Transcript Polycystic Ovary Syndrome

Polycystic Ovary Syndrome
Obstetrics & Gynecology
Vol 103, No 1, Jau 2004
부산백병원 산부인과
R4 강영미
Introduction
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Chronic anovulation and androgen excess not
attributable to another cause
Occurs in approximately 4% of women
Fundamental pathophysiologic defect
 Unknown
 Important characteristics ; insulin resistance,
hyperandrogenism, and altered gonadotropin
dynamics
 Inadequate FSH ; hypothesized to be a proximate
cause of anovulation
 Obesity complicates PCOS but is not a defining
characteristic
Introduction
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Diagnostic approach ; should based on history and
physical exam
Irregular bleeding, hirsutism and/or infertility
 Treated with OCs, OCs with spironolactone and
ovulation induction
Higher prevalence of diabetes and increased risk
factors for cardiovascular ds.
 should also be screened
 for obese women with PCOS,
behavioral weight management ; central
component of the overall treatment strategy
Definition
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Since its first description in 1935, a variety of
histologic, biochemical, sonographic and clinical
characteristics ; associated with PCOS
Practical and useful clinical definition of PCOS in the
United States
 If have chronic anovulation and evidence of
androgen excess for which there is no other cause
 Referred to as the "NIH Conference" definition,
despite wide variety of views regarding the clinical,
endocrinologic features (Table 1)
Prevalence
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Best prevalence study, reported in 1998, with
unselected sample of white and African-American
women between the ages of 18 and 45 years
 277 women who consented to a history, physical
exam, and hormonal evaluation, overall prevalence
of PCOS
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4-4.7% for white women
3.4% for African American women
Clinical Importance
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In clinical gynecologic practice,
 Primarily for menstrual irregularity, hirsutism, and
infertility
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Treatment is directed at the immediate presenting
complaint
Long-term goals
 Prevent diabetes, coronary heart ds.
 Screen cancer
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Unopposed estrogen exposure -> increased risk of
endometrial ca.
Pathophysiology
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Fundamental pathophysiologic defect in PCOS
 Unknown
 Several interrelated characteristics ; insulin
resistance, hyperandrogenism, and altered
gonadotropin dynamics
 Hypothesis that inadequate FSH stimulation ;
proximate cause of anovulation in PCOS
Pathophysiology
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Insulin resistance
 Defined as a subnormal biological response to
insulin
 Associated with obesity
 Extent of insulin resistance - cannot be explained
entirely by obesity
Pathophysiology
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Hyperandrogenism
 strong correlation between insulin resistance and
hyperandrogenism
HAIR-AN syndrome
 Acanthosis nigricans
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Strongly suggests insulin resistance
Dermatologic disorder characterized by velvety
hyperpigmented skin, usually over the nape of the neck,
in the axillae, or beneath the breasts)
Pathophysiology
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what is the directionality of the relationship between
insulin resistance and hyperandrogenism?
 Direction of causation is from insulin to androgen
and not reverse
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Administration of diazoxide -> results in reduction in
circulating androgen concentrations
Weight loss and insulin sensitizers -> reduction in
androgen
in vivo effect on ovarian androgens by insulin
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insulin synergizes with LH to promote androgen production
by the thecal cells
Pathophysiology
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Altered gonadotropin-releasing hormone dynamics
 Another key pathophysiologic feature of PCOS
 Increased LH pulse frequency and amplitude,
leading to increased 24-hour mean concentrations
in both lean and obese women with PCOS
 Elevated LH levels
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Responsible for the excess androgen production
Androgen production by theca cell is LH dependent
Suppression of LH by GnRH agonists or by OCs reduces
circulating testosterone and androstenedione
Pathophysiology
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Inadequate concentrations of endogenous FSH
 Absolute concentrations of FSH above a specified
threshold
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Essential for both the initiation of preovulatory follicle
development as well as the selection of a single
preovulatory follicle
Pathophysiology
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In PCOS,
 E2 production ; limited
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Follicles not mature fully
Granulosa cells number and in aromatase activity
decreased
Therefore, E2 production is limited, in the range of 70-80
pg/mL higher than early follicular E2
 Suppressing FSH, but never reaching the levels
needed to initiate an LH surge
Concentration of FSH
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Not rise above levels seen in the mid-follicular range
Insufficient to stimulate preovulatroy follicle development
Constrained by negative feedback inhibition of E2 which
never exceeds mid-follicular levels
Pathophysiology
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Currently lack a satisfactory integrative model of
PCOS pathophysiology
 Genetic factors are at the root of the condition
 In view of characteristics such as insulin
resistance and gonadotropin changes
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Likely that more than one genetic "hit"
Influenced by environmental factors
Diagnostic Approach
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Relatively safe ground on combination of chronic
anovulation and androgen excess
With respect to ovulatory history
 History of irregular menstrual cycles dating to
menarche
 Report 6 or fewer episodes of spontaneous
vaginal bleeding per year
Diagnostic Approach
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oily skin and acne
 subtle signs of androgen excess
Hirsutism
 Most common manifestation of the androgen
component of PCOS
should inquire about and examine for
 "male-pattern" hair(hair located on the upper lip,
chin, chest, lower abdomen, and inner aspects of
the thighs)
Diagnostic Approach
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Differing opinions on what laboratory studies should
be ordered in evaluating a woman with PCOS
 Primarily a clinical diagnosis - few laboratory
studies are needed
 Only condition that needs to be excluded to
secure the diagnosis of PCOS - nonclassical CAH
 Diagnostic pathway in Figure 3
Diagnostic Approach
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Figure 3
Diagnostic Approach
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Ratio of LH to FSH greater than 2;1 - consistent with
PCOS
 LH ; FSH ratio often in the "normal range"
∵ pulsatile nature of gonadotropins, resulting in
broad range of LH ; FSH ratios in PCOS when a
single blood sample is drawn
In author's practice, evaluating a women with chronic
anovulation since menarche and hirsutism
 Only blood sample - 17-hydroxyprogesterone
concentration to rule out 21-hydroxylase-deficient
nonclassical adrenal hyperplasia
Diagnostic Approach
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Testosterone
 Not necessary for diagnosis when clear hirsutism
is present
 Sometimes helpful in evaluating a women with
chronic anovulation but who does not have clinical
evidence of hirsutism or other signs of androgen
excess
 Total testosterone concentration greater than 60
ng/dL ; consistent with PCOS
Diagnostic Approach
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Ovarian anatomy
 Show multiple, small, subcapsular cysts, reflecting
repeated episodes of incomplete follicular growth
 Dense, hyperplastic stroma, reflecting an active
thecal component that is over-secreting
androgens
Ultrasound picture
 Numerous, small subcapsular cysts that produces
a "string of pearls" sign(Figure 4)
 Small subcapsular cysts and hyperechogenic
stroma
Diagnostic Approach
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Figure 4
Diagnostic Approach
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In summary,
 Best diagnosed clinically with a minimum of
laboratory tests
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History of chronic anovulation dating since menarche
Evidence of androgen excess, principally hirsutism
Blood sample for serum 17hydroxyprogesterone concentration to rule-out 21hydroxylase-deficient nonclassical adrenal hyperplasia
Obesity in conjunction with anovulation and
androgen excess
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Increase further one's suspicion of PCOS
Diagnostic Approach
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In cases in which the clinical diagnosis is not clear
 Chronic anovulation without hirsutism
 Hirsutism with a history of cyclic menses
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Obesity ; increases the clinical suspicion of
PCOS
Serum testosterone greater than 60 ng/dL ; suggests
diagnosis of PCOS
Long-term risk of PCOS
Increased risk of endometrial cancer
∵ Unopposed estrogen that results from chronic
anovulation
 In recent years, diabetes and cardiovascular ds.
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Long-term risk of PCOS
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Dramatically increased risk of impaired glucose
tolerance and non-insulin-dependent diabetes
mellitus
 Fasting glucose concentrations - poor predictors
of non-insulin-dependent diabetes mellitus
∵ As shown in Figure 5, women with PCOS
- Normal fasting glucose concentration
- IGT and DM based on 2-hour oral glucose
tolerance test value
 30% for IGT, 8-10% DM(Figure 6)
Long-term risk of PCOS
Long-term risk of PCOS
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Do the diabetes, adverse lipid profile and preclinical
atherosclerotic changes seen in women with PCOS
translate into an increase in actual cardiovascular
events?
 Limited and inconsistent
 Clear need for a prospective study
Treatment
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Figure 8
Treatment
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Patient's height and weight to calculate her body
mass index
BP at the first visit
Fasting lipid panel to evaluate cardiovascular risk
Fasting glucose concentration to evlauate the
possibility of IGT or non-insulin-dependent diabetes
mellitus
 2-hour oral glucose tolerance test is preferable
Treatment
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In overweight patient(body mass index 26 or higher),
major component of any treatment should be
directed at weight reduction
 Best weight loss strategy - integrated behavioral
program
 Include exercise, moderate calorie restriction
 Result in significant favorable impact on insulin,
androgens, and ovulation
 No data on long-term outcomes of such lifestyle
modification programs
Treatment
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Initial therapeutic strategy in the management of
PCOS
 Behavioral weight management in obese patients
follows directly from the patient's chief complaint
 Metformin - not sliver bullet for all aspects of
PCOS treatment
Treatment
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Irregular menstruation
 Without the additional concerns of hirsutism or
infertility
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OCs remain an excellent choice
Present hirsutism
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OCs plus spironolactone, at a dose of 200 mg/d is
standard choice
Treatment
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Several clear benefits in the treatment of irregular
menstrual cycles in women with PCOS
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1.Regular withdrawal bleeding
2. Reduction in the risk of endometrial hyperplasia or cancer
because of progestin opposition of estrogen
3. Reduction in LH secretion and consequent reduction of
ovarian androgens
4. Increased sex hormone binding globulin production and
consequent reduction in free testosterone
5. Improvement in hirsutism and acne
Measruable decline in hirsutism after 6 months of
treatment, while no effect on hirsutism was seen with
metformin
Treatment
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Common reason for a physician consultation ;
infertility
 Assuming a normal semen analysis, ovulation
induction
 Recommended approach in Figure 9
 Hysterosalpingography to confirm a normal genital
tract if history of PID, endometriosis, or previous
abdominal surgery
Treatment
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Figure 9
Treatment
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Most physiologic approach to ovulation induction ;
weight loss
Failing that -> clomiphene citrate
 Excellent initial pharmacologic strategy
 Use the lowest clomiphene citrate dose that will
initiate the smallest number of ovulatory
follicles(hopefully, only one!)
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Starting dose ; 50 mg/d for 5 days(usually days 5-9)
approximately 50% ovulation on 50 mg
Treatment
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Ultrasound on day 13 to assess follicle development
 More than 2 preovulatory follicles on day 13 ;
reduced to 25 mg/d in subsequent cycles
 No follicle development ; dose and duration of
treatment increased
Never exceed 150 mg/d for 5 days
Once regimen that induces ovulation if there is no
pregnancy
 Should repeat that regimen and not increase the
dose in subsequent cycles
-> Goal is ovulation, not superovulation
Overall, approximately 80% of women with PCOS ovulate on clomiphene citrate
Treatment
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How should ovulation be induced in the 20% of
women who are refractory to clomiphene citrate?
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Use of metformin hydrochloride
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Common and effective strategy
Used extensively in the treatment of non-insulin-dependent
diabetes mellitus
Helps with glycemic control by reducing hepatic glucose
output and by increasing peripheral uptake of glucose
Kidney or liver ds., alcoholism, heart failure treated with
furosemide should not take metformin
∵ lactic acidosis risk ↑
Begun at a dose of 500 mg/d to minimize
gastrointestinal side effects and increased gradually
as tolerated
Treatment
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Small percentage of women with PCOS (about 510%) who are refractory to clomiphene citrate alone
and to metformin plus clomiphene citrate or who
cannot tolerate these medications
 Laparoscopic ovarian drilling or injectable
gonadotropin
Gonadotropins
 Hypersensitive to exogenous FSH
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Risk of multiple pregnancy and hyperstimulation
Should be used in conjunction with in vitro fertilization
; Number of embryos that are transferred to the uterine
cavity controlled
Follow-Up
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Women with PCOS who are being seen for infertility
 Followed closely with regards to ovulation
induction
 If no pregnancy after 6 months of documented
ovulation
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If no pregnancy after 9-12 months of documented
ovulation, and if no other infertility factors
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Additional infertility evaluation
Blend with unexplained infertility
Intrauterine insemination is added
If lack of pregnancy despite multiple cycles of
ovulation induction and intrauterine insemination
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Lead to consideration of the use of gonadotropins
Follow-Up
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For women with PCOS who are not interested in
pregnancy
 Follow-up at 6 month intervals