KatCarney

Oral Contraceptives Plus Metformin for the Treatment of the Polycystic Ovary Syndrome
Posted 09/04/2002

from Medscape Ob/Gyn & Women's Health


Question
Would the combination of levonorgestrel ethinyl estradiol plus metformin be effective for the treatment of patients with the polycystic ovary syndrome?

Carlos Andres Valverde, MD

Response
from Robert L. Barbieri, MD, 09/04/2002

The polycystic ovary syndrome (PCOS) is defined as the presence of both ovulatory dysfunction and hyperandrogenism. In women with PCOS, oligo- or anovulation manifests itself as irregular cycles with oligo- or amenorrhea. Hyperandrogenism can be identified by physical examination, ie, the presence of hirsutism or by laboratory tests that demonstrate an elevated circulating concentration of a major androgen, ie, free testosterone, total testosterone, and/or androstenedione. A third criterion for the diagnosis of PCOS is to exclude other causes of hyperandrogenism, such as nonclassic adrenal hyperplasia resulting from a 21-hydroxylase defect or an androgen-producing adrenal or ovarian tumor. PCOS occurs in approximately 5% to 7% of women of reproductive age.[1,2] This makes PCOS the most common endocrinopathy of women.

Women with PCOS have both abnormally elevated luteinizing hormone (LH) secretion[3,4] and hyperinsulinemia as a result of insulin resistance.[5] The combination of hypersecretion of LH and insulin causes ovarian androgen overproduction.[6] In turn, ovarian androgen overproduction causes hirsutism and prevents normal ovarian follicle growth, preventing regular ovulation. PCOS can be treated by lowering LH hypersecretion (oral contraceptive pills or GnRH agonist analogues) or by reversing the hyperinsulinemia that is caused by insulin resistance (weight loss or metformin). An intriguing idea is to use oral contraceptives plus metformin in combination to simultaneously attack the 2 principle causes of PCOS: hypersecretion of LH and insulin.

In one recently reported clinical trial, Elter and colleagues[7] randomized 40 nonobese women with PCOS to treatment with either an oral contraceptive alone (ethinyl estradiol 35 micrograms daily plus cyproterone acetate 2 mg daily, Diane) or the oral contraceptive (Diane) plus metformin 500 mg 3 times daily for 4 months. In both groups, circulating androgens, such as androstenedione and testosterone, were significantly suppressed from baseline by 4 months of treatment. However, androstenedione levels were more suppressed by the combination therapy of the oral contraceptive plus metformin than by the oral contraceptive alone (Figure). In addition, weight loss occurred in the combination therapy group, but weight loss did not occur in the group treated with the oral contraceptive alone. An objective measure of hirsutism, the Ferriman-Gallwey score, was similarly improved in both treatment groups. This study suggests that the combination of metformin plus an oral contraceptive may be especially useful when an important objective of treatment is weight loss. For the treatment of hirsutism, at least over 4 months, the oral contraceptive performed as well as the combination of metformin plus the oral contraceptive.

Figure 1 (click image to zoom) The effect of an oral contraceptive plus metformin vs an oral contraceptive alone on circulating androstenedione levels in women with PCOS. Both treatments significantly reduced circulating androstenedione levels. However, the oral contraceptive plus metformin produced more suppression of androstenedione than the oral contraceptive alone. From Elter et al.[7]



Metformin is available in a generic form as 500-mg, 850-mg, and 1000-mg tablets. The target dose of metformin is in the range of 1500 -2550 mg. Clinically significant responses are not regularly observed at doses less than 1000 mg daily. Metformin is given with meals to reduce the gastrointestinal side effects. Many clinicians begin treatment with 500 mg taken with the patient's largest meal, to reduce the gastrointestinal side effects. If the medication is tolerated, it can be increased to 500 mg at both lunch and dinner, and then to 500 mg at breakfast, lunch, and dinner. Clinicians should allow 1-2 weeks between increases in dose. The maximum dose of metformin is 850 mg 3 times daily (2550 mg daily). An extended-release formulation is available as a 500-mg tablet (Glucophage XR). When using metformin extended-release tablets, the entire daily dose is given at dinner time. The initial dose is 500 mg daily at dinner time, with escalation to a maximum of 2000 mg once daily.

The most common side effects of metformin are diarrhea, nausea or vomiting, flatulence, indigestion, and abdominal discomfort. In one clinical trial of metformin at a dose of 2250 mg daily, diarrhea was reported in 53% of the patients taking metformin and 12% of patients taking placebo. In the same study, nausea or vomiting was reported in 26% of those taking metformin and 8% of those taking placebo. However, only about 5% of patients discontinue the medication because of side effects.[8,9]

A rare problem caused by metformin is lactic acidosis, which is fatal in as many as 30% to 50% of cases.[10] Metformin is excreted by the kidney and the risk of metformin-induced lactic acidosis is increased when patients have renal insufficiency (creatinine > 1.4 mg/dL). Before initiating metformin treatment, a serum creatinine should be demonstrated to be < 1.4 mg/dL. In addition, women with conditions that increase the risk of lactic acidosis, such as congestive heart failure or sepsis, should not be prescribed metformin.[11] Other contraindications to the use of metformin are concurrent liver disease and a previous history of lactic acidosis. Metformin therapy should be temporarily suspended for all major surgical procedures that entail restriction of fluid intake. Metformin should not be restarted until normal fluid intake has resumed and renal function has been shown to be normal.



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References
Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab. 1998;83:3078-3082.
Asuncion M, Calvo RM, San Millan JL, Sancho J, Avila S, Escobar-Morreale HF. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab. 2000;85:2434-2438
Yen SSC, Vela P, Rankin J. Inappropriate secretion of follicle stimulating hormone and luteinizing hormone in polycystic ovarian disease. J Clin Endocrinol Metab. 1970;30:435-442.
Rebar R, Judd HL, Yen SSC, Rakoff J, Vandenberg G, Naftolin F. Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome. J Clin Invest. 1976;57:1320-1329.
Barbieri RL, Ryan KJ. Hyperandrogenism, insulin resistance and acanthosis nigricans syndrome: a common endocrinopathy with distinct pathophysiologic features. Am J Obstet Gynecol. 1983;147:90-101.
Barbieri RL, Makris A, Randall RW, Daniels G, Kistner RW, Ryan KJ. Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. J Clin Endocrinol Metab. 1986;62:904-910.
Elter K, Imir G, Durmusoglu F. Clinical endocrine and metabolic effects of metformin added to ethinyl estradiol-cyproterone acetate in non-obese women with polycystic ovary syndrome: a randomized controlled study. Human Reprod. 2002;17:1729-1737.
Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose response trial. Am J Med. 1997;103:491-497.
DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131:281-303.
Lalau JD, Lacroix C, Compagnon P, et al. Role of metformin accumulation in metformin-associated lactic acidosis. Diabetes Care. 1995;18:779-784.
Misbin RI, Green L, Stadel BV, Gueriguian JL, Gubbi A, Fleming GA. Lactic acidosis in patients with diabetes treated with metformin. N Engl J Med. 1998;338:265-266.
About the Panel Members
Robert Barbieri, MD, Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, Massachusetts; Chairman, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, Massachusetts

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