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 linsufficiance 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 hyperinsulinemia and insulin resistance Neuroendocrine defect - high LH pulse frequency and amplitude Defect of androgen synthesis - enhanced ovarian androgen production Defect in cortisol metabolism - enhanced adrenal androgen 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 alpha Dihydrotestosterone 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 (0.320.87 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 Placebo

34% ovulated 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