BACKGROUND: The third generation aromatase inhibitors (AIs) have become an established component of postmenopausal estrogen receptor positive breast cancer therapy. Unfortunately, up to half of AI-users experience the AI-induced musculoskeletal syndrome (AIMSS) (arthralgia, carpal tunnel syndrome, start pains, stiffness, etc.), which can severely impact quality of life and treatment compliance. We have previously demonstrated that loss of hand grip strength is part of AIMSS and involves tenosynovial changes and fluid retention in joints. REVIEW OF LITERATURE AND HYPOTHESIS GENERATING FINDINGS: Our presentation during this AI-symposium focuses on available literature regarding AIMSS with new data from a prospective study generating a hypothesis for its pathogenesis. Profound estrogen deprivation as a consequence of AI-use is thought to be the underlying reason but the exact pathway remains unknown. A potential hypothesis is that the growth hormone/insulin like growth factor-I (GH/IGF-I) pathway may be involved. This possibility is based on the non-linear association between body mass index (BMI) and loss of hand grip strength that we observed. It appears that in lean and overweight women, hand grip strength decreases most following intake of an AI. This observation suggests an underlying biological process which probably evolves through the GH/IGF-I pathway, controlled by sex steroids. CONCLUSION: Estrogen deprivation leads to incapacitating AIMSS and hampers treatment compliance. In our search for the missing link between 'lowering postmenopausal estrogens' and 'arthralgia' we here report on AI-induced changes in grip strength by BMI which we believe are hypothesis generating for an effect of AIs on the GH/IGF-I axis. This needs to be explored prospectively.