To the Editor: I read with interest the excellent review article on the metabolic syndrome by Chew et al in the 16 October 2006 issue of the Journal.1 In their article the authors claim there is a lack of data about the relationship between hyperinsulinaemia and changes in free testosterone levels.

As part of the Kuopio Ischaemic Heart Disease (KIHD) Risk Factor Study, an ongoing prospective epidemiological study of 2682 middle-aged Finnish men investigating risk factors for chronic disease, our research group has shown an association between the presence of metabolic syndrome at baseline and a change in sex hormone levels at follow-up after 11 years.2 In our study, men who met the World Health Organization criteria for metabolic syndrome both at baseline and at 11-year follow-up were at 2.6-fold increased risk of developing hypogonadism (serum total testosterone concentration < 11 nmol/L) during the study period compared with men who did not have metabolic syndrome. There was also a non-significant trend for men with metabolic syndrome to develop hypogonadism as defined by calculated free testosterone levels of < 225 pmol/L at 11-year follow-up.2

In the same cohort, we also reported a reverse association — that is, hypogonadism predicting metabolic syndrome.3,4 However, as the question posed by Chew et al was whether hyperinsulinaemia affects free testosterone levels, I examined the KIHD data further for evidence of such an association. I found that subjects grouped in ascending baseline fasting serum insulin quartiles had baseline mean free testosterone levels of 316 pmol/L (SD, 72 pmol/L), 312 pmol/L (SD, 77 pmol/L), 299 pmol/L (SD, 74 pmol/L) and 271 pmol/L (SD, 79 pmol/L), respectively (P < 0.001 for trend). At 11-year follow-up, mean free testosterone levels for subjects in each quartile were 248 pmol/L (SD, 64 pmol/L), 242 pmol/L (SD, 68 pmol/L), 229 pmol/L (SD, 70 pmol/L) and 216 pmol/L (SD, 67 pmol/L), respectively (P < 0.001 for trend).

The proportional drop in free testosterone levels over 11 years was approximately the same in each quartile, ranging from 20% to 23%. On the basis of these data, it seems that hyperinsulinaemia is associated not only with a fall in serum total testosterone levels but also with a fall in free testosterone levels in a general population.

In reply: We thank Tuomainen for his interest in our review article, and for sharing with us his data showing an inverse association between fasting serum insulin levels and calculated serum free testosterone levels. We were cautious in our statement about the relationship between hyperinsulinaemia and free testosterone levels, as there are conflicting data in the literature regarding this,1,2 and few studies that directly measure free or bioavailable testosterone. Moreover, there is ongoing controversy about the calculation of free testosterone levels using total testosterone and sex hormone-binding globulin concentrations, with the validity and assumptions of some of these widely used estimation equations being called into question.3,4

We also echo the concerns of Allan et al5 about the potential pitfalls of diagnosing hypogonadism based on testosterone levels only. As the presence of low total (and even calculated free) testosterone in obese men may not necessarily reflect deficient androgen action, the diagnosis of androgen deficiency should only be made in the context of supportive clinical features. Furthermore, in abdominally obese men with the metabolic syndrome, levels of sex hormone-binding globulin and both total and calculated free testosterone can increase following weight loss,6 thereby obviating the inappropriate use of testosterone supplementation in such patients.