Polycystic Ovarian Syndrome

John Miell

University Hospital Lewisham

Kings College Hospital

A heterogenous condition (or many conditions)

Stein-Leventhal Syndrome (1935)

Menstrual Irregularity Hirsutism, Acne, Alopecia Obesity

Stein I and Leventhal M (1935) Amenorrhoea associated with bilateral polycystic ovaries. Am J Obst Gyn 29:181

Hyperinsulinism, glucose intolerance and hyperandrogenism Achard C and Thiers J (1921): Le virilisme

pilaire et son association a l’insufficiance glycolytique (diabetes des femmes a barb)

Bulletin of the Academy of National Medicine

Features of PCOS

Clinical: Menstrual abnormalities Anovulatory subfertility Hirsutes, acne, alopecia Weight gain ?recurrent miscarriage

Features of PCOS

Endocrine: Elevated androgen Elevated LH Elevated estrogen and prolactin Elevated androstenedione Decreased SHBG

Biochemistry not reliable

LH elevated in 40% Serum testosterone not always elevated In a study of 1741 women with PCOS

confirmed on clinical features and USS only 28.9% had elevated testosterone

Features of PCOS

Metabolic: Insulin resistance Impaired GT and T2 DM Lipid abnormalities Cardiovascular risks Neoplastic risk (?)

PCOS-Definition Ovulatory dysfunction and clinical features

of hyperandrogenism

Polycystic ovaries plus one or more of the clinical features

Revised Diagnostic criteria for PCOS 1999: Chronic anovulation Clinical/biochemical signs of hyperandrogenism and

exclusion of other pathologies*

2003: 2/3 of Oligo and/or anovulation Clinical/biochemical signs of hyperandrogenism Polycystic ovaries

USS appearance of PCO

PCOS Definition

Two out of the following Oligo/anovulation Clinical or Biochemical hyperandrogenism PCO

Rotterdam consensus meeting 2003

Cause of PCOS 1 Unknown - but probably a vicious cycle

with a number of entry points: Defect in insulin action and secretion - Defect in insulin action and secretion -

hyperinsulinemia and insulin resistancehyperinsulinemia and insulin resistance Neuroendocrine defect - high LH pulse frequency and Neuroendocrine defect - high LH pulse frequency and

amplitudeamplitude Defect of androgen synthesis - enhanced ovarian Defect of androgen synthesis - enhanced ovarian

androgen productionandrogen production Defect in cortisol metabolism - enhanced adrenal Defect in cortisol metabolism - enhanced adrenal

androgen productionandrogen production

Cause of PCOS 2 Insulin resistance

-Hyperinsulinaemia

-Increased ovarian androgen

-inhibits SHBG production in liver

-increased free Testosterone

-inhibits IGFBP-1 production

-more free IGF-I Weight gain

-hyperinsulinaemia

Mechanism of hyperinsulinemia Insulin resistance:

Obese PCOS>obese>lean PCOS>Lean

Pancreatic Beta cell secretory dysfunction Decreased hepatic clearance of insulin Abnormal insulin signalling -

serine vs tyrosine phosphorylation serine phosphorylation inhibits receptor TK

activity and accentuates P450c17 activity

Ovarian steroid biosynthesis

Pathways leading to androgen excess in PCOS

Increased cortisol metabolism Increased adrenal androgen production

may occur secondary to alteration in cortisol metabolism

Increased 5alphaR or reduced 11betaHSD may lead to reduced cortisol

This leads to increased ACTH (to maintain normal cortisol levels) at the expense of excess adrenal androgen stimulation

Increased cortisol metabolism

                         

                             

5alpha reductase mediates conversion of testosterone to 5 alphaDihydrotestosterone and cortisol to 5alpha dihydrocortisol

Genetics of PCOS High correlation between twin pairs for hyperinsulnemia and

hyperandrogenism (monogenic trait, 2 alleles, autosomal locus) Prospective study of 1st degree relatives of women with PCOS –

46% affected – half have hyperandrogenemia with regular cycles, half have PCOS

Association between PCOS and polymorphism at INS VNTR No difference in polymorphisms at CYP17 (encoding P450c17a) No real luck looking at follistatin or CYP11a (coding P450scc) ?type I IGF receptor/insulin receptor

Long term consequences of PCOS

Increased risk of diabetes Increased risk of cardiovascular disease Increased risk of carcinoma

Increased risk of diabetes Insulin resistance and beta cell dysfunction

precede Type2 DM Up to 40% of PCOS have IGT or T2DM (vs

10.3% in normal population studies) Legor et al (1999): 31.1% IGT (vs 7.8% in

age, weight, race matched controls) and 7.5% frank diabetes (vs 1.0%). Lean PCOS – 10.3% IGT, 1.5% frank T2DM.

Increased risk of diabetes Gestational diabetes is very common in

PCOS (? Role for Metformin in pregnancy).

PCOS and cardiovascular disease The metabolic syndrome:

Impaired glucose tolerance Type 2 DM Abdominal obesity Adverse lipid profiles

PCOS and cardiovascular disease The metabolic syndrome Diagnosis based on 3/5 of:

Fasting Triglycerides >1.7 mmol/L HDL – C < 1.3 mmol/L BP > 135/85 FBG > 6 mmol/L Waist circumference > 88cms

PCOS and cardiovascular disease Angiography reveals increased incidence in

coronary artery disease in women with Hirsutism (Wild et 1990)

USS evidence of PCO (Birdsall et al 1997)

PCOS and cardiovascular disease Follow up of women who have had wedge

resection

7.4 fold increase in risk of MI

PCOS and cardiovascular disease 30 year follow up of 786 women fulfilling reasonable

diagnostic criteria for PCOS ( Pierpoint et al 1998, Wild et al, 2000)

Increase in mortality/morbidity from diabetes and increased risk of non-fatal cerebrovascular disease.

No increase in deaths from heart disease mean BMI was 27 kg/m2 No increase in prevalence of T2DM in this study ? Protective effects of unopposed estrogen and increased

levels of VEGF

PCOS and cardiovascular risk factors

Dyslipidemia – secondary to: Elevated androgens, body fat distribution and

hyperinsulinemia Raised triglycerides Marginal elevation of LDL Reduced HDL Raised small dense LDL-III Increased hepatic lipase activity Elevated plasminogen activator inhibitor, PAI-1

?Consequence of androgens or hyperinsulinemia.

PCOS prevention of long term consequences

Advise to modify risk factors

Lose weight – diet/exercise

Stop smoking

Insulin sensitisation (?)

Screen for diabetes

Increased risk of cancer (??) No powerful well controlled studies using

accurately defined diagnostic criteria Possibly no overall increased risk of cancer in

practice (Venn et al, Lancet, 1999)

Increased risk of cancer (??) Endometrial cancer Theoretical risk of amenorrhoea and unopposed estrogen Mayo clinic – 3X increased risk of endometrial cancer in

women with anovulation without hypoestrogenemia (prob PCOS – Coulam, ObsGyn, 1983)

BUT – no good studies, poordiagnostic criteria, retrospective analyses etc.

Increased risk of cancer (??) Breast cancer Theoretical risk of amenorrhoea and unopposed

estrogen PCOS protective against Breast cancer in a self

reported historical study (Odd ratio 0.52 (0.32-0.87 – Gammon 1991)

No significant excess deaths from Breast cancer in a large group of PCOS (Pierpoint, J Clin Epidemiol, 1998)

Increased risk of cancer (??) Ovarian cancer The jury is out 2 studies suggest an increased risk - possibly

both subject to recall bias 3 studies suggest no increased risk

Treatment Depends on Symptoms

Clinical Presentation Oligo/amenorrhoea Subfertility Obesity Acne Hirsutism

Exercise and weight loss Improves insulin sensitivity Reduces serum testosterone Improves menstrual regularity Induces regular ovulation

Visceral fat Responsible for the adverse effects of

obesity Strong correlation with insulin resistance

Obesity and PCOS Waist circumference is better guide to

metabolic risk factors than is waist:hip ratio or BMI

waist ideally should be < 87cm

( and possibly <79cm) Exercise is more important than diet in

reducing visceral fat and correcting metabolic abnormalities

Oligo/amenorrhoea Risk of endometrial pathology

Combined oral contraceptive Cyclical progestagen

OR Annual TVS assessment of endometrium

Treatment of Hirsutism Shaving, Electrolysis or waxing Ornithine decarboxylase inhibitors COC Cyproterone acetate Spironolactone Flutamide and Finasteride Metformin

Hirsutism Oestrogen

suppresses ovarian testosterone

Increases SHBG Cyproterone acetate (progestogen)

Androgen antagonist

Suppresses LH

Oral contraceptive Ethinyl oestradiol 35mcg

Cyproterone Acetate 2mg Ethinyl Oestradiol 30 or 50mcg

Desogestrel 150mcg

Equally effective in treatment of Hirsutism

Porcile & Gallardo 1991

Ethinyl oestradiol +drosperinone

Reverse sequential Regime Dianette

Plus Cyproterone acetate 50-100mg

day 1-10 of pill packet

Earlier improvement in hirsutism

Barth et al 1991

Metformin Reduces insulin resistance 1000mg -1500mg daily

reduces serum insulin reduces serum testosterone Improves lipid profile Improves menstrual irregularity Improves fertility

Metformin & Clomiphene 61 women with BMI>28 Received Metformin 500mg tds or placebo

Metformin and clomiphene Metfomin 34% ovulated Placebo 4% ovulated

Metformin + clomiphene

90% ovulated Placebo + Clomiphene

8% ovulated

PCOS - conclusions Insulin resistance, hyperandrogenism, unusual

gonadotrophin dynamics Familial though no stron evidence of candidate

gene identity Links with obesity, cardiovascular disease, DM

and maybe endometrial cancer Needs lifestyle modification which remains the

mainstay of treatment Metformin has been a revelation

Surgical or medical treatment of PCOS

And/or