Ovarian Stimulation Protocols in Assisted Reproductive Technologies
Summary
Controlled ovarian stimulation lies at the heart of assisted reproductive technologies, aiming to recruit multiple follicles to increase oocyte yield and enhance the chances of successful fertilisation and pregnancy. Protocols typically employ gonadotropins to mimic or augment endogenous follicle-stimulating hormone activity, combined with modulators of the hypothalamic–pituitary–ovarian axis such as gonadotropin-releasing hormone (GnRH) agonists or antagonists. Variations in protocol design—ranging from high-dose gonadotropin regimens to minimal stimulation approaches—seek to balance efficacy, safety and cost-effectiveness. Add-on agents such as aromatase inhibitors and selective oestrogen modulators have been incorporated to reduce oestrogen excess, improve follicular synchronisation and potentially lower gonadotropin requirements. Patient stratification by ovarian reserve markers, including anti-Müllerian hormone levels and antral follicle count, guides the selection of tailored stimulation strategies for poor, normal and high responders. Recent efforts have focused on optimising protocols for advanced maternal age, diminished ovarian reserve and suboptimal responders, while minimising risks such as ovarian hyperstimulation syndrome. The evolution of stimulation regimens reflects a drive towards individualised treatment, cost containment and improved cumulative live birth rates over successive cycles.
Research from Nature Portfolio
Recent comparative analyses in women over 35 have evaluated a clomiphene citrate and gonadotropin cotreatment protocol against a gonadotropin-releasing hormone agonist long protocol. Propensity-matched data demonstrate equivalent cumulative live birth rates between the two approaches over a 24-month follow-up. Although the cotreatment arm exhibited a slightly higher cancellation rate and longer time to live birth, it achieved a substantial reduction in average cost per live birth without compromising embryo quality or delivery outcomes. These findings support the cotreatment protocol as a cost-effective alternative for older women undergoing in vitro fertilisation.
Ovarian Stimulation Protocols in Assisted Reproductive Technologies publication trend
The graph below shows the total number of articles in ovarian stimulation protocols in assisted reproductive technologies across all publications each year (not limited to Nature Index journals).
Technical terms
Controlled Ovarian Stimulation (COS): Administration of exogenous gonadotropins to recruit multiple ovarian follicles.
GnRH Agonist Protocol: Use of a gonadotropin-releasing hormone analogue to downregulate pituitary gonadotropin release before stimulation.
GnRH Antagonist Protocol: Immediate blockade of GnRH receptors to prevent premature luteinising hormone surge during stimulation.
Aromatase Inhibitors: Agents that reduce oestrogen synthesis, used to modulate hormonal feedback and lower gonadotropin requirements.
Antral Follicle Count (AFC): Ultrasonographic assessment of small follicles as a marker of ovarian reserve.
Anti-Müllerian Hormone (AMH): Glycoprotein secreted by small follicles, used to predict ovarian response.
Cumulative Live Birth Rate (CLBR): Probability of live birth over one or more stimulated treatment cycles.
References
- The cumulative live birth rate and cost-effectiveness of the clomiphene and gonadotropin cotreatment protocol versus the mid-luteal GnRH agonist protocol in women over 35 years old. Scientific Reports (2024).
- Impact of 2.5 mg versus 5 mg letrozole co-treatment in an antagonist protocol for IVF: a retrospective study. Frontiers in Endocrinology (2023).
- Value of estrogen pretreatment in patients with diminished ovarian reserve and elevated FSH on a line antagonist regimen: a retrospective controlled study. Journal of Ovarian Research (2024).
- Corifolitropin-Alfa plus Five Days Letrozole Versus Daily Recombinant-FSH in Expected Normo-Responder Patients: A Retrospective Comparative Study. Diagnostics (2023).
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