ENDOCRINOLOGY Key advances ■■ Familial hyperaldosteronism type II (FH-II) may account for at least 6% of primary aldosteronism cases and is approximately 5–10 times more common than FH‑I4 ■■ A germline mutation in KCNJ5 is associated with severe, early-onset familial primary aldosteronism, and somatic KCNJ5 mutations are common in aldosterone-producing adenoma5 ■■ Patients with primary aldosteronism have reduced circulating levels of endothelial progenitor cells, which might contribute to the development of vasculopathy in these individuals9 ■■ The degree of left ventricular enlargement in primary aldosteronism is largely determined by dietary salt; dietary salt restriction might reduce cardiovascular risk in this condition10
their origin? Do KCNJ5 mutations bestow ZF-like characteristics (including histol ogy, 17α-hydroxylase expression, hybrid steroid formation, and loss of aldosterone responsiveness to angiotensin-II) to ZG cells, or are ZG-like characteristics (aldo sterone synthase expression) bestowed onto ZF cells? Further studies should shed light on this fascinating issue. Other studies in 2011 have focused on the mechanisms underlying adverse cardio vascular effects of aldosterone excess. In a novel study by Wu et al.,9 levels of endothelial progenitor cells (EPCs), which are thought to protect against cardiovascular disease by repairing endothelial injury, were lower in 113 patients with primary aldo steronism (APA n = 87; BAH n = 26) than in 55 patients with essential hypertension.9 Differences in pulse-wave velocity, a marker of arterial stiffness, and high-s ensitivity C‑reactive protein (hsCRP) levels, a marker of cardiovascular inflammation, and EPC counts were attenuated following uni lateral adrenalectomy or during treatment with aldosterone antagonists. Overall, the findings suggest that increased circulating aldosterone levels in patients with primary aldosteronism contribute to vasculopathy by reducing EPC numbers, partly by activating EPC mineralocorticoid receptors and possibly indirectly by raising hsCRP levels.9 Animal studies have demonstrated a cri tical role for salt in the development of aldosterone-induced cardiovascular damage; however, corroborative data in humans were lacking. In a case–control study of 21 patients with primary aldosteronism and 21 matched individuals with essential hypertension, Pimenta and co-workers reported in 2011 S24 | JANUARY 2012
that patients with primary aldosteronism had greater thickness of the left ventricular wall, end-diastolic diameter and mass. More over, urinary sodium excretion, a marker of dietary salt intake, positively correlated with and was an independent predictor of left ventricular wall thickness and mass in patients with primary aldosteronism, but not in those with essential hypertension.10 Hence, as in animal studies, salt appears to interact with autonomous aldosterone excess to bring about cardiovascular damage in patients with primary aldosteronism. The lack of a positive correlation between plasma aldosterone and left ventricular dimensions in patients with primary aldosteronism raises the possibility that, above a certain threshold, aldosterone plays a more permissive part, whereas salt has a more graduated effect. Either way, these results argue for a role of dietary salt restriction to reduce the risk of cardiovascular disease in patients with primary aldosteronism. Endocrine Hypertension Research Center, University of Queensland School of Medicine, Greenslopes and Princess Alexandra Hospitals, Ipswich Road, Woolloongabba, Brisbane 4102, Australia. m.stowasser@uq.edu.au Competing interests The author declares no competing interests. 1.
Sutherland, D. J., Ruse, J. L. & Laidlaw, J. C. Hypertension, increased aldosterone secretion and low plasma renin activity relieved by
dexamethasone. Can. Med. Assoc. J. 95, 1109–1119 (1966). 2. Lifton, R. P. et al. Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase. Nat. Genet. 2, 66–74 (1992). 3. Stowasser, M., Pimenta, E. & Gordon, R. D. Familial or genetic primary aldosteronism and Gordon syndrome. Endocrinol. Metab. Clin. North Am. 40, 343–368, viii (2011). 4. Mulatero, P. et al. Prevalence and characteristics of familial hyperaldosteronism: the PATOGEN study (Primary Aldosteronism in TOrino-GENetic forms). Hypertension 58, 797–803 (2011). 5. Choi, M. et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 331, 768–772 (2011). 6. Geller, D. S. et al. A novel form of human mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism. J. Clin. Endocrinol. Metab. 93, 3117–3123 (2008). 7. Gordon, R. D., Hamlet, S. M., Tunny, T. J. & Klemm, S. A. Aldosterone-producing adenomas responsive to angiotensin pose problems in diagnosis. Clin. Exp. Pharmacol. Physiol. 14, 175–179 (1987). 8. Tunny, T. J., Gordon, R. D., Klemm, S. A. & Cohn, D. Histological and biochemical distinctiveness of atypical aldosteroneproducing adenomas responsive to upright posture and angiotensin. Clin. Endocrinol. (Oxf.) 34, 363–369 (1991). 9. Wu, V. C. et al. Endothelial progenitor cells in primary aldosteronism: a biomarker of severity for aldosterone vasculopathy and prognosis. J. Clin. Endocrinol. Metab. 96, 3175–3183 (2011). 10. Pimenta, E. et al. Cardiac dimensions are largely determined by dietary salt in patients with primary aldosteronism: results of a case– control study. J. Clin. Endocrinol. Metab. 96, 2813–2820 (2011).
POLYCYSTIC OVARY SYNDROME IN 2011
Genes, aging and sleep apnea in polycystic ovary syndrome Andrea Dunaif
Polycystic ovary syndrome (PCOS) is a complex genetic disease that affects approximately 7% of women of reproductive age worldwide. From novel pathways implicated in the etiology of PCOS through genome-wide association to characterization of the reproductive and metabolic changes that occur in ageing women with PCOS, the year 2011 has seen a number of studies published that highlight the intricacies of this condition. Dunaif, A. Nat. Rev. Endocrinol. 8, 72–74 (2012); published online 20 December 2011; doi:10.1038/nrendo.2011.227
The year 2011 saw the advent of the first genome-wide association study (GWAS) in polycystic ovary syndrome (PCOS).1 GWAS have been widely used, since the publication of the human haplotype map in 2005, to localize susceptibility genes for complex traits, such as obesity and type 2 diabetes
mellitus (T2DM).2 This analysis permits an unbiased examination of the entire genome for novel disease susceptibility loci and, unlike candidate gene approaches, is hypothesis-generating. 2 The first GWAS of PCOS was conducted in Han Chinese women with PCOS, who were diagnosed www.nature.com/reviews