To the Editor: As the person who introduced metformin as adjunctive therapy for polycystic ovary syndrome (PCOS) in Australia in 1996,1 and subsequently introduced measurement of insulin levels during glucose tolerance testing,2 I would like to respond to the article by Samaras et al.3 These nine endocrinologists and epidemiologists have a patient population that is mostly middle-aged and older, quite different to my practice in PCOS, in which 80% of patients are aged between 12 and 45 years.
For 80%–85% of women with PCOS, the condition is a result of hyperinsulinaemia secondary to inherited insulin resistance. However, a significant proportion of PCOS is caused by dysfunction of the hypothalamic centre for control of fertility. This may be a result of incomplete maturation, stress, excessive exercise, or previous anorexia and bulimia. These women will not respond to restrictive diets, weight loss, or more exercise, or to metformin. Hence, they must be differentiated from women with insulin resistance or hyperinsulinaemia4 by history, examination, and measurement of insulin and sex hormone binding globulin (SHBG) levels. More than 30% of insulin-resistant women with PCOS are not obese, and elevated insulin levels or depressed SHBG levels are often the only means to distinguish them from women with PCOS from other causes.
For insulin-resistant women with PCOS, lowering insulin levels restores regular ovulatory cycles, clears acne and slowly reverses hirsutism, while preserving beta cell function. Reducing insulin levels must, therefore, be the objective of therapy, initially with diet and exercise. Metformin may be added if lifestyle change is ineffective.
Although I agree that the fasting insulin test does not completely correlate with the “gold standard” research tests, mathematical computations involving both fasting insulin and fasting glucose, such as the HOMA and QUICKI indices, do correlate extremely well with these tests, and require nothing more than a desk calculator.5 The best gold standard correlation in PCOS is achieved with the area under the insulin curve during a 3-hour glucose tolerance test.6 This formula, ½ fasting + 1-hour + 2-hour + ½ 3-hour insulin, gives far greater numerical emphasis to the 1- and 2-hour insulin values than to the fasting insulin level, contradicting the assertions by Samaras et al that 1- and 2-hour insulin measurements are useless.3
In summary, insulin levels are elevated in adolescence and early adulthood in women with PCOS, and often in their siblings and children. This can give an earlier warning of future metabolic and cardiovascular problems than by conventional screening, at an age when people are less resistant to implementing lifestyle change, and giving a longer period for preventing pathology.
- 1. Kidson W. Polycystic ovary syndrome: a new direction in treatment. Med J Aust 1998; 169: 537-540. <MJA full text>
- 2. Kidson W. Insulin resistance — is testing worthwhile? Commonsense Pathology. Sydney: Royal College of Pathologists of Australasia, 2002. http://www.rcpa.edu.au/applications/DocumentLibrary Manager2/upload/CSF%20final%20for%202002.pdf (accessed Jan 2007).
- 3. Samaras K, McElduff A, Twigg SM, et al. Insulin levels in insulin resistance: phantom of the metabolic opera? Med J Aust 2006; 185: 159-161. <MJA full text>
- 4. Azziz R. Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: the Rotterdam criteria are premature. J Clin Endocrinol Metab 2006; 91: 781-785.
- 5. Carmina E, Lobo RA. Use of fasting blood to assess the prevalence of insulin resistance in women with polycystic ovary syndrome. Fertil Steril 2004; 82: 661-665.
- 6. Ciampelli M, Leoni F, Cucinelli F, et al. Assessment of insulin sensitivity from measurements in the fasting state and during an oral glucose tolerance test in polycystic ovary syndrome and menopausal patients. J Clin Endocrinol Metab 2005; 90: 1398-1406.
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