A guide to understanding polycystic ovary syndrome (PCOS)

Abstract

Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder affecting women of reproductive age. Some 20% of women will have polycystic ovaries on an ultrasound scan and around 7% of women have the additional clinical or biochemical features of PCOS. As a complex multisystem disorder its background can be confusing to understand. They key feature, however, is an increased production of androgen by the ovaries. This review uses ovarian biology to describe a strategy to aid understanding and explanation of PCOS. This framework can be also be used to teach about PCOS and to inform different approaches to its management.

Full text

A guide to understanding polycystic
ovary syndrome (PCOS)
W Colin Duncan
Scottish Senior Clinical Fellow
and Consultant in Reproductive
Medicine, MRC Centre for
Reproductive Health, The
University of Edinburgh,
Edinburgh, UK
Correspondence to
Dr W Colin Duncan,
MRC Centre for Reproductive
Health, The Queen’s Medical
Research Institute, The University
of Edinburgh, 47 Little France
Crescent, Edinburgh
EH16 4TJ, UK;
W.C.Duncan@ed.ac.uk
Received 18 June 2013
Revised 10 January 2014
Accepted 6 February 2014
Published Online First
3 March 2014
To cite: Duncan WC. JFam
Plann Reprod Health Care
2014;40:217–225.
ABSTRACT
Polycystic ovary syndrome (PCOS) is the
commonest endocrine disorder affecting women
of reproductive age. Some 20% of women will
have polycystic ovaries on an ultrasound scan
and around 7% of women have the additional
clinical or biochemical features of PCOS. As a
complex multisystem disorder its background can
be confusing to understand. They key feature,
however, is an increased production of androgen
by the ovaries. This review uses ovarian biology
to describe a strategy to aid understanding and
explanation of PCOS. This framework can be also
be used to teach about PCOS and to inform
different approaches to its management.
INTRODUCTION
Polycystic ovary syndrome (PCOS) is the
commonest endocrine disorder to affect
women in their reproductive years.
Around 20% of women have the charac-
teristic appearance of polycystic ovaries
on ultrasound scans
1
and 7–8% have the
additional clinical and biochemical fea-
tures of PCOS itself.
2
As obesity increases
the proportion of women with polycystic
ovaries who develop the syndrome, the
current epidemic of obesity is likely to
make PCOS even more common.
3
Polycystic ovaries found on ultrasound
scanning will often have no clinical
effects, but PCOS is the most common
diagnosis made in women presenting
with amenorrhoea, oligomenorrhoea or
heavy, irregular and prolonged periods. It
is the commonest cause of hirsutism and
of infertility due to anovulation. Women
with PCOS have increased concentrations
of circulating androgens and there is a
marked association with insulin resist-
ance, dyslipidaemia, obesity, gestational
diabetes, type 2 diabetes and heart
disease. In addition, it is an established
cause of endometrial hyperplasia and it is
therefore linked to endometrial cancer.
The short- and long-term consequences
of PCOS represent an increasing burden
on health resources.
In recent years there has been increas-
ing consensus about the criteria required
to establish the diagnosis of PCOS. Two
out of the three features below are used
when other causes of those clinical fea-
tures have been excluded.
4
Exclusion of
these other, much rarer, causes often
needs no more than a routine clinical
assessment.
The three features are:
▸anovulation or oligo-ovulation;
▸the presence of polycystic ovaries on
pelvic ultrasonography;
▸clinical and/or biochemical signs of
hyperandrogenism.
While awareness of PCOS, its diagnosis
and associated morbidity is high, its basic
pathophysiology is often poorly under-
stood. This article presents a framework
for teaching and increasing understanding
about the causes and management of
PCOS.
AN APPROACH TO TEACHING AND
LEARNING ABOUT PCOS
Undergraduate students, nurses, specialist
trainees and even trained gynaecologists
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Key message points
▸Polycystic ovary syndrome (PCOS) is a
common condition affecting 7% of
women but its background can be con-
fusing to understand.
▸The key feature is increased production
of androgen by the ovaries.
▸Understanding ovarian biology clarifies
pathways to androgen increase and
provides a framework to facilitate
teaching on PCOS.
▸This approach can be also used to
inform management strategies.
REVIEW
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often find PCOS difficult to understand, particularly
as the clinical features vary from patient to patient.
One strategy that can be used when teaching about
PCOS is to go back to basic ovarian biology and to
use that as a starting point. This leads to a framework
that lends itself to formal presentation, but also to
informal illustrations in the clinic or in a tutorial. In
addition it allows the management strategies to be
described and understood. While different experts
may have alternative views of its pathophysiological
basis, and some assumptions can be questioned, the
following model gives a useful framework to build
upon and to introduce key concepts and management
pathways.
In this framework there are six stages of develop-
ment of information on the biology of the ovary and
the factors that interact with it that help to clarify the
background to the development of PCOS. Knowledge
of these stages is then used as the key to understand-
ing the approaches available for its management.
How follicles make estrogen
The first stage in this approach is to look at the pro-
duction of sex steroids, particularly estradiol, within
the ovarian follicle (Figure 1a). The follicle has two
steroidogenic cell layers: the outer theca cell layer and
the inner granulosa cell layer, separated by a basement
membrane
5
(Figure 1b). It is the granulosa cells that
are responsible for the synthesis and secretion of estra-
diol. They do this initially under the stimulation of
follicle-stimulating hormone (FSH) from the anterior
pituitary gland, which binds to and activates their
FSH receptors
6
(Figure 1c).
Estradiol is a sex steroid and all steroids are derived
from cholesterol.
7
Cholesterol therefore has to be
changed into estradiol by enzymatic modification
through a series of intermediate steroids. In the pathway
from cholesterol to estrogen, the step before estrogen is
androgen (Figure 1d). Androgen is converted into estro-
gen by the action of the aromatase enzyme
7
(Figure 1e).
Granulosa cells contain large amounts of aromatase but
they do not express the proteins and enzymes (steroido-
genic acute regulatory protein, cholesterol side chain
cleavage enzyme, 3β-hydroxysteroid dehydrogenase and
17α-hydroxylase) that are required for the conversion
of cholesterol into androgen, so they cannot produce
androgen themselves (Figure 1f).
As they cannot synthesise the androgen substrate, in
order to make estradiol the granulosa cells need to get
androgen from another source. The androgen is made
in the theca cells and converted into estrogen in the
granulosa cells (Figure 2a). Theca cells produce andro-
gen under the stimulation of luteinising hormone
(LH) from the anterior pituitary gland, which acti-
vates their LH receptors (Figure 2b).
8
Thus to facili-
tate follicular estradiol secretion, LH causes the
production of androgen from cholesterol in theca
cells, and FSH promotes the conversion of those
androgens into estrogens in the granulosa cells
(Figure 2c). This synergy between the theca and gran-
ulosa cells is known as the two-cell, two-
gonadotrophin model of estrogen synthesis
9
and the
hormones are physiologically balanced (Figure 2d).
The effect of increased androgen on the ovary
The second stage in describing the development of
PCOS is to highlight that the development of a poly-
cystic ovary is associated with increased exposure to
androgens as these have their own effects on follicular
growth and development. A polycystic ovary contains
an increased number of small antral follicles which are
the small fluid-filled follicles that are seen on
naked-eye inspection of opened polycystic ovaries and
are clearly visible on ultrasound scanning. They are
Figure 1 The pathway involved in estrogen synthesis in the ovary. Granulosa cells (G), theca cells (T) and the oocyte (O) are the key
cells in the follicle. It produces estradiol (E) from cholesterol (C) after stimulation by follicle-stimulating hormone (FSH), with androgen
(A) as an intermediary. See text for an explanation of stages a–f.
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not ’cysts’as they contain a potentially healthy
oocyte
10
and they can be stimulated to grow normally
by exogenously administered FSH.
11
This is why
women with PCOS are at a much greater risk of
developing ovarian hyperstimulation syndrome after
administration of FSH during assisted conception.
12
The ovarian ‘cysts’in PCOS are therefore essentially
paused follicles, with reduced cell growth as well as
reduced cell death (atresia).
Androgen inhibits the growth of larger antral folli-
cles but, if anything, stimulates the growth of smaller
antral follicles (Figure 3a–c). Treating rhesus monkeys
with normal ovaries with exogenous androgen for just
10 days resulted in a polycystic ovarian morphology,
with an increased proportion of small antral follicles
showing more cell proliferation in smaller follicles
and less atresia in the remaining follicles.
13
This high-
lights the ability of androgen to promote follicular
growth and survival, inhibit later follicular develop-
ment and directly cause a polycystic ovarian
morphology.
Clinically, this polycystic ovarian morphology is
associated with increased endogenous androgens.
Conditions in which endogenous androgen levels are
pathologically raised include androgen-secreting
tumours and late-onset congenital adrenal hyperplasia,
in which adrenal androgen secretion is increased.
14
Women with both these conditions develop polycystic
ovaries.
15
The response of the ovary to increased
androgens is therefore the development of a polycystic
morphology and inhibition of later follicular growth.
This results in an increased incidence of anovulation.
Why the ovary might experience more androgen
The third stage is to discuss the mechanisms by which
the ovary might be exposed to increased local andro-
gen concentrations. Using the two-cell, two-
gonadotrophin model illustrated in Figure 2d it can be
demonstrated that if a hormone imbalance occurred,
such that circulating LH concentrations were higher
than FSH concentrations, ovarian androgen produc-
tion would increase (Figure 4a). Previously an
increased LH:FSH ratio was thought to be required
for the diagnosis of PCOS. This is no longer part of
the diagnostic criteria, which focus on the resulting
increased androgens.
4
However, it is clear that women
with PCOS are more likely to have increased basal LH
concentrations
16
as well as increased LH pulse ampli-
tude and frequency.
17
While chronic anovulation can result in raised LH
concentrations,
18
it is likely that the LH:FSH imbal-
ance is something that women with a tendency to
PCOS are born with and that this causes anovulation.
There is increasing evidence from human and animal
models that PCOS can be programmed by increased
fetal exposure to androgen before birth.
19 20
This
may permanently programme increased basal LH
secretion
21
as well as augmenting the amount of LH
released in response to gonadotrophin-releasing
hormone (GnRH)
22
and thus the amplitude of LH
Figure 2 Illustration highlighting the two-cell two-gonadotrophin model of ovarian estradiol synthesis and its regulation. Luteinising
hormone (LH) stimulates androgen (A) from theca cells which are converted to estrogen (E) in granulosa cells by follicle-stimulating
hormone (FSH). See text for an explanation of stages a–d.
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pulses. One way the ovary can be exposed to
increased androgen is therefore by an increased LH:
FSH ratio, which may be prenatally programmed.
Regulation of androgen action
The fourth stage is to describe a regulator of androgen
bioavailability. This could be imagined as a ‘sponge’
that can mop up excess androgen (Figure 4b) in order
to prevent it affecting follicular growth and develop-
ment. The sponge could normalise slightly increased
ovarian androgen production (Figure 4c). However, if
the sponge is small it would not fully mop up the
excess androgens that are normally produced during
follicular estrogen synthesis (Figure 4d). That means
that there may be increased androgen bioavailability
in the presence of normal LH concentrations –and if
there is an increased LH:FSH ratio a small sponge
would augment the increased androgen exposure
(Figure 4e).
That ‘sponge’exists in the form of sex hormone
binding globulin (SHBG), the circulating protein that
binds to and inhibits androgens and to a lesser extent
estrogens (Figure 4f). For the purpose of this frame-
work it is now useful to highlight that SHBG is
inversely related to weight (Figure 4g).
23
As weight
increases, SHBG decreases and androgen availability
will therefore increase (Figure 4h). This means that
polycystic ovaries or PCOS will worsen. Conversely,
as weight reduces SHBG will increase and bioavailable
androgen will decrease (Figure 4i), meaning that
PCOS will improve. Weight is therefore a controller of
LH action on the ovary and thus the effects of LH
will be exaggerated by obesity.
Regulation of androgen synthesis
The fifth stage is to focus on the molecular regulation
of LH-dependent androgen synthesis by the theca
cells (Figure 5a). The key here is to imagine the effect
that a multiplier of LH action would have at the level
of the theca cell (Figure 5b). The presence of a multi-
plier would augment androgen production for a given
concentration of LH. That means that ovarian andro-
gen could be increased in the presence of normal con-
centrations of LH (Figure 5c).
That multiplier exists in the form of insulin
(Figure 5d). This ubiquitous hormone regulates
glucose transport and has growth factor and anabolic
actions.
24
It is also a co-factor that augments
LH-induced thecal androgen secretion.
25 26
In the
presence of peripheral insulin resistance (IR), which is
a precursor to impaired glucose tolerance, increased
insulin concentrations are required to promote
glucose uptake in tissues with a key metabolic role,
such as muscle and fat. While these may be resistant
to the metabolic effects of insulin, the ovary remains
sensitive to its growth factor effects. The hyperinsuli-
naemia associated with IR therefore means that more
androgen will be produced in the ovary. As IR
worsens and insulin concentrations rise, ovarian
androgens will increase and PCOS will worsen
(Figure 5e). If IR improves and insulin concentrations
fall, ovarian androgens will reduce and PCOS will
improve (Figure 5f).
Figure 3 Diagram highlighting the role of androgens (A) in the
conversion of a normal ovary to one with a polycystic ovarian
morphology. See text for an explanation of stages a–c.
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Interaction between weight and IR
The sixth and final stage in understanding the caus-
ation of PCOS pulls together the information gained
in the first five stages. As LH-induced androgen con-
centrations can be modified both by weight (through
SHBG change) and by insulin, this can alter the
degree by which PCOS is manifested. However the
mechanism is not so straightforward, as insulin is an
anabolic hormone and the hormone of energy
storage.
27
That means that high levels of insulin are
Figure 4 Illustration highlighting the ‘sponge’analogy for the role for sex hormone binding globulin (SHBG) in reducing luteinising
hormone (LH)-dependent thecal androgen (A) availability, and the link of SHBG to weight and to the increase in free androgen when
its level reduces. This does not affect follicle-stimulating hormone (FSH)-stimulated estradiol (E) secretion. See text for an explanation
of stages a–i.
Figure 5 Illustration highlighting the role of insulin in augmenting luteinising hormone (LH)-dependent thecal androgen (A)
synthesis, and the reduction in that synthesis if hyperinsulinaemia improves. Follicle-stimulating hormone (FSH)-driven estradiol (E)
synthesis continues. See text for an explanation of stages a–f.
Review
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associated with ease of weight gain and difficulty in
weight loss (Figure 6a).
28
As weight increases, IR
increases and circulating insulin levels rise,
29
produ-
cing a vicious cycle with weight and IR linked
together (Figure 6b). Insulin itself can inhibit hepatic
SHBG synthesis.
30
There are therefore three drivers to increased
ovarian androgen production: increased LH, hyperin-
sulinaemia and increased weight (Figure 6c). So slim
women with PCOS have more elevation in LH than
obese women with PCOS.
31
While some women with
PCOS primarily have a high LH:FSH ratio, some are
primarily insulin resistant and some have a major
weight problem. The common consequence is the
augmentation of androgens that results in PCOS
(Figure 6d). In reality most women with PCOS will
have each of these drivers in varying degrees.
A FRAMEWORK FOR THE MANAGEMENT
OF PCOS
The model where LH-stimulated androgen action is
augmented by weight and insulin (Figure 6d) provides
a useful framework with which to understand PCOS
and to explain it to patients and students. But it also
provides a useful approach to describe the strategies
available for the management of patients with PCOS.
The foci could be targeting gonadotrophin concentra-
tions, reducing weight, lowering insulin or
ameliorating the systemic effects of ovarian dysfunc-
tion and increased androgen levels.
Targeting gonadotrophins
Any treatment that lowers circulating LH concentra-
tions will reduce ovarian androgen production and
improve PCOS (Figure 7a). We do not yet have a
treatment to specifically lower LH, so treatment gen-
erally involves reducing both LH and FSH. The main
way to do that is with the combined oral contracep-
tive pill (COC), which is the mainstay of the manage-
ment of PCOS
32
if pregnancy is not desired. Any
COC will do this effectively, although it has been
argued that the more recent, less androgenic pills may
be particularly useful.
33
As half the androgens in
women come from the adrenal gland,
34
the combin-
ation of ethinylestradiol with an anti-androgen such as
cyproterone acetate (co-cyprindiol), or a higher dose
of cyproterone acetate in a reverse-sequential
regimen,
35
may have additional benefit for certain
androgenic symptoms, particularly hirsutism.
For fertility treatment, the strategy is to raise FSH
levels to facilitate the conversion of androgens into
estrogens in order to remove the brake on follicle
growth. As estrogens feed back to inhibit FSH secre-
tion, the use of estrogen antagonists, such as clomi-
fene citrate, or aromatase inhibitors such as letrozole,
will raise FSH and improve ovarian function.
However estrogen is needed for endometrial growth
Figure 6 Drawing illustrating the interaction between weight and insulin resistance, leading to augmentation of luteinising
hormone (LH)-stimulated androgen (A) secretion, resulting in development of polycystic ovary syndrome (PCOS). See text for an
explanation of stages a–d.
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and to stimulate the ovulatory LH surge. Treatment is
therefore given only for 5 days at the beginning of the
cycle, either from Day 2 or Day 3. If treatment with
anti-estrogens at various doses is not effective, then
FSH may be directly raised by injections.
Gonadotrophin ovulation induction is very successful
in the management of subfertility secondary to anovu-
lation in PCOS.
36
Targeting weight
Weight loss improves the symptoms PCOS in both
non-fertility and fertility contexts (Figure 7b). In the
fertility setting the results are quite dramatic.
37 38
Thus a weight loss strategy is very important in the
management of all overweight and obese women with
PCOS. A loss of 10% of body weight increased fertil-
ity, ovulation rate and menstrual regularity even when
women remained obese.
37
In addition there were
associated improvements in serum biochemistry, blood
pressure and self-esteem scores.
37 38
It is important to
highlight diet, with an emphasis on developing a
weight maintenance/weight loss cycle involving
regular small healthy meals, not skipping meals and
avoiding refined carbohydrate.
39
However, increased
physical activity should always be a key message in
weight management. Even in the absence of weight
loss, exercise improves PCOS.
40
Targeting insulin
Metformin treatment improves insulin sensitivity, thus
enhancing glucose clearance, resulting in reduced
circulating insulin concentrations (Figure 7c). There is
no doubt that metformin can have beneficial effects in
some women with PCOS.
41 42
It can improve feelings
of wellbeing, ovarian cyclicity and fertility as a main
or as adjunct therapy.
43
While metformin reduces
hyperinsulinaemia
44
and improves metabolic para-
meters, its effect on weight loss is more controver-
sial.
45
The degree of weight loss may relate to how
engaged the patient is with a concurrent weight-loss
programme. Recent results with metformin have been
less impressive than initially reported.
46
As not all
women with PCOS benefit equally from metformin it
may be that the key is adequate patient selection.
More research is needed into such personalised medi-
cine. However, metformin remains one of the tools
available in the management of PCOS. The data on its
prolonged use and discontinuation are scanty and
variable, so it should not yet be used in the long-term
with a goal of preventing future health problems.
47–49
A current improvement in symptoms associated with
PCOS seems a sensible rationale for its continuation.
Holistic targeting
One of the main areas to focus on is endometrial pro-
tection. Women with PCOS who are anovulatory are
exposed to unopposed estrogen and are at risk of
both prolonged heavy bleeding and the development
of endometrial hyperplasia.
50
It is generally advocated
that women with PCOS who are amenorrhoeic should
have three or four periods (in the form of withdrawal
bleeds) a year to maintain endometrial health.
51
A
Figure 7 Illustration highlighting the roles of luteinising hormone (LH), increased weight and hyperinsulinaemia in raising
intraovarian androgen (A) that results in polycystic ovary syndrome (PCOS). See text for an explanation of stages a–d.
Review
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common strategy is to use an intermittent progestogen
such as medroxyprogesterone acetate 10 mg twice
daily for 7 days or once daily for 10 days. A few days
after stopping treatment a withdrawal bleed will
occur. If this is particularly heavy it may be that a
shorter time between induced periods is required. An
alternative approach is to use a COC or the levonor-
gestrel intrauterine system, both of which will provide
full endometrial protection as well as effective contra-
ception, as occasional ovulation could occur despite
the amenorrhoea.
Hirsutism is a problem for many women with
PCOS. While hormonal treatments such as the COC
are designed to reduce ovarian androgens by lowering
gonadotrophins, as already mentioned approximately
50% of androgens in women are of adrenal origin.
34
Increased androgen promotes the transformation of
vellus hair into longer, thicker and more noticeable
terminal hair and sometimes reduction of ovarian
androgen is insufficient alone to reverse this process.
Management of hirsutism may therefore require add-
itional treatments such as cosmetic strategies, local
treatment such as topical eflornithine cream or laser
therapy (which can be very effective in suitable
patients, particularly those with darkly pigmented
hair) or systemic treatment with an anti-androgen
such as cyproterone acetate
52 53
(Figure 7d).
CONCLUSION
PCOS is a common condition with a varied pheno-
type. While there might be alternative views on some
elements of any framework to understand and
manage the syndrome, it is hoped that practitioners
involved in teaching students and trainees, and in
managing patients, will find that this approach to
understanding the condition is helpful.
Author’s note This review article is based on a presentation
given at a ‘Meet the Expert’session at the annual meeting of
the British Endocrine Society in 2012.
Competing interests The author is supported by a Scottish
Senior Clinical Fellowship from the SFC with grant support
from the Medical Research Council (G0901807).
Provenance and peer review Commissioned; externally peer
reviewed.
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Review
Duncan WC. J Fam Plann Reprod Health Care 2014;40:217–225. doi:10.1136/jfprhc-2012-100505 225
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syndrome (PCOS)
A guide to understanding polycystic ovary
W Colin Duncan
doi: 10.1136/jfprhc-2012-100505
online March 3, 2014 2014 40: 217-225 originally publishedJ Fam Plann Reprod Health Care
http://jfprhc.bmj.com/content/40/3/217
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