REVIEW A guide to understanding polycystic ovary syndrome ... · 3/3/2014 · 100505 ABSTRACT Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder affecting women

A guide to understanding polycysticovary syndrome (PCOS)

W Colin Duncan

Scottish Senior Clinical Fellowand Consultant in ReproductiveMedicine, MRC Centre forReproductive Health, TheUniversity of Edinburgh,Edinburgh, UK

Correspondence toDr W Colin Duncan,MRC Centre for ReproductiveHealth, The Queen’s MedicalResearch Institute, The Universityof Edinburgh, 47 Little FranceCrescent, EdinburghEH16 4TJ, UK;[email protected]

Received 18 June 2013Revised 10 January 2014Accepted 6 February 2014

To cite: Duncan WC. J FamPlann Reprod Health CarePublished Online First: [pleaseinclude Day Month Year]doi:10.1136/jfprhc-2012-100505

ABSTRACTPolycystic ovary syndrome (PCOS) is thecommonest endocrine disorder affecting womenof reproductive age. Some 20% of women willhave polycystic ovaries on an ultrasound scanand around 7% of women have the additionalclinical or biochemical features of PCOS. As acomplex multisystem disorder its background canbe confusing to understand. They key feature,however, is an increased production of androgenby the ovaries. This review uses ovarian biologyto describe a strategy to aid understanding andexplanation of PCOS. This framework can be alsobe used to teach about PCOS and to informdifferent approaches to its management.

INTRODUCTIONPolycystic ovary syndrome (PCOS) is thecommonest endocrine disorder to affectwomen in their reproductive years.Around 20% of women have the charac-teristic appearance of polycystic ovarieson ultrasound scans1 and 7–8% have theadditional clinical and biochemical fea-tures of PCOS itself.2 As obesity increasesthe proportion of women with polycysticovaries who develop the syndrome, thecurrent epidemic of obesity is likely tomake PCOS even more common.3

Polycystic ovaries found on ultrasoundscanning will often have no clinicaleffects, but PCOS is the most commondiagnosis made in women presentingwith amenorrhoea, oligomenorrhoea orheavy, irregular and prolonged periods. Itis the commonest cause of hirsutism andof infertility due to anovulation. Womenwith PCOS have increased concentrationsof circulating androgens and there is amarked association with insulin resist-ance, dyslipidaemia, obesity, gestationaldiabetes, type 2 diabetes and heartdisease. In addition, it is an establishedcause of endometrial hyperplasia and it istherefore linked to endometrial cancer.The short- and long-term consequences

of PCOS represent an increasing burdenon health resources.In recent years there has been increas-

ing consensus about the criteria requiredto establish the diagnosis of PCOS. Twoout of the three features below are usedwhen other causes of those clinical fea-tures have been excluded.4 Exclusion ofthese other, much rarer, causes oftenneeds no more than a routine clinicalassessment.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 basicpathophysiology is often poorly under-stood. This article presents a frameworkfor teaching and increasing understandingabout the causes and management ofPCOS.

AN APPROACH TO TEACHING ANDLEARNING ABOUT PCOSUndergraduate students, nurses, specialisttrainees and even trained gynaecologists

Key message points

▸ Polycystic ovary syndrome (PCOS) is acommon condition affecting 7% ofwomen but its background can be con-fusing to understand.

▸ The key feature is increased productionof androgen by the ovaries.

▸ Understanding ovarian biology clarifiespathways to androgen increase andprovides a framework to facilitateteaching on PCOS.

▸ This approach can be also used toinform management strategies.

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Duncan WC. J Fam Plann Reprod Health Care 2014;0:1–9. doi:10.1136/jfprhc-2012-100505 1

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often find PCOS difficult to understand, particularlyas the clinical features vary from patient to patient.One strategy that can be used when teaching aboutPCOS is to go back to basic ovarian biology and touse that as a starting point. This leads to a frameworkthat lends itself to formal presentation, but also toinformal illustrations in the clinic or in a tutorial. Inaddition it allows the management strategies to bedescribed and understood. While different expertsmay have alternative views of its pathophysiologicalbasis, and some assumptions can be questioned, thefollowing model gives a useful framework to buildupon and to introduce key concepts and managementpathways.In this framework there are six stages of develop-

ment of information on the biology of the ovary andthe factors that interact with it that help to clarify thebackground to the development of PCOS. Knowledgeof these stages is then used as the key to understand-ing the approaches available for its management.

How follicles make estrogenThe first stage in this approach is to look at the pro-duction of sex steroids, particularly estradiol, withinthe ovarian follicle (Figure 1a). The follicle has twosteroidogenic cell layers: the outer theca cell layer andthe inner granulosa cell layer, separated by a basementmembrane5 (Figure 1b). It is the granulosa cells thatare responsible for the synthesis and secretion of estra-diol. They do this initially under the stimulation offollicle-stimulating hormone (FSH) from the anteriorpituitary gland, which binds to and activates theirFSH receptors6 (Figure 1c).Estradiol is a sex steroid and all steroids are derived

from cholesterol.7 Cholesterol therefore has to bechanged into estradiol by enzymatic modificationthrough a series of intermediate steroids. In the pathway

from cholesterol to estrogen, the step before estrogen isandrogen (Figure 1d). Androgen is converted into estro-gen by the action of the aromatase enzyme7 (Figure 1e).Granulosa cells contain large amounts of aromatase butthey do not express the proteins and enzymes (steroido-genic acute regulatory protein, cholesterol side chaincleavage enzyme, 3β-hydroxysteroid dehydrogenase and17α-hydroxylase) that are required for the conversionof cholesterol into androgen, so they cannot produceandrogen themselves (Figure 1f).As they cannot synthesise the androgen substrate, in

order to make estradiol the granulosa cells need to getandrogen from another source. The androgen is madein the theca cells and converted into estrogen in thegranulosa 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 theproduction of androgen from cholesterol in thecacells, and FSH promotes the conversion of thoseandrogens 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 synthesis9 and thehormones are physiologically balanced (Figure 2d).

The effect of increased androgen on the ovaryThe second stage in describing the development ofPCOS is to highlight that the development of a poly-cystic ovary is associated with increased exposure toandrogens as these have their own effects on folliculargrowth and development. A polycystic ovary containsan increased number of small antral follicles which arethe small fluid-filled follicles that are seen onnaked-eye inspection of opened polycystic ovaries andare 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 keycells 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 healthyoocyte10 and they can be stimulated to grow normallyby exogenously administered FSH.11 This is whywomen with PCOS are at a much greater risk ofdeveloping ovarian hyperstimulation syndrome afteradministration of FSH during assisted conception.12

The ovarian ‘cysts’ in PCOS are therefore essentiallypaused follicles, with reduced cell growth as well asreduced cell death (atresia).Androgen inhibits the growth of larger antral folli-

cles but, if anything, stimulates the growth of smallerantral follicles (Figure 3a–c). Treating rhesus monkeyswith normal ovaries with exogenous androgen for just10 days resulted in a polycystic ovarian morphology,with an increased proportion of small antral folliclesshowing more cell proliferation in smaller folliclesand less atresia in the remaining follicles.13 This high-lights the ability of androgen to promote folliculargrowth and survival, inhibit later follicular develop-ment and directly cause a polycystic ovarianmorphology.Clinically, this polycystic ovarian morphology is

associated with increased endogenous androgens.Conditions in which endogenous androgen levels arepathologically raised include androgen-secretingtumours and late-onset congenital adrenal hyperplasia,in which adrenal androgen secretion is increased.14

Women with both these conditions develop polycysticovaries.15 The response of the ovary to increasedandrogens 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 androgenThe third stage is to discuss the mechanisms by whichthe ovary might be exposed to increased local andro-gen concentrations. Using the two-cell, two-gonadotrophin model illustrated in Figure 2d it can bedemonstrated that if a hormone imbalance occurred,such that circulating LH concentrations were higherthan FSH concentrations, ovarian androgen produc-tion would increase (Figure 4a). Previously anincreased LH:FSH ratio was thought to be requiredfor the diagnosis of PCOS. This is no longer part ofthe diagnostic criteria, which focus on the resultingincreased androgens.4 However, it is clear that womenwith PCOS are more likely to have increased basal LHconcentrations16 as well as increased LH pulse ampli-tude and frequency.17

While chronic anovulation can result in raised LHconcentrations,18 it is likely that the LH:FSH imbal-ance is something that women with a tendency toPCOS are born with and that this causes anovulation.There is increasing evidence from human and animalmodels that PCOS can be programmed by increasedfetal exposure to androgen before birth.19 20 Thismay permanently programme increased basal LHsecretion21 as well as augmenting the amount of LHreleased in response to gonadotrophin-releasinghormone (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. Luteinisinghormone (LH) stimulates androgen (A) from theca cells which are converted to estrogen (E) in granulosa cells by follicle-stimulatinghormone (FSH). See text for an explanation of stages a–d.

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pulses. One way the ovary can be exposed toincreased androgen is therefore by an increased LH:FSH ratio, which may be prenatally programmed.

Regulation of androgen actionThe fourth stage is to describe a regulator of androgenbioavailability. 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 increasedovarian androgen production (Figure 4c). However, ifthe sponge is small it would not fully mop up theexcess androgens that are normally produced duringfollicular estrogen synthesis (Figure 4d). That meansthat there may be increased androgen bioavailabilityin the presence of normal LH concentrations – and ifthere is an increased LH:FSH ratio a small spongewould augment the increased androgen exposure(Figure 4e).That ‘sponge’ exists in the form of sex hormone

binding globulin (SHBG), the circulating protein thatbinds to and inhibits androgens and to a lesser extentestrogens (Figure 4f). For the purpose of this frame-work it is now useful to highlight that SHBG isinversely related to weight (Figure 4g).23 As weightincreases, SHBG decreases and androgen availabilitywill therefore increase (Figure 4h). This means thatpolycystic ovaries or PCOS will worsen. Conversely,as weight reduces SHBG will increase and bioavailableandrogen will decrease (Figure 4i), meaning thatPCOS will improve. Weight is therefore a controller ofLH action on the ovary and thus the effects of LHwill be exaggerated by obesity.

Regulation of androgen synthesisThe fifth stage is to focus on the molecular regulationof LH-dependent androgen synthesis by the thecacells (Figure 5a). The key here is to imagine the effectthat a multiplier of LH action would have at the levelof the theca cell (Figure 5b). The presence of a multi-plier would augment androgen production for a givenconcentration 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 regulatesglucose transport and has growth factor and anabolicactions.24 It is also a co-factor that augmentsLH-induced thecal androgen secretion.25 26 In thepresence of peripheral insulin resistance (IR), which isa precursor to impaired glucose tolerance, increasedinsulin concentrations are required to promoteglucose uptake in tissues with a key metabolic role,such as muscle and fat. While these may be resistantto the metabolic effects of insulin, the ovary remainssensitive to its growth factor effects. The hyperinsuli-naemia associated with IR therefore means that moreandrogen will be produced in the ovary. As IRworsens and insulin concentrations rise, ovarianandrogens will increase and PCOS will worsen(Figure 5e). If IR improves and insulin concentrationsfall, ovarian androgens will reduce and PCOS willimprove (Figure 5f).

Figure 3 Diagram highlighting the role of androgens (A) in theconversion of a normal ovary to one with a polycystic ovarianmorphology. See text for an explanation of stages a–c.

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Interaction between weight and IRThe sixth and final stage in understanding the caus-ation of PCOS pulls together the information gainedin 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 thedegree by which PCOS is manifested. However themechanism is not so straightforward, as insulin is ananabolic hormone and the hormone of energystorage.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 luteinisinghormone (LH)-dependent thecal androgen (A) availability, and the link of SHBG to weight and to the increase in free androgen whenits level reduces. This does not affect follicle-stimulating hormone (FSH)-stimulated estradiol (E) secretion. See text for an explanationof 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.

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associated with ease of weight gain and difficulty inweight loss (Figure 6a).28 As weight increases, IRincreases and circulating insulin levels rise,29 produ-cing a vicious cycle with weight and IR linkedtogether (Figure 6b). Insulin itself can inhibit hepaticSHBG synthesis.30

There are therefore three drivers to increasedovarian androgen production: increased LH, hyperin-sulinaemia and increased weight (Figure 6c). So slimwomen with PCOS have more elevation in LH thanobese women with PCOS.31 While some women withPCOS primarily have a high LH:FSH ratio, some areprimarily insulin resistant and some have a majorweight problem. The common consequence is theaugmentation of androgens that results in PCOS(Figure 6d). In reality most women with PCOS willhave each of these drivers in varying degrees.

A FRAMEWORK FOR THE MANAGEMENTOF PCOSThe model where LH-stimulated androgen action isaugmented by weight and insulin (Figure 6d) providesa useful framework with which to understand PCOSand to explain it to patients and students. But it alsoprovides a useful approach to describe the strategiesavailable 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 gonadotrophinsAny treatment that lowers circulating LH concentra-tions will reduce ovarian androgen production andimprove PCOS (Figure 7a). We do not yet have atreatment to specifically lower LH, so treatment gen-erally involves reducing both LH and FSH. The mainway to do that is with the combined oral contracep-tive pill (COC), which is the mainstay of the manage-ment of PCOS32 if pregnancy is not desired. AnyCOC will do this effectively, although it has beenargued that the more recent, less androgenic pills maybe particularly useful.33 As half the androgens inwomen come from the adrenal gland,34 the combin-ation of ethinylestradiol with an anti-androgen such ascyproterone acetate (co-cyprindiol), or a higher doseof cyproterone acetate in a reverse-sequentialregimen,35 may have additional benefit for certainandrogenic symptoms, particularly hirsutism.For fertility treatment, the strategy is to raise FSH

levels to facilitate the conversion of androgens intoestrogens in order to remove the brake on folliclegrowth. 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 luteinisinghormone (LH)-stimulated androgen (A) secretion, resulting in development of polycystic ovary syndrome (PCOS). See text for anexplanation of stages a–d.

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and to stimulate the ovulatory LH surge. Treatment istherefore given only for 5 days at the beginning of thecycle, either from Day 2 or Day 3. If treatment withanti-estrogens at various doses is not effective, thenFSH may be directly raised by injections.Gonadotrophin ovulation induction is very successfulin the management of subfertility secondary to anovu-lation in PCOS.36

Targeting weightWeight loss improves the symptoms PCOS in bothnon-fertility and fertility contexts (Figure 7b). In thefertility setting the results are quite dramatic.37 38

Thus a weight loss strategy is very important in themanagement of all overweight and obese women withPCOS. A loss of 10% of body weight increased fertil-ity, ovulation rate and menstrual regularity even whenwomen remained obese.37 In addition there wereassociated improvements in serum biochemistry, bloodpressure and self-esteem scores.37 38 It is important tohighlight diet, with an emphasis on developing aweight maintenance/weight loss cycle involvingregular small healthy meals, not skipping meals andavoiding refined carbohydrate.39 However, increasedphysical activity should always be a key message inweight management. Even in the absence of weightloss, exercise improves PCOS.40

Targeting insulinMetformin treatment improves insulin sensitivity, thusenhancing glucose clearance, resulting in reduced

circulating insulin concentrations (Figure 7c). There isno doubt that metformin can have beneficial effects insome women with PCOS.41 42 It can improve feelingsof wellbeing, ovarian cyclicity and fertility as a mainor as adjunct therapy.43 While metformin reduceshyperinsulinaemia44 and improves metabolic para-meters, its effect on weight loss is more controver-sial.45 The degree of weight loss may relate to howengaged the patient is with a concurrent weight-lossprogramme. Recent results with metformin have beenless impressive than initially reported.46 As not allwomen with PCOS benefit equally from metformin itmay be that the key is adequate patient selection.More research is needed into such personalised medi-cine. However, metformin remains one of the toolsavailable in the management of PCOS. The data on itsprolonged use and discontinuation are scanty andvariable, so it should not yet be used in the long-termwith a goal of preventing future health problems.47–49

A current improvement in symptoms associated withPCOS seems a sensible rationale for its continuation.

Holistic targetingOne of the main areas to focus on is endometrial pro-tection. Women with PCOS who are anovulatory areexposed to unopposed estrogen and are at risk ofboth prolonged heavy bleeding and the developmentof endometrial hyperplasia.50 It is generally advocatedthat women with PCOS who are amenorrhoeic shouldhave three or four periods (in the form of withdrawalbleeds) a year to maintain endometrial health.51 A

Figure 7 Illustration highlighting the roles of luteinising hormone (LH), increased weight and hyperinsulinaemia in raisingintraovarian androgen (A) that results in polycystic ovary syndrome (PCOS). See text for an explanation of stages a–d.

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common strategy is to use an intermittent progestogensuch as medroxyprogesterone acetate 10 mg twicedaily for 7 days or once daily for 10 days. A few daysafter stopping treatment a withdrawal bleed willoccur. If this is particularly heavy it may be that ashorter time between induced periods is required. Analternative approach is to use a COC or the levonor-gestrel intrauterine system, both of which will providefull endometrial protection as well as effective contra-ception, as occasional ovulation could occur despitethe amenorrhoea.Hirsutism is a problem for many women with

PCOS. While hormonal treatments such as the COCare designed to reduce ovarian androgens by loweringgonadotrophins, as already mentioned approximately50% of androgens in women are of adrenal origin.34

Increased androgen promotes the transformation ofvellus hair into longer, thicker and more noticeableterminal hair and sometimes reduction of ovarianandrogen is insufficient alone to reverse this process.Management of hirsutism may therefore require add-itional treatments such as cosmetic strategies, localtreatment such as topical eflornithine cream or lasertherapy (which can be very effective in suitablepatients, particularly those with darkly pigmentedhair) or systemic treatment with an anti-androgensuch as cyproterone acetate52 53 (Figure 7d).

CONCLUSIONPCOS is a common condition with a varied pheno-type. While there might be alternative views on someelements of any framework to understand andmanage the syndrome, it is hoped that practitionersinvolved in teaching students and trainees, and inmanaging patients, will find that this approach tounderstanding the condition is helpful.

Author’s note This review article is based on a presentationgiven at a ‘Meet the Expert’ session at the annual meeting ofthe British Endocrine Society in 2012.

Competing interests The author is supported by a ScottishSenior Clinical Fellowship from the SFC with grant supportfrom the Medical Research Council (G0901807).

Provenance and peer review Commissioned; externally peerreviewed.

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REVIEW A guide to understanding polycystic ovary syndrome ... · 3/3/2014 · 100505 ABSTRACT Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder affecting women