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Sex steroids are mainly synthesized in the reproductive organs and the adrenal glands. Sex steroid levels are regulated by the hypothalamic-pituitary-gonadal axis, via a classical feedback system. Testosterone (T) represents the main androgen and estradiol (E2) the main estrogen. Androgens can be aromatized into estrogens by the aromatase enzyme. This key enzyme in the biosynthesis of estrogens is highly expressed in adipose tissue.In circulation, sex steroids are bound to sex hormone-binding globulin (SHBG) and albumin with a high and low affinity respectively. Only a small fraction circulates in a non-protein bound or free form. According to the ‘free hormone hypothesis’, the free fraction is responsible for the biological activity of sex steroids, as only the free hormone can enter the cell and can activate its nuclear receptor.In routine clinical practice, total T and total E2 concentrations are most often measured by immunoassays. These assays are not standardized for low concentrations, such as T levels in women and E2 levels in men, resulting in inaccurate measurements in this clinically important low range. To measure low total T and E2 levels accurately, liquid or gas chromatography-tandem mass spectrometry (LC-MS/MS or GC-MS/MS) is the method of choice. Furthermore, free T and E2 levels are currently calculated from total T and E2, SHBG and albumin levels. Inevitably, these calculations rely on accurate measurements of total sex steroid levels.In this project, we studied the clinical correlates of mass-spectrometry measured sex steroids. In the first part of this project, we performed the clinical validation of a new LC-MS/MS method to measure estrogens (E2 and estrone), which was recently developed in the clinical laboratory of the University Hospitals. With this highly sensitive method, we can measure estrogen concentrations in patients with low to very low levels, such as adolescents, postmenopausal women and men, including men treated with anti-androgens.Furthermore, concentrations of sex steroids and SHBG change considerably in ageing and disease. From the third decade, male testosterone levels decrease by 0.4-2% per year, together with a rise in SHBG, which results in a greater rate of decline of free T compared to total T. However, to date, it is not clear if total T or free T levels are more important in assessing the androgen status in ageing men.Moreover, in epidemiologic research, low SHBG and low testosterone levels have been identified as risk factors for the development of the metabolic syndrome. It is however unclear if BMI, insulin resistance or body composition mediate this risk.In the second part of this project, we used the framework of the European Male Ageing Study (EMAS). In this large European cohort, 3369 healthy men between 40-79 years from 8 European countries participated. The main research question in EMAS is to investigate the association between age-related hormonal changes and a broad range of health outcomes in elderly men.In a first paper, we showed that low total T is a risk factor for developing metabolic syndrome, independently of BMI, insulin resistance or body composition. On the other hand, E2 levels do not contribute to this risk, but a lower aromatization of T into E2 can be protective for developing metabolic syndrome.In a second paper, we found that men with low free T, but normal total T, have more androgen deficiency-related symptoms than men with normal total T and free T. Moreover, symptoms were not different in men with low total T, but normal free T. We thus provide strong evidence that not only total, but also free T levels are important in the diagnostic workup of men with hypogonadal symptoms.In women, high androgen levels have a negative impact on the menstrual cycle and fertility. In the third part of the project, we investigated the role of androgens and SHBG in diagnosing and classifying women with subfertility and oligomenorrhea. We showed that also in these women, free T is the most sensitive marker for identifying women with hormonal, ovarian and metabolic disturbances.In conclusion, we studied the clinical correlates of mass-spectrometry measured sex steroids in several patient groups and diseases in which precise measurements of sex steroid levels in the low range are important and determine further clinical management. In men and postmenopausal women, we can now perform precise measurements of estradiol and estrone. We showed that low total T and low free T are risk factors for metabolic syndrome, whereas estradiol is not. We also proved that free T is important in the diagnostic workup of androgen deficiency in men. Furthermore, free T proved to be a sensitive marker in evaluating androgen excess in women.