Metformin for PCOS symptoms: 5 challenging cases
This inexpensive and versatile drug broadens the choices for treating polycystic ovary syndrome. An expert describes its efficacy for common manifestations of PCOS.
- Metformin’s role in treatment of PCOS varies with the patient’s chief complaint, clinical characteristics, and lifestyle.
- The primary uses of metformin in treating PCOS are to induce ovulation in women resistant to clomiphene alone and to treat oligomenorrhea in women who can’t or won’t use oral contraceptives.
- To be a candidate for metformin treatment, a patient must have a serum creatinine lower than 1.4 mg/dL to avoid the risk of developing lactic acidosis.
Inducing ovulation. Decreasing insulin resistance. Facilitating weight loss. These are a few of the benefits metformin offers women with polycystic ovary syndrome (PCOS). This article’s 5 case histories illustrate a range of major complaints and secondary factors to consider in making prescribing decisions.
The decision to use metformin depends on the patient’s major PCOS-related complaint (TABLE 1), as well as other considerations. In some cases, metformin may not be appropriate at all.
Metformin, which is an oral biguanide unrelated to the sulfonylureas, has the potential to correct:
- Anovulatory infertility. Used alone, metformin induces ovulatory cycles in many cases. In patients with clomiphene-resistance, it can be added to the regimen to enhance ovulation rates.
- Oligomenorrhea. Although oral contraceptives remain the first-line agent, metformin is a second-line agent that restores normal menstruation in about 50% of treated women.
- Obesity. Clinical trials indicate that metformin may add helpful pharmacologic support to a diet and exercise program.
- Gestational diabetes. Early evidence suggests that use of metformin in pregnancy may reduce the incidence of gestational diabetes and spontaneous abortion, although more study is needed.
More study also will be necessary to understand the role of metformin in the treatment of hirsutism.
First- and second-line therapy for the chief complaints of PCOS
Oral contraceptive plus an anti-androgen (eg, spironolactone 100mg)
Metformin plus an anti-androgen
Clomiphene or metformin alone
Clomiphene plus metformin
Lifestyle changes: Increased exercise Decreased calorie intake
Metformin plus lifestyle changes
Characteristics of PCOS
According to a group of experts working with the National Institutes of Health (NIH), polycystic ovary syndrome is the presence of oligomenorrhea or amenorrhea with clinical or laboratory evidence of hyperandrogenism (hirsutism, elevated free testosterone) in the absence of other causes such as a testosterone-producing ovarian tumor or nonclassical adrenal hyperplasia (21-hydroxylase deficiency). Using the NIH definition, a diagnosis of PCOS is not appropriate for women with regular ovulatory menses. Many authorities believe the combination of regular ovulatory menses and hirsutism should be diagnosed as idiopathic hirsutism.
Three key endocrine abnormalities characterize PCOS:
- Elevated luteinizing hormone (LH) secretion—seen in almost all women with PCOS.7-9
- Increased circulating insulin caused by insulin resistance, found in many women with PCOS.10,11
- Elevated ovarian androgen production—present in virtually all women with PCOS. Increased androgen production causes hirsutism and, in some women, acne.
These abnormalities prevent growth of a dominant follicle (FIGURE 1), leading to anovulation and oligomenorrhea.
Combating PCOS-related oligomenorrhea
The primary care doctor of a 25-year-old student has established a PCOS diagnosis based on the patient’s report of 2 menstrual periods per year and an elevated serum free-testosterone measurement. Her body mass index (BMI) is 24.5, and her main problems are hirsutism, oligomenorrhea, and a propensity for gaining weight. She took the birth control pill and believes it was responsible for a 25-lb weight gain. When the patient discontinued the pill, she lost 20 lb, and she is adamantly opposed to taking it again. The patient’s pelvic examination is normal, with no evidence of virilization. She read about metformin on the Internet and asks if you will prescribe it for her oligomenorrhea.
Oral contraceptives remain first-line treatment
Metformin may be effective in some women for the treatment of oligomenorrhea. However, as mentioned earlier, more study is needed into its effects on hirsutism.
Oligomenorrhea. No large-scale clinical trial evaluating the efficacy of metformin for oligomenorrhea in women with PCOS has been reported. However, a number of smallscale clinical trials and case series suggest that metformin restores normal ovulatory menses in some women. For women with PCOS treated with metformin alone, about 25% begin regular menses within 3 months,12,13 and about 50% 14 to 95%15,16 begin regular menses within 6 months. In my practice, about 50% of women begin having regular ovulatory menses after 6 months of treatment.
Patient characteristics that predict successful induction of regular ovulatory menses are not fully delineated. It appears, however, that women with elevated serum testosterone have a greater response to metformin.17
Many months of treatment may be required to reestablish regular menses when metformin is used as a second-line agent in this context. Some women initially may have increased estrogen production (paralleled by an increase in cervical mucus secretion) without ovulation. Treatment with a progestin to prevent endometrial hyperplasia may be necessary during the initial months of therapy.
Hirsutism. In 1 small-scale clinical trial that directly compared the efficacy of oral contraceptives and metformin, 17 women with PCOS were randomized to receive metformin (500 mg twice daily for 3 months, followed by 1,000 mg twice daily for 3 months) or an oral contraceptive (ethinyl estradiol 35 μg and cyproterone acetate 2 mg daily).18 Both regimens produced an approximate 30% decrease in serum testosterone. The OC also decreased the hirsutism score and ovarian volume, as determined by sonography. Metformin did not decrease hirsutism or ovarian volume. Half the women in the metformin group had restoration of menses, and 100% of the women in the OC group had regular withdrawal bleeding.
Clinical courseTrial of metformin, switch to spironolactone, cyclic progestins
Because this patient believes OCs caused her to gain weight, the recommended first-line treatment for oligomenorrhea is not an option. She is started on metformin at a dose of 500 mg 3 times daily. After 4 months of therapy, she still does not have regular ovulatory menstrual cycles, and cyclic progestins are instituted to reduce the risk of endometrial hyperplasia and induce withdrawal bleeding.
After 6 months of treatment, the patient reports little reduction in her hirsutism. She discontinues metformin and starts spironolactone (an anti-androgen), taking 100 mg daily and using a barrier contraceptive to prevent pregnancy. The combination of spironolactone and cyclic progestin withdrawal results in satisfactory symptom control.
When renal insufficiency accompanies oligomenorrhea
A 40-year-old woman with PCOS and eczema presents for treatment of oligomenorrhea. She cannot take OCs because she once experienced deep vein thrombosis while using them. Her eczema is being treated with cyclosporine. Her serum creatinine measurement is high—1.8 mg/dL—and her internist believes the cyclosporine caused this renal dysfunction. She asks if she can take metformin for her oligomenorrhea.
Watch for lactic acidosis risks
A serum creatinine of less than 1.4 mg/dL must be demonstrated in all patients before metformin treatment is initiated. In rare instances, metformin causes lactic acidosis, which is fatal in as many as half of patients who develop it. 19 Because the kidney excretes metformin, patients with renal insufficiency (creatinine higher than 1.4 mg/dL) are at increased risk of metformin-induced lactic acidosis.
Other conditions that contraindicate metformin because of increased risk of lactic acidosis include congestive heart failure, sepsis, concurrent liver disease, and a previous history of lactic acidosis. 20,21 The risk of lactic acidosis with metformin treatment is very low when clinicians follow these prescribing guidelines.22 Unfortunately, physicians often prescribe metformin for patients with contraindications.23
Surgery. Lactic acidosis also poses a threat at the time of surgery. 24 Therefore, metformin therapy should be suspended temporarily for all major surgical procedures where fluid intake is restricted. Metformin can be reinstituted once the patient’s fluid intake and renal function are normal.
Clinical courseCylcosporine reduced, cyclic progestins offered
This patient’s elevated creatinine level puts her at increased risk of metformin-induced lactic acidosis. For this reason, metformin is not prescribed at the time of the evaluation, and the cyclosporine dose is reduced in an effort to reduce her creatinine level. She is offered treatment with cyclic progestins for her oligomenorrhea.
A tool for ovulation induction
A 30-year-old woman with PCOS and primary infertility requests a consultation after failing to ovulate with clomiphene. She has a long history of oligomenorrhea, hirsutism, elevated serum free testosterone, and a serum dehydroepiandrosterone (DHEAS) of 2.3 μg/mL (normal range: 0.7 to 3.4 μg/mL). Her BMI is 27.8. The patient’s hysterosalpingogram is normal, as is her partner’s semen analysis. Her physician prescribed clomiphene 50 mg daily for cycle days 5 to 9, but the patient did not ovulate. She then was given clomiphene 100 mg daily for cycle days 5 to 9, but still did not ovulate. She asks if the next step should be in vitro fertilization (IVF).
Low-cost, low-risk options include metformin
The initial treatment of ovulatory infertility caused by PCOS should focus on interventions that are inexpensive and associated with a low risk of multiple gestation. These include weight loss, clomiphene or metformin monotherapy, and combination treatment such as clomiphene plus metformin or clomiphene plus a glucocorticoid. If these interventions are ineffective, then treatments such as follicle-stimulating hormone (FSH) injections, ovarian surgery, or IVF may be warranted (TABLE 2).25
The combination of clomiphene and metformin was superior to clomiphene alone in inducing ovulation in women with PCOS, in 3 randomized clinical trials.26-28 In 1 trial, 56 infertile women with PCOS, oligoovulation, and resistance to clomiphene monotherapy received either metformin 850 mg twice daily or placebo for 1 month.28 The average BMI of the subjects was about 31. Metformin treatment was associated with a significant decrease in serum LH and testosterone concentration.
In the first month of the trial, 1 woman in the metformin group became pregnant. After the initial month, clomiphene citrate 100 mg daily for cycle days 4 to 7 was administered to both groups. In the metformin plus clomiphene group, 21 women (78%) ovulated, compared with 4 women (14%) in the placebo plus clomiphene group.
Early evidence suggests higher pregnancy rates. Data about the impact of metformin plus clomiphene on pregnancy and delivery rates in women with PCOS are limited. In 1 study, investigators reported that the pregnancy rate was 55% in women treated with metformin plus clomiphene compared with 7% in women treated with placebo plus clomiphene.26 In this study, women with PCOS who did not ovulate when treated with clomiphene (150 mg daily for 5 days) received either metformin (1,500 mg daily) or placebo for 7 weeks. During the initial 7-week treatment period, 1 of the 12 women in the metformin group and none of the 15 women in the placebo group ovulated.
After this initial treatment period, all women received clomiphene citrate, beginning at a dose of 50 mg daily for 5 days, with dosage escalation in the absence of ovulation. Nine of the 12 women in the metformin plus clomiphene group ovulated, compared with 4 of the 15 women in the placebo plus clomiphene group. Of the women who completed the clinical trial, 6 of 11 in the metformin plus clomiphene group became pregnant, compared with 1 of 14 in the placebo plus clomiphene group.
Another clinical trial demonstrated the merit of a trial of clomiphene plus metformin when ovulation does not occur with clomiphene alone, before advancing to a resource-intensive regimen such as gonadotropin therapy. Women were given either clomiphene plus metformin or gonadotropin injections.29 Pregnancy rates after both treatments were similar. However, the cost of treatment for the clomiphene plus metformin therapy was 25% that of gonadotropin therapy.
Treatment of anovulatory infertility associated with PCOS: A stepwise approach
RISK OF MULTIPLE GESTATION
Weight loss (if baseline weight is elevated)
Modest increase (7% risk of twins, 0.5% risk of triplets)
Clomiphene plus metformin
Clomiphene plus glucocorticoid
Significantly increased (20% risk of twins, 5% risk of triplets)
In vitro fertilization
Markedly increased (30% risk of twins, 4% risk of triplets; risk dependent on number of embryos transferred)
FSH = follicle-stimulating hormone
Clinical courseRecommend alternatives to in vitro fertilization
At this point in her care, this patient should not be offered IVF treatment. IVF is a resource-intensive treatment that is associated with a high rate of multiple gestation. This patient could instead be directed to any of the low-resource options that she has not yet tried: weight loss, metformin monotherapy, or clomiphene plus a glucocorticoid or clomiphene plus metformin.30 Even though this patient is only slightly overweight (her BMI of 27.8 is near normal), losing weight sometimes restores ovulatory menses in women with PCOS.31- 35