The impact of obesity on hyperandrogenism and polycystic ovary syndrome in premenopausal women

Abstract

In this review we have analysed the clinical characteristics and physiopathological aspects of obesity-associated hyperandrogenism. Various lines of evidence suggest that obesity may be responsible for exaggerated androgen secretion in several obese women with PCOS with or without acanthosis nigricans. Simple obesity represents a condition where androgen production rate and metabolic clearance rate are increased and the maintenance of normal peripheral androgen concentrations seems to be regulated by the presence of a feed-back mechanism that registers body size and adjusts their production rates according to their metabolic clearance rate. However, epidemiological and clinical evidence exists that, in premenopausal women, obesity may frequently be associated with menstrual disorders, infertility and hirsutism. This seems particularly true for women with abdominal obesity. Moreover, in young obese women with PCOS a close relationship can be found between the onset of obesity and that of oligo or amenorrhoea and nearly half of PCOS women are overweight or frankly obese. This association therefore suggests a causal relationship with hyperandrogenism and related disorders. These women with PCOS seem to be characterized by a different hormonal environment from that of normal weight affected women. The main differences are higher oestrogen concentrations and lower SHBG levels whereas usually no differences are found in androgen concentrations. Obese PCOS women also have more severe hyperinsulinaemia and insulin resistance when compared with either normal weight PCOS women or weight-matched controls. In PCOS women with acanthosis nigricans, the presence of obesity is much more frequent and the level of hyperinsulinism and insulin resistance much more severe. In women with PCOS, particularly when they are also obese, a significant positive correlation between the degree of hyperandrogenism and that of hyperinsulinism has been found. A current hypothesis is that hyperinsulinaemia may cause increased androgen concentrations and this hypothesis has been supported by a substantial body of both clinical and experimental data. In fact insulin is capable of stimulating the LH-mediated ovarian androgen synthesis and also of regulating their metabolic pathways and delivery to target tissues. Studies in vitro seem to suggest that obese women with PCOS may be particularly susceptible to the effects of insulin on ovarian steroidogenesis. In vivo studies proved that inhibition of hyperinsulinaemia in obese PCOS women but not in normal weight controls leads to a reduction of androgen concentrations and an increase in SHBG levels. Finally, it was demonstrated that in obese women with PCOS weight loss can reduce androgen and LH concentrations and increase SHBG levels and that these effects were significantly correlated with the reduction of insulin levels. Additionally, weight loss was shown to improve significantly hirsutism, acanthosis nigricans, menstrual cyclicity and, most importantly, fertility rate. These findings form the basis for the hypothesis that hyperinsulinaemia and insulin resistance represent some of the pathogenetic factors involved in the development of PCOS in susceptible women. The fact that they are invariably associated with obesity, particularly with abdominal obesity, represents the main fact on which the hypothesis connecting obesity with the development of hyperandrogenism in PCOS is based. Other additional factors, such as hyperoestrogenaemia, increased activity of the opioid system and, perhaps, high dietary lipid intake could be involved in the complex mechanism by which obesity may stimulate the development of hyperandrogenaemia. A schematic representation of the sequence of these interactions between obesity and hyperandrogenism in premenopausal women with PCOS is represented in Fig. 1.