Department of Obstetrics & Gynaecology, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, People's Republic of China
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Abstract |
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Key words: clomiphene-resistant/metformin/polycystic ovaries
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Introduction |
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Weight loss in obese women with PCOS leads to a reduction of hyperinsulinaemia (Kiddy et al.1992). Insulin-sensitizing agents have been tried in the management of PCOS patients. Metformin is used extensively in the management of type II diabetes and can reduce peripheral insulin concentrations whilst improving glucose tolerance and metabolism. A number of studies (Table I
) have shown significant improvements in insulin sensitivity and hyperinsulinaemia in obese PCOS women after metformin administration. These improvements were associated with a reduction in serum androgen concentrations and an increase in SHBG concentrations. However, recent studies have failed to show any benefit in terms of insulin concentrations or hormonal and metabolic profiles (Acbay and Gundogdu, 1996; Ehrmann et al.1997
).
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The aims of this prospective, randomized, double blind, placebo-controlled study were to (i) determine the ovulation rate and (ii) examine the changes in hormonal and metabolic profiles, in women with CC-resistant PCO after taking metformin for 3 months. The hypothesis was that women with CC-resistant PCO would experience a significant increase in the ovulation rate after taking metformin for 3 months.
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Materials and methods |
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Baseline screening tests were performed on the second day of a spontaneous period or progestogen-induced withdrawal bleeding. Transvaginal scanning was performed using a 5 MHz vaginal probe (Aloka, Model SSD-620, Aloka Co. Ltd., Tokyo, Japan) to measure the length, height and width of each ovary in the sagittal and coronal planes. The ovarian volume was obtained using a formula for the volume of an ellipsoid (/6xlengthxheightxwidth) and the volume of both ovaries gave the total ovarian volume. Blood was then taken for: (i) hormonal profile-serum FSH, LH, testosterone, androstenedione, dehydroepiandrosterone-sulphate (DHEAS), SHBG, fasting insulin and fasting leptin; and (ii) metabolic profile-fasting glucose and 2 hour glucose after 75 g oral glucose load, fasting cholesterol, triglycerides (TG), high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol.
Assignment
Women were randomized according to a computer-generated randomization list in sealed envelopes to receive either placebo or metformin (Lipha Santè, Lyon, France) 500 mg three times a day for 3 months. Blood was taken weekly for serum progesterone and ovulation was considered to be present if serum progesterone concentrations were >16 nmol/l. Body weight, menstrual pattern and side-effects such as nausea, vomiting and diarrhoea were recorded at each monthly out-patient visit. Pregnancy tests were carried out in those having ovulatory responses. Once the patient was found to be pregnant, the drug was discontinued and pelvic ultrasound was arranged to confirm an intrauterine pregnancy.
The above hormonal and metabolic tests were repeated in women who were not pregnant after three months of therapy (placebo and metformin). CC (Clomid, Merrell, Staines, Middlesex, UK) 100 mg for 5 days was then started in only those women who had no evidence of ovulation after three months of therapy. Ovulation was determined again by measuring serum progesterone concentrations. If there was still no ovulation after CC treatment for one cycle, the woman was advised to have gonadotrophin treatment.
Concentrations of glucose and lipids were measured in the hospital laboratory. Hormonal parameters were determined in duplicate on a single batch of frozen (20°C) stored samples. Serum FSH, LH and progesterone concentrations were determined by immunoassay using direct chemiluminometric technology (Chiron Diagnostics Corporation, East Walpole, MA, USA). Serum testosterone, androstenedione, DHEAS, SHBG and insulin were measured by radioimmunoassay (Diagnostic Products Corporation, Los Angeles, CA, USA) as was serum leptin (Linco Research, St Louis, MO, USA).
Masking
Both the women and the doctor were blinded to the content of tablets, which had identical appearance and were packaged by the hospital pharmacist. The codes for the drugs were unblinded only after the completion of the study and statistical analysis.
Statistical analysis
It has been demonstrated that 31 of the 35 women (89%) treated with metformin ovulated spontaneously or in response to CC, compared with 3 of the 26 women (12%) treated with placebo (Nestler et al.1998). Assuming similar ovulatory responses in women with CC-resistant PCO, the sample size required would be 8 in each group to give a test of significance of 0.05 and a power of 0.8 (Sigmastat, Jandel Scientific, San Rafael, CA, USA). Ten women were recruited in each group. The outcome measures were ovulation rate, as well as hormonal and metabolic profiles. Ovulation rates were calculated as [(luteal weeks/observation weeks)x100]. The maximum ovulation rate possible was 50% in a woman with regular menstrual pattern having a cycle of two follicular and two luteal weeks. Continuous variables were not normally distributed and are given as median (range), unless indicated. Statistical comparison was carried out on an intention to treat basis by MannWhitney U-test,
2-test and Wilcoxon ranked sum test, as appropriate. P value (two-tailed) of < 0.05 was taken as significant.
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Results |
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Analysis
Both groups were comparable with respect to age of women, duration of infertility, proportion of primary/secondary infertility, total ovarian volume, baseline body mass index (BMI), baseline hormonal and metabolic profiles (Table II and Table III
). Seven women (70.0%) in the placebo group had evidence of ovulation during the study period: three with placebo only and another four with placebo and CC. Four women (40.0%) in the metformin group had evidence of ovulation: three with metformin only and another one with metformin and CC. The median ovulation rate in the placebo group was 0% (050.0%) after placebo only and 6.9% (050.0%) after placebo and CC whereas the corresponding rates in the metformin group were 0% (022.2%) and 0% (022.2%) respectively. No significant differences were found in the number of women having evidence of ovulation and the ovulation rates between two groups after placebo/metformin alone and with CC.
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Discussion |
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In a randomized placebo-controlled study, Vandermolen et al. (2001) first reported significant improvements in ovulation and pregnancy rates from CC treatment after taking metformin in women with CC-resistant PCO. The women that enrolled in the study were anovulatory in response to a 5 day course of CC, 150 mg daily and were given increasing doses of CC from 50 to 150 mg daily if they were still anovulatory after taking metformin. In the metformin and placebo groups, nine of 12 women (75%) and four of 15 women (27%) ovulated and six of 11 women (55%) and 1 of 14 women (7%) conceived respectively (Vandermolen et al., 2001).
In contrast, here we report no improvement in the number of women having evidence of ovulation and in the ovulation rate in women with CC-resistant PCO after metformin alone or with CC, when compared to the placebo. Women in the metformin group showed a significant decrease in BMI, serum testosterone concentration and fasting leptin concentration after 3 months, whereas those in the placebo group experienced a significant increase in serum testosterone concentration. Our results implied that metformin may not be useful for ovulation induction in all women with CC-resistant PCO, although it has been successfully used as the first-line therapy to induce ovulation in PCOS patients (Nestler et al.1998; Moghetti et al.2000
).
In this study, only 100 mg of CC was tried because previous reports have demonstrated that patients failing to respond to this dose do not ovulate when given higher doses (Polson et al.1979). It remains uncertain whether ovulation rate in the metformin group would have increased if the dose of CC was given in a step-up fashion as was used in the study by Vandermolen et al. mentioned above (Vandermolen et al., 2001
). The discrepancy of our finding from other studies may be also due to recruitment of women with CC-resistant PCO, diagnosis of PCO by ultrasound criteria only and inclusion of non-obese women in this study. Non-responders to CC may represent a more resistant form of PCO (Mitwally et al.1999
). Non-responders are more likely to be obese (Lobo et al.1982
) and have greater ovarian volumes and greater numbers of small follicles on ultrasound examination (Fiçicioglu et al.1996
) than responders. Concentrations of serum LH or androgens have not differed consistently between responders and non-responders (Polson et al.1979
; Lobo et al.1982
; Fiçicioglu et al.1996
).
There is substantial heterogeneity of symptoms and signs among women with PCOS and different criteria have been used to confirm the diagnosis. Ultrasound assessment of ovarian morphology is considered to be essential and has become the gold standard for defining PCO (Adams et al.1985; Homburg, 1996
; Balen, 1999
). Characteristic ovarian morphology is not required in the American definition, which states that PCOS is the association of hyperandrogenism with chronic anovulation in women without specific underlying diseases of the adrenal or pituitary glands (Dunaif, 1997
). Hyperandrogenism, characterized clinically by hirsutism or biochemically by elevated serum concentrations of androgens, was included as one of selection criteria in many studies on the use of metformin in PCOS (Table I
).
Metformin treatment seemed to have no effect on ovarian function in women with normal testosterone concentrations whereas patients with elevated pretreatment testosterone concentrations showed the most marked increase in ovulation rate (Pirwany et al.1999). Serum androgen concentrations may be normal in 3050% of women with oligomenorrhea with PCO (Robinson et al.1992
). The majority of our patients did not have clinical or laboratory features of hyperandrogenism. This may also explain the absence of ovarian response to metformin in this study. Similar to other studies, serum testosterone concentrations were significantly reduced in the metformin group after 3 months. Significant heterogeneity in the hormonal and metabolic responses after metformin was observed (Table I
). Interestingly, there was a significant increase of serum testosterone in the placebo group but the reason for this change is unknown.
Obese PCOS women with average BMI ranging from 27 to 37 kg/m2 were recruited in many studies (Table I). The median BMI in this study was only 24 kg/m2, ranging from 17.9 to 34.2 kg/m2. The ability of metformin to alter insulin sensitivity seems to depend on the body weight and it has been reported (Kahn et al.1993
) that substantial reductions in BMI were required to improve insulin sensitivity in individuals whose BMI exceeded 30 kg/m2. Although improvement in insulin sensitivity was also observed in lean women with PCOS after metformin (Nestler and Jakubowicz, 1997
), it remains uncertain whether ovulation rate can be improved in these women also. The significant reduction of fasting leptin concentration in the metformin group may be the result of the decrease in BMI. There was no change in the lipid profile after 3 months of metformin and a longer duration up to 6 months may increase HDL (Moghetti et al.2000
). This has significant implications in the long-term management of patients with PCOS as they are more prone to hypertension and diabetes mellitus (Dahlgren et al.1992
; Mather et al.2000
).
Troglitazone, another insulin-sensitizing agent, has been shown to induce ovulation in 15 of 18 (83%) women with CC-resistant PCOS (Mitwally et al.1999). Different insulin-sensitizing agents have different mechanisms of action. The major action of metformin is to reduce gluconeogenesis, resulting in decreased hepatic glucose production whilst troglitazone improves muscle insulin sensitivity and total body insulin action (Dunaif et al.1996
), after amelioration of defects in insulin action and insulin secretion. Because of the risk of hepatic damage due to an idiosyncratic reaction, troglitazone has been withdrawn from the market.
In summary, metformin treatment for 3 months in women with CC-resistant PCO showed no improvement in the ovulation rate despite significant reduction of BMI, serum testosterone and fasting leptin concentrations. Metformin may not be indicated to induce ovulation in women with PCO after they failed to respond to CC. Ovulation induction may be successful in certain subgroups such as obese women or women with hyperandrogenism. Further studies are required to clarify these issues.
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Acknowledgements |
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Notes |
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References |
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Submitted on January 9, 2001; accepted on May 16, 2001.