PCOS

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OBJECTIVES

Define PCOS Understand pathophysiology Form an appropriate differential

diagnosis Establish the work-up for PCOS Develop an array of therapies to treat

complaints and prevent bad outcomes

POLYCYSTIC OVARIAN SYNDROME (PCOS) OVERVIEW

PCOS is a complex endocrine disorder affecting women of childbearing age characterized by increased androgen production and ovulatory dysfunction

Prevalence 6-8% of normal populationLeading cause of anovulatory

infertility and hirsutismWomen with PCOS have an increased

risk of miscarriage, insulin resistance, hyperlipidemia, type 2 diabetes, cardiovascular disease, and endometrial cancer

PCOS AND STEIN-LEVENTHAL SYNDROME

oPCOS was first identified by Stein and Leventhal in 1935

oThey described a group of women who were obese and infertile, with enlarged ovaries with multiple cysts

oFew of these original features are now considered consistent findings in PCOS

PATHOPHISIOLOGY

Insulin secretion and actionGonadotropin secretion and action

Androgen biosynthesis and action

Weight and energy regulationEnvironment factor

DIAGNOSTIC CRITERIA

AND CLINICAL MANIFESTATIONS

NIH Criteria 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)

Rotterdam Criteria (2 out of 3) Menstrual irregularity due to anovulation

oligo-ovulation Evidence of clinical or biochemical

hyperandrogenism Polycystic ovaries by US

presence of 12 or more follicles in each ovary measuring 2 to 9 mm in diameter and/or increased ovarian volume

* In addition, other etiologies (congenital adrenal hyperplasias, androgen-secreting tumors, Cushing's syndrome) must be excluded.

AES criteriapresence of three features

androgen excess (clinical and/or biochemical hyperandrogenism)

ovarian dysfunction (oligo-anovulation and/or polycystic ovarian morphology)

exclusion of other androgen excess or ovulatory disorders

MENSTRUAL DYSFUNCTION

Oligo or amenorrheaMenstrual irregularity typically begins

in the peripubertal periodDelayed menarche

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

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Hormone Level

EstradiolProgesteroneFSHLH

Menstrual Cycle Day

Ovulation

Endometrial Thickness

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Normal Menstrual Cycle

Hormone Level

EstradiolProgesterone

Endometrial Thickness

0 2 4 6 8 10 12 14 16 18 20

0 2 4 6 8 10 12 14 16 18 20 Weeks

Breakthrough

Withdrawal

Anovulatory Bleeding in

PCOS

Lower limit of normal

HYPERANDROGENISM

Hirsutism, acne, male pattern balding, alopecia

50-90% patients have elevated serum androgen levels

Free testosterone levels most sensitive Rare: increased muscle mass,

deepening voice, clitormegaly (should prompt search for underlying neoplasm)

OVARIAN ABNORMALITIES

Thickened sclerotic cortex

Multiple follicles in peripheral location

80% of women with PCOS have classic cysts

Polycystic Ovaries

Cystic Follicles

Uterus

Tube

Anatomic Features of the Polycystic Ovary

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

OBESITY AND INSULIN RESISTANCE ½ patients with PCOS are obese > 80% are hyperinsulinemic and have

insulin resistance (independent of obesity)

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

Acanthosis Nigricans

• Velvety plaques on nape of neck and intertriginous areas• Epidermal hyperkeratosis• Associated with insulin resistance

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

TESTING

Serum HCG Serum prolactin Thyroid function test FSH: r/o ovarian failure Serum luteinizing hormone (LH)—

elevated Serum estradiol—normal Serum estrone—elevated

TESTING

Fasting glucose: elevated 2 hour OGTT: elevated Fasting insulin: elevated Free testosterone: elevated DHEA-S: normal 17-hydroxyprogesterone: normal Pelvic US Lipids

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

TREATMENT

Depend on goal of treatment

WEIGHT LOSS

Weight loss Weight loss Weight loss

HIRSUTISM

Mechanical hair removal Vaniqa (eflornithine hydrochloride) OCPs with minimal androgenicity OCP plus antiandrogen (spironolactone) Spironolactone, 50-200 mg per day Flutamide

Potential hepatic dysfunction

ORAL CONTRACEPTIVES

• Suppress ovarian androgen

• Increase SHBG

• Regular menstrual cyclicity

• Progestin opposition

• Contraception

ANTI-ANDROGENS

Spironolactone

Flutamide

Finasteride

SPIRONOLACTONE

Androgen receptor blockade

Steroid enzyme inhibition

Aldosterone antagonismLower blood pressurePotassium sparing

Dose: 100-200 mg/day

FLUTAMIDE

Non-steroidal, selective anti-androgen

Liver function tests

Dose: 125-250 mg/day

OLIGOMENORRHEA Combination estrogen-progestin pill

first line when fertility is not desired Decrease in LH secretion and decrease in

androgen production Increase in hepatic production of sex-

hormone binding globulin Decreased bioavailablity of testosterone Decreased adrenal androgen secretion Regular withdrawal bleeds Prevention of endometrial hyperplasia

TREATMENT—NO FERTILITY DESIRED

Monophasic antiandrogenic OCPON 1/35 (norethindrone)Orthocyclen (norgestimate)Desogen or Orthocept

(desogestrel)Yasmin

- insulin sensitizing agents

Metforminwill restore ovulation and menses in > 50% of patients

Treat with cyclic progestin to reduce endometrial hyperplasia if regular menses not attained10 mg for 7 to 10 days every two to four months

METFORMIN

Decreases hepatic glucose production Reduces need for insulin secretion Improves insulin sensitivity (increases

peripheral glucose uptake and utilization)

Antilipolytic effect—reduces fatty acid concentrations and reduces gluconeogenesis

SIDE EFFECTSDiarrhea, nausea, vomiting,

flatulence, indigestion, abdominal discomfortCaused by lactic acid in the bowel wallMinimized by slow increase in dosage

Lactic acidosis—rareAvoid in CHF, renal insufficiency, sepsisDiscontinue for procedures using

contrast (withhold X 48 hours)Temporarily suspend for all surgical

procedures that involve fluid restrictionCimetidine causes increased metformin

levels

INFERTILITY TREATMENT

Metformin Metformin 500 mg once a day with

breakfast for 4 days Metformin 500 mg twice a day with

breakfast and dinner for 4 days Metformin 500 mg with breakfast and

1,000 mg with dinner for 4 days Metformin 1,000 mg twice daily

Clomid 50 mg days 3-7 for 3 months 100 mg days 3-7 for 3 months

METFORMIN DOSING Target—1500-2000 mg per day

Clinically significant responses not regularly observed at doses less than 1000 mg per day

INFERTILITY

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

Clomid: 80% will ovulate, 50% will conceive

Metformin: when added to clomid, improves ovulatory rates

Laparoscopic surgery: wedge resections, laparoscopic ovarian laser electrocautery

IVF

Key point PCOS is the most common endocrine diso

- rder in reproductive aged women. PCOS is a lifelong disease beginning in fa

tal life and extending into the postmeno pausal period.

Hyperinsulinemia is the pivotal factor in the pathogenesis.

PCOS is an inherited disorder the follows an autosomal dominant inheritance patt ern although the gene or genes involve a

re unknown

Hyperandrogenemia with or witho ut hyperandrogenism along with ol

igomenorrhea are hallmark feature s of PCOS

Anovulatory resulting in infertility i s a common presentation

Obesity worsens metabolic abnorm alities such as hyperinsulinemia an

d hyperandrogenemia.

Diabetes, lipid disorder, heart dise ase and endometrial cancer are me

tabolic sequelae of PCOS. - Insulin sensitizing agent heave dra

matically changes the managemen -t of PCOS. Metformin, an insulin se

nsitizing agent, is now first choice f or the treatment of anovulation in

PCOS. Weight loss and exercise are the best long term therapy to decr

ease the metabolic sequelae of PCOS.

REFERENCES Berek & Novak’s Gynecology Clinical gynecology / [edited by] Eric J. Bieber, Joseph

S. Sanfilippo, Ira R. Horowitz Uptodate.com Polycystic ovary syndrome : a guide to clinical

management / Adam Balen ... [et al.] Polycystic ovary syndrome / edited by R. Jeffrey

Chang, Jerrold J. Heindel, Andrea Dunaif. ACOG practice bulletin, polycystic ovary syndrome The ovary / editors, Peter C.K. Leung, Eli Y. Adashi Clinical gynecologic endocrinology and infertility /

Leon Speroff, Marc A. Fritz

THANK YOU

Wt. increase

Insulin receptor disorder

Insulin increase

Free estradiolincrease

High LHLow FSH

Free testosteronincrease

Androstenandion increase

SHBG decrease

atresia

Theca (IGF-I)

Endometrial cancer

Testosteronincrease

Estroneincrease

hirsutism

IGFBP-I **** decrease

IGFBP*** insulin like growth factor binding protein

INSULIN SENSITIVITY

Insulin

Liver Muscle

Pancreas

Hepatic Glucose Output

Glucose Utilization

INSULIN RESISTANCE

Insulin

Liver Muscle

Pancreas

Hepatic Glucose Output

Glucose Utilization

Increased