Preventing Ovarian Hyperstimulation With Metformin

Peter Kovacs, MD, PhD


February 29, 2012

Metformin Reduces Risk of Ovarian Hyperstimulation Syndrome in Patients With Polycystic Ovary Syndrome During Gonadotropin-Stimulated In Vitro Fertilization Cycles: A Randomized, Controlled Trial

Palomba S, Falbo A, Carrillo L, et al
Fertil Steril. 2011;96:1384-1390


Controlled ovarian hyperstimulation (COH) is an important phase of in vitro fertilization (IVF) treatment. This step should generate an adequate number of follicles and provide the lab with sufficient eggs for fertilization. Numerous stimulation protocols and various types of gonadotropins can be used for stimulation. The treatment plan is typically individualized on the basis of age, ovarian function markers, morphology of the ovaries, weight, and previous response to treatment. In general, the simultaneous growth of 8-12 follicles is sufficient. Recruiting fewer follicles could negatively affect the outcome, whereas recruiting more follicles puts the patient at risk for ovarian hyperstimulation syndrome (OHSS).

OHSS is characterized by excessive response to the selected medication regimen. The ovaries are significantly enlarged and the number of follicles and eggs collected is high. The hyperstimulated ovaries leak fluid into the abdominal cavity and a significant shift of fluid into the extravascular space can occur. This can lead to significant abdominal distention, pain, hemoconcentration, electrolyte imbalance, reduced urine output, and respiratory difficulty. In severe cases, the syndrome can be associated with life-threatening complications.[1]

Women with polycystic ovary syndrome (PCOS) are at a higher risk for OHSS; therefore, any intervention that reduces this risk should be investigated and used if proven effective. This randomized trial evaluated the potential benefit of metformin for OHSS prevention in women with PCOS.

Study Summary

The study included 120 infertile women with PCOS and a history of OHSS or cycles cancelled as a result of OHSS. The women were randomly assigned to receive 3 doses of either 500-mg metformin or a similar-looking placebo during COH in a repeat IVF cycle. Baseline characteristics were similar in both groups. All patients used the midluteal long stimulation protocol, but various gonadotropin preparations could be administered for stimulation. The proportion of participants using the different preparations was similar in the 2 groups. Metformin and placebo were started with the injections.

Women in the metformin group used more gonadotropins and had longer stimulation, but a similar number of follicles developed and a similar number of eggs were retrieved in both study groups. Peak estradiol levels were lower in women who took metformin. Fewer cycles had to be cancelled in the metformin group (3/60 vs 11/60; relative risk [RR]: 0.40; 95% confidence interval [CI]: 0.14-0.91).

The risk of developing OHSS was significantly lower with metformin (5/60 vs 18/60; RR: 0.2; 95% CI: 0.05-0.88). Clinical outcomes (implantation rate, pregnancy rate, live birth rate) were comparable.


OHSS complicates a small percentage of IVF treatments. The incidence, however, is increasing in lean, young women with polycystic ovaries or with PCOS. No treatment exists for OHSS; once it develops, the symptoms can be managed and, ultimately, OHSS resolves on its own. OHSS develops only in cycles in which human chorionic gonadotropin (hCG) is used to trigger ovulation. Early OHSS develops in response to the hCG injection, whereas the latter form develops as a result of endogenous hCG production.

Because no treatment can be offered for OHSS, trying to prevent it is essential. The first step is to identify patients at risk and select a proper stimulation protocol for them. Gonadotropin-releasing hormone (GnRH) antagonist-based protocols appear to be associated with lower risk, as well as the use of GnRH agonist instead of hCG to trigger final oocyte maturation. A lower gonadotropin dose with careful monitoring and further dose reduction, if needed, is also important. Once follicles reach a 14-15-mm size, luteinizing hormone or low-dose hCG can be used to support their growth, whereas the smaller follicles will undergo atresia at the same time. Cycle cancellation and elective embryo cryopreservation are other measures that can be offered. Withholding gonadotropins also is effective when the response is excessive. Dopamine agonists appear to be associated with a reduced risk for OHSS, and albumin infusion at the time of retrieval has been shown to have beneficial effects as well.[2]

Women with PCOS commonly have elevated insulin levels. Insulin promotes theca cell androgen synthesis and androgens increase the granulosa cell follicle-stimulating hormone receptor expression and sensitivity. Therefore, women with higher androgen levels often respond explosively to gonadotropins. Metformin is associated with lower insulin levels and improved polycystic ovarian morphology. By lowering the insulin level, the intraovarian androgen levels should be reduced and a more predictable response with a lower risk for OHSS could be expected. This hypothesis was confirmed by this trial.

The management of women with PCOS during COH is an exceptionally challenging task. All measures that could lower risk should be applied, and on the basis of available information, metformin is one of these tools. If not required for other reasons, women with PCOS who are at high risk for OHSS should be counseled about this drug's beneficial role.



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