Which fertility treatment carries the highest risk of ovarian hyperstimulation syndrome (OHSS)?

• A. Clomiphene citrate used alone
• B. Gonadotropin stimulation, especially with IVF protocols
• C. Metformin therapy for PCOS without gonadotropins
• D. Natural cycle with timed intercourse

Answer: (B)

High stimulation of the ovaries with gonadotropins carries the greatest risk of ovarian hyperstimulation syndrome. When medications like FSH (and sometimes LH) are used to induce the development of many follicles, the ovaries swell and produce high levels of estradiol. In IVF, an hCG trigger is often given to induce ovulation, and the combination of multiple growing follicles and this trigger can lead to increased vascular permeability driven by VEGF, causing fluid shifts into third spaces (ascites, pleural effusions) and other symptoms of OHSS. The risk rises with more and larger follicles, and is especially higher in PCOS patients who are prone to an excessive ovarian response.

Clomiphene citrate used alone typically induces ovulation without markedly overstimulating the ovaries, so OHSS risk is low. Metformin given for PCOS without adding gonadotropins doesn’t cause OHSS. A natural cycle with timed intercourse involves no pharmacologic ovarian stimulation, so OHSS risk is essentially absent. Thus, the option involving gonadotropin stimulation, particularly in IVF protocols, best explains the highest OHSS risk.