A lesson from polycystic ovarian syndrome: untangling the role of renal sympathetic nervous system on hypertension and insulin resistance (2011)

The sympathetic nervous system (SNS) is responsible for several homeostatic mechanisms in living organisms and it is known to be the main interpreter of the fight or flight response accompanying stress [1,2]. Almost all tissues are innervated by fibers from the SNS, regulating functions like rate and force of contraction of the heart, vascular and bronchioles tone, urinary output, pupil diameter, gut motility, and so on. All these sympathetic influences are recruited by the release of noradrenaline into the synaptic cleft at tissue level. It is well clear that adrenergic drive is subtly patterned for each organ and depends not only on the amount of local nerve firing but also on the selective presence of several tissue adrenergic receptors able to transduce the nervous influences into cellular functions. Several diseases have been associated with abnormalities of SNS activity and, consequently, many pharmacological interventions have been developed to target it [3–5]. So far, the main approach to modulate adrenergic overdrive has been the use of drugs managing adrenergic receptor response. Although this strategy allows the investigator to finely tune the sympathetic influences on selective cellular effects, in medical practice the systemic administration fails to restrict the drug action to the organ targeted by the abnormal SNS activity, and the effects are spread out to the whole body. Similarly, therapeutic strategies targeting central autonomic control reduce whole body adrenergic activity but recruit several undesired collateral effects. Renal denervation and polycystic ovary syndrome In this issue of the Journal Schlaich et al.[6] report a novel approach to selectively target local SNS overactivity, inducing several beneficial effects. In particular, the authors report the cases of two obese hypertensive women with polycystic ovary syndrome, a condition that has been recently associated with an overactivity of the SNS. Interestingly, the two main traits that accompany polycystic ovary syndrome, namely obesity and hypertension, are typically characterized by increased firing of renal sympathetic nerves [7,8]. Thus, the authors attempted to selectively target renal sympathetic nerves, ablating them with radiofrequency, by using a catheter-based approach. Although their findings are limited to just two observations, they confirm that this novel therapeutic strategy reduced two direct indexes of sympathetic neural activity: whole body noradrenaline spillover and efferent postganglionic muscle sympathetic nerve traffic [9]. In addition the renal denervation procedure markedly lowered heart rate values, a finding which supports the view that this indirect adrenergic marker may mirror in a number of circumstances the response of direct indices of sympathetic function [10]. Interestingly, the targeted ablation of renal sympathetic neural drive improves blood pressure control, insulin sensitivity, ovarian function and glomerular hyperfiltration. The impact of whole body SNS inhibition on blood pressure and insulin sensitivity has been greatly documented, both in experimental models and humans [11,12]. However, these case reports emphasize that the same beneficial effects of the adrenergic inhibition can be achieved by a targeted approach to regional adrenergic activity. Renal sympathetic activity has a crucial role in blood pressure homeostasis and the beneficial effects on blood pressure control can be easily expected. On the contrary, the concomitant reduction in muscle sympathetic nerve traffic, obtained by intervention on renal sympathetic nerves, may indicate that central sympathetic inhibition has also taken place. Insulin/sympathetic interactions and hormonal balance Whichever the case, the observations of Schlaich et al. strongly support previous data reporting that muscle sympathetic nerve traffic is one of the main determinants of insulin resistance [12]. This latter is known to be dependent on two muscle components: a hemodynamic one (glucose uptake being proportional to blood flow), and direct noradrenaline negative cellular effects. Thus, the observed improvement in insulin sensitivity can be attributed to reduced sympathetic nerve traffic, which is known to increase muscle blood flow and to reduce noradrenaline release. Nevertheless, we cannot exclude a further positive contribution to insulin sensitivity due to a possible amelioration of ovarian function. Indeed, the authors report that renal sympathetic nerves ablation could partially restore regular menses, thus strongly supporting a causal role of SNS overactivity in polycystic ovary syndrome. This interpretation is also supported by experimental data showing that ablation of ovarian sympathetic nerves re-establishes a normal response of steroid hormones for ovulation and cycles initiation. Overall, these observations suggest that the renal SNS acts upstream to ovarian sympathetic control. Thus, a strategy to approach the renal sympathetic fibers in a complex and multifaceted syndrome such as the polycystic ovary syndrome, may obtain beneficial effects at many levels, targeting at the same time hypertension, insulin resistance and endocrine abnormalities. Further studies on a larger number of cases are mandatory before definitively recommending radiofrequency-based ablation of renal sympathetic fibers as a novel therapeutic strategy to be applied not only to uncontrolled hypertension [9,13], but also to the polycystic ovary syndrome. Acknowledgements Sources of funding: This work was supported by Italian Ministry of Health ‘Ricerca Corrente’ and ‘Cinque per mille’ to G.L.