommendations across all stages of stimulation — from pre-treatment considerations to triggering ovulation, luteal support, and the prevention of ovarian hyperstimulation syndrome (OHSS). This article unpacks those recommendations, contextualizes them in clinical practice, and explores the implications for patients and healthcare providers alike.
Understanding Ovarian Stimulation
Ovarian stimulation (OS) refers to the use of pharmacological agents to induce the growth of multiple ovarian follicles. Unlike the natural cycle, which culminates in the release of a single dominant oocyte, OS seeks to maximize the cohort of eggs retrieved during follicular aspiration. This multiplicity enhances the chances of successful fertilization, viable embryo development, and ultimately, live birth.
The process relies primarily on exogenous gonadotrophins, sometimes combined with other agents to suppress premature luteinizing hormone (LH) surges. The goal is not only quantitative — producing many oocytes — but also qualitative, as the competence of retrieved oocytes strongly influences outcomes. Moreover, clinicians must vigilantly avoid complications, chief among them OHSS, a potentially life-threatening iatrogenic condition characterized by excessive ovarian response.
While ovarian stimulation has been practiced for decades, its protocols remain a subject of debate and refinement. No universal regimen fits all women; instead, patient characteristics such as age, ovarian reserve, polycystic ovary syndrome (PCOS), and prior treatment responses guide individualized decision-making. The ESHRE guideline serves to harmonize this complex decision-making with evidence-based recommendations.
Pre-Stimulation Considerations
Before commencing stimulation, assessing a woman’s ovarian reserve is essential to predict her likely response. ESHRE strongly recommends two key biomarkers: antral follicle count (AFC) and anti-Müllerian hormone (AMH). Both have demonstrated superior predictive value over other markers, providing clinicians with reliable insights into whether a patient is likely to be a poor, normal, or high responder.
Interestingly, the guideline discourages reliance on baseline oestradiol or progesterone levels, as their predictive utility is minimal. Similarly, routine pre-treatment with estrogen, progesterone, or combined oral contraceptives offers little benefit in terms of efficacy or safety. The latter, in fact, may reduce stimulation efficiency in antagonist protocols. These findings underscore a recurring theme in the guideline: much of what has historically been considered helpful may in fact be unnecessary, or even counterproductive.
From a clinical perspective, pre-treatment strategies should not be applied reflexively. Their use may remain justified for scheduling convenience, but not as a means to enhance outcomes. This represents a shift away from ritualistic medical practices toward interventions that are demonstrably useful.
Protocol Selection and LH Suppression
At the core of OS lies the choice of stimulation protocol. ESHRE emphasizes the GnRH antagonist protocol as the preferred option in the general IVF/ICSI population. Compared with GnRH agonist regimens, antagonist protocols offer comparable efficacy but superior safety, largely due to a reduced risk of OHSS. For predicted poor responders, both agonist and antagonist regimens are considered equally acceptable, reflecting the lack of evidence favoring one over the other.
Protocol choice is further refined by predicted ovarian response:
- High responders, including women with PCOS, benefit most from antagonist regimens due to reduced OHSS risk. Agonist protocols may still be used but require dose reduction.
- Normal responders should also receive antagonist-based stimulation, again balancing safety with equivalent success rates.
- Poor responders can be managed with either approach, though adjuvant therapies such as clomiphene citrate may play a role. Importantly, increasing gonadotrophin doses above 300 IU is not recommended, as evidence does not support improved outcomes.
In summary, protocol selection is less about tradition and more about tailoring treatment to the individual’s ovarian biology. The antagonist protocol emerges as a versatile and safe default, while exceptions are made only where evidence or patient-specific considerations dictate otherwise.
Stimulation Drugs and Adjuvants
The pharmacological toolkit for OS includes recombinant FSH, highly purified FSH, human menopausal gonadotrophin (hMG), and recombinant LH. ESHRE finds little to distinguish among these options in terms of efficacy, recommending them as largely interchangeable. This pragmatic conclusion allows clinicians to consider availability, cost, and patient preference when selecting agents.
Where the guideline takes a firmer stance is in relation to adjuvants. Despite their popularity, most add-on treatments fail to demonstrate consistent benefit. Metformin, growth hormone, testosterone, dehydroepiandrosterone (DHEA), aspirin, and sildenafil all fall into the “not recommended” category, either due to lack of efficacy or insufficient evidence. This challenges a culture of empirical “add-ons” in reproductive medicine, reminding clinicians that enthusiasm is not a substitute for robust data.
The message is clear: less is more. Rather than layering unproven therapies onto already complex regimens, clinicians are advised to rely on established pharmacological agents that have been validated through rigorous study.
Monitoring During Stimulation
Monitoring OS traditionally involves ultrasound assessment of follicular growth, often combined with hormonal assays. ESHRE’s guideline questions the routine use of the latter. Adding oestradiol, progesterone, or LH measurements to ultrasound does not meaningfully improve safety or efficacy and thus is not recommended as standard practice. Similarly, routine monitoring of endometrial thickness offers little predictive value for outcomes, though a single measurement at trigger may be useful for patient counseling.
The guideline also discourages mid-cycle adjustment of gonadotrophin doses, finding no clear evidence of improved results. Taken together, these recommendations signal a move toward simplification, reducing unnecessary interventions that add cost and burden without demonstrable benefit.
Triggering Ovulation and Luteal Support
Triggering final oocyte maturation is a critical step, ensuring that oocytes are competent for fertilization. ESHRE recommends both recombinant and urinary hCG as equally effective agents for this purpose. However, in women at risk of OHSS, a GnRH agonist trigger is preferred, paired with a freeze-all strategy to eliminate the risk of late-onset complications.
Luteal phase support remains indispensable. Progesterone, in various non-oral formulations, is the mainstay, with dydrogesterone emerging as an alternative. Interestingly, the addition of estradiol or hCG for luteal support is discouraged, again reflecting a commitment to interventions that are evidence-based rather than habitual. In all cases, progesterone support should extend at least until the pregnancy test, a detail that underscores the fine calibration required in ART protocols.
Preventing Ovarian Hyperstimulation Syndrome
OHSS is the most feared complication of OS. Characterized by enlarged ovaries, fluid shifts, and in severe cases, thromboembolism or renal failure, it is a condition to be prevented at all costs. ESHRE’s guideline advocates for several key strategies:
- Preferential use of antagonist protocols in high responders
- GnRH agonist triggers in women at risk
- Adoption of freeze-all approaches to avoid late-onset OHSS
- Avoidance of “coasting” strategies, which are less effective than modern alternatives
Adjunctive measures such as cabergoline or albumin are not recommended when a GnRH agonist trigger is used. The overarching principle is proactive prevention: risk assessment before OS and the use of safer trigger and transfer strategies in vulnerable patients.
Areas of Uncertainty and Research Needs
Perhaps the most sobering conclusion of the guideline is the limited quality of evidence underpinning many recommendations. Of the 61 evidence-based statements, none were supported by high-quality evidence, and more than half relied on very low-quality data. This reveals both the complexity of ART and the urgent need for robust randomized controlled trials.
Particularly lacking are data on interventions for poor responders, a group often subjected to empirical therapies despite weak evidence. Similarly, strategies such as double stimulation cycles remain research-only recommendations, highlighting the gap between clinical innovation and validated practice.
The guideline thus serves not only as a clinical manual but also as a research agenda, identifying areas where definitive studies are urgently required.
Implications for Patients
For patients, the message is both reassuring and empowering. Ovarian stimulation is highly effective, but it is not a one-size-fits-all process. Individualized care, guided by reliable biomarkers and evidence-based strategies, offers the best chance of success with the lowest risk. Equally important, patients should be wary of add-on treatments marketed as miracle enhancers but lacking scientific support. In reproductive medicine, skepticism is not cynicism — it is prudence.
FAQ
1. Why is the GnRH antagonist protocol preferred over the agonist protocol?
Because it offers similar success rates but with a lower risk of ovarian hyperstimulation syndrome, making it safer for most women undergoing IVF/ICSI.
2. Do add-on treatments like growth hormone or DHEA improve success rates?
No. Current evidence does not support routine use of these adjuvants. The guideline specifically advises against them due to lack of efficacy and safety data.
3. How can the risk of OHSS be reduced?
Risk is minimized through careful patient assessment, use of antagonist protocols in high responders, GnRH agonist triggers, and freeze-all strategies when necessary. These measures effectively prevent severe OHSS in most patients.
