Polycystic ovarian syndrome(PCOS）

Polycystic ovarian syndrome(PCOS）

Wei Zhang

OB/GYN Hospital, Fudan University

Content

OVERVIEW of PCOS

PATHOPHYSIOLOGY

SIGNS and SYMPTOMS

DIAGNOSTIC CRITERIA

TREATMENT

OVERVIEWOVERVIEW

PCOS

1 st described by Stein and Leventhal as a triad of amenorrhea, obesity and hirsutism (1935)

The symptoms and severity of the syndrome vary greatly among affected women

It is one of the leading causes of female infertility

Definition & Abbreviations

Definition :Polycystic ovarian syndrome is a common endocrine disfunction typified by oligo-ovulation or anovulation, signs of androgen excess, and multiple small ovarian cysts

Abbreviations PCOS = Polycystic Ovarian Syndrome PCO= Polycystic Ovarian

Incidence

PCOS is the most common disorder of reproductive-aged women

Affects approximately 4-12%

PCOS appears to equally affect all races and nationalities

Etiology

Genetic basis Aggregation of the syndrome within

families • An increased prevalence has been noted

between affected individuals and their sisters and mothers

• The first-degree male relatives of women with PCOS have significantly higher circulating DHEAS levels

.

Environment causes Life style Exercise Diet Androgen exposure, et. al

Interaction of Genetics and environment

PCOS may be a genetically determined

ovarian disorder , the heterogeneity can be explained on the basis of interaction of the disorder with other genes and with the environment

PATHOPHYSIOLOGYPATHOPHYSIOLOGY

Hypothalamus

GnRH

Pituitary

FSH LH

ProgesteroneEstradiol

Ovary

内膜

Reproductive cycle regulated by HPO axis

Gn

Pathopysiologyz:What we think we know

Abnormal gonadotropin secretion Excess LH and low, tonic FSH

Hypersecretion of androgens Disrupts follicle maturation Substrate for peripheral aromatization

Negative feedback on pituitary Decreased FSH secreation

Insulin resistance, Elevated insulin levels

Disorder of H-P-O axis

Increased GnRH from hypothalamus Excessive LH secretion relative to FSH by

pituitary gland LH stimulates ovarian thecal cells to

produce excessive androgen Ineffective suppression of the LH pulse

frequency by estradiol and progesterone Androgen excess increases LH by blocking

the hypothalamic inhibitory feedback of progesterone

LH, FSH androgenEstrogen

GnRH

Anovulation

H-P-O axis Dysfunction in PCOS

Abnormal steroidogenesis

Intraovarian androgen excess results in excessive growth of small ovarian follicles

Follicular maturation is inhibited

Excess androgen causes thecal and stromal hyperplasia

PCO

These "cysts" are actually immature follicles. The follicles development stopped at an early antral stage due to the disturbed ovarian function

Polycystic is >12 follicles per ovary less than 10mm in diameter, ovary itself is enlarged

Metabolism disorder

Hyperinsulinemia Excess insulin production and insulin

resistance Hyperinsulinemia contributes to

hyperandrogenism through production in the theca cell and through its suppressive effects on sex hormone binding globulin production by the liver

Hyperandrogenism vs. hyperinsulinemia: Which came first?

Dyslipidemia

Current theories of pathopysiology

AutosomalDominant Gene

Insulin Resistance

PCOS

GnRH

LH

A

E2DownstreamSignal Defect

A=androgens, E2=estradiol

SIGNS and SYMPTOMSIGNS and SYMPTOM

Clinical Features of PCOS

Hyperandrogenism Hirsutism Acne

Chronic anovulation (irregular menses)

Irregular menses

Infertility

Endocrine Dysfunction Obesity Insulin resistance

• Acanthosis Nigricans• Impaired Glucose Tolerance and Type 2 Diabetes Mellitus

Dyslipidemia Metabolic Syndrome and Cardiovascular Disease

Polycystic ovaries

Hyperandrogenism

Hirsutism, acne, male pattern balding, alopecia

50-90% patients have elevated serum androgen levels

Rare: increased muscle mass, deepening voice,

Hirsutism:Ferriman-Gallwey Scoring System

Acne: 50%Mild moderate severe

Facial Hirsutism in PCOS

Menstrual Dysfunction

Oligomenorrhea : 70-75 %Amenorrhea: 20 %Regular cycles: 5-10 %

Infertility: 30-70%

Chronic anovulation/oligo-ovulation

Menstrual Dysfunction

Oligo or amenorrhea Menstrual irregularity typically begins in the

peripubertal period

Reduction in ovulatory events leads to deficient progesterone secretion

Chronic estrogen stimulation of the endometrium with no progesterone for differentiation—intermittent breakthrough bleeding or dysfunctional uterine bleeding

Increased risk for endometrial hyperplasia and/or endometrial CA

INFERTILITY

Intermittent ovulation or anovulation

Inherent ovarian disorder—studies show reduced rated of conception despite therapy with clomid

Obesity

Prevalence of obesity varies from 30-75%

2/3 of patients with PCOS who are not obese have excessive body fat and central adiposity

Obese patients can be hirsute and/or have menstrual irregularities without having PCOS

Insulin Resistance

> 80% are hyperinsulinemic and have insulin resistance (independent of obesity)

Acanthosis Nigricans

• Velvety plaques on nape of neck and intertriginous areas

• Epidermal hyperkeratosis

• Associated with insulin resistance

Ovarian Abnormalities

Thickened sclerotic cortex

Multiple follicles in peripheral location

80% of women with PCOS have classic cysts

Associated Medical Conditions

Increased risk of developing Type 2 Diabetes and Gestational diabetes

Low HDL and high triglyceridesSleep apneaNonalcoholic steatohepatitisMetabolic syndrome—43% of PCOS

patients (2 fold higher than age-matched population)

Elevated heart diseaseAdvanced atherosclerosis

Consequences of PCOS

Short-term consequences Irregular menses Hirsutism/acne/androgenic alopecia   Infertility Obesity  Metabolic disturbances : Abnormal lipid

levels/glucose intolerance

Long-term consequences Diabetes mellitus (DM) Cardiovascular disease(CVD) Endometrial cancer

Consequences of PCOS

PCOS

hyperandrogen

Elevated insulin

diabetes

Menstrual irregularity

Obesity

Hirsutism, acne

CVD

Dyslipidemia

infertility

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hyperplasia/cancer

DIAGNOSTIC CRITERIADIAGNOSTIC CRITERIA

Difficult to diagnosis Changing criteria Varying symptoms over time

• Not all women with PCOS have polycystic ovaries (PCO), nor do all women with ovarian cysts have PCOS

• although a pelvic ultrasound is a major diagnostic tool, it is not the only one

• The diagnosis is straightforward using the Rotterdam criteria

NIH Criteria(1990) Menstrual irregularity due to anovulation or

oligo-ovulation Evidence of clinical or biochemical

hyperandrogenism• Hirsutism, acne, male pattern baldness• High serum androgen levels

Exclusion of other causes (CAH, tumors, hyperprolactinemia)

Menstrual irregularity due to anovulation oligo-ovulation

Evidence of clinical or biochemical hyperandrogenism

Polycystic ovaries by US• 12 or more follicles measuring 2-9 mm in diameter• Increased ovarian volume (>10 cm 3 )

Exclusion of other causes (CAH, tumors, hyperprolactinemia)

In 2003 in Rotterdam, Netherlands, a consensus meeting between the European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine (ESHRE/ASRM) redefined PCOS

2003 Rotterdam Criteria (2 out of 3)

Differential Diagnosis

1. Hyperprolactinemia Prominent menstrual dysfunction Little hyperandrogenism

2. Congenital Adrenal Hyperplasia morning serum 17-hydroxyprogesterone

concentration greater than 200 ng/dL in the early follicular phase strongly suggests the diagnosis

confirmed by a high dose (250 mcg) ACTH stimulation test: post-ACTH serum 17-hydroxyprogesterone value less than 1000 ng/dL

3. Ovarian and adrenal tumors serum testosterone concentrations are always

higher than 150 ng/dL adrenal tumors: serum DHEA-S

concentrations higher than 800 mcg/dL LOW serum LH concentrations

4. Cushing’s syndrome5. Drugs: danazol; OCPs with high

androgenicity

Diagnostic Approaches

• Clinical history (hair growth rate, onset of symptoms)

• Physical examination (hirsutism or virilization, rounded facies, buffalo hump)

• Laboratory testing (hormones)

• Ultrasonography (ovary, endometrium)

Laboratory Testing

Fasting glucose: elevated 2 hour OGTT: elevated Fasting insulin: elevated Free testosterone: elevatedDHEA-S: normal17-hydroxyprogesterone: normalPelvic USLipids profile

Total Testosterone (T)DHEA-S (DS)17-hyroxyprogesterone (17-OHP)

T > 200 ng/dlDS > 700 μg/dl

Suspect Tumor

17-OHP > 2 ng/ml

Suspect CAH

T Elevated ±DS Elevated

DS Elevated

T & DS Normal PCOS

Adrenal

Idiopathic

Laboratory Evaluation

TREATMENTTREATMENT

Treatment

Goals of PCOS Treatment Restoration a normal cycle and fertility Lowering of insulin levels Treatment of hirsutism, acne Prenvention of endometrial cancer Prevention of DM,CVD and metabolic

syndrome

Treatment Option

Lifestyle modification

Anti-androgens

Insulin lowering agents

Induced ovulation-for pregnancy desired

Lifestyle modification

Weight loss:

Low-carbohydrate diets

sustained regular exercise

90% of anovulatory women restored to full

ovulation despite relatively small amounts

of weight loss following exercise and

change of diet

BMI of 21 is ideal but the patient often

respond to much less stringent body mass

index

Anti-Androgen

OCPs: first option when fertility is not desired Decrease in LH secretion and decrease in

androgen production Increase in hepatic production of sex-hormone

binding globulin(SHBG) Decreased bioavailablity of testosterone Decreased adrenal androgen secretion Regular withdrawal bleeding Prevention of endometrial hyperplasia

Spironolactone, 50-200 mg per day Androgen receptor blockade

Steroid enzyme inhibition

Aldosterone antagonism Lower blood pressure Potassium sparing

ProgestinsProgestins

progesterone withdrawal: every 1 to 3 months Regular withdrawal bleeding Prevention of endometrial hyperplasia and cancer

regimens include MPA: 5 to 10 mg daily for 10-14 days Micronized progesterone: 200 mg each evening

for 10-14 days

Insulin-Sensitizing Agents

Induction of ovulation

Some reduced hair growth

Improved glucose utilization

Lowered serum insulin

Lipid lowering properties

Metformin Dosage: 1500-2550 mg per day Clinically significant responses not regularly

observed at doses less than 1000 mg per day Treat with cyclic progestin to reduce

endometrial hyperplasia if regular menses not attained

•10 mg for 7 to 10 days every one to three months

Infertility

Weight loss—reduction in serum testosterone concentration and resumption of ovulation

Clomid: 80% will ovulate, 50% will conceive

Metformin will restore ovulation and menses in > 50% of

patients added to clomid, improves ovulatory rates

CC/FSH/hCG Laparoscopic surgery: wedge resections,

laparoscopic ovarian laser electrocautery IVF

Pathophysiology

Clinincal Features of PCOS

Diagnosis criteria

Treatment Option of PCOS

Key points

References John O. Schorge . Williams Gynecology,2008

ISBN 978-0-07-147257-9

丰有吉 . 妇产科学，八年制本科教材，人民卫生出版社， 2008

曹泽毅 .中华妇产科学 . 人民卫生出版社 .2005

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2012.06.15