open access: Nature Reviews: Key Advances in Medicine

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-I 4
■ A germline mutation in KCNJ5 is
associated with severe, early-onset
familial primary aldosteronism, and
somatic KCNJ5 mutations are common in
aldosterone-producing adenoma 5
■ Patients with primary aldosteronism have
reduced circulating levels of endothelial
progenitor cells, which might contribute
to the development of vasculopathy in
these individuals 9
■ The degree of left ventricular enlargement
in primary aldosteronism is largely
determined by dietary salt; dietary salt
restriction might reduce cardiovascular
risk in this condition 10
their origin? Do KCNJ5 mutations bestow
ZF-like characteristics (including his tology,
17α-hydroxylase expression, hybrid
steroid formation, and loss of aldosterone
responsive ness to angiotensin-II) to ZG
cells, or are ZG-like characteristics (aldosterone
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 cardiovascular
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 aldosteronism
(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 unilateral
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 critical
role for salt in the development of aldosterone-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. Moreover,
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 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 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 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
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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 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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