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Definition

PCOS is the commonest endocrine condition to affect women with an estimated prevalence of 10–15% of women of reproductive age affected

It is associated with increased risk of developing type II diabetes, metabolic syndrome and endometrial cancer.

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Diagnostic Criteria for PCOS

Rotterdam Criteria

Two out of three criteria should be met:-

(1) clinical or biochemical features of hyperandrogenism,

(2) oligo-ovulation or anovulation (i.e. menstrual cycle disturbance) and/or

(3) polycystic ovaries on ultrasound.

The diagnosis requires the exclusion of specific underlying diseases of the adrenal or pituitary glands (e.g. hyperprolactinemia, acromegaly, congenital adrenal hyperplasia, Cushing’s syndrome and androgen-secreting tumours of the ovary or adrenal gland), which could predispose to similar ultrasound and biochemical features and also the exclusion of other causes of menstrual cycle irregularity secondary to hypothalamic, pituitary or ovarian dysfunction.

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Clinical features of PCOS :-

  • Hyperandrogenism (hirsutism, acne, alopecia)
  • Menstrual disturbance
  • Infertility
  • Obesity
Possible Late Sequelae :-
  • Type II Diabetes Mellitus
  • Dyslipidemia
  • Hypertension
  • Cardiovascular Disease

Mechanism of ovarian hyperandrogenism :-

In slim women – Ovarian hyperandrogenism is driven by LH.

In overweight women – By insulin which acts as a ‘co – gonadotropin’ and amplifies the effect of LH.

Ultrasound

Polycystic ovaries are detected by ultrasound with prevalence of 20 – 33%.

Morphology of the polycystic ovary – as defined by ESHRE/ASRM consensus –

  • ovary with 12 or more follicles.
  • measuring 2–9 mm in diameter.
  •   and/or an increased ovarian volume (>10 cm3).
With improvements in the resolution of ultrasound technology, it has more recently been suggested that the threshold number of follicles to define a polycystic ovary should be 25, and that the biochemical marker of anti-mullerian hormone (AMH) may be even more precise than ultrasound, with a threshold serum concentration of >35 pmol/l. However, this figure has not been universally accepted, and the use of AMH as a surrogate for follicle number is currently being debated.

Serum endocrinology in PCOS

  • Increased or normal androgens (testosterone and androstenedione)
  • Increased or normal LH – elevated in 40%, usually slim women.
  • Normal FSH levels.
  • Increased or normal fasting insulin (NOT routinely measured; insulin resistance assessed by Glucose Tolerance Test, GTT).
  • Decreased or normal SHBG.
  • Elevated “Free androgen index” [(T x 100)÷SHBG] 
  • Increased or normal estradiol.
  • Increased Anti – mullerian hormone (AMH).
  • Prolactin is usually normal, occasionally slightly elevated.

Survival of PCOS in population

A plausible hypothesis for the survival of PCOS in the population is that of the ‘thrifty phenotype/genotype’ whereby in times of famine, individuals who have a tendency to obesity preserve the population by maintaining fertility, while those of normal body weight fall below the threshold body weight for fertility.

Insulin Resistance in PCOS

Both obese and non-obese women with PCOS are more insulin resistant than age- and weight-matched women with normal ovaries.

Women with PCOS who are oligomenorrheic are also more likely to be insulin resistant than are those with regular cycles, irrespective of body mass index (BMI).

Fasting insulin levels are not measured in routine practice, 75g oral glucose tolerance test (OGTT) be performed in women with a BMI > 30 kg/m².

South Asian women should have an assessment of glucose tolerance if their BMI is greater than 25 kg/m².

Insulin regulates metabolic and mitogenic pathways that function independent of each other.  This might explain the paradoxical insulin sensitivity patterns seen in different tissues, for example, resistance in peripheral tissues and retained sensitivity in the ovarian cortex.
 
Metabolic inertia to insulin has been attributed to a post-binding defect in the insulin signalling pathway caused by abnormal serine phosphorylation of the insulin receptor.
 
In adipocytes, IR leads to the increased shunting of free fatty acids (FFA) from fat tissue to the liver. FFAs induce hepatic synthesis of very low-density lipoprotein (VLDL), resulting in elevated triglycerides and apolipoprotein B and decreased HDL. These alterations in lipid parameters lead to atherogenic dyslipidaemia.

Obesity - An assessment of Cardiovascular Risk

Assessment of BMI alone is not thought to provide a reliable prediction of cardiovascular risk.

Rather than BMI itself it is the distribution of fat that is important, with android obesity being more of a risk factor than gynecoid obesity.

Hence the value of measuring waist circumference, which detects abdominal visceral fat rather than subcutaneous fat. It is the visceral fat which is metabolically active and when increased results in increased rates of insulin resistance, type II diabetes, dyslipidaemia, hypertension and left ventricular enlargement. Waist circumference should ideally be less than 80 cm, while a measurement that is greater than 87 cm carries a significant risk.

Hyperandrogenaemia increases a person’s predilection for central adiposity and worsens insulin resistance and dyslipidaemia.

Glucose Tolerance after 75 g Glucose Tolerance Tests.

Diabetes Mellitus Impaired Glucose Tolerance Impaired Fasting Glycaemia
Fasting glucose (mmol/l)

≥ 7.0

< 7.0

≥ 6.1 and < 7.0

2 hour glucose (mmol/l)

≥ 11.1

≥ 7.8 and ≤ 11.1

< 7.8

PCOS in adolescence :

The diagnosis of PCOS should not be made until 2 years after menarche.

All elements of the Rotterdam consensus are required for diagnosing PCOS during adolescence (and not just two out of three).

Acne is common during the adolescent years and in most subjects is a transitory phenomenon. Hirsutism may be a better marker of hyperandrogenism, and progressive hirsutism during the adolescent years may be an important sign of PCOS.

It is important to exclude non-classical (late onset) congenital adrenal hyperplasia.

Management of hyperandrogenism

Elevated serum androgen concentrations stimulate peripheral androgen receptors, resulting in an increase in 5-alpha reductase activity, directly increasing the conversion of testosterone to the more potent metabolite
dihydrotestosterone. Women with PCOS do not become virilised.

A total testosterone level of greater than 5 nmol/l (depending upon the
assay) or rapid onset of signs of hyperandrogenism requires further investigation.

To evaluate the degree of hirsutism before and during treatments, modified Ferriman and Gallwey Score is used.

Therapies for hirsutism :-

Drug therapy may take 6 – 9 months or longer before any improvement of hirsutism is perceived.

Physical treatments including electrolysis, waxing and bleaching may be helpful while waiting for medical treatments to work. Electrolysis is time-consuming, painful and expensive and should be performed by an expert practitioner.

Laser and photothermolysis techniques are more expensive, but may have a longer duration of effect.

Repeated treatments are required for a near-permanent effect because only hair follicles in the growing phase are obliterated at each treatment.

Hair growth occurs in three cycles, so 6–9 months of regular treatments are typical.

The topical use of eflornithine may be effective.  Eflornithine may cause some thinning of the skin and so high factor sun – block is recommended when exposed to the sun.

Mechanism of action of Eflornithine :-

It works by inhibiting the enzyme ornithine decarboxylase in hair follicles and may be a useful therapy for those who wish to avoid hormonal treatments, but may also be used in conjunction with hormonal therapy.

Contraceptives :-

Adequate contraception is important in women of reproductive age as transplacental passage of anti-androgens may disturb the genital development of a male fetus.

First-line therapy has traditionally been the preparation Dianette® (Bayer PLC, Newbury, Berkshire, UK), which contains ethinyloestradiol (35 μg) in combination with cyproterone acetate (2 mg).

Spironolactone is a weak diuretic with antiandrogenic properties that may be used in women in whom the combined oral contraceptive pill is contraindicated at a daily dose of 25– 100 mg. Drosperinone is a derivative of spironolactone and is contained in the combined oral contraceptive pill Yasmin® (Bayer PLC, Newbury, Berkshire, UK), which may also be beneficial for women with PCOS. In reality all combined oral contraceptive preparations should benefit both the control of the menstrual cycle and suppress hyperandrogenism.

Alopecia :-

The management of alopecia is difficult but may be stabilised by the anti-androgen preparations mentioned above. Iron deficiency may have an impact on hair loss and so ferritin levels should be assessed.

Management of menstrual problems:

Amenorrhea and Withdrawal Bleed:

Women with unpredictable, irregular and heavy periods are likely to benefit from cyclical hormone therapy. Furthermore, women with PCOS who experience amenorrhea have unopposed estrogen production from the conversion of androgens and the absence of postovulatory secretion of progesterone. Therefore, the induction of artificial withdrawal bleeds to prevent endometrial hyperplasia is prudent management.

The risk of developing endometrial cancer is adversely influenced by a number of factors including obesity, long-term use of unopposed estrogens, nulliparity and infertility.

Endometrial hyperplasia may be a precursor to adenocarcinoma, with cystic glandular hyperplasia progressing in perhaps 0.4% of cases and adenomatous hyperplasia in up to 18% of cases over 2–10 years.

It is therefore important that women with PCOS shed their endometrium at least every 3 months. For those women with oligo/amenorrhea who do not wish to use cyclical hormone therapy, we recommend an ultrasound scan to measure endometrial thickness and morphology every 6–12 months (depending on menstrual history). An endometrial thickness greater than 10 mm in an amenorrheic woman warrants an artificially induced bleed, which should be followed by a repeat ultrasound scan and endometrial biopsy if the endometrium has not been shed.

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.

Metabolic syndrome has a higher incidence of pancreatic, postmenopausal breast and colorectal cancers.

Management of anovulatory infertility: -

PCOS accounts for approximately 80–90% of women with anovulatory infertility.

The principles of the management of anovulatory infertility are first to optimise health before commencing therapy (e.g. lose weight in those who are overweight) and then to induce regular unifollicular ovulation. Folic acid should be taken at a daily dose of 400 micrograms or, in those who are obese, 5 mg.

Various factors influence ovarian function and fertility, the most important being obesity.

The British Fertility Society guidance suggests that treatment should be deferred until the BMI is less than 35 kg/m2, although in those with more time (e.g. less than 37 years, normal ovarian reserve) a weight reduction to a BMI of less than 30 kg/m2 is preferable.  Even a moderate weight loss of 5–10% of body weight can be sufficient to restore fertility and improve metabolic parameters.

Ovulation induction therapies :

Strategies to induce ovulation include oral anti-estrogens (principally clomifene citrate [CC]), parenteral gonadotrophin therapy and laparoscopic ovarian surgery.

Amenorrhea and Withdrawal Bleed:

If the patient has not menstruated by day 35 and she is not pregnant, a progestogen-induced withdrawal bleed should be initiated.

To induce a withdrawal bleed, a short course of a progestogen, such as medroxyprogesterone acetate 20 mg/day for 5–10 days can be given.

The starting dose of CC is 50 mg/day.

The dose of CC may be increased to 100 mg if there is no response. Doses of 150 mg/day or more do not appear to be of benefit. If there is an exuberant response to 50 mg/day, as in some women with PCOS, the dose can be decreased to 25 mg/day.

Hypersecretion of LH is found in 40% of women with PCOS and is associated with a reduced chance of conception and an increased risk of miscarriage, possibly through an adverse effect of LH on oocyte maturation. Elevated LH concentrations are more often found in slim women with PCOS.

Clomifene citrate may cause an exaggeration in the hypersecretion of LH and have anti-estrogenic effects on the endometrium and cervical mucus. It is suggested that LH be measured on day 8 of the cycle and if persistently elevated then move on to alternative therapy as the chance of
conception is reduced and the risk of miscarriage increased.

All women who are prescribed CC should be carefully monitored with ultrasonographic assessment of follicular growth because of the risk of multiple pregnancy, which is approximately 10%.

If pregnancy has not occurred after 6–9 normal ovulatory cycles, it is then reasonable to offer the couple assisted conception (that is in vitro fertilisation [IVF]).

Clomifene Resistance:

Failure to ovulate with clomifene ovulation induction.

Clomifene Failure:

Failure to conceive despite ovulation with clomifene ovulation induction.

Gonadotrophin therapy:

Gonadotrophin therapy is indicated for women with anovulatory PCOS who have been treated with anti-estrogens if they have failed to ovulate or if they have a response to CC that is likely to reduce their chance of conception (e.g. persistent hypersecretion of LH, or anti-estrogenic effect on endometrium).

In order to prevent the risks of overstimulation and multiple pregnancy, a low-dose step-up regimen should be used with a daily starting dose of 25–50 IU of FSH or human menopausal gonadotrophin. This is only increased after 14 days if there is no response and then by only half of the starting dose every 7 days. Treatment cycles using this approach can be quite long – up to 28–35 days – but the risk of multiple follicular growth is low and the multiple pregnancy rate should be less than 5%.

Exclusion Criteria for hCG administration :

In order to reduce the risks of multiple pregnancy and OHSS, the exclusion criteria for hCG administration are the development of a total of two or more follicles larger than 14 mm in diameter.

Surgical Ovulation Induction:

In addition laparoscopic ovarian surgery is a useful therapy for anovulatory women with PCOS who fail to respond to CC and who persistently hypersecrete LH, need a laparoscopic assessment of their pelvis or who live too far away from the clinic to be able to attend for the intensive monitoring required of gonadotrophin therapy.

Laparoscopic Ovarian Drilling :

To minimise the number of diathermy points to four per ovary for 4 seconds at 40 watts.

The instillation of 500–1000 ml of an isotonic solution into the pouch of Douglas cools the ovaries to prevent heat injury to adjacent tissues and reduce the risk of adhesion formation.

Ovarian electrocautery should be considered for selected anovulatory patients, especially those with a normal BMI, as an alternative to ovulation induction.

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Screening in Women with PCOS

Screening for Gestational Diabetes

Screening for Gestational Diabetes should be offered to women who have been diagnosed as having PCOS before pregnancy.  This should be performed at 24 – 28 weeks of gestation, with referral to a specialist obstetric service if abnormalities are detected.

Screening for Type II Diabetes

Women presenting with PCOS

  • who are overweight (body mass index [BMI] ≥ 25 kg/m2)
  • who are not overweight (BMI <25 kg/m2), but who have additional risk factors 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 glucose tolerance test performed.

In women with impaired fasting glucose (fasting plasma glucose level from 6.1 mmol/l to 6.9 mmol/l) or impaired glucose tolerance (plasma glucose of 7.8 mmol/l or more but less than 11.1 mmol/l after a 2-hour oral glucose tolerance test), an oral glucose tolerance test should be performed annually.

Long term management of women with PCOS

Insulin-sensitising agents have not been licensed in the UK for use in patients without diabetes.

Use of weight reduction drugs may be helpful in reducing hyperandrogenaemia.

Hypertension in Women with PCOS

Hypertension should be treated; however, lipid-lowering treatment is not recommended routinely and should only be prescribed by a specialist.

Metabolic Syndrome in Women with PCOS

Metabolic syndrome affects 33% of women with polycystic ovary syndrome (PCOS).
 
Consequences of metabolic syndrome include cardiovascular disease, type II diabetes, cancer, sleep apnoea and psychological problems.
 
Cardiometabolic risk screening involves obtaining data on smoking history, weight, body mass index, waist circumference, blood pressure, lipid profile, and taking an oral glucose tolerance test.
 
Management of metabolic syndrome should focus on risk factors and individual components. Lifestyle modification is the only recommended intervention at present. 

Diagnostic Criteria for Metabolic Syndrome

Measure Diagnostic Cut - Offs
Elevated waist circumference

≥ 88 cm - significant risk.

≥ 80 cm

Elevated triglycerides

≥ 150 mg/dl (1.7mmol/l), or receiving drug treatment.

Reduced HDL - C levels

< 50 mg/dl (1.3 mmol/l), or receiving drug treatment.

Elevated BP

Systolic BP ≥ 130 or diastolic BP ≥ 85 mmHg, or treatment of previously diagnosed hypertension.

Elevated fasting glucose levels

≥ 100 mg/dl (5.6 mmol/l)

≥ 110 mg/dl (6.1 mmol/l)

or receiving drug treatment

Screening for Metabolic Syndrome in women with PCOS

Screenign Parameters Frequency of assessment
Cigarette smoking

At every visit

Obesity (weight, BMI, waist circumference)

At every visit (1.7mmol/l), or receiving drug treatment.

Blood Pressure

Annually, for women with a BMI of < 25 kg/m².

At every visit, for women with a BMI of ≥ 25 kg/m².

Elevated BP

Systolic BP ≥ 130 or diastolic BP ≥ 85 mmHg, or treatment of previously diagnosed hypertension.

Complete lipid profile

Every 2 years, for women with a normal profile.

Annually, for women with an abnormal profile or excess weight.

Oral glucose tolerance test (75g)

Every 2 years, all women

Annually, Women with risk factors (age >40 years, ethnicity, physical inactivity, smoking, waist circumference (>80 cm), BMI 25 kg/m², hypertension, previous gestational diabetes mellitus, family history of diabetes mellitus).

Cardiovascular Risk with Metabolic Syndrome in Women with PCOS

Women with metabolic syndrome are three to six times more likely to develop CHD, with a 12% increase in mortality.  

Risk of Diabetes Mellitus with Metabolic Syndrome in Women with PCOS

Metabolic syndrome confers a five-fold increase in risk for diabetes type II, and PCOS has been identified as a significant non-modifiable risk factor.
 
Up to 16% of women with PCOS convert to IGT per year. Women with baseline IGT have a 2% risk of progressing to diabetes type II per year, and over 6 years this risk maybe as high as 54%.

Obstructive Sleep Apnoea with Metabolic Syndrome in Women with PCOS

PCOS is associated with up to a 30-fold higher risk of obstructive sleep apnoea (OSA), and a nine-fold increase in excessive daytime sleepiness. IR has emerged as a principal predictor for the risk of OSA, independent of elevated testosterone levels and obesity.

Psychological Problems with Metabolic Syndrome in Women with PCOS

The prevalence of depression is higher in women with PCOS than the general population, with increased severity of symptoms.  This association is independent of BMI. These women are also more likely to develop anxiety, eating disorders and dysfunctional relationships.
 
Metabolic syndrome is associated with depression, mainly with neurovegetative features such as fatigue. 

Management of Obesity in Women with PCOS and Metabolic Syndrome.

Exercise

Thirty minutes per day (150 minutes per week) of brisk exercise is encouraged to maintain health, and should include atleast 90 minutes per week of moderate – intensity aerobic activity.

To lose weight, or sustain weight loss, 60 to 90 minutes per day is advised.

There are no medications that have been shown to assist with long-term weight reduction.

It is recommended by some that anyone with a BMI of greater than 40 kg/m2 should be referred for consideration of bariatric surgery. If there are comorbidities, such as diabetes, then the BMI cut-off for surgery may be lower (35 kg/m²).

Diet
In obese women with PCOS, incorporating carbohydrates with a low glycaemic index (GI) has demonstrated considerable improvement in insulin sensitivity.
 
However, low-GI foods are not necessarily high in nutritive value. Dietary fibre is the indigestible part of food that causes satiety, lowers cholesterol and slows absorption of carbohydrates. Proteins take longer to digest than carbohydrates, hence they can improve the insulin profile. Monounsaturated fatty acids improve cholesterol and glucose levels, as well as insulin response. Very long – chain polyunsaturated fatty acids, including omega-3 and omega-6 fats have a hypotriglyceridaemic effect and may ameliorate inflammation in metabolic syndrome.
 
Major omega-3 fats include eicosopentanoic acid, docosohexanoic acid and alpha-linolenic acid. Adequate omega-3 fat intake is important in PCOS.
Insulin Sensitizing agents
Metformin improves insulin sensitivity in women with PCOS.
 
Inositols are compounds with insulin-mimetic properties, particularly the isomers myoinositol (MI) and d-chiro-inositol (DCI). MI and DCI are involved in downstream signalling pathways following the activation of insulin receptors and are considered mediators of insulin action.
 
DCI leads to decreased basal insulin levels, an improved lipid profile and reduced systolic blood pressure.
Anti - Obesity Drugs
Orlistat, rimonabant and sibutramine have been used in the pharmacotherapy of obesity in PCOS.
 
Orlistat is an irreversible gastric lipase inhibitor that prevents the breakdown of dietary fat and thus, its absorption.
 
Its use is also associated with an improved lipid profile, including significant reductions in the levels of total cholesterol, low-density lipoprotein and triglycerides.
Bariatric Surgery
Bariatric surgery should be offered to women with 
  • Class III Obesity (BMI ≥ 40 kg/m²).
  • Class II Obesity (BMI 35 – 39.9 kg/m²) and associated diabetes and hypertension.

Women undergoing bariatric surgery have demonstrated reduced cardiometabolic risk factors reflected by an improved lipid profile and reduced insulin resistance.

Revise Numbers and Percentages in this article.

PCOS affects 10 – 18% of women of reproductive age.

The prevalence of metabolic syndrome is as high as 33% in women with PCOS.

Women with metabolic syndrome are three to six times more likely to develop CHD, with a 12% increase in mortality.

PCOS is associated with up to a 30-fold higher risk of obstructive sleep apnoea (OSA), and a nine-fold increase in excessive daytime sleepiness.

Metabolic syndrome confers a five-fold increase in risk for diabetes type II.

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