Medical journal vol.2 no.

A N T I B A C T E R I A L U S E B Y R U R A L A M I S H C H I L D R E
Authors:
Pregnancy and Other Clinical Outcomes Using Paul D. Silva, MD†Fertility and Reproductive Endocrinology Center Department of Obstetrics and Induction Agents: Results of a Prospectively Katie M. U. Larson Fertility and Reproductive A prospectively designed case series using metformin in women with Polycystic Ovary Syndrome (PCOS) who had failed standard ovulation induction agents is presented. Metformin, which has been used to treat diabetes mellitus, is thought to improve ovulatory function in PCOS by lowering insulin levels and/or inducing weight loss. Twenty-two clomiphene-resistant, clinically obese women with PCOS were given a 3-month trial ofmetformin to bring about pregnancy. Two normal delivered pregnancies and 2 spontaneous abortions occurred. Fourteen women had baseline elevated total cholesterol (64 percent) while 13 had elevated LDL (59 percent), and 6 had elevated triglycerides (27 percent). These findings, similar to previous studies, indicate a strong correlation between PCOS and elevated lipid levels. With two-thirds of the study population displaying abnormal lipid profiles, it seems that lipid screening is worthwhile in women with PCOS. Supported in part by a grant from Gundersen Lutheran MedicalFoundation metformin is being increasingly used in North ovulatory and anovulatory cycles. The mean number of cycles M American infertility clinics, because of its positive failed was 5.5 (range 3-18). Twenty of the women had failed at
effect on the metabolic changes of polycystic ovary syndrome least 150 mg of clomiphene (91 percent). Nine of the women (PCOS). Metformin alone has been shown to induce ovulation had failed gonadotropin cycles as well (41 percent). Three others in 30 percent of clomiphene-resistant PCOS patients.1 had failed a short midcycle gonadotropin boost with at least one However, a literature review shows few pregnancies, and, cycle of clomiphene citrate (14 percent). One woman had failed therefore, there is insufficient data to counsel PCOS patients as gamete intrafallopian transfer (GIFT), and 1 had failed in vitro to pregnancy prognosis with metformin. Accordingly, we report our results with metformin in PCOS patients. Baseline Tests
MATERIALS AND METHODS
All of the women’s TSH levels were screened to ascertain Patient Characteristics and Inclusion Criteria
that their anovulation might not be related to thyroid disease.
Twenty-two women presented with infertility and a We did not screen for 21-hydroxylase deficiency because this is diagnosis of PCOS. The criteria used to diagnose PCOS were rare in our population. If the patients exhibited glactorrhea, we anovulation with signs of androgen excess or anovulation with tested their prolactin levels to exclude hyperprolactinemia as a polycystic ovarian morphology on ultrasound. The mean age at possible cause for their anovulatory infertility.
the beginning of treatment was 29 years (range 23-35). All of Hysterosalpingograms were done to establish that the women the women were overweight (BMI>25), and a majority of the had open fallopian tubes, if necessary. They are done in our women were obese (BMI> 27) (82 percent). The mean BMI for program if there is a history of pelvic infection or prior to the group was 36 kg/m2 (range, 25-52). Infertility was defined gonadotropin therapy. Semen analyses were performed on the as the inability to conceive without medical intervention for one partners. One of the 22 men had less than 20 million sperm per year. The average length of infertility was 5 years (range, 1-17).
milliliter, 3 had less than 40 percent sperm motility, and one While 12 of the women had been pregnant previously, only 6 man declined a semen analysis. Serum creatinine was evaluated to assure normal renal function; fasting insulin, fasting plasma The subjects had all failed to have a viable pregnancy with at glucose, and fasting lipid profiles were also performed.
least 3 cycles of clomiphene citrate. This included both Gundersen Lutheran Medical Journal • Volume 2, Number 1, March 2003 M E T F O R M I N I N W O M E N W I T H P O LY C Y S T I C O V A R Y S Y N D R O M E
Dosing of Metformin
shortly after clinical pregnancy had been established by The women were started at 500 mg of metformin with sonogram. One pregnancy that terminated with spontaneous breakfast; increasing one tablet every week until they were abortion occurred at 2 months of treatment. The other occurred taking two tablets with breakfast and with supper, giving a at 4 months of treatment. There were 2 normal delivered maximum dose of 2000mg. If side effects occurred, the dose was pregnancies. One conceived at 2 months of treatment. The reduced to the highest level at which it was tolerated. The patients were encouraged to use metformin for 3 months beforechanging therapy, unless they had intolerable side effects. For Side Effects
purposes of the study, the length of metformin therapy was from Ten of the patients reported side effects. The most common the day that the first dose was taken. The patients were was diarrhea, reported by 7 women. Four subjects experienced encouraged to use basal body temperature charting.
diarrhea alone, 2 of whom stopped metformin. These 2 patients Unfortunately, these were not reliably performed; therefore, a had intolerable diarrhea even at the 500mg per day dose. The rate of ovulation and cycle fecundity could not be calculated. A other three experienced diarrhea plus cramps, nausea, or pregnancy test was done as soon as pregnancy was suspected.
dizziness. One woman who experienced dizziness alone at the 1 Metformin was stopped during pregnancy. Clinical pregnancy gram per day dose stopped metformin. Another experienced was defined as an intrauterine gestational sac on sonogram.
clamminess, hot flashes, and faintness, and 1 experiencedvaginal itching and burning. Therefore, a total of 3 subjects stopped metformin due to intolerable side effects. The sideeffects all resolved upon discontinuation of the drug. No medical intervention besides stopping or reducing treatment Fourteen women had an elevated total cholesterol (64 was necessary. The side effects of the patients who continued in percent). Thirteen had elevated LDL (59 percent). Six had the study were ameliorated by dose alteration. elevated triglycerides (27 percent). Six of the women werereferred to Internal Medicine or dietary therapy for DISCUSSION
management. Two were already receiving treatment.
Metformin has been well studied in the management of the Glucose Metabolism
metabolic effects of PCOS except for fertility. Several groups One woman had a fasting glucose level above 115 mg/dl have studied the drug’s effect on insulin levels and glucose (121 mg/dl).2 She was already receiving dietary therapy for her tolerance in women with PCOS, as well as its effect on obesity. There were 4 women whose fasting blood sugar levels androgen levels, ovulatory function, and menstrual regularity.1,3-7 were in the range of 105-115. They were also obese and were all Some of the studies reported favorable effects in every area. The referred to the nutrition department for dietary care. There were investigators who have assessed metformin’s effects on ovulation 7 women with elevated fasting insulin levels above 14 µIU/mL and menstrual regulation have all reported positive results.1,6,7 It (32 percent). The mean values for glucose, insulin and lipids are is interesting that several groups that were studying metformin’s effect on the metabolic or menstrual changes of PCOS, but notits effects on fertility, have reported pregnancies in theirsubjects.3-7 Ehrmann et al3, Diamanti-Kandarakis et al4, andMorin-Paupunen et al6 reported 1 pregnancy in 20 women, 2 pregnancies in 16 and 1 pregnancy in 31, respectively.
Parameter
Mean Value ± S.D. (range)
Normal Values
However, these studies did not list the clinical outcomes for thepregnancies, nor the number of their patients who were attempting pregnancy. In 2 studies by Velazquez et al5,7, more detail is given on pregnancy outcome. The first study had 3 pregnancies in 29 women with 1 spontaneous abortion and 2 ongoing pregnancies. The second study had 4 pregnancies in 21women, which were all carried to term. None of these studies reported whether any of their subjects had other infertility evaluations or treatment, nor how many of the subjects wereactively seeking pregnancy. Because of this lack of information,it is difficult to determine whether metformin may have a Pregnancy
positive effect on fecundity in PCOS women who are actively Four of the women became pregnant on metformin alone.
seeking pregnancy. Our study attempted to address this They had fasting glucose levels of 104, 98, 99, and 91mg/dL.
question in at least 1 subgroup of PCOS women by assessing Their fasting insulin levels were: 7.2, 11.0, 6.8, and 7.9 fecundity in PCOS women on metformin who had failed µIU/mL. These values were within the normal range. Two had clomiphene citrate with or without gonadotropins. spontaneous abortions early in the first trimester of pregnancy Our results seem to indicate that a 3-month trial of metformin results in a low term pregnancy rate in PCOS Gundersen Lutheran Medical Journal • Volume 2, Number 1, March 2003 A N T I B A C T E R I A L U S E B Y R U R A L A M I S H C H I L D R E
women who have failed standard ovulation induction. Our rate REFERENCES
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screening is worthwhile in women with PCOS. 8. Meirow D, Raz I, Yosepowitch O, Brzezinski A, Rosler A, Schenken JG, Berry In conclusion, it seems that a 3-month trial of metformin at EM. Dyslipidemia in polycystic ovarian syndrome: different groups, different 2g/day may offer limited success for women with PCOS who aetologies? Human Reprod 1996;11(9):1848-53.
wish to conceive but have already failed clomiphene citrate.
However, further studies will need to be reported before firm † Address for correspondence:
conclusions may be made. At this point, screening for lipid abnormalities in this subgroup of women with PCOS seems Fertility and Reproductive Endocrinology Center, Department of Obstetrics and Gynecology Gundersen Lutheran ADDENDUM
Since acceptance of this article, a randomized study of clomiphene citrate with metformin versus clomiphene citrate with placebo in clomiphene-resistant women with PCOS has been published (Kocak M et al. Fertil Steril 2002:77:101-6).
This study showed improved ovulatory and total pregnancyrates with the addition of metformin although the ultrasound-confirmed clinical pregnancy rate was not statistically improved(11 percent).
Gundersen Lutheran Medical Journal • Volume 2, Number 1, March 2003

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