Metformin for PCOS symptoms: 5 challenging cases

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.

CASE 2

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.

CASE 3

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