polycystic ovarian syndrome (pcos ) wei zhang ob/gyn hospital, fudan university
TRANSCRIPT
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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ort-term
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g-term
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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
hyperandrogenismHirsutism, acne, male pattern baldnessHigh 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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