Polycystic Ovary Syndrome Obstetrics & Gynecology Vol 103, No 1, Jau 2004 부산백병원...

Polycystic Ovary Polycystic Ovary SyndromeSyndrome

Obstetrics & Gynecology Obstetrics & Gynecology Vol 103, No 1, Jau 2004Vol 103, No 1, Jau 2004

부산백병원 산부인과부산백병원 산부인과R4 R4 강영미강영미

IntroductionIntroduction

Chronic anovulation and androgen excess not attributable Chronic anovulation and androgen excess not attributable to another cause to another cause

Occurs in approximately 4% of women Occurs in approximately 4% of women Fundamental pathophysiologic defect Fundamental pathophysiologic defect

Unknown Unknown Important characteristics ; insulin resistance, hyperanImportant characteristics ; insulin resistance, hyperan

drogenism, and altered gonadotropin dynamics drogenism, and altered gonadotropin dynamics Inadequate FSH ; hypothesized to be a proximate causInadequate FSH ; hypothesized to be a proximate caus

e of anovulation e of anovulation Obesity complicates PCOS but is not a defining characObesity complicates PCOS but is not a defining charac

teristic teristic

IntroductionIntroduction

Diagnostic approach ; should based on history and physicDiagnostic approach ; should based on history and physical exam al exam

Irregular bleeding, hirsutism and/or infertility Irregular bleeding, hirsutism and/or infertility Treated with OCs, OCs with spironolactone and ovulatiTreated with OCs, OCs with spironolactone and ovulati

on induction on induction Higher prevalence of diabetes and increased risk factors Higher prevalence of diabetes and increased risk factors

for cardiovascular ds. for cardiovascular ds. should also be screened should also be screened for obese women with PCOS, for obese women with PCOS,

behavioral weight management ; central behavioral weight management ; central component of the overall treatment strategy component of the overall treatment strategy

DefinitionDefinition

Since its first description in 1935, a variety of histologic, Since its first description in 1935, a variety of histologic, biochemical, sonographic and clinical characteristics ; asbiochemical, sonographic and clinical characteristics ; associated with PCOSsociated with PCOS

Practical and useful clinical definition of PCOS in the UnitPractical and useful clinical definition of PCOS in the United States ed States If have chronic anovulation and evidence of androgen If have chronic anovulation and evidence of androgen

excess for which there is no other cause excess for which there is no other cause Referred to as the "NIH Conference" definition, despitReferred to as the "NIH Conference" definition, despit

e wide variety of views regarding the clinical, endocrine wide variety of views regarding the clinical, endocrinologic features (Table 1)ologic features (Table 1)

PrevalencePrevalence

Best prevalence study, reported in 1998, with Best prevalence study, reported in 1998, with unselected sample of white and African-American unselected sample of white and African-American women between the ages of 18 and 45 years women between the ages of 18 and 45 years 277 women who consented to a history, 277 women who consented to a history,

physical exam, and hormonal evaluation, physical exam, and hormonal evaluation, overall prevalence of PCOS overall prevalence of PCOS

4-4.7% for white women 4-4.7% for white women 3.4% for African American women 3.4% for African American women

Clinical ImportanceClinical Importance

In clinical gynecologic practice,In clinical gynecologic practice, Primarily for menstrual irregularity, hirsutism, and inferPrimarily for menstrual irregularity, hirsutism, and infer

tility tility Treatment is directed at the immediate presenting complaint Treatment is directed at the immediate presenting complaint

Long-term goalsLong-term goals Prevent diabetes, coronary heart ds.Prevent diabetes, coronary heart ds. Screen cancerScreen cancer

Unopposed estrogen exposure -> increased risk of endometriUnopposed estrogen exposure -> increased risk of endometrial ca.al ca.

PathophysiologyPathophysiology

Fundamental pathophysiologic defect in PCOSFundamental pathophysiologic defect in PCOS Unknown Unknown Several interrelated characteristics ; insulin resistancSeveral interrelated characteristics ; insulin resistanc

e, hyperandrogenism, and altered gonadotropin dyname, hyperandrogenism, and altered gonadotropin dynamics ics

Hypothesis that inadequate FSH stimulation ; proximatHypothesis that inadequate FSH stimulation ; proximate cause of anovulation in PCOS e cause of anovulation in PCOS


Insulin resistance Insulin resistance Defined as a subnormal biological response to Defined as a subnormal biological response to

insulin insulin Associated with obesity Associated with obesity Extent of insulin resistance - cannot be Extent of insulin resistance - cannot be

explained entirely by obesity explained entirely by obesity


Hyperandrogenism Hyperandrogenism strong correlation between insulin resistance and hypestrong correlation between insulin resistance and hype

randrogenism randrogenism HAIR-AN syndrome HAIR-AN syndrome

Acanthosis nigricans Acanthosis nigricans Strongly suggests insulin resistance Strongly suggests insulin resistance Dermatologic disorder characterized by velvety hyperpigmenteDermatologic disorder characterized by velvety hyperpigmente

d skin, usually over the nape of the neck, in the axillae, or bed skin, usually over the nape of the neck, in the axillae, or beneath the breasts) neath the breasts)


what is the directionality of the relationship between insulwhat is the directionality of the relationship between insulin resistance and hyperandrogenism? in resistance and hyperandrogenism? Direction of causation is from insulin to androgen and Direction of causation is from insulin to androgen and

not reversenot reverse Administration of diazoxide -> results in reduction in Administration of diazoxide -> results in reduction in

circulating androgen concentrations circulating androgen concentrations Weight loss and insulin sensitizers -> reduction in androgen Weight loss and insulin sensitizers -> reduction in androgen

in vivo effect on ovarian androgens by insulin in vivo effect on ovarian androgens by insulin insulin synergizes with LH to promote androgen production by insulin synergizes with LH to promote androgen production by

the thecal cellsthe thecal cells


Altered gonadotropin-releasing hormone dynamics Altered gonadotropin-releasing hormone dynamics Another key pathophysiologic feature of PCOS Another key pathophysiologic feature of PCOS Increased LH pulse frequency and amplitude, leading tIncreased LH pulse frequency and amplitude, leading t

o increased 24-hour mean concentrations in both lean o increased 24-hour mean concentrations in both lean and obese women with PCOS and obese women with PCOS

Elevated LH levels Elevated LH levels Responsible for the excess androgen production Responsible for the excess androgen production Androgen production by theca cell is LH dependent Androgen production by theca cell is LH dependent Suppression of LH by GnRH agonists or by OCs reduces circulSuppression of LH by GnRH agonists or by OCs reduces circul

ating testosterone and androstenedione ating testosterone and androstenedione


Inadequate concentrations of endogenous FSHInadequate concentrations of endogenous FSH Absolute concentrations of FSH above a specified threAbsolute concentrations of FSH above a specified thre

shold shold Essential for both the initiation of preovulatory follicle developEssential for both the initiation of preovulatory follicle develop

ment as well as the selection of a single preovulatory follicle ment as well as the selection of a single preovulatory follicle

PathophysiologyPathophysiology In PCOS,In PCOS,

E2 production ; limitedE2 production ; limited Follicles not mature fully Follicles not mature fully Granulosa cells number and in aromatase activity decreasedGranulosa cells number and in aromatase activity decreased Therefore, E2 production is limited, in the range of 70-80 pg/Therefore, E2 production is limited, in the range of 70-80 pg/

mL higher than early follicular E2 mL higher than early follicular E2 Suppressing FSH, but never reaching the levels needed toSuppressing FSH, but never reaching the levels needed to

initiate an LH surge initiate an LH surge Concentration of FSH Concentration of FSH

Not rise above levels seen in the mid-follicular range Not rise above levels seen in the mid-follicular range Insufficient to stimulate preovulatroy follicle developmentInsufficient to stimulate preovulatroy follicle development Constrained by negative feedback inhibition of E2 which never Constrained by negative feedback inhibition of E2 which never

exceeds mid-follicular levelsexceeds mid-follicular levels


Currently lack a satisfactory integrative model of PCOS paCurrently lack a satisfactory integrative model of PCOS pathophysiology thophysiology Genetic factors are at the root of the condition Genetic factors are at the root of the condition In view of characteristics such as insulin resistance anIn view of characteristics such as insulin resistance an

d gonadotropin changes d gonadotropin changes Likely that more than one genetic "hit" Likely that more than one genetic "hit"

Influenced by environmental factors Influenced by environmental factors

Diagnostic ApproachDiagnostic Approach

Relatively safe ground on combination of chronic anovulatRelatively safe ground on combination of chronic anovulation and androgen excess ion and androgen excess

With respect to ovulatory history With respect to ovulatory history History of irregular menstrual cycles dating to menarchHistory of irregular menstrual cycles dating to menarch

e e Report 6 or fewer episodes of spontaneous vaginal bleReport 6 or fewer episodes of spontaneous vaginal ble

eding per year eding per year


oily skin and acne oily skin and acne subtle signs of androgen excess subtle signs of androgen excess

Hirsutism Hirsutism Most common manifestation of the androgen componMost common manifestation of the androgen compon

ent of PCOS ent of PCOS should inquire about and examine for should inquire about and examine for

"male-pattern" hair(hair located on the upper lip, chin, "male-pattern" hair(hair located on the upper lip, chin, chest, lower abdomen, and inner aspects of the thighchest, lower abdomen, and inner aspects of the thighs) s)


Differing opinions on what laboratory studies should be orDiffering opinions on what laboratory studies should be ordered in evaluating a woman with PCOS dered in evaluating a woman with PCOS Primarily a clinical diagnosis - few laboratory studies aPrimarily a clinical diagnosis - few laboratory studies a

re needed re needed Only condition that needs to be excluded to secure the Only condition that needs to be excluded to secure the

diagnosis of PCOS - nonclassical CAH diagnosis of PCOS - nonclassical CAH Diagnostic pathway in Figure 3 Diagnostic pathway in Figure 3


Figure 3Figure 3


Ratio of LH to FSH greater than 2;1 - consistent with PCORatio of LH to FSH greater than 2;1 - consistent with PCOS S LH ; FSH ratio often in the "normal range" LH ; FSH ratio often in the "normal range" ∵ ∵ pulsatile nature of gonadotropins, resulting in broad pulsatile nature of gonadotropins, resulting in broad

range of LH ; FSH ratios in PCOS when a single blood range of LH ; FSH ratios in PCOS when a single blood sample is drawn sample is drawn

In author's practice, evaluating a women with chronic anoIn author's practice, evaluating a women with chronic anovulation since menarche and hirsutismvulation since menarche and hirsutism Only blood sample - 17-hydroxyprogesterone concentrOnly blood sample - 17-hydroxyprogesterone concentr

ation to rule out 21-hydroxylase-deficient nonclassical ation to rule out 21-hydroxylase-deficient nonclassical adrenal hyperplasia adrenal hyperplasia


Testosterone Testosterone Not necessary for diagnosis when clear hirsutism is prNot necessary for diagnosis when clear hirsutism is pr

esent esent Sometimes helpful in evaluating a women with chronic Sometimes helpful in evaluating a women with chronic

anovulation but who does not have clinical evidence of anovulation but who does not have clinical evidence of hirsutism or other signs of androgen excess hirsutism or other signs of androgen excess

Total testosterone concentration greater than 60 ng/dTotal testosterone concentration greater than 60 ng/dL ; consistent with PCOS L ; consistent with PCOS


Ovarian anatomy Ovarian anatomy Show multiple, small, subcapsular cysts, reflecting repShow multiple, small, subcapsular cysts, reflecting rep

eated episodes of incomplete follicular growtheated episodes of incomplete follicular growth Dense, hyperplastic stroma, reflecting an active thecal Dense, hyperplastic stroma, reflecting an active thecal

component that is over-secreting androgens component that is over-secreting androgens Ultrasound picture Ultrasound picture

Numerous, small subcapsular cysts that produces Numerous, small subcapsular cysts that produces a "string of pearls" sign(Figure 4) a "string of pearls" sign(Figure 4)

Small subcapsular cysts and hyperechogenic stroma Small subcapsular cysts and hyperechogenic stroma


Figure 4Figure 4


In summary,In summary, Best diagnosed clinically with a minimum of laboratory Best diagnosed clinically with a minimum of laboratory

tests tests History of chronic anovulation dating since menarcheHistory of chronic anovulation dating since menarche Evidence of androgen excess, principally hirsutismEvidence of androgen excess, principally hirsutism Blood sample for serum 17-hydroxyprogesterone concentratioBlood sample for serum 17-hydroxyprogesterone concentratio

n to rule-out 21-hydroxylase-deficient nonclassical adrenal hyn to rule-out 21-hydroxylase-deficient nonclassical adrenal hyperplasia perplasia

Obesity in conjunction with anovulation and androgen Obesity in conjunction with anovulation and androgen excess excess

Increase further one's suspicion of PCOS Increase further one's suspicion of PCOS


In cases in which the clinical diagnosis is not clearIn cases in which the clinical diagnosis is not clear Chronic anovulation without hirsutism Chronic anovulation without hirsutism Hirsutism with a history of cyclic mensesHirsutism with a history of cyclic menses

Obesity ; increases the clinical suspicion of PCOS Obesity ; increases the clinical suspicion of PCOS Serum testosterone greater than 60 ng/dL ; suggests diagnoSerum testosterone greater than 60 ng/dL ; suggests diagno

sis of PCOS sis of PCOS

Long-term risk of PCOSLong-term risk of PCOS

Increased risk of endometrial cancer Increased risk of endometrial cancer ∵ ∵ Unopposed estrogen that results from chronic anovulatiUnopposed estrogen that results from chronic anovulati

on on In recent years, diabetes and cardiovascular ds. In recent years, diabetes and cardiovascular ds.


Dramatically increased risk of impaired glucose tolerance Dramatically increased risk of impaired glucose tolerance and non-insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus Fasting glucose concentrations - poor predictors of noFasting glucose concentrations - poor predictors of no

n-insulin-dependent diabetes mellitus n-insulin-dependent diabetes mellitus ∵ ∵ As shown in Figure 5, women with PCOS As shown in Figure 5, women with PCOS - Normal fasting glucose concentration - Normal fasting glucose concentration - IGT and DM based on 2-hour oral glucose- IGT and DM based on 2-hour oral glucose tolerance test value tolerance test value

30% for IGT, 8-10% DM(Figure 6) 30% for IGT, 8-10% DM(Figure 6)


Do the diabetes, adverse lipid profile and Do the diabetes, adverse lipid profile and preclinical atherosclerotic changes seen in preclinical atherosclerotic changes seen in women with PCOS translate into an increase in women with PCOS translate into an increase in actual cardiovascular events? actual cardiovascular events? Limited and inconsistent Limited and inconsistent Clear need for a prospective study Clear need for a prospective study

TreatmentTreatment

Figure 8Figure 8

TreatmentTreatment

Patient's height and weight to calculate her body mass inPatient's height and weight to calculate her body mass index dex

BP at the first visit BP at the first visit Fasting lipid panel to evaluate cardiovascular riskFasting lipid panel to evaluate cardiovascular risk Fasting glucose concentration to evlauate the possibility Fasting glucose concentration to evlauate the possibility

of IGT or non-insulin-dependent diabetes mellitus of IGT or non-insulin-dependent diabetes mellitus 2-hour oral glucose tolerance test is preferable 2-hour oral glucose tolerance test is preferable

TreatmentTreatment

In overweight patient(body mass index 26 or higher), In overweight patient(body mass index 26 or higher), major component of any treatment should be directed at major component of any treatment should be directed at

weight reduction weight reduction Best weight loss strategy - integrated behavioral progrBest weight loss strategy - integrated behavioral progr

am am Include exercise, moderate calorie restriction Include exercise, moderate calorie restriction Result in significant favorable impact on insulin, anResult in significant favorable impact on insulin, an

drogens, and ovulationdrogens, and ovulation No data on long-term outcomes of such lifestyle modifNo data on long-term outcomes of such lifestyle modif

ication programsication programs

TreatmentTreatment

Initial therapeutic strategy in the management of PCOS Initial therapeutic strategy in the management of PCOS Behavioral weight management in obese patients folloBehavioral weight management in obese patients follo

ws directly from the patient's chief complaint ws directly from the patient's chief complaint Metformin - not sliver bullet for all aspects of PCOS trMetformin - not sliver bullet for all aspects of PCOS tr

eatment eatment

TreatmentTreatment

Irregular menstruation Irregular menstruation Without the additional concerns of hirsutism or infertiliWithout the additional concerns of hirsutism or infertili

ty ty OCs remain an excellent choice OCs remain an excellent choice

Present hirsutism Present hirsutism OCs plus spironolactone, at a dose of 200 mg/d is standard OCs plus spironolactone, at a dose of 200 mg/d is standard

choice choice

TreatmentTreatment

Several clear benefits in the treatment of irregular menstrSeveral clear benefits in the treatment of irregular menstrual cycles in women with PCOSual cycles in women with PCOS 1.Regular withdrawal bleeding 1.Regular withdrawal bleeding 2. Reduction in the risk of endometrial hyperplasia or cancer bec2. Reduction in the risk of endometrial hyperplasia or cancer bec

ause of progestin opposition of estrogen ause of progestin opposition of estrogen 3. Reduction in LH secretion and consequent reduction of ovarian 3. Reduction in LH secretion and consequent reduction of ovarian

androgens androgens 4. Increased sex hormone binding globulin production and conse4. Increased sex hormone binding globulin production and conse

quent reduction in free testosterone quent reduction in free testosterone 5. Improvement in hirsutism and acne 5. Improvement in hirsutism and acne

Measruable decline in hirsutism after 6 months of treatmMeasruable decline in hirsutism after 6 months of treatment, while no effect on hirsutism was seen with metformient, while no effect on hirsutism was seen with metformin n

TreatmentTreatment

Common reason for a physician consultation ; infertility Common reason for a physician consultation ; infertility Assuming a normal semen analysis, ovulation inductioAssuming a normal semen analysis, ovulation inductio

n n Recommended approach in Figure 9 Recommended approach in Figure 9 Hysterosalpingography to confirm a normal genital tracHysterosalpingography to confirm a normal genital trac

t if history of PID, endometriosis, or previous abdomint if history of PID, endometriosis, or previous abdominal surgery al surgery

TreatmentTreatment

Figure 9Figure 9

TreatmentTreatment

Most physiologic approach to ovulation induction ; weight Most physiologic approach to ovulation induction ; weight loss loss

Failing that -> clomiphene citrate Failing that -> clomiphene citrate Excellent initial pharmacologic strategy Excellent initial pharmacologic strategy Use the lowest clomiphene citrate dose that will initiatUse the lowest clomiphene citrate dose that will initiat

e the smallest number of ovulatory follicles(hopefully, e the smallest number of ovulatory follicles(hopefully, only one!) only one!)

Starting dose ; 50 mg/d for 5 days(usually days 5-9) Starting dose ; 50 mg/d for 5 days(usually days 5-9) approximately 50% ovulation on 50 mg approximately 50% ovulation on 50 mg

TreatmentTreatment

Ultrasound on day 13 to assess follicle development Ultrasound on day 13 to assess follicle development More than 2 preovulatory follicles on day 13 ; reduced More than 2 preovulatory follicles on day 13 ; reduced

to 25 mg/d in subsequent cycles to 25 mg/d in subsequent cycles No follicle development ; dose and duration of treatmeNo follicle development ; dose and duration of treatme

nt increased nt increased Never exceed 150 mg/d for 5 days Never exceed 150 mg/d for 5 days Once regimen that induces ovulation if there is no pregnaOnce regimen that induces ovulation if there is no pregna

ncy ncy Should repeat that regimen and not increase the dose Should repeat that regimen and not increase the dose

in subsequent cycles in subsequent cycles -> Goal is ovulation, not superovulation -> Goal is ovulation, not superovulation Overall, approximately 80% of women with PCOS - ovulate Overall, approximately 80% of women with PCOS - ovulate

on clomiphene citrate on clomiphene citrate

TreatmentTreatment

How should ovulation be induced in the 20% of women wHow should ovulation be induced in the 20% of women who are refractory to clomiphene citrate?ho are refractory to clomiphene citrate? Use of metformin hydrochloride Use of metformin hydrochloride

Common and effective strategy Common and effective strategy Used extensively in the treatment of non-insulin-dependent diabetes Used extensively in the treatment of non-insulin-dependent diabetes

mellitus mellitus Helps with glycemic control by reducing hepatic glucose output anHelps with glycemic control by reducing hepatic glucose output an

d by increasing peripheral uptake of glucose d by increasing peripheral uptake of glucose Kidney or liver ds., alcoholism, heart failure treated with furosemiKidney or liver ds., alcoholism, heart failure treated with furosemi

de should not take metformin de should not take metformin ∵ ∵ lactic acidosis risk ↑lactic acidosis risk ↑ Begun at a dose of 500 mg/d to minimize gastrointestinaBegun at a dose of 500 mg/d to minimize gastrointestina

l side effects and increased gradually as tolerated l side effects and increased gradually as tolerated

TreatmentTreatment

Small percentage of women with PCOS (about 5-10%) whSmall percentage of women with PCOS (about 5-10%) who are refractory to clomiphene citrate alone and to metforo are refractory to clomiphene citrate alone and to metformin plus clomiphene citrate or who cannot tolerate these min plus clomiphene citrate or who cannot tolerate these medications medications Laparoscopic ovarian drilling or injectable gonadotropiLaparoscopic ovarian drilling or injectable gonadotropi

n n Gonadotropins Gonadotropins

Hypersensitive to exogenous FSH Hypersensitive to exogenous FSH Risk of multiple pregnancy and hyperstimulation Risk of multiple pregnancy and hyperstimulation Should be used in conjunction with in vitro fertilizationShould be used in conjunction with in vitro fertilization

; Number of embryos that are transferred to the uterine cavi; Number of embryos that are transferred to the uterine cavity controlled ty controlled

Follow-UpFollow-Up

Women with PCOS who are being seen for infertility Women with PCOS who are being seen for infertility Followed closely with regards to ovulation induction Followed closely with regards to ovulation induction If no pregnancy after 6 months of documented ovulatiIf no pregnancy after 6 months of documented ovulati

onon Additional infertility evaluation Additional infertility evaluation

If no pregnancy after 9-12 months of documented ovulIf no pregnancy after 9-12 months of documented ovulation, and if no other infertility factors ation, and if no other infertility factors

Blend with unexplained infertility Blend with unexplained infertility Intrauterine insemination is addedIntrauterine insemination is added

If lack of pregnancy despite multiple cycles of ovulatioIf lack of pregnancy despite multiple cycles of ovulation induction and intrauterine insemination n induction and intrauterine insemination

Lead to consideration of the use of gonadotropins Lead to consideration of the use of gonadotropins

Follow-UpFollow-Up

For women with PCOS who are not interested in For women with PCOS who are not interested in pregnancypregnancy Follow-up at 6 month intervals Follow-up at 6 month intervals

Polycystic Ovary Syndrome Obstetrics & Gynecology Vol 103, No 1, Jau 2004 부산백병원...

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