Polycystic Ovarian Syndrome (PCOS)

Polycystic Ovarian Syndrome (PCOS)
Dr Michelle M Fynes MB BAO BCH (Hons) MD (Research) MRCOG DU DipUS
Locum Consultant Reproductive Medicine
Department of Obstetrics and Gynecology
Cambridge University Hospitals NHS Foundation Trust 2018

Objectives
• Introduce and overview the topic of PCOS
• History of PCOS
• What have we learnt about PCOS 1970-2018
• Review the neuroendocrine control of adrenal and ovarian function
• Review the functional anatomy of the ovary
• Review the physiology of ovulation and the menstrual cycle
• Summarize the pathophysiology of PCOS
• Epidemiology of PCOS
• Genetic basis of PCOS
• Symptoms and signs of PCOS
• Short, intermediate and long-term impact of untreated PCOS
• Assessment and investigations for PCOS
• Review best practice management of PCOS
• Summary of topic
• Provide references for further reading
MM Fynes 2018

Introduction to PCOS:
• This is the most common endocrine disorder diagnosed in females aged 18-44 years.
• It affects 2-20% depending on how it is defined.
• It is a disorder of the adrenal-ovarian endocrine axis.
• Affected females may have elevated adrenal and or ovarian androgens.
• It may present with a variety of symptoms that can remit or relapse over time.
• These include; irregular or no menses, menorrhagia, excess facial and/or body hair,
pelvic pain, subfertility/infertility, patches of thick darker velvety skin, truncal
obesity, difficulty losing weight (due to insulin resistance).
• It is one of the leading causes of infertility.
• Associated conditions include; Type 2 Diabetes , obstructive sleep apnoea, mood
disorders, and endometrial cancer.
• Other metabolic sequelae include; hypertension, dyslipidaemia, visceral obesity,
insulin resistance, hyperinsulinaemia and CHD.
MM Fynes 2018

History of PCOS:
• First published description 1721 in Italy.
• Cyst-related ovarian changes described 1844.
• Other names for PCOS; polycystic ovary disease, functional
ovarian hyperandrogenism, ovarian hyperthecosis and Stein–
Leventhal syndrome.
• The last option only used for subset with amenorrhea, infertility,
hirsutism, enlarged PCO.
• Most common name for the disorder PCOS is based on the
finding at US of PCO. These ovaries have an abnormally large
number of developing eggs arrested in development.
• At US these cysts are usually peripheral and circumferentially
arranged within the ovary and appear as a ‘string of pearls’.
• Not all women with PCO will have PCOS and not all women with
PCOS have PCO.
MM Fynes 2018

History of PCOS 1970-2018:
What have we learned about PCOS over the last 50 years?
• PCOS has no cure.
• Treatment involves lifestyle changes such as weight loss and exercise.
• The OCP may help improving the regularity of periods, excess hair growth, and acne.
• Metformin and anti-androgens may also help.
• Other typical acne treatments and hair removal techniques may be used.
• Efforts to improve fertility include weight loss, ovulation induction (e.g. clomiphene),
or metformin and IVF is used by some in whom other measures are not effective.
• Laparoscopic ovarian drilling may be helpful in resistant cases or where hormonal
therapy is contra-indicated or associated with severe side effects.
• Fertility therapy with PCO is associated with an increased risk OHSS.
• Untreated patients are at higher risk fo metabolic syndrome and cancer.
MM Fynes 2018

Neuro-endocrinology:
Hypothalamic Pituitary Ovarian Axis (HPOA)

HPOA control of ovarian function:

Normal HPOA neuro-endocrine-regulation

Menstrual cycle and ovarian function:

Prevalence of PCOS:
• The prevalence of PCOS depends on the choice of diagnostic criteria.
• The WHO estimated that 116 million women worldwide (3.4%) were affected in 2010.
• One community-based prevalence study using the Rotterdam criteria found that about 18%
of women had PCOS, and 70% were previously undiagnosed.
• Ultrasonographic findings of PCO are found in 8–25% of normal women.
• 14% women on oral contraceptives are found to have PCO.
• PCO may also be found in women with levonorgestrel-releasing IUDs.

Aetiology of PCOS:- Genetics
• PCOS is a heterogenous disorder of unknown aetiology.
• Familial clustering and concordance in monozygotic twins suggests some genetic component
inherited in an autosomal dominant manner with high penetrance but variable expressivity.
• Each child thus has a 50% chance of inheriting the predisposing genetic variant(s) from a
parent, and, if a daughter receives the variant(s) she will have the disease to some extent.
• The genetic variant(s) can be inherited from father or mother and passed along to both sons
• These may be asymptomatic carriers or have symptoms such as early baldness and/or
excessive hair) and daughters, who show signs of PCOS.
• The phenotype manifests itself at least partially via raised androgen levels secreted by
ovarian follicle theca cells from women with the allele.
• The exact gene has not yet been identified. In In rare instances, single-gene mutations can
give rise to the phenotype of PCOS.
• Current understanding of the pathogenesis suggests it is a complex multigenic disorder.

Aetiology of PCOS: Obesity
• Severity of PCOS symptoms appears largely determined by
factors such as obesity. PCOS has some aspects of a
metabolic disorder since symptoms are partly reversible.
Considered a gynecological problem, PCOS consists of 28
clinical symptoms.
• PCOS suggests ovaries central to disease pathology but
cysts are symptoms not cause. Some symptoms persist
even with removal of the ovaries. PCOS can appear minus
ovarian cysts.
• Gynecologists see it as a gynecological wth ovaries being
the primary organ affected. However, research identifies a
multisystem disorder, the main issue is
hypothalamichormonal regulation, with the involvement
of many organs.
• PCOD is used when there is US evidence and the term
PCOS where there is a wider spectrum of symptoms. Cysts
are only seen in 15% PCOS cases.
• PCOS may be related or worsened by exposure during the
prenatal period, epigenetic or environmental factors
(especially industrial endocrine disruptors e.g. bisphenol
A) and certain drugs) as well as increasing rates of obesity.
• IUGR increase risk of adult metabolic syndrome and PCOS

Fetal Growth Restriction and PCOS:

Pathogenesis of PCOS:
PCOS arises due to stimulation of genetically susceptible ovaries to produce
excess androgenic hormones (e.g. testosterone) via one or more
mechanisms including:
• Excess release of LH from the anterior pituitary
• High levels of blood insulin in women whose ovaries are sensitive to this stimulus
• PCO (identified at TVUS), the sign being due to multiple immature ovarian follicles
that develop from primordial follicles but whose development has been arrested
at an early antral stage due to the disturbed ovarian function. These follicles
oriented along the ovarian periphery may appear as a 'string of pearls' at US.
• Women with PCOS experience increased frequency of hypothalamic GnRH pulses,
resulting in an increase in the LH/FSH ratio.

• Most have insulin resistance and/or are obese. Elevated insulin levels contribute to
/cause abnormalities seen in the Hypothalamic-Pituitary-Ovarian Axis (HPOA)
leading to PCOS. Hyperinsulinemia increases GnRH pulse frequency, LH over FSH
dominance, increased ovarian androgen production, decreased follicular
maturation, and decreased SHBG binding.
• Excess insulin, acting through its cognate receptor in the presence of component
cAMP signalling, upregulates 17 alpha-hydroxylase activity via P13K, 17α-
hydroxylase activity being responsible for synthesising androgen precursors. The
combined effects of hyperinsulinemia contribute to an increased risk of
PCOS. Insulin resistance is a common finding among women with a normal weight
as well as overweight women.

• Adipose tissue possesses aromatase converting androstenedione to oestrone and
testosterone to oestradiol. The excess of adipose tissue in obese women creates
the paradox of having both excess androgens (causing hirsutism/virilization) and
oestrogens (inhibit FSH via negative feedback).
• PCOS may be associated with chronic inflammation and several researchers have
linked inflammatory mediators with anovulation and other PCOS
symptoms. Similarly, there seems to be a relation between PCOS and increased
level of oxidative stress.
• It has previously been suggested that the excessive androgen production in PCOS
could be caused by a decreased serum level of IGFBP-1, in turn increasing the level
of free IGF-1, which stimulates ovarian androgen production, but recent data
concludes this mechanism to be unlikely.

• PCOS has also been associated with a specific FMR-1 sub-genotype. The research
suggests that women with heterozygous-normal/low FMR1 have polycystic-like
symptoms of excessive follicle-activity and hyperactive ovarian function.
• Transgender men may experience a higher than expected rate of PCOS due to
increased testosterone, if they choose to take hormone therapy as part of their
gender presentation.
• Not everyone with PCOS has polycystic ovaries (PCO), nor does everyone with
ovarian cysts have PCOS; although a TVUS is a major diagnostic tool, it is not the
only one. The diagnosis is straightforward using the Rotterdam criteria, even when
the syndrome is associated with a wide range of symptoms.

So what is PCOS?
• PCOS is thus due to a combination of genetic/environmental factors.
• Risk factors include obesity, lack physical exercise, family history of someone with the condition.
• Diagnosis is based on two of the following three findings: no ovulation, high androgen levels, and
ovarian cysts. Cysts may be detectable by ultrasound.
• Other conditions producing similar symptoms include; adrenal hyperplasia, hypothyroidism, high
blood levels of prolactin.
MM Fynes 2018

PCOS- Definitions and
diagnostic criteria
Two definitions are commonly used:
• NIH: In 1990 a consensus workshop sponsored by the NIH/NICHD suggested that a person
has PCOS if they have all of the following: Oligoovulation, signs androgen excess (clinical or
biochemical), exclude disorders that result in menstrual irregularity and hyperandrogenism.
• Rotterdam: 2003 consensus workshop ESHRE/ASRM in Rotterdam indicated PCOS to be
present if any 2 of 3 criteria are met, in the absence of other entities that might cause these
findings; oligo-ovulation and/or anovulation, excess androgen activity, PCO at TVUS. This
definition is wider, including > women, the most notable being those without androgen
excess. Critics say findings obtained from the study of women with androgen excess cannot
necessarily be extrapolated to women without androgen excess.
• Androgen Excess PCOS Society: In 2006, the Androgen Excess PCOS Society suggested a
tightening of the diagnostic criteria to all of the following: excess androgen activity,
oligoovulation/anovulation and/or PCO, exclusion of other entities causing excess androgen.
MM Fynes 2018

Features of PCOS:
• Menstrual: PCOS mostly produces oligo-menorrhoea (fewer than nine menstrual periods in a
year) or amenorrhoea (no menstrual periods for 3 or more consecutive months), but other
types of menstrual disorders may also occur.
• Infertility: Generally results directly from chronic anovulation (lack of ovulation).
• Metabolic syndrome: This appears as a tendency towards central obesity and other
symptoms associated with insulin resistance; Serum insulin, insulin resistance, and
homocysteine levels are higher in women with PCOS.
• High levels of masculinizing hormones: Known as hyperandrogenism, the most common
signs are acne and hirsutism (male pattern of hair growth, such as on the chin or chest), but it
may produce hypermenorrhoea (heavy and prolonged menstrual periods), androgenic
alopecia (increased hair thinning or diffuse hair loss), or other symptoms.
• Rate: Approximately three-quarters of women with PCOS (by the diagnostic criteria of
NIH/NICHD 1990) have evidence of hyperandrogenemia.

Long-term risks of untreated PCOS?
• Endometrial hyperplasia and cancer
• Type 2 DM even controlling for BMI and also gestational DM.
• Hypertension particularly if obese or during pregnancy
• Depression and anxiety.
• Disorders lipid metabolism: hypercholesterolaemia and
triglyceridaemia. PCOS women decreased removal atherosclerosis inducing remnants,
seemingly independent of insulin resistance/Type II diabetes.
• Cardiovascular disease: two-fold risk of arterial disease for women with PCOS relative to
women without PCOS, independent of BMI and stroke.
• Weight gain and obesity.
• Miscarriage.
• Sleep apnoea.
• Non-Alcoholic Steato-Hepatosis (NASH) particularly if obesity is present.
• Acanthosis Nigrans (patches darkened skin under arms, groin area, on the back of the neck)
• Autoimmune thyroiditis
• The risk of ovarian and breast cancer is not significantly increased overall.
MM Fynes 2018

Patient assessment and diagnosis

Patient assessment
• History- Menstrual dysfunction, hirsutism, acne
central obesity (sensitivity 77%/specificity 93%)
•
• Examination- BP, BMI, skin changes, hirsutism
(Ferriman Galway score)
• Targeted investigations – Blood and US imaging
• Provisional diagnosis
• Patient counselling
• Patient information leaflets
• Information on support groups
• Outline care plan for individual
• Detailed discussion of risks versus benefits
• Advice on long-term sequelae for untreated PCOS
MM Fynes 2018

Hirsutism: Ferriman Galway Score:
Score 1-4 for 9 body areas. Total score <8 is normal.
Score 8-15 mild hirsutism and >15 indicates moderate or
severe hirsutism. Score of 0 absence of terminal hair.

Diagnostic criteria
Rotterdam consensus criteria 2 out of 3 criteria must be met including;
• PCO with >12 or more follicles or increased ovarian volume [> 10 cm3 ]. No single
follicle should reach the pre-ovulatory size 16mm. At laparoscopy (not a diagnostic
test) the ovaries would appear enlarged and have a sooth pearl like appearance.
• Oligo-ovulation or anovulation
• Clinical and/or biochemical signs of hyperandrogenism.
• Exclusion other aetiologies for irregular cycles (e.g. thyroid dysfunction, acromegaly
or hyperprolactinaemia, have been excluded if there is clinical suspicion.
• Features of hyperandrogenism include hirsutism (excess facial, body and midline hair)
MM Fynes 2018

Differential diagnosis
• If signs of virilisation (e.g. deep voice, reduced breast size, increased muscle bulk,
clitoral hypertrophy), rapidly progressing hirsutism (<1 year between hirsutism being
noticed and seeking medical advice), then exclude other diagnoses.
• High total testosterone levels (> 5 nmol/l or >2 upper limit normal range) exclude
androgen-secreting tumours and late-onset/non-classical Congenital Adrenal
Hyperplasia (CAH).
• 17-OH Progesterone should be measured in follicular phase and will be raised in CAH.
• It is possible to have CAH without testosterone >5 nmol/l, particularly if the woman is
heterozygous for this condition. Hence measurement of 17-hydroxyprogesterone with
high index of suspicion (e.g. Ashkenazi Jews, or family history of CAH).
• Since management of CAH is different than that of PCOS if 17-OH Progesterone is
borderline, it will have to be confirmed by an ACTH stimulation test to diagnose CAH.
• If clinical suspicion of Cushing’s syndrome or acromegaly, this should be investigated
as per local practice.
MM Fynes 2018

Other diagnostic considerations
• It should be noted that the diagnosis of PCOS can only be made when other
aetiologies for irregular cycles, such as thyroid dysfunction, acromegaly or
hyperprolactinaemia, have been excluded if there is clinical suspicion.
• Women with non-Caucasian ethnicity might need different criteria to diagnose PCOS.
MM Fynes 2018

Treatment
Lifestyle measures;
Weight loss
Exercise
Low CHO diet
Homeopathy dietary supplements
Pharmacological therapies;
• Combined Oral Contraceptive (COC)
• Anti-Androgen (AA)
• Metformin
• Spironolactone
• Flutamide
• Inositol
• Ovarian drilling
Hirsutism; LASER, Electrolysis, waxing, bleaching
Acne; COC/AA, topical agents, oral antibiotics.
Subfertility/infertility; Clomiphene; ovulation induction
MM Fynes 2018

Treatment PCOS:
• Therapeutic approaches for adult patients not seeking fertility include combined oral
contraceptives (COC), antiandrogens (AA) and/or insulin sensitizers, although these practices
are supported by limited high-quality evidence.
• Metanalysis published Human Reproduction 2017; COC versus AA versus Metformin alone of
in combination for the treatment of PCOS. Outcome measures included hirsutism scores, IR,
BMI, menses pattern, BP, lipid profile, GTT.
• COC and AA are more effective than metformin for hyperandrogenic symptoms and
endometrial protection. Their combination with metformin adds a positive effect on BMI and
glucose tolerance.
• Examples COC; Yasmin Microgynon etc
• Examples COC +AA; Dianette (Cyproterone Acetate)
• Examples AA; Cyproterone Acetate
• Examples AA; Spironolactone or Flutamide

PCOS and Metformin:
• Metformin was logically introduced to establish the extent to which
hyperinsulinaemia influences the pathogenesis of PCOS.
• Early studies were very encouraging but RCTs and several meta-analyses have
changed the picture.
• In PCOS failure of the target cells to respond to normal or ordinary levels of insulin
is regarded as insulin resistance (IR).
• IR leads to a compensatory increased production of insulin by the pancreatic beta
cells to control the hyperglycaemia which ultimately fails leading to T2DM.
• In PCOS, hyperinsulinaemia has been thought to increase hyperandrogenaemia via
a central role or by decreasing the circulating levels of SHBG.
• IR is not considered a diagnostic criterion in PCOS. However, it is recognized by
many as a common feature in PCOS independent of obesity

PCOS and Metformin:
• Metformin improves sensitivity of peripheral tissues to insulin reducing serum levels.
• Metformin inhibits hepatic gluconeogenesis and it also increases the glucose uptake by
peripheral tissues and reduces fatty acid oxidation.
• Metformin has a positive effect on the endothelium and adipose tissue independent of its
action on insulin and glucose levels.
• Main side effects are GI; nausea, diarrhoea, flatulence, bloating, anorexia, metallic taste and
abdominal pain. These symptoms occur with variable degrees in patients and in most cases
resolve spontaneously.
• Start dose of 500 mg daily during the main meal of the day for 1–2 weeks can lessen side
effects and allow tolerance to develop. A weekly or biweekly increase by 500 mg a day can
then be pursued up to maximum 2500–2550 mg/day.
• Slow release metformin can be associated with fewer side effects. Metformin can also lead to
vitamin B12 malabsorption in the distal ileum in approximately 10–30% of patients which is an
effect dependent on age, dose and duration of treatment.

Metformin in PCOS:
• Metformin works by reducing the circulating insulin levels.
• Conflicting evidence as to whether it can directly affect ovarian steroidogenesis.
• May restore ovulation, reduce weight, reducing circulating androgen levels, reducing the risk
of miscarriage and reducing the risk of gestational diabetes mellitus (GDM).
• Other studies have reported that the addition of metformin to the ovarian stimulation
regime in in vitro fertilization (IVF) improves the pregnancy outcome.
• The lack of an emphatic or overwhelming efficacy for Metformin in females with PCOS is
largely due to the patients' variability in phenotypes and their metabolic parameters. Some
studies have tried to identify the patients that are most likely to benefit from metformin, yet
again the results have not been forthcoming.
• Metformin does not replace the need for lifestyle modification among obese and overweight
PCOS women. The evidence categorically does not encourage its use to help weight loss
either although it may be useful in redistributing adiposity according to some evidence.
• The long-term use of Metformin to prevent remote complications of PCOS is uncertain and a
significant amount of work is needed before a decision can be made on this front.
Stipulations from studies carried out on the general population is not the same and can be
misleading given the diversity of PCOS patients with regard to their metabolic comorbidities.
•

Laparoscopic ovarian drilling:
• Laparoscopic drilling for PCOS was first used 1984 involving
multiple micro-perforations of the ovarian surface via diathermy or
LASER destroying ovarian stroma and peripheral follicles of PCOS.
• Punctures ovarian cortex 4–10 mm deep/3 mm wide and number
of punctures related to subsequent ability to conceive. 5-10
punctures more likely to produce conception.
• Use monopolar needle/hook and electrocoagulation at 40 W,
(range from 30-400 W). Laparoscopic approach < morbidity then
ovarian wedge resection.
• Aims to reduce the amount of androgen producing tissue, may
reduce circulating E2 levels, LH level/pulsations, and inhibin B.
• The most plausible theory is that reduction of these leads to an
increase in the secretion of FSH and SHBG leading to effective
follicular maturation and ovulation.
• Low serum E2 associated with <aromatase activity. IGF-1 produced
with injury aids effects of FSH through greater blood flow GnRH
delivery. AMH levels fall after drilling
• Goal of drilling treatment is induction of mono-ovulatory cycles.
MM Fynes 2018

Laparoscopic ovarian drilling:
• Weight loss and Clomiphene Citrate (CC) first line therapy.
• CC is a Selective Estrogen Receptor Modulator (SERM) with; 49%
ovulation rate, 30% pregnancy rate, 23% live birth rate at
6 months, and 8% rate of multiple gestation.
• Other non-surgical PCOS medical therapy options include; the
SERM Tamoxifen or aromatase inhibitors, insulin sensitising drugs,
and hormonal ovarian stimulation.
• 25% women are resistant to CC therapy
• CC therapy is followed by GnRH therapy but >risk OHSS
• Laparoscopic drilling may reduce the risk of OHSS
• The effectiveness of the surgical procedure is similar to CC but
results in fewer multiple pregnancies per ongoing pregnancy
regardless if the technique is unilaterally or bilaterally performed
• If patients do not become pregnant 6 months after ovulation is
induced by ovarian drilling then GnRH therapy and IVF warranted
MM Fynes 2018

Summary of the metabolic consequences of
PCOS and screening recommendations:
• PCOS should be diagnosed according to the Rotterdam consensus criteria.
• Women with PCOS should be informed of the possible long-term risks to health
that are associated with their condition by their healthcare professional.
• Clinicians may consider offering screening for gestational diabetes to women who
have been diagnosed as having PCOS before pregnancy.
• During pregnancy a GTT may be performed at 24–28 weeks of gestation, with
referral to a specialist obstetric diabetic service if abnormalities are detected.
• Women with PCOS and a BMI ≥ 25 kg/m2 ) and women with PCOS <a BMI<
25Kg/M2 who have added risks such as advanced age (> 40 years), personal
history of gestational diabetes, or family history of type II diabetes, should have a
2-hour post 75 g oral GTT test performed.
• Those with impaired fasting glucose (6.1-6.9 mmol/l) or impaired GTT plasma
glucose of 7.8 mmol/l or more but <11.1 mmol/l after a 2-hour oral GTT should
undergo annual testing.
MM Fynes 2018

Summary of cancer and PCOS: What are the risks and
how should these women be screened?
• PCOS related oligo- or amenorrhoea may predispose to endometrial hyperplasia
and later carcinoma.
• It is good practice to recommend treatment with gestogens to induce a withdrawal
bleed at least every 3 to 4 months.
• Transvaginal ultrasound should be considered in the absence of withdrawal bleeds
or abnormal uterine bleeding.
• In PCOS, an endometrial thickness of less than 7 mm is unlikely to be hyperplasia.
• A thickened endometrium or an endometrial polyp should prompt consideration
of endometrial biopsy and/or hysteroscopy.
• There does not appear to be an association with breast or ovarian cancer and no
additional surveillance is required.
MM Fynes 2018

Clinical standards and auditable topics:
100% of women with PCOS should have;
• An accurate diagnosis of PCOS made as defined by at least two out of three
Rotterdam criteria.
• A GTT undertaken if overweight (BMI > 25), or where BMI <25 but other
risks present (age > 40, previous gestational DM, family history type 2 DM).
• BMI, waist circumference and BP checked at every visit.
• Advice given on diet and lifestyle.
• Psychological issues considered and addressed.

Polycystic Ovarian Syndrome (PCOS)

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