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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 population
Leading cause of anovulatory infertility
and hirsutism
Women with PCOS have an increased
risk of miscarriage, insulin resistance,
hyperlipidemia, type 2 diabetes,
cardiovascular disease, and endometrial
cancer

PCOS AND STEIN-LEVENTHAL


SYNDROME
o PCOS was first identified by Stein

and Leventhal in 1935


o They described a group of women
who were obese and infertile, with
enlarged ovaries with multiple cysts
o Few of these original features are
now considered consistent findings
in PCOS

PATHOPHISIOLOGY

Insulin

secretion and action

Gonadotropin

secretion and

action
Androgen biosynthesis and
action
Weight and energy regulation
Environment 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 criteria
presence 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 amenorrhea

Menstrual

irregularity typically begins


in the peripubertal period
Delayed menarche

Reduction

in ovulatory events leads


to deficient progesterone secretion
Chronic estrogen stimulation of the
endometrium with no progesterone
for differentiationintermittent
breakthrough bleeding or
dysfunctional uterine bleeding
Increased risk for endometrial
hyperplasia and/or endometrial CA

Estradiol
Progesterone
FSH
LH

Ovulation

Normal
Menstru
al Cycle

Hormone
Level

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

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

Endometrial
Thickness

Menstrual Cycle Day

Anovulatory
Bleeding in
PCOS

Estradiol
Progesterone
Hormone
Level

Lower limit
of normal

10

12

14

16

18

20
Endometrial
Thickness

Breakthrough
Withdrawal
0

2
20

10
Weeks

12

14

16

18

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
Multiple
80%

sclerotic cortex

follicles in peripheral location

of women with PCOS have classic


cysts

Anatomic Features of
the Polycystic Ovary
Tube

Uterus

Polycystic
Ovaries

Cystic
Follicles

INFERTILITY

Intermittent ovulation or anovulation


Inherent ovarian disorderstudies 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
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

2.

Prominent menstrual dysfunction


Little hyperandrogenism

Congenital Adrenal Hyperplasia

morning serum 17hydroxyprogesterone 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. Cushings syndrome
5. 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 estradiolnormal
Serum estroneelevated

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

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

T Elevated

DS Elevated
PCOS

DS Elevated
Adrenal
T & DS Normal
Idiopathic

T > 200 ng/dl


DS > 700 g/dl
Suspect Tumor
17-OHP > 2 ng/ml
Suspect CAH

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
Steroid

receptor blockade

enzyme inhibition

Aldosterone

antagonism
Lower blood pressure
Potassium 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

TREATMENTNO FERTILITY
DESIRED
Monophasic

OCP

ON

antiandrogenic

1/35 (norethindrone)
Orthocyclen (norgestimate)
Desogen or Orthocept
(desogestrel)
Yasmin

insulin-sensitizing agents
Metformin

will

restore ovulation and


menses in > 50% of patients
Treat with cyclic progestin to
reduce endometrial
hyperplasia if regular menses
not attained

10 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 effectreduces fatty acid
concentrations and reduces
gluconeogenesis

SIDE EFFECTS
Diarrhea,

nausea, vomiting, flatulence,


indigestion, abdominal discomfort
Caused

by lactic acid in the bowel wall


Minimized by slow increase in dosage

Lactic

acidosisrare

Avoid

in CHF, renal insufficiency, sepsis


Discontinue for procedures using contrast
(withhold X 48 hours)
Temporarily suspend for all surgical
procedures that involve fluid restriction
Cimetidine 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

Target1500-2000 mg per day


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

INFERTILITY
Weight

lossreduction 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
disorder in reproductive-aged women.
PCOS is a lifelong disease beginning in
fatal life and extending into the postme
nopausal period.
Hyperinsulinemia is the pivotal factor in
the pathogenesis.
PCOS is an inherited disorder the
follows an autosomal dominant inherita
nce pattern although the gene or genes
involve are unknown

Hyperandrogenemia

with or
without hyperandrogenism along
with oligomenorrhea are hallmark
features of PCOS
Anovulatory resulting in infertility
is a common presentation
Obesity worsens metabolic
abnormalities such as hyperinsulin
emia and hyperandrogenemia.

Diabetes,

lipid disorder, heart


disease and endometrial cancer ar
e metabolic sequelae of PCOS.
Insulin-sensitizing agent heave
dramatically changes the manage
ment of PCOS. Metformin, an insul
in-sensitizing agent, is now first c
hoice for the treatment of anovula
tion in PCOS. Weight loss and exer
cise are the best long term therap
y to decrease the metabolic seque
lae of PCOS.

REFERENCES

Berek & Novaks 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

SHBG
decrease

Wt. increase
Insulin receptor
disorder

High LH
Low FSH

Insulin increase
IGFBP-I ****
decrease

Theca (IGF-I)

Free testosteron Free estradiol


increase
increase

Testosteron
increase

Androstenandion
increase

Estrone
increase

atresia

Endometrial
cancer

IGFBP*** insulin like growth factor binding protein

hirsutism

INSULIN SENSITIVITY

Liver

Muscle

Hepatic
Glucose
Output

Glucose
Utilization

Insulin

Pancreas

INSULIN RESISTANCE

Liver

Muscle

Hepatic
Glucose
Output

Glucose
Utilization

Insulin
Increased

Pancreas