open access: Nature Reviews: Key Advances in Medicine

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 significance
3 between PCOS and loci on chromosomes
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 replication
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 variation
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 individuals
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 aminopeptidase
1. Elevations of circulating endoplasmic
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 disequilibrium
with these loci, requires further
genetic analyses. In addition, the roles
of these loci in PCOS suscepti bility in other
racial or eth nic groups and in other phenotypes,
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
Key advances
■ Three genetic susceptibility loci
have been mapped by genome-wide
association study in Han Chinese women
with PCOS 1
■ Increased ovarian and adrenal androgen
production and insulin resistance persist
in postmenopausal women with PCOS 6,7,8
■ Obstructive sleep apnea contributes
to insulin resistance and continuous
positive airway pressure improves insulin
sensitivity in women with PCOS 10
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 crosssectional
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 contained
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 postmenopausal
women with PCOS had significantly
elevated levels of circulating total
testosterone, androstenedione, dehydroepiandrosterone
sulfate (DHEAS) and
17-hydroxyprogesterone and an increased
free androgen index (FAI). Sex hormonebinding
globulin (SHBG) levels, how ever,
were significantly decreased compared
with the control group. No evidence of
increased sensitivity to corticoliberin
(also known as
corticotropin- releasing
hormone) or adrenocortico
tro pic hormone
was reported in women
with PCOS, which suggests
that increases in
adrenal androgen production
did not result from changes in responsiveness
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,
ENDOCRINOLOGY
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 postmenopausal
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 menopause.
The prevalence of hypo thyroidism
was lower in post menopausal women with
PCOS than in control individuals.
Taken together, these three studies 6,7,8 suggest
that hyperandrogenism of both ova rian
and adrenal origin, as well as insulin resistance,
persist in postmenopausal women
with PCOS. Increased androgen levels
declined with age in older post menopausal
women with PCOS such that only differences
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
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