Studies of hyperandrogenicity and the metabolic syndrome in premenopausal women

Abstract: An androgenic sex hormone profile appears to be a typical feature of the metabolic syndrome (MetS) and a powerful risk factor for the development of type 2 diabetes in women. The causes of relative hyperandrogenicity (HA) are not clearly defined. Among possible pathophysiological pathways, the effect of insulin, abdominal obesity, ovarian dysfunction, environmental factors and disturbed hypothalamic-pituitary-adrenal (HPA) axis activity, as well as genetic factors, have been discussed.The overall aim was to study the associations of endogenous sex hormones and sex hormone-binding globulin (SHBG) with the features of the MetS, HPA axis estimates, ovarian morphology and genetic as well as psychosocial and socioeconomic factors.This thesis is based on a cross-sectional, population-based cohort of premenopausal healthy women born in 1956. The first stage of the investigations was performed in 1997-1998 and comprised 270 subjects. Examinations included assessments of anthropometry, blood pressure, endocrine and metabolic parameters, salivary cortisol levels on repeated occasions over a random working day and a dexamethasone suppression test. Symptoms of anxiety and depression, socioeconomic status and quality of life were determined using validated questionnaires. The influence of sex steroid-related gene polymorphisms (genes encoding androgen receptor (AR), estrogen receptor ¦Á (ER¦Á), estrogen receptor ¦Â (ER¦Â), CYP19 aromatase and SHBG) on sex hormones and SHBG levels was studied. A subgroup of this cohort (n = 55) within the highest and lowest quartiles of free testosterone values were included in a follow-up study in 2001 to perform a detailed gynecological examination, including ovarian sonography.The results revealed that women with HA, defined as the highest 25% levels of free testosterone (free T ¡Ý 6 pmol/L) in this population sample, displayed higher levels of cardiovascular disease (CVD) risk factors, such as fasting insulin, glucose, abdominal obesity, blood pressure, triglycerides and LDL-cholesterol levels, as well as lower HDL-cholesterol, compared with the remaining subjects. Increased adrenal androgen, dehydroepiandrosterone sulfate (DHEAS), appears to be related to some features of the MetS, including dyslipidemia and abdominal obesity. An unfavorable socioeconomic environment and impaired quality of life were associated with an androgenic sex hormone profile. It appears that a chronic challenge to the HPA axis in women due to stress factors may primarily lead to the elevated secretion of the adrenal androgens. Genetic influence may be at least partly responsible for the individual variations in androgen levels and SHBG concentrations. SHBG may play a central role in the regulation of the lipid profile in women, independent of other metabolic and CVD risk factors. There was no clear over-representation of women with polycystic ovaries (PCO) or polycystic ovary syndrome (PCOS). PCO appearance was associated with a tendency towards some non-beneficial changes in cardiovascular risk factors and was correlated with hirsutism. Insulin and free T were independently associated with ovarian volume. The results underline the complexity of HA in women.