Treating Infertility in Polycystic Ovary Syndrome

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Treating Infertility in Polycystic Ovary SyndromePeter Kovacs, MD, PhD

Authors and Disclosures

Author(s)

Peter Kovacs, MD, PhD

Medical Director, Kaali Institute IVF Center, Budapest, Hungary

Disclosure: Peter Kovacs, MD, PhD, has disclosed no relevantfinancial relationships.

Posted: 08/09/2011

Use of Metformin Before and During Assisted Reproductive Technology in Non-Obese Young Infertile Women With Polycystic Ovary Syndrome: A

Prospective, Randomized, Double-Blind, Multi-Centre Study

Kjtrd SB, Carlsen SM, Rasmussen PE, et al

Hum Reprod.2011;26:2045-2053

Study Background

Polycystic ovary syndrome (PCOS) affects 5%-10% of reproductive-age women, making it the most common

endocrine abnormality in this population. PCOS is characterized by chronic anovulation, hyperandrogenism,

and polycystic ovaries.[1] Currently, the most widely accepted theory for the pathomechanism of PCOS is insulin

resistance. Insulin resistance appears to be organ specific. Although the liver and muscles display insulin

resistance and are responsible for hyperinsulinism, other organs (eg, the ovaries) maintain their sensitivity and

respond to excess insulin. As a result, androgen production is augmented in the ovaries and this, in turn,

arrests follicle growth. Approximately half of all women with PCOS are obese, and obesity worsens insulin

resistance.

Women with PCOS often present with infertility resulting from anovulation. Several interventions can improve

ovulation and pregnancy rates in affected women. Insulin-sensitizing medications have been studied for this

purpose and have been shown to improve ovulation and pregnancy rates but not live birth rates.[2,3] This

randomized trial assessed the effect of metformin on in vitro fertilization (IVF) outcomes in women with PCOS.

Study Summary

Women were identified on the basis of the Rotterdam criteria.[1] All study participants had a body mass index

below 28 kg/m2. All patients were given metformin (2000 mg/day) or placebo for at least 12 weeks prior to the

start of IVF. The primary outcome of interest was clinical pregnancy rate. The planned study size was not

achieved (150 women were randomly assigned instead of the planned 300) because of problems related to

recruitment.


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Prior to the start of IVF treatment, 23 patients conceived (15 in the metformin group and 8 in the placebo

group). A significant weight loss was observed in the metformin group compared with the placebo group. With

respect to spontaneous and IVF-related pregnancies, significantly more clinical pregnancies occurred in the

metformin group (50% vs 33.3%). IVF laboratory outcomes were similar in the 2 groups. When the outcomes of

the IVF cycles were analyzed separately, the clinical pregnancy and live birth rates were similar in the 2 study

arms. Significantly more adverse events were reported with metformin therapy. On the basis of intention-to-treat analysis (spontaneous and IVF-related pregnancies combined), this study found a benefit with metformin

therapy.

Viewpoint

Infertile women with PCOS need to undergo a thorough infertility work-up to look for causes of infertility other

than anovulation. If the only cause is anovulation, several treatment options are available. Diet, exercise,

lifestyle changes, and weight loss must be the first line of therapy, especially in obese woman. Clomiphene

citrate is the recommended ovulation-inducing agent for obese women when the desired weight loss has been

achieved and for lean women with PCOS.[2] This agent will lead to ovulation in up to 80% of cases. Women who

are resistant to increased doses of clomiphene citrate can choose from several additional options, beginning

with insulin-sensitizing agents (mainly metformin), gonadotropins, or surgery. For women who fail clomiphenein combination with metformin, gonadotropin stimulation is the typical next step. If this cannot be carried out

safely (without the risk for multiple gestation or ovarian hyperstimulation syndrome), IVF may be offered.[2]In

combination with clomiphene, metformin was shown to improve ovulation and pregnancy rates but not live birth

rates.[3]

In this study, the recommendation to more than half of the patients, if they failed clomiphene citrate, was to

proceed to IVF, rather than to other stimulation methods, despite any additional indication for IVF. Therefore, it

is not surprising that significantly more women in the metformin group achieved a pregnancy before they

actually started IVF. The selection methods for IVF treatment used by these investigators could bias the

results, especially if the pregnancies achieved prior to IVF are accounted for during the analysis, because

some of these patients probably did not need IVF. When the IVF population is analyzed separately, the benefit

of metformin is no longer apparent.

Fasting insulin and glucose levels were measured but not reported. It would have been interesting to see

whether these values differed in women who showed a benefit with metformin compared with those who did

not. This finding could help the selection of women with PCOS for insulin-sensitizing therapy.

Metformin and other insulin-sensitizing agents play an important role in the care of women with PCOS. Women

who have glucose intolerance, are obese, and fail to respond to clomiphene alone could benefit from these

agents. In addition, lower rates of ovarian hyperstimulation syndrome have been reported with metformin use

during IVF. However, it is unclear whether women with PCOS who don't have these indications, but who need

IVF or intracytoplasmic sperm injection, should be placed on metformin, and this study does not lend support to

this practice.


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Use of metformin before and during assisted reproductivetechnology in non-obese young infertile women with polycystic

ovary syndrome: a prospective, randomized, double-blind, multi-centre study.

Hum Reprod. 2011; 26(8):2045-53 (ISSN: 1460-2350)

Kjtrd SB; Carlsen SM; Rasmussen PE; Holst-Larsen T; Mellembakken J; Thurin-Kjellberg A;

Haapaniemikouru K; Morin-Papunen L; Humaidan P; Sunde A; von Dring V

Department of Gynaecology and Obstetrics, Fertility Clinic, Trondheim University Hospital, 7030 Trondheim,

Norway. [email protected]

BACKGROUND: To study the effect of metformin before and during assisted reproductive technology (ART) on

the clinical pregnancy rate (CPR) in non-obese women with polycystic ovary syndrome (PCOS).

METHODS: A multi-centre, prospective, randomized, double-blind study was conducted in eight IVF clinics in

four Nordic countries. We enrolled 150 PCOS women with a body mass index

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Treating Infertility in Polycystic Ovary Syndrome