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their origin? Do KCNJ5 mutations bestow ZF-like characteristics (including his tol-ogy, 17α-hydroxylase expression, hybrid steroid formation, and loss of aldosterone responsive ness 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 endo-thelial 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- sensitivity 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 acti-vating 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 aldo-sterone-induced cardiovascular damage; how ever, corroborative data in humans were lack ing. In a case–control study of 21 patients with primary aldosteronism and 21 matched individuals with essential hyperten sion, Pimenta and co-workers reported in 2011

that patients with primary aldosteronism had greater thickness of the left ventricular wall, end-diastolic dia meter and mass. More-over, urinary sodium excretion, a mar ker of dietary salt intake, positively correlated with and was an indepen dent predictor of left ventricular wall thickness and mass in patients with pri mary aldosteronism, but not in those with essential hypertension.10 Hence, as in animal studies, salt appears to interact with auto nomous aldosterone excess to bring about cardio vascular damage in patients with primary aldosteronism. The lack of a posi tive correlation between plasma aldoster one and left ventricular dimen sions in patients with primary aldosteronism raises the possibility that, above a certain thres hold, aldosterone plays a more permis-sive 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 cardiovascu lar 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 interestsThe 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

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

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 aldosterone-producing 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 syndromeAndrea 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 publica-tion of the human haplotype map in 2005, to localize susceptibility genes for com plex traits, such as obesity and type 2 dia betes

mellitus (T2DM).2 This analysis per mits 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

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using the Rotterdam cri teria (two of three of the following findings: oligomenor rhea, hyperandrogen ism and/or poly cystic ovaries detected on ultrasono graphy).1 Asso cia tions achiev ing genome-wide levels of signifi-cance3 between PCOS and loci on chromo-somes 2p16.3 (OR 0.71), 2p21 (OR 0.67) and 9q33.3 (OR 1.34) were observed in a dis covery sample of 744 PCOS cases and 895 con trols and in two indepen dent replica-tion cohorts of 2,840 PCOS cases and 5,012 controls, and 498 PCOS and 780 controls.1

Several known genes are located near the locus at 2p16.3, which showed the great est association with PCOS, includ ing GTF2A1L and LHCGR. GTF2A1L, which encodes TFIIAα/β-like factor (ALF), is a germ-cell-specific transcription factor that is highly expressed in adult testis and may play a part in spermato genesis. How varia-tion in GTF2A1L might contribute to PCOS is unclear. LHCGR encodes the lutropin– choriogonadotropic hormone recep tor (LH/CG-R) and is a highly plau si ble PCOS candidate gene. The strongest asso ci ation at the locus on chromo some 2p21 was with THADA, a gene origi nally iden tified in thy -roid adenomas. A GWAS in white indivi-duals of European ances try reported an associa tion of THADA with T2DM.4 The region on chromosome 9q33.3 associ ated with PCOS was located within DENND1A, which encodes a domain differen tially expressed in normal and neoplastic cells (DENN) that can bind to and negatively regulate endo plasmic reticulum amino-peptidase 1. Elevations of circulating endo-plasmic reti culum amino peptidase 1 have been reported in obese women with PCOS. Thus, it is possible that varia tion in THADA and DENND1A contribute to T2DM and obesity risk in women with PCOS.

Confirmation that the GWAS signals reflect a variation in these genes, rather than in other genes that are in linkage dis-equilibrium with these loci, requires fur-ther genetic analyses. In addition, the roles of these loci in PCOS suscepti bility in other racial or eth nic groups and in other pheno-types, for instance, in women with PCOS diag nosed using the National Insti tute of Child Health and Human Develop ment (NICHD) criteria (history of oligo menorrhea and clinical and/or biochemi cal evidence of hyper androgenism), will require further investigation. Studies in monozygotic twins indicate that the herit ability of PCOS is close to 80%. However, the loci identified in the PCOS GWAS confer modest (~30%) changes in disease risk and do not account

in postmenopausal women with PCOS compared with postmenopausal control women. Furthermore, they found persistent evidence for insulin resistance and increased inflammation, independent of BMI, in post-menopausal women with PCOS compared to those without the disease.

In a 2011 prospective study, Schmidt et al.8 diagnosed PCOS on the basis of ovarian histology from ovarian wedge resec tion or unilateral oophorectomy per formed in 1956–1965. These women were examined in 1987 and compared with control women from a population-based study. Both groups were recalled for repeat examination in 2008, in their eighth decade of life. The PCOS group had higher FAI and lower follitropin (also known as follicle-stimulating hormone; FSH) and SHBG levels than the control group, as was the case in 1987. DHEAS, total testo sterone and androstenedione levels were significantly increased in premenopausal women with PCOS in 1987, but were similar to those of the control group after meno-pause. The prevalence of hypo thyroidism was lower in post menopausal women with PCOS than in control individuals.

Taken together, these three studies6,7,8 sug-gest that hyperandrogenism of both ova rian and adrenal origin, as well as insulin resis-tance, persist in postmenopausal women with PCOS. Increased androgen levels declined with age in older post menopausal women with PCOS such that only differ-ences in FAI were present in women aged >70 years.8 By contrast, decreases in SHBG and FSH levels persist into old age. All of the studies are limited by small sample sizes, which might account for the differences in the prevalence of hypothyroidism. In

Key advances

■ Three genetic susceptibility loci have been mapped by genome-wide association study in Han Chinese women with PCOS1

■ Increased ovarian and adrenal androgen production and insulin resistance persist in postmenopausal women with PCOS6,7,8

■ Obstructive sleep apnea contributes to insulin resistance and continuous positive airway pressure improves insulin sensitivity in women with PCOS10

for the observed herit ability of PCOS.5 This so-called ‘missing heritability’ has been seen in other common complex traits, such as T2DM, and might reflect the fact that rare rather than common variants contribute to complex diseases.5 Nevertheless, GWAS has been important for implicating novel b iologic pathways in disease pathogenesis.

Little was known about the reproductive and metabolic changes that occur with age in women with PCOS. In 2011, two cross-sectional studies compared postmenopausal women in the sixth decade of life with and without PCOS.6,7 In both studies, the diagnosis of PCOS was made on the basis of the NICHD diagnostic criteria, although the study by Puurunen et al.7 also con-tained premenopausal women with PCOS diagnosed by the Rotterdam criteria and a control group consisting of reproductively normal, premenopausal women. The study by Markopoulos et al.6 found that post-menopausal women with PCOS had sig-nificantly elevated levels of circulating total testosterone, androstenedione, dehydro-epiandrosterone sulfate (DHEAS) and 17-hydroxyprogesterone and an increased free androgen index (FAI). Sex hormone-binding globulin (SHBG) levels, how ever, were significantly decreased compared with the control group. No evidence of increased sensitivity to cor-ticoliberin (also known as corticotropin- releasing hormone) or adreno-cortico tro pic hormone was reported in women with PCOS, which sug-gests that increases in adrenal androgen production did not result from changes in responsive-ness to tropic hor mones. Dexamethasone suppression sug gested that elevated total testosterone and DHEAS levels were partly adrenal in origin. Puurunen et al.7 also found increased androstenedione levels, basally and in response to chorio gonado tropin,

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the cross-sectional studies, the accuracy of diagnosis of PCOS on the basis of medical records is a potential limitation, although oligo menorrhea and symptoms of androgen excess, such as hirsutism, have been shown to be excellent proxies for PCOS.9

The prevalence of obstructive sleep apnea (OSA) is significantly increased in women with PCOS, independent of obesity—a well-known risk factor for OSA. Androgen levels and insulin resistance are positively associ-ated with OSA in PCOS. In 2011, Tasali and colleagues proposed that OSA contributes to insulin resistance in PCOS, as it does in other OSA populations.10 The investigators directly tested this hypothesis by treating affected women with continuous positive airway pressure (CPAP), which resulted in a modest but significant improvement in insulin sensitivity.10 A dose–response effect of CPAP on insulin sensitivity was observed, with greater improvements in sensitivity with longer duration of CPAP. A signifi-cant decrease in circulating norepinephrine levels was also reported, without changes in epinephrine, cortisol or leptin levels. This observation suggests that the decrease in insulin sensitivity is mediated by sympa-thetic nervous system activation. Diastolic blood pressure, which was not elevated in women with PCOS who had OSA, decreased significantly with CPAP.

The limitations of this study were the small number of women (n = 9) who completed the CPAP intervention with acceptable com-pliance (≥4 h of use per night).10 Further-more, the study population was extremely obese, with a mean BMI of 48.4 kg/m2. The improvements in insulin sensitivity, although significant, were very modest (on average 7%); the study par ticipants remained profoundly insulin resistant after CPAP treatment. Modeling of the data suggested that the beneficial effect of CPAP would be greater in overweight or mildly obese patients with PCOS. How ever, the robust-ness of the model is questionable given the small sample size. Never the less, this study suggests that OSA con tributes to insulin resistance in PCOS and that CPAP improves insulin sensitivity in affected women.

In conclusion, these 2011 publications will have a major effect on the field. It is now clear from an adequately powered and rep-licated study that genetic variation contri-butes to the etiology of PCOS. Furthermore, reproductive and metabolic features of the dis order persist beyond the reproductive years, increasing the impact of PCOS as a leading women’s health issue. Finally, a

component of the insulin resistance associ-ated with PCOS is secondary to OSA and improves with CPAP treatment.

Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Tarry 15‑745, Chicago, IL 60611, USA. a‑dunaif@northwestern.edu

Competing interestsThe author declares no competing interests.

1. Chen, Z. J. et al. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat. Genet. 43, 55–59 (2011).

2. Hirschhorn, J. N. & Daly, M. J. Genome-wide association studies for common diseases and complex traits. Nat. Rev. Genet. 6, 95–108 (2005).

3. Hoggart, C. J., Clark, T. G., De Iorio, M., Whittaker, J. C. & Balding, D. J. Genome-wide significance for dense SNP and resequencing data. Genet. Epidemiol. 32, 179–185 (2008).

4. Zeggini, E. et al. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat. Genet. 40, 638–645 (2008).

5. Manolio, T. A. et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009).

6. Markopoulos, M. C. et al. Hyperandrogenism in women with polycystic ovary syndrome persists after menopause. J. Clin. Endocrinol. Metab. 96, 623–631 (2011).

7. Puurunen, J. et al. Unfavorable hormonal, metabolic, and Inflammatory alterations persist after menopause in women with PCOS. J. Clin. Endocrinol. Metab. 96, 1827–1834 (2011).

8. Schmidt, J., Brännström, M., Landin-Wilhelmsen, K. & Dahlgren, E. Reproductive hormone levels and anthropometry in postmenopausal women with polycystic ovary syndrome (PCOS): a 21-year follow-up study of women diagnosed with PCOS around 50 years ago and their age-matched controls. J. Clin. Endocrinol. Metab. 96, 2178–2185 (2011).

9. Taponen, S. et al. Hormonal profile of women with self-reported symptoms of oligomenorrhea and/or hirsutism: Northern Finland Birth Cohort 1966 Study. J. Clin. Endocrinol. Metab. 88, 141–147 (2003).

10. Tasali, E., Chapotot, F., Leproult, R., Whitmore, H. & Ehrmann, D. A. Treatment of obstructive sleep apnea improves cardiometabolic function in young obese women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 96, 365–374 (2011).

EPIGENETICS AND METABOLISM IN 2011

Epigenetics, the life-course and metabolic diseasePeter D. Gluckman

Clinical and experimental studies suggest that early life experiences, perhaps spanning multiple generations, affect lifelong risk of metabolic dysfunction through epigenetic mechanisms. Data published in 2011 suggest that epigenetic analysis could potentially have utility as a marker of early metabolic pathology and might enable early life prophylaxis.Gluckman, P. D. Nat. Rev. Endocrinol. 8, 74–76 (2012); published online 20 December 2011; doi:10.1038/nrendo.2011.226

Both population and individual variation in sus ceptibility to an obesogenic environ-ment exist. Genome-wide association studies have been disappointing in explaining this variation, and there is a growing focus on possible epigenetic explanations. Epigenetic variation is most likely to arise early in the life-course. An extensive body of experimen-tal, clini cal and epidemiological evidence demon strates that early life develop mental factors— including the maternal diet, but operating within the normative range of develop mental exposures—affect the risk of developing meta bolic disease later in life.1 This phe nomenon is sometimes termed developmental programming. The early observations were largely ignored because of the absence of a plausible biological

mechanism, but explana tions developed over the past decade have been framed in terms of developmental plasticity—the

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