Review
Correction of hyperinsulinemia in oligoovulatory women with clomiphene-resistant polycystic ovary syndrome: a review of therapeutic rationale and reproductive outcomes

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Abstract

Polycystic ovary syndrome (PCOS) describes a convergence of chronic multisystem endocrine derangements, including irregular menses, hirsutism, obesity, hyperlipidemia, androgenization, large and cystic-appearing ovaries, insulin resistance and subfertility. Few PCOS patients exhibit all of these features, and often only one sign or symptom is evident. The sequelae of PCOS reach beyond reproductive health, as women affected with PCOS have increased relative risks for myocardial infarction, hypertension, ischemic heart disease, thromboembolic disease and diabetes. Although the adverse health consequences associated with PCOS are substantial, unfortunately most women are not aware of these risks. Indeed, in infertility practice such concerns are secondary as most patients are referred for treatment specifically to achieve a pregnancy. Impairments in insulin metabolism appear central to the physiologic cascade of PCOS, yet clomiphene therapy fails to remedy this defect. Several investigators have described satisfactory reproductive outcomes for PCOS patients treated with oral insulin-lowering agents. In this report, we outline a diagnostic and therapeutic approach for women with PCOS refractory to clomiphene with attention to the underlying insulin imbalance associated with impaired fertility.

Section snippets

Introduction: clomiphene resistance defined

While a formal classification system for PCOS patient response following clomiphene therapy has not been developed, a thorough review of a patient’s prior clomiphene treatment outcomes is needed to recognize ineffective therapy. Ovulation induction with clomiphene has been extensively studied; clinical experience has demonstrated this agent will elicit a safe, ovulatory response in an impressive proportion of women who use it [1]. Importantly, over 80% of women who successfully achieve a

Initial evaluation

After a thorough history and focused physical examination (including transvaginal ultrasound assessment of ovaries and endometrium), objective laboratory evidence supporting hyperandrogenism and/or hyperinsulinemia should be sought. PCOS patients should undergo endometrial biopsy whenever endometrial hyperplasia is suggested by transvaginal sonography. When present, hirsutism, acanthosis nigricans and obesity should be recorded.

Helpful laboratory tests include fasting insulin and glucose,

Metformin as a normogonadotropin in gynecology practice

Like clomiphene, metformin is a nonsteroidal compound that indirectly influences ovarian function. Metformin is a water soluable, oral biguanide insulin-lowering drug; it is chemically and pharmacologically distinct from sulfonylureas (see Fig. 1). Metformin results in blunting of hepatic gluconeogenesis, diminished intestinal absorption of glucose, and increased peripheral glucose uptake and utilization [10]. In contrast to the physiological response to sulfonylureas, metformin does not modify

Metformin precautions and patient counseling

All women receiving metformin therapy for PCOS should be thoroughly briefed about the risk of lactic acidosis associated with this medication. Lactic acidosis is a rare (1:33 000) metabolic complication of metformin therapy, thought to be secondary to significant tissue hypoxia [16]. When lactic acidosis occurs it is a medical emergency; the case fatality rate is 50%. Such risk calculations were extrapolated from diabetic study populations prior to marketing the drug specifically for diabetes

Metformin dosing and monitoring

Metformin therapy for ovulation induction in PCOS generally commences in the early follicular phase, but since most PCOS women are acyclic this guideline is of little clinical value. Induction of menses following progestational challenge should be considered when endometrial thickness is extreme (>10 mm), but routine pre-treatment with progestins in the setting of PCOS is probably unnecessary.

A supervised, incremental dosage protocol is used to administer metformin to PCOS patients at this

Clinical results

During the initial month of metformin treatment, often no appreciable impact on the BBT characteristics compared to pre-treatment controls is evident (see Fig. 3a). The disorganized, monophasic pattern associated with oligoovulatory or anovulatory cycles occasionally persists through the first 4–6 weeks of metfomin therapy. At this center, prolonged latency of non-biphasic BBT patterns has been observed more commonly among heavier (BMI >32) patients who have failed to implement a structured

Ovulatory response and conception following metformin

Evidence supporting ovarian responsiveness to metformin has accumulated from several institutions through small studies published during the past decade. For example, among 22 PCOS patients receiving metformin at a Venezuelan center, all but one achieved normal menstrual cyclicity within six months [20]. In this group, healthy infants were delivered from four study patients who conceived spontaneously within the first seven months of metformin therapy. Similarly, a study of 15 adolescents with

Conclusion

At present, mainstream clinical opinion still regards clomiphene as the first-line strategy to induce ovulation in patients with PCOS. Any associated insulin/glucose dysfunction of PCOS remains uncorrected with this regimen, however. Fasting insulin levels may be inversely related to the ovulatory response manifested by clomiphene in some women. Beneficial metabolic effects of insulin reduction among PCOS patients seem to include improved menstrual regularity and fertility. Several small

Condensation

Restoration of normal insulin homeostasis should be a prime clinical objective in the management of polycystic ovary syndrome.

Acknowledgements

The authors are grateful to Dr. Delphine P.Levy for review of this manuscript, and to the clinical and scientific staffs at Georgia Reproductive Specialists LLC, and The Center For Reproductive Medicine & Infertility, Weill Medical College of Cornell University for technical and research support.

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