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ENDOCRINOLOGY
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 wellknown
risk factor for OSA. Androgen levels
and insulin resistance are positively associated
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 significant
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 sympathetic
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 compliance
(≥4 h of use per night). 10 Furthermore,
the study population was extremely
obese, with a mean BMI of 48.4 kg/m 2 .
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 robustness
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 replicated
study that genetic variation contributes
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 associated
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 interests
The author declares no competing interests.
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EPIGENETICS AND METABOLISM IN 2011
Epigenetics, the life-course
and metabolic disease
Peter 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 environment
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 experimental,
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
adaptive processes enabling an organism
to respond to environmental cues acting in
early life and adjust its develop mental trajectory.
Developmental plasticity is at least
partly underpinned by epigenetic mechanisms,
including DNA methylation and
histone modifications. A number of papers
published during 2011 have re inforced the
validity of these conclusions.
Extensive previous work has shown that
rats whose mothers are underfed during
preg nancy and lactation develop an insulin
resis tant and obese phenotype in adulthood.
Moreover, mice lacking the transcription
factor hepatocyte nuclear factor 4α
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