The purpose of this study is to assess the potential relationships of circulating IGF-I, adrenal and gonadal steroids, and polymorphism ER22/23EK of the glucocorticoid receptor (GC-R) gene with nutritional, functional and cognitive deterioration in a group of elderly people living independently. This is a population-based prospective study with 313 individuals (160 women and 153 men, 76.7 ± 7 years) who participated. A physical exam, evaluation of functional capacity (Barthel scale), cognitive function (mini-mental state examination-MMSE), geriatric depression scale (GDS), mininutritional assessment (MNA-SF) and cardiometabolic status were performed at basal time point and at 2 years of follow-up. Biological measurements included cortisol, dehydroepiandrosterone (DHEA), DHEA sulphate, testosterone, estradiol, IGF-I and polymorphism ER22/23EK of the GC-R gene. Estradiol was associated with MNA-SF decrease over time (p < 0.01, adjusted for age and gender, beta = -0.17, p = 0.03). Weight loss was related to testosterone in men (8.6 vs 12.1 pg/ml in no losers; p = 0.03), and in women with GDS (13.0% with depression vs 3.3% with no depression; p = 0.05) and MMSE (22.2% with cognitive deterioration vs 4.8% with no cognitive deterioration; p = 0.049). Barthel decrease was associated with testosterone (p = 0.02, after adjusting for age and gender, beta = -0.520, p < 0.001), and SHBG (p < 0.01, adjusted for age and gender, beta = 0.18, p < 0.01). DHEA was associated with deterioration in the MMSE (p = 0.01, after adjusting for age, gender, GDS scale and academic status, beta = -0.26, p = 0.01). Frailty development was related only in men with testosterone levels at the beginning of the study (p = 0.017). ER22/23EK was found in 3% of the subjects and carriers had a lower prevalence of hypertension. Adrenal and gonadal steroids are associated to impairment of the ageing health condition in elderly individuals living independently in Spain. ER22/23EK polymorphism of the GC-R gene has a low prevalence in our population.