M.R. Druce, S.A. Akker, S.L. Chew, W.M. Drake and A.B. Grossman Department of Endocrinology, Barts and the London Medical School, UK E-mail: Maralyn.druce@bartsandthelondon.nhs.uk doi: 10.1111/j.1365-2265.2009.03656.x References 1 Bergthorsdottir, R., Leonsson-Zachrisson, M., Ode ´n, A. et al. (2006) Premature mortality in patients with Addison’s disease: a popula- tion-based study. Journal of Clinical Endocrinology and Metabolism, 91, 4849–4853. 2 Erichsen, M.M., Løva ˚s, K., Fougner, K.J. et al. (2009) Normal overall mortality rate in Addison’s disease, but young patients are at risk of premature death. European Journal of Endocrinology, 160, 233–237. 3 Løva ˚s, K., Loge, J.H. & Husebye, E.S. (2002) Subjective health status in Norwegian patients with Addison’s disease. Clin Endocrinol (Oxf), 56, 581–588. 4 Tomlinson, J.W., Holden, N., Hills, R.K. et al. (2001) Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. Lancet, 357, 425–431. 5 Asari, R., Scheuba, C., Kaczirek, K. et al. (2006) Estimated risk of pheochromocytoma recurrence after adrenal-sparing surgery in patients with multiple endocrine neoplasia type 2A. Archives of Sur- gery, 141, 1199–1205. Atorvastatin pretreatment augments the effect of metformin in patients with polycystic ovary syndrome (PCOS) The pleotrophic effects of HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors are increasingly recognized. We have recently shown that atorvastatin improves biochemical hyper- androgenaemia, insulin resistance and inflammatory markers in patients with polycystic ovary syndrome (PCOS). 1 This is an exten- sion arm of that randomized double blind placebo-controlled study with atorvastatin 20 mg daily in patients with PCOS. 1 Immediately after stopping the trial medication 37 patients (19 patients from the atorvastatin group and 18 patients from the placebo group) who completed the study were given metformin 500 mg three times daily for 3 months. Subjects and methods This study was undertaken to determine if metformin would main- tain any changes seen in insulin resistance and hyperandrogen- aemia in patients with PCOS following atorvastatin, compared to treating the placebo pretreatment group with metformin also. The study was approved by the South Humber Research Ethics com- mittee. The primary end points of the study were the change in HOMA-IR, total testosterone and hs-CRP. Blood samples were processed and analysed as noted previously. 1 The paired t-test was used to compare changes from baseline for the biochemical data and clinical observations between groups. Data are reported as mean ± SEM. The Wilcoxon-signed rank test was applied to biochemical data that violated the assumptions of normality when tested using the Kolmogorov–Smirnov test. The effect of treatment was evaluated by first computing the percentage change from baseline in all variables studied and then the percent- age change seen for each variable in both groups was compared, thus negating the differences in the baseline values between the two groups. Between-group comparison of percent changes was per- formed using independent samples t-test. Results All the patients completed the study. The mean age group of patients was 27Æ7±1Æ4 years and the mean BMI was 33Æ42 ± 1Æ6 kg/m 2 . The mean age group of patients was 27Æ7±1Æ4 years (atorvastatin pretreated group 26Æ6±1Æ2 vs Placebo-pretreated group 28Æ8±1Æ8; P value )0Æ44). There were no significant differ- ences in baseline parameters between the two groups. There was no change in menstrual cycle length in the atorvastatin pretreatment group (50 ± 6 vs48 ± 10 days) or placebo pretreated group (52 ± 10 vs 50 ± 10 days). There were significant improvements in insulin and the HOMA- IR index, total testosterone, FAI, SHBG and hsCRP with metfor- min in the atorvastatin pretreated group (Table 1). There were no significant changes in any of these parameters with metformin in the placebo pretreatment group. The percentage change in HOMA-IR, FAI and hsCRP, were greater in the atorvastatin pre- treated group compared with patients who were randomized to placebo pretreatment. Discussion In this study, atorvastatin pretreatment both augmented and facili- tated the effect of metformin in the improvement of the metabolic parameters, biochemical hyperandrogenaemia and inflammatory markers in patients with PCOS. The improvements of these para- meters were independent of the deterioration in LDL and total cho- lesterol following cessation of atorvastatin. There was a significant reduction in total testosterone with metformin after atorvastatin, over and above the initial changes through atorvastatin treatment. There were no significant changes in insulin resistance, biochemi- cal hyperandrogenaemia and hsCRP in patients who went on to 12 weeks of metformin treatment following placebo. The lack of response to metformin in the placebo-pretreated group could be due to the shorter duration of treatment, lower dose or due to obesity. 2 Since the atorvastatin pretreatment group was less insulin resis- tant and had a better lipid and hormonal profile than the placebo group during the second visit the effect of further treatment was evaluated by first computing the percentage change from baseline in all variables studied and then the percentage change seen for each variable in both groups was compared, thus negating the differences in the baseline values of the two groups. There was a significant percentage change in both the groups in FAI, HOMA-IR and hs-CRP when between-group comparison of percent changes was performed using independent samples t-test (Table 1). The potentiating effect of metformin in statin pretreated patients could be due to synergestic effects of atorvastatin and metformin. 566 Letters to the Editor Ó 2010 Blackwell Publishing Ltd, Clinical Endocrinology, 72, 564–570